Patent Publication Number: US-2019175633-A1

Title: Reactive, lipophilic nucleoside building blocks for the synthesis of hydrophobic nucleic acids

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. application Ser. No. 14/432,317, filed Mar. 30, 2015, which is a national phase application of International Application No. PCT/EP2013/069936, filed Sep. 25, 2013. 
    
    
     BACKGROUND OF THE INVENTION 
     The invention relates to a method for the isolation and/or identification of known or unknown sequences of nucleic acids (target sequences) optionally marked with reporter groups by base specific hybridation with, essentially, complementary sequences (in the following referred to as sample oligo-nucleotides, sample sequences or sample nucleic acids), which belong to a library of sequences. Further, the invention relates to nucleolipids used in the method of the invention and a process for the preparation of said nucleolipids. In addition, the invention relates to a pharmaceutical composition comprising said nucleolipids. 
     With the discovery of gene silencing—also of human genes—by short nucleic acids (siRNA) a new therapeutic principle has evolved. This culminated in the synthesis of the so-called antagomires, short modified oligomers which are built-up from 2′-O-methyl-β-D-ribonucleosides and which carry at both termini several phosphorothioate internucleotide linkages as well as a cholesterol tag at the 5′-end. Particularly, the latter modification makes the oligomer permeable for the cell membrane. However, it has been reported that already one cholesterol moiety fraughts the oligomer synthesis and its purification and handling with difficulties. 
     Moreover, cholesterol binds very tightly into bilayer membranes, therewith handicapping an effective transfection of an appending nucleic acid. 
     For these reasons there is a demand for alternative methods for a less strong and stepped lipophilization of oligonucleotides. 
     BRIEF SUMMARY OF THE INVENTION 
     An object of the invention is the provision of lipophilized oligonucleotides and lipophilized building blocks for the oligonucleotide synthesis which overcome the drawbacks of the prior art. 
     A first embodiment of the present invention is a compound as represented by formula (I). Further, preferred embodiments of the compound of the invention are reflected in the dependent claims. 
     The substituents of present invention are described in the following in more detail. 
     R 2  is H, or 
     R 2  is selected from a Mono-phosphate, Di-phosphate, Tri-phosphate or phosphoramidite moiety, or 
     R 2  is —Y—X or —Y-L-Y 1 —X; 
     R 3  and R 4  represent independently from each other a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, which may optionally be substituted or interrupted by one or more heteroatom(s)(Het1) and/or functional group(s)(G1), or 
     R 3  and R 4  form a ring having at least 5 members, preferably a ring having 5 to 8 carbon atoms and wherein the ring may be substituted or interrupted by one or more hetero atom(s)(Het1) and/or functional group(s)(G1), or 
     R 3  and R 4  represent independently from each other a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, substituted with one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, or 
     R 3  and R 4  represent independently from each other —Y—X or —Y-L-Y 1 —X; 
     R 5  and R 6  represent independently from each other a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, which may optionally be substituted or interrupted by one or more heteroatom(s)(Het1) and/or functional group(s)(G1), or 
     R 5  and R 6  represent independently from each other a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, substituted with one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, or 
     R 5  and R 6  form a ring having at least 5 members, preferably a ring having 5 to 18 carbon atoms and wherein the ring may be substituted or interrupted by one or more hetero atom(s)(Het1) and/or functional group(s)(G1), 
     and/or one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, or 
     R 5  and R 6  represent independently from each other —Y—X or —Y-L-Y 1 —X; 
     R 45  is H or a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, which may optionally be substituted or interrupted by one or more hetero atom(s)(Het1) and/or functional group(s)(G1), or 
     R 45  is a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, substituted with one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, or 
     R 45  is —Y—X or —Y-L-Y 1 —X; 
     R 7  is a hydrogen atom or —O—R 8 ; 
     R 8  is H or C 1 -C 28  chain, preferably a C 2 -C 20  chain, more preferably C 8 -C 18  chain, which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or 
     R 8  is —Y—X or —Y-L-Y 1 —X; 
     wherein 
     Y and Y 1  are independently from each other a single bond or a functional connecting moiety, 
     X is a fluorescence marker (FA) and/or a polynucleotide moiety having up to 50 nucleotide residues, preferably 10 to 25 nucleotides, especially a polynucleotide having an antisense or antigen effect, and 
     L is a linker by means of which Y and X are covalently linked together; 
     R 10 , R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , R 23 , R 24 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 38 , R 39  and R 40  are independently selected from H or a C 1 -C 50  chain, preferably a C 2 -C 30  chain, more preferably C 5 -C 18  is chain, which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or 
     R 10 , R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 19 , R 23 , R 24 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 38 , R 39  and R 40  represent independently from each other a C 3 -C 28  moiety, preferably C 5 -C 20  moiety, more preferably C 8 -C 18  moiety, which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); 
     R 15 , R 18 , R 21 , R 22 , R 25 , R 36  and R 37  are independently selected from a C 1 -C 50  chain, preferably a C 2 -C 30  chain, more preferably C 5 -C 18  chain, which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1) or a C 3 -C 28  moiety, preferably C 5 -C 20  moiety, more preferably C 5 -C 18  moiety, which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); 
     R 20  and R 41  are selected from H, Cl, Br, I, CH 3 , C 2 -C 50  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or 
     R 20  and R 41  represent independently from each other a C 3 -C 28  moiety, preferably C 5 -C 20  moiety, more preferably C 8 -C 18  moiety, which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1), or 
     R 20  and R 41  represent independently from each other —O—C 1-28 -alkyl, —S—C 1-28 -alkyl, —NR 42 R 43  with R 42  and R 43  independently being H or a C 1-28 -alkyl; 
     R 34 =H or CH 3 ; 
     R 44  is selected from H, F, Cl, Br and I; 
     Z is O or S; and 
     A is CH or N. 
     In a preferred embodiment substituents R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are a linear or branched chain comprising 1 to 50 carbon, preferably 2 to 30 carbon, which may be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s) (GI). Preferably, R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are selected from a linear or branched chain comprising 2 to 40, more preferably 3 to 30, especially 4 to 28 or 6 to 20 or 8 to 16 carbon atoms. In one aspect of the invention R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are a linear or branched C 1 -C 28 -alkyl, preferably C 2 -C 20 -alkyl, more preferably C 4 -C 20 -alkyl or C 6 -C 18 -alkyl, especially C 5 -C 16 -alkyl which may be substituted or unsubstituted. In a further aspect of the invention the carbon chain is interrupted by one or more hetero atom(s) (Het1) wherein the Het1 is preferably selected from O, S and N, more preferably selected from O or N. In one aspect the substituents R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are interrupted by up to 3 hetero atom(s) (Het1), preferably 1 or 2 hetero atoms such as O. In a further aspect of the invention the carbon chain of substituent R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are interrupted by nitrogen which preferably further branches the chain. An exemplary embodiment of this type of substituent is reflected in the following formula: 
     
       
         
         
             
             
         
       
     
     wherein R 9  and R 9′  are independently selected from a C 1  to C 30  chain which can be saturated or unsaturated, preferably a C 1  to C 30  alkyl, further preferably C 4  to C 24  alkyl, more preferably C 8  to C 22  alkyl and especially C 12  to C 18  alkyl; or a C 2  to C 30  chain having one or more carbon-carbon double and/or carbon-carbon triple bond(s); and 
     “a” is an integer ranging from 1 to 20, preferably 2 to 18, more preferably 3 to 12 or 4 to 8. However, the linking moiety which links the nitrogen atom with substituents R 9  and R 9′  to the base moiety can also be a unsaturated carbon chain having one 2 to 20 carbon atoms and one or more carbon-carbon double and or carbon-carbon triple bonds. The exemplary substituent of the following formula: 
     
       
         
         
             
             
         
       
     
     can be synthesized by various synthetic routes. Scheme 7 shows exemplary synthetic routes for precursors which can be attached to the base moiety to form the compound of the present invention. 
     In a preferred embodiment R 45  and R 7  are H. 
     In one embodiment of the invention R 12 , R 16 , R 17 , R 19 , R 30  and R 35  comprise one or more carbon-carbon double bond(s) and/or one or more carbon-carbon triple bond(s). In a particular preferred embodiment R 12 , R 16 , R 17 , R 19 , R 30  and R 35  comprise two or more, especially 2 to 6, such as 2 to 4 carbon-carbon double bonds. 
     In a specially preferred embodiment the substituents are derived from nature. Suitable naturally derived substituents have a structure derived from terpenes. When terpenes are chemically modified such as by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as terpenoids. In a preferred embodiment R 12 , R 16 , R 17 , R 19 , R 30  and R 35  is a cyclic or alicyclic terpenoid, preferably a terpenoid having 8 to 36 carbon atoms. 
     The terpenes are preferably selected from monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes and sesquaterpenes. 
     Suitable monoterpenes or monoterpenoids which can be acyclic or cyclic are selected from the group consisting of geraniol, limonene, pinen, bornylen, nerol. 
     Suitable sesquiterpenes sesquiterpenoids which can be acyclic or cyclic may inter alia be selected from farnesol. 
     Suitable sesterterpenes or sesterterpenoids are inter alia selected from geranylfarnesol. 
     Suitable diterpenes or diterpenoids can be selected from the group consisting of abietic acid, aphidicolin, cafestol, cembrene, ferruginol, forskolin, guanacastepene A, kahweol, labdane, lagochilin, sclarene, stemarene, steviol, taxadiene (precursor of taxol), tiamulin, geranylgeraniol and phytol. 
     According to an especially preferred embodiment of the invention R 12 , R 16 , R 17 , R 19 , R 30  and R 35  is selected from the group consisting of geranyl, farnesyl, neryl and phythyl. 
     According to a further alternative aspect R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are H or C 3 -C 28  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1); or R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are a C 1 -C 28  moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1). 
     According to a preferred embodiment R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are selected from H, and 
     
       
         
         
             
             
         
       
     
     and 
     substituted or unsubstituted cyclic terpene moieties, 
     wherein 
     R 9  and R 9′  are independently selected from C 1  to C 30  alkyl, 
     n is an integer ranging 1 to 4, preferably n is 1 or 2; 
     a is an integer ranging from 1 to 20, preferably 2 to 18. 
     According to a preferred embodiment R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are 
     
       
         
         
             
             
         
       
     
     wherein b is an integer ranging from 1 to 20, preferably 4 to 16, more preferably 8 to 16. 
     Preferably, Y and Y 1  are functional connecting groups which are independently selected from a group consisting of carboxylic acid ester (such as —OC(O)— or —C(O)O—), carboxylic acid amides (such as —NHC(O)— or —C(O)NH—), urethane (such as —NHC(O)NH—), ether, amino group, thioester (such as —SC(O)— or —C(O)S—), thioamides (such as —C(S)NH— or —NHC(S)—), thioether and phosphate ester (such as —OP(O) 2 O—). 
     In a preferred embodiment the compound according to the invention is represented by formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein Q is selected from the group of formulae (II) to (IV) 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 2  is H, or 
             R 2  is a Mono-phosphate, Di-phosphate, Tri-phosphate or phosphoramidite moiety, or 
             R 2  is —Y—X or —Y-L-Y 1 —X; 
             R 3  and R 4  represent independently from each other a C 1 -C 28 -alkyl moiety which may optionally be substituted or interrupted by one or more heteroatom(s) and/or functional group(s), or 
             R 3  and R 4  form a ring having at least 5 members, preferably a ring having 5 to 8 carbon atoms and wherein the ring may be substituted or interrupted by one or more hetero atom(s) and/or functional group(s), or 
             R 3  and R 4  represent independently from each other a C 1 -C 28 -alkyl moiety substituted with one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, or 
             R 3  and R 4  represent independently from each other —Y—X or —Y-L-Y 1 —X; 
             R 5  and R 6  represent independently from each other a C 1 -C 28 -alkyl moiety which may optionally be substituted or interrupted by one or more heteroatom(s) and/or functional group(s), or 
             R 5  and R 6  represent independently from each other a C 1 -C 28 -alkyl moiety substituted with one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, or 
             R 5  and R 6  form a ring having at least 5 members, preferably a ring having 5 to 18 carbon atoms and wherein the ring may be substituted or interrupted by one or more hetero atom(s) and/or functional group(s), 
             and/or one or more moieties selected from the group —Y—X or —Y-L-Y 1 —X, 
             R 5  and R 6  represent independently from each other —Y—X or —Y-L-Y 1 —X; 
             R 45  is H or a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, which may optionally be substituted or interrupted by one or more heteroatom(s) and/or functional group(s), or 
             R 45  is a C 1 -C 28 -alkyl moiety, preferably a C 2 -C 20 -alkyl moiety, more preferably C 8 -C 18 -alkyl moiety, substituted with one or more moieties selected from the group —Y—X or —Y— 
             L-Y 1 —X, or 
             R 45  is —Y—X or —Y-L-Y 1 —X; 
             R 7  is a hydrogen atom or —O—R 8 ; 
             R 8  is H or C 1 -C 28  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or 
             R 8  is —Y—X or —Y-L-Y 1 —X; and 
             wherein 
             Y and Y 1  are independently from each other a single bond or a functional connecting moiety, 
             X is a fluorescence marker (FA) and/or a polynucleotide moiety having up to 50 nucleotide residues, preferably 10 to 25 nucleotides, especially a polynucleotide having an antisense or antigen effect, 
             L is a linker by means of which Y and X are covalently linked together; and wherein 
             Bas is selected from the group of following formulae: 
           
         
       
    
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
         
         
           
             wherein 
             R 13 , R 14 , R 23 , R 24 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 34 , R 38 , R 39  and R 40  are independently selected from H, or a C 1 -C 50  chain which may be branched or linear and which may be saturated, or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or a C 1 -C 28  moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); 
             R 15 , R 18 , R 21 , R 22 , R 25 , R 36  and R 37  are independently selected from a C 1 -C 50  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or 
             a C 1 -C 28  moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); 
             R 12 , R 16 , R 17 , R 19 , R 30  and R 35  are selected from 
           
         
       
    
     
       
         
         
             
             
         
       
     
     and
         substituted or unsubstituted cyclic terpene moieties,   wherein   R 9  and R 9′  are independently selected from C 1  to C 30  alkyl, preferably C 5  to C 25 -alkyl,   n is an integer ranging 1 to 4, preferably n is 1 or 2, and   a is an integer ranging from 1 to 20, preferably 2 to 18, more preferably 6 to 16;   R 20  is selected from H, Cl, Br, I, CH 3 , C 2 -C 50  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or   a C 1 -C 28  moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1), or —O—C 1-28 -alkyl, —S—C 1-28 -alkyl, —NR 42 R 43  with R 42  and R 43  independently being H or a C 1-28 -alkyl;   R 34 =H or CH 3 ;   Z is O or S; and   A is CH or N.       

     According to a preferred embodiment the hetero atom(s) (Het1) is/are selected from O, S and NH. 
     Further, preferably the functional group(s) (GI) are selected from ester, amide, carboxylic acid, thioester, thioamides and thioether. 
     In a further aspect of the invention linker L is a moiety comprising 1 to 30 carbon atoms which can be saturated or unsaturated, cyclic or alicyclic, branched or unbranched and which may be substituted or interrupted by heteroatoms. 
     Preferably, linker L is selected from C 2  to C 20 -alkandiyls, preferably selected from ethylene or propylene. 
     In a further aspect of the invention linker L is selected from a single bond or a saturated or unsaturated moiety having 1 to 30, preferably 2 to 20 carbon atoms, more preferably a carbon chain which may be substituted and/or interrupted by one or more functional groups selected from carboxylic acid ester, phosphate ester, carboxylic acid amides, urethane, ether and amine groups. L may also comprise cyclic moieties. 
     According to a preferred embodiment linker L is selected from a single bond; alkandiyl, preferably C 1 -C 20 -alkandiyl; alkendiyl, preferably a C 2 -C 20 -alkendiyl; alkyndiyl, preferably a C 2 -C 20 -alkyndiyl; aryl moiety, aralkyl moiety and herterocyclic moiety. 
     Preferably, the alkandiyl represents a straight-chain or branched-chain alkandiyl group bound by two different carbon atoms to the molecule, it preferably represents a straight-chain or branched-chain C 1-12  alkandiyl, particularly preferably represents a straight-chain or branched-chain C 1-6  alkandiyl; for example, methandiyl (—CH 2 —), 1,2-ethanediyl (—CH 2 —CH 2 —), 1,1-ethanediyl ((—CH(CH 3 )—), 1,1-, 1,2-, 1,3-propanediyl and 1,1-, 1,2-, 1,3-, 1,4-butanediyl, with particular preference given to methandiyl, 1,1-ethanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl. 
     Further, preferably the alkendiyl represents a straight-chain or branched-chain alkendiyl group bound by two different carbon atoms to the molecule, it preferably represents a straight-chain or branched-chain C 2-6  alkendiyl; for example, —CH═CH—, —CH═C(CH 3 )—, —CH═CH—CH 2 —, —C(CH 3 )═CH—CH 2 —, —CH═C(CH 3 )—CH 2 —, —CH═CH—C(CH 3 )H—, —CH═CH—CH═CH—, —C(CH 3 )═CH—CH═CH—, —CH═C(CH 3 )—CH═CH—, with particular preference given to —CH═CH—CH 2 —, —CH═CH—CH═CH—. 
     The aryl moiety preferably represents an aromatic hydrocarbon group, preferably a C 6 -10 aromatic hydrocarbon group; for example phenyl, naphthyl, especially phenyl which may optionally be substituted. 
     Aralkyl moiety denotes an “Aryl” bound to an “Alkyl” and represents, for example benzyl, α-methylbenzyl, 2-phenylethyl, α,α-dimethylbenzyl, especially benzyl. 
     Heterocyclic moiety represents a saturated, partly saturated or aromatic ring system containing at least one hetero atom. Preferably, heterocycles consist of 3 to 11 ring atoms of which 1-3 ring atoms are hetero atoms. Heterocycles may be present as a single ring system or as bicyclic or tricyclic ring systems; preferably as single ring system or as benz-annelated ring system. Bicyclic or tricyclic ring systems may be formed by annelation of two or more rings, by a bridging atom, e.g. oxygen, sulfur, nitrogen or by a bridging group, e.g. alkandiyl or alkenediyl. A Heterocycle may be substituted by one or more substituents selected from the group consisting of oxo (═O), halogen, nitro, cyano, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, halogenalkyl, aryl, aryloxy, arylalkyl. Examples of heterocyclic moieties are: pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane, tetrahydrofurane, furazane (oxadiazole), dioxolane, thiophene, dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine, isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline, thiazlolidine, isothiazole, istothiazoline, isothiazolidine, thiadiazole, thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine, pyrazine, piperazine, triazine, pyrane, tetrahydropyrane, thiopyrane, tetrahydrothiopyrane, oxazine, thiazine, dioxine, morpholine, purine, pterine, and the corresponding benz-annelated heterocycles, e.g. indole, isoindole, cumarine, cumaronecinoline, isochinoline, cinnoline and the like. 
     Hetero atoms are atoms other than carbon and hydrogen, preferably nitrogen (N), oxygen (O) or sulfur (S). 
     In a preferred embodiment of the present invention linker L is selected from the group consisting of a single bond and a C 1 -C 10  alkandiyl, preferably a C 2 -C 6 -alkandiyl, especially ethan-1,2-diyl (ethylene) or propan-1,2-diyl or propan-1,3-diyl. 
     According to an alternative embodiment X is a fluorescence marker which is selected from the group consisting of fluorescein isothiocyanate (FITC), phycoerythrin, rhodamide and 2-amino-pyridine, carbocyamine dyes, bodipy dyes, trityl and trityl derivatives such as methoxy trityl, e.g. 4-methoxy trityl. 
     According to a further alternative embodiment X is a polynucleotide moiety having up to 50 nucleotide residues, preferably 10 to 25 nucleotides, especially a polynucleotide having an antisense or antigen effect wherein the polynucleotide residue has preferably been coupled via a phosphoamidite precursor. 
     According to a preferred aspect of the invention the compound of the present invention and represented in formula (I) comprises one or more, preferably two or more, substituents having a C 6  to C 30  moiety, more preferably a C 10  to C 24  moiety which is saturated or unsaturated. 
     According to a further preferred aspect of the invention the compound of the present invention and represented in formula (I) comprises one or more, preferably two or more, C 6  to C 30  chains, more preferably a C 10  to C 24  chain which is saturated or preferably unsaturated. The compound of the invention preferably comprises one or more, preferably two or more, carbon chains having 6 to 30 carbon atoms wherein the chains comprise one or more, especially preferred two or more, unsaturated carbon-carbon bonds, in particular carbon-carbon double bonds. The chains may be branched or unbranched. Preferably the carbon chains have one or no substituent, especially substituents comprising hetero atoms, such as oxygen, sulfur or nitrogen, and more preferably the carbon chains are interrupted by one or no functional group. 
     In a preferred embodiment the compound of the invention comprises at least two chains each of which having 4 or more, preferably 6 or more, especially 8 or more carbon atoms which may be carbon chains wherein the carbon atoms are linearly-linked. The chains may not be part of a cyclic system. The chains are usually not interrupted by hetero atoms. 
     In an especially preferred embodiment the compound according to the invention is represented by formula (I) wherein 
     Q is represented by formula (IV), wherein R 2 , R 3  and R 7  are H; and 
     wherein Bas is represented by formula (VIIa) wherein 
     R 12  is 
     
       
         
         
             
             
         
       
     
     with n being an integer ranging from 1 to 4; and 
     wherein Z is O. 
     In an alternatively preferred embodiment the compound according to the invention is represented by formula (I) wherein 
     Q is represented by formula (IV), wherein R 2 , R 3  and R 7  are H; or 
     R 2  and R 7  are H and R 3  is —Y—X or and —Y-L-Y 1 —X; or 
     R 3  and R 7  are H and R 2  is —Y—X or —Y-L-Y 1 —X; and 
     wherein Bas is represented by formula (IXa) wherein 
     R 20  is H or methyl; and 
     R 19  is 
     
       
         
         
             
             
         
       
     
     with n being an integer ranging from 1 to 4; and 
     wherein Z is O; and 
     wherein Y, Y 1 , X and L are as defined above. 
     In a further alternatively preferred embodiment the compound according to the invention is represented by formula (I) wherein 
     Q is represented by formula (III) wherein R 2  is H or —Y—X or —Y-L-Y 1 —X; and 
     R 5  and R 6  are independently from each other a C 1 -C 28 -alkyl moiety or a C 1 -C 10  carbon chain which is interrupted by Heteroatom(s), especially O, and/or functional group(s), especially oxycarbonyl groups or carbonyl oxy groups such as —C(O)O— or —OC(O)—; and wherein Bas is represented by formula (IXa) wherein 
     R 20  is H or methyl; and 
     R 19  is H or 
     
       
         
         
             
             
         
       
     
     with n being an integer ranging from 1 to 4; and 
     wherein Z is O; and 
     wherein A is CH or N; and 
     wherein Y, Y 1 , X and L are as defined above. 
     Preferably Y is a single bond and X is 
     
       
         
         
             
             
         
       
     
     (4-methoxy trityl). 
     In an alternatively preferred embodiment the compound according to the invention is represented by formula (I) wherein 
     Q is is represented by formula (III) wherein 
     R 2  is H or —Y—X or —Y-L-Y 1 —X; and 
     R 5  and R 6  are independently from each other a C 1 -C 28 -alkyl moiety or a C 1 -C 10  carbon chain which is interrupted by Heteroatom(s), especially O and/or functional group(s), especially oxycarbonyl groups or carbonyl oxy groups such as —C(O)O— or —OC(O)—; and wherein Bas is represented by the following formula (IXa) 
     wherein 
     R 20  is H or methyl; and 
     R 19  is 
     
       
         
         
             
             
         
       
     
     with b being an integer ranging from 1 to 20, preferably 4 to 16; and 
     wherein A is CH or N; and 
     wherein Z is O. 
     In a preferred embodiment the compound according to the invention comprises at least one terpene moiety, preferably 
     
       
         
         
             
             
         
       
     
     wherein n is an integer ranging from 1 to 4, preferably located at the base moiety. More preferably the compound according to the invention comprises at least one farnesyl moiety, preferably located at the base moiety. In a further preferred embodiment the compound of the invention comprises additionally an ester moiety which is preferably located at the sugar moiety. 
     The ester moiety is preferably an ester having 5 carbon atoms, such as —CH 2 CH 2 C(O)OCH 2 CH 3 . 
     According to a preferred embodiment the compound of formula (I) is represented by 
     
       
         
         
             
             
         
       
     
     wherein Q is represented by formula (III) wherein 
     R 2  is H or 4-methoxytriptyl, 
     at least either of R 5  and R 6  are an ester moiety, preferably an ester moiety having at least 5 carbon atoms, such as —CH 2 CH 2 C(O)OCH 2 CH 3  and wherein 
     Bas is represented by a formula selected from the group of formulae (VIa), (VIIa), (VIIIa), (VIIIb), (VIIId), (IXa), (XI), (XIIa) and (XIV), wherein at least one of the substituents, preferably at least one of the substituents located at the nitrogen atom of the base moiety, is 
     
       
         
         
             
             
         
       
     
     preferably farnesyl, and wherein 
     n is an integer ranging from 1 to 4, and 
     Z is O and A is CH or N. 
     In a very preferred embodiment R 5  and R 6  comprise both, methyl and —CH 2 CH 2 C(O)OCH 2 CH 3 . 
     It has surprisingly been found that embodiments of the invention comprising at least one terpene moiety, preferably 
     
       
         
         
             
             
         
       
     
     wherein n is an integer ranging from 1 to 4, preferably located at the base moiety, and at least one ester moiety, such as —CH 2 CH 2 C(O)OCH 2 CH 3 , and wherein the at least one ester moiety is preferably located at the sugar moiety, are particular suitable for the treatment of cancer. 
     It has been found that the compounds of the invention demonstrate a higher permeability for cell membranes. Due to the pharmacological activity of the compounds of the invention a further embodiment of the invention refers to a pharmaceutical composition comprising the compound of the invention. 
     Surprisingly it has been found that the hydroxyl functional lipophilic precursor (such as the amino alcohols reflected in Scheme 7 and 8) can be selectively reacted with the unsubstituted nitrogen atom of the base moiety by a Mitsunobu reaction. This reaction is carried out by first protecting any hydroxyl groups which may be present in the nucleotide. 
     A further embodiment of the invention is a process for preparing a compound represented by formula (I) 
     
       
         
         
             
             
         
       
     
     wherein 
     the introduction of a carbon containing substituent as defined in the compound of the present invention to the H-containing nitrogen ring atom, if present, comprises the following steps: 
     a) providing a compound of formula (I) wherein nitrogen ring atoms bonded to H are present and introducing protecting groups for hydroxyl groups, if present 
     b) converting an alcohol group containing carbon containing substituent in a Mitsunobu type reaction with the compound of step a) and 
     c) optionally, removing the protecting groups. 
     An embodiment of the invention is a process for preparing a compound represented by formula (Ia) 
     
       
         
         
             
             
         
       
     
     wherein 
     Q is represented by formulae (II) to (IV) as defined above, and 
     wherein Bas is represented by formulae (VIa), (VIIa); (VIIIa), (VIIIb), (VIIId), (IXa); (XI), (XIIa) or (XIV), as defined above for formula (I), and 
     wherein R 12 , R 16 , R 17 , R 19 , R 30 , R 35  and R 40  are H, and 
     wherein R 13 , R 14 , R 26 , R 27 , R 28 , R 34 , R 38  and R 39  are independently selected from H or a C 1 -C 50  chain, preferably a C 2 -C 30  chain, more preferably C 5 -C 18  chain, which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or represent independently from each other a C 3 -C 28  moiety, preferably C 5 -C 20  moiety, more preferably C 5 -C 18  moiety, which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); and 
     wherein R 15  and R 18  are independently selected from a C 1 -C 50  chain, preferably a C 2 -C 30  chain, 30 more preferably C 5 -C 18  chain, which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1) or a C 3 -C 28  moiety, preferably C 5 -C 20  moiety, more preferably C 8 -C 18  moiety, which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); and 
     wherein R 20  is selected from H, Cl, Br, I, CH 3 , C 2 -C 50  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or from a C 3 -C 28  moiety, preferably C 5 -C 20  moiety, more preferably C 8 -C 18  moiety, which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1), or represents —O—C 1-28 -alkyl, —S—C 1-28 -alkyl, —NR 42 R 43  with R 42  and R 43  independently being H or a C 1-28 -alkyl; 
     and wherein Z is O or S; 
     wherein the introduction containing carbon substituents having a C 1 -C 50  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or a C 1 -C 28  moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1); 
     to the H containing Nitrogen ring atom, comprises the following steps: 
     a) Providing a compound of formula (Ia) and introducing protecting groups for hydroxyl groups, if present, 
     b) converting an alcohol having a C 1 -C 50  chain which may be branched or linear and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and/or functional group(s)(G1), or a C 1 -C 28  moiety which comprises at least one cyclic structure and which may be saturated or unsaturated and which may optionally be interrupted and/or substituted by one or more hetero atom(s) (Het1) and functional group(s)(G1), 
     with the compound provided in step a) in the presence of triphenylphosphine and diisopropylazo dicarboxylate (DIAD) and 
     c) optionally, removing the protecting groups. 
     The Mitsunobu type reaction is generally carried out by reacting the alcohol and the nucleotide derivative which comprises the unsubstituted ring nitrogen atom in the presence of triphenylphosphine and diisopropylazo dicarboxylate (DIAD). 
     Preferably, the carbon containing substituent having a hydroxyl group is selected from the group consisting of nerol, phythol, abietol, eicosapentaenol and docosahexaenol. 
     Preferably the Mitsunobu type reaction is carried out in a solvent, preferably diethylether or tetrahydrofurane (THF). 
     Further preferred the reaction is carried at temperatures below 10° C., preferably below 5° C. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
         FIG. 1  shows the different possible positions of nucleolipids within a nucleic acid, conjugation to the 5′ end of the nucleic acid (upper drawing), to the 3′ end (center drawing), or between two bases of the nucleic acid (lower drawing). 3′ designates the 3′ end of the oligonucleotide, 5′ the 5′ end, n means n repeats of the structure in brackets, “hydrophibic part” means lipid moieties. 
         FIG. 2 a    shows a schematic drawing of the Laser Scanning Microscope, the optical transparent microfluidic bilayer slide, and the lipid bilayer with incorporated double-tailed nucleolipids. 
         FIG. 2 b    shows a stage unit of the “Ionovation Explorer” from Ionovation GmbH, Osnabrück, Germany, mounted on a standard inverted fluorescence microscope. 
         FIG. 2 c    shows a “Ionovation Bilayer Slide”; a disposable, optical transparent microfluidic sample carrier with perfusion capabilities. 
         FIG. 3  shows the protocol of the insertion of the oligonucleotides 18-20 into an artificial bilayer. 
         FIG. 3-1  shown a z-scan of an empty bilayer; both channels (cis and trans) were perfused (30 s, 1.1 ml/min, each). 
         FIG. 3-2  shows a pixel-resolved 3D scan of an empty bilayer. 
         FIG. 3-3  shows an z-scan after addition of 18 (4 al, 50 nM) to the cis channel and 25 min of incubation. 
         FIG. 3-4  shows a z-scan after 1. perfusion of the cis compartment (60 s, 1.1 ml/min). 
         FIG. 3-5  shows a tilted 3D view onto the bilayer, filled with 18, after 1. perfusion. 
         FIG. 3-6  shows a pixel-resolved 3D scan of the bilayer, filled with 18, after 1. perfusion. 
         FIG. 3-7  shows a z-scan after 2. perfusion of the cis compartment (60 s, 1.1 ml/min. 
         FIG. 3-8  shows a pixel-resolved 3D scan of the bilayer, filled with 18, after 2. perfusion. 
         FIG. 3-9  shows a z-scan of the bilayer after addition of 19 (4 al, 50 nM) to the cis compartment and 25 min of incubation. 
         FIG. 3-10  shows a z-scan of the bilayer after 1. perfusion of the cis compartment (60 s, 1.1 ml/min). 
         FIG. 3-11  shows a z-scan of the bilayer after 2. perfusion of the cis compartment (60 s, 1.1 ml/min). 
         FIG. 3-12  shows a z-scan of the bilayer after 3. perfusion of the cis compartment (60 s, 1.1 ml/min). 
         FIG. 3-13  shows a tilted 3D view onto the empty bilayer. 
         FIG. 3-14  shows a z-scan of the bilayer after addition of 20 (4 al, 50 nM) and 25 min of incubation. 
         FIG. 3-15  shows a z-scan of the bilayer, filled with 20, after 1. perfusion of the cis compartment (60 s, 1.1 ml/min). 
         FIG. 3-16  shows a z-scan of the bilayer after 2. perfusion of the cis compartment (60 s, 1.1 ml/min). 
         FIG. 4  shows the relative bilayer brightness as a function of the perfusion number. 
         FIG. 5  shows a chronological protocol of duplex formation of the oligonucleotide EW3 with the complementary, CY3-labelled oligomer EW5 at an artificial lipid bilayer—aq. buffer boundary, followed by a perfusion. 
         FIG. 5-1  shows a z-scan of an empty bilayer. 
         FIG. 5-2  shows a tilted 3D view on an empty bilayer. 
         FIG. 5-3  shows a pixel-resolved 3D scan of an empty bilayer. 
         FIG. 5-4  shows a z-scan after addition of the oligomer EW3 (6 al, 500 nM) to the cis compartment and 60 min of incubation. 
         FIG. 5-5  shows a z-scan after addition of the Cy-5-labelled oligomer (6 al, 50 nM) to the cis compartment and 60 min of incubation. 
         FIG. 5-6  shows a z-scan after perfusion of the cis compartment (30 s, 1.1 ml/min). 
         FIG. 5-7  shows a tilted 3D view on the bilayer as in 6. 
         FIG. 5-8  shows a pixel-resolved 3D scan of the bilayer as in 6. 
         FIG. 6  shows a chronological control experiment with the non-complementary oligonucleotides EW4 and EW5. 
         FIG. 6-1  shows a z-scan of the empty bilayer. 
         FIG. 6-2  shows a tilted 3D view of the empty bilayer. 
         FIG. 6-3  shows a z-scan after addition of the oligomer EW4 (6 al, 500 nM) to the cis compartment and 50 min of incubation and perfusion (30 s, 1.1 ml/min). 
         FIG. 6-4  shows a z-scan after addition of the CY-5-labelled oligonucleotide (6 al, 50 nM) to the cis compartment and 40 min of incubation. 
         FIG. 6-5  shows a z-scan after perfusion of the cis compartment (30 s, 1.1 ml/min). 
         FIG. 6-6  shows a z-scan after further incubation for 20 min and two perfusions of the cis compartment (60 s, 1.1 ml/min, each). 
         FIG. 7  shows the relative bilayer brightness. 
         FIG. 8  shows a z-scan of a lipid bilayer showing two locations for measurements of the diffusion times. Location 1: bilayer; location 2: solution in close proximity, i.e. in a distance of ca. 5-10 m from the bilayer surface. “cis” means the compartment where the compound is added, “trans” the compartment on the other side of the membrane. The membrane also bears the “1”. 
         FIG. 9  shows the R f  values of the various uridine- and methyluridine O-2′,3′-ketals as a function of the carbon chain length. 
         FIG. 10  shows the activity of compounds ESP_2.2 and ESP_2.5 according to the invention and comparative compound ESP_2 against a human epithelial carcinoma cell line of the ovary (OVCAR-5 cancer cells). The y-axis shows the cell growth in percent, wherein the range from +125 to 0 represents an inhibition of the growth of the cancer cells and the range from 0 to −125 represents a cytotoxic effect. The x-axis depicts the molar concentration of the respective compound on a logarithmical scale. 
         FIG. 11  shows the activity of compounds ESP_3.1 according to the invention and comparative compound ESP_3 against OVCAR-5 cancer cells. 
         FIG. 12  shows the results of oncological tests of compounds ESP_2 (comparative) and ESP_2.2 and ESP_2.5 (both according to the invention) against IGR-OV1 cells. 
         FIG. 13  shows the test results of the unmodified nucleoside uridine (ESP_3) and the modified uridine derivative ESP_3.1 which is lipophilized at the sugar moiety against IGR-OV1 cells. 
         FIG. 14  shows the results of the oncological tests of compounds ESP_2, ESP_2.2 and ESP_2.5 against the human colorectal adenocarcinoma cell line HCT15. 
         FIG. 15  shows the data obtained in the oncological tests of compounds ESP_3 (comparative) and ESP_31 (according to the invention) when tested against HCT-15. 
         FIG. 16  shows the pharmaceutical activity of compounds ESP_2 (comparative), ESP_2.2 and ESP_2.5 (both according to the invention) when tested against a primary clear renal cell adenocarcinoma (cell line 786-0). 
         FIG. 17  shows that compound ESP_31, carrying lipophilc substituents at the sugar moiety, possesses a cytotoxic effect when tested against 786-0 cells, whereas the unmodified uridine (ESP_3, comparative) does not show any activity at all. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In an aspect of the invention a series of (i) base-alkylated 2′-deoxyinosine- and -thymidine as well as of (ii) sugar- and/or base-alkylated uridine- and 5-methyluridine cyanoethyl phosphoramidites are provided which can be used for the preparation of 5′-lipophilized oligonucleotides. Principally, phosphoramidites of the first group can be incorporated at each position of a growing nucleic acid chain using conventional solid-phase synthesis, so that the oligonucleotide can be hydrophobized at each predetermined locus ( FIG. 1 ). Phosphoramidites of the second group can be appended as 5′-terminators to a nucleic acid chain. 
     The synthesis of the first group (i) of nucleolipid phosphoramidites positioning of the lipophilic side chain can be performed at a nucleobase atom which is involved in Watson-Crick base pairing so that the resulting DNA building blocks are pure hydrophobization tools with a basic nucleoside structure. As side chains acyclic mono- and sesquiterpenes, particularly geranyl-, farnesyl- and other residues are preferably chosen because such residues are used in post-translational prenylation of various proteins in order to embed them within biological membranes. 
     Further, it has been found that for the hydrophobization of the various base moieties either direct alkylation with alkyl halogenides or Mitsunobu reactions can be performed. 
     For the synthesis of the second group (ii) of nucleolipid phosphoramidites the lipid moieties can be introduced into the glyconic part of the nucleoside and/or into the base moiety for example via ketalization. 
     One of the major drawbacks of many chemotherapeutics is their insufficient penetration through cell membranes as well as the crossing of the blood-brain barrier due to their high hydrophilicity. This is particularly true for antisense and antigene oligonucleotides. One method to overcome these problems is the introduction of lipophilic residues to the drug in order to render them hydrophobic and to improve their pharmacokinetics. In the case of low-molecular-weight drugs this kind of chemical modification is heading for the fulfilment of ‘Lipinski&#39;s Rule of Five’. The rule describes molecular properties important for a drug&#39;s pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion and is important for drug development where a pharmacologically active lead structure is optimized step-wise for increased activity and selectivity. One part of the rule concerns the drug&#39;s partition coefficient (log P between n-octanol and water) within the range of −0.4 and +5.5. In another aspect, the present invention further refers to the synthesis of a series of single- and double-chained lipids carrying different functional groups. Via these functional groups such as halogene, carboxylic ester, carboxylic acid, hydroxyl, ammonium, and alkine groups, the lipid residue can be introduced into chemotherapeutics such as nucleoside antimetabolites and others as well as into canonical nucleosides. A further embodiment of the invention refers to a process for preparing the compounds represented by formula (I) via a Mitsunobu type reaction. The compounds of the invention may be used in various fields. 
     Besides the applications in medicinal chemistry also other applications in nucleic acid analytics (detection and isolation) can be performed. The analysis of genes or gene segments is currently based on DNA chips. These chips or DNA microarrays are made up of a solid carrier (usually a glass object plate), on which single-stranded DNA molecules with a known sequence are attached in a regular and dense pattern. These DNA chips are either produced by direct synthesis on the solid carrier using masks and a photo-lithographic procedure, 
     or prefabricated, and terminally functionalized samples of nucleic acids are chemically attached to activated surfaces by covalent bonds. The DNA analysis may involve multiple steps: i) preparation of the sample (extraction, PCR, etc.), ii) hybridization on the chip, iii) stringend washing, iv) detection, and v) bioinformatic analysis. Both ways of producing DNA chips are afflicted with numerous issues. The first method requires the synthesis of oligonucleotides directly on the carrier, and includes several deprotection reactions and washing steps. This renders a complex method, especially when the array includes a multitude of different nucleic acid samples. In case of the second method, the solid surface—usually a glass plate—has to be activated with functional groups in a complicated manner in order to apply the likewise pre-made functionalized nucleic acids with a known sequence. This spotting is also a challenging procedure and requires special equipment. What follows is a chemical reaction between the ready-made functionalized nucleic acids and the activated functional groups on the surface of the array in order to achieve a covalent bond between the array and the nucleic acid. The present invention refers to a novel DNA chip technology which renounces any chemistry on solid supports by using instead the self-organization and duplex formation of lipid oligonucleotide conjugates at a lipid bilayer water interface. 
     In an exemplary embodiment of the invention the compound of the invention is a base-alkylated 2′-deoxynucleoside such as 2′-deoxyinosine and 2′-deoxythymidine. Preferably the alkylation/lipophilization is carrid out with terpenoid moieties. 
     For the preparation of N-geranylated and -farnesylated nucleoterpenes of 2′-deoxyinosine (1) and thymidine (7), respectively, base-catalyzed alkylation, for example in dimethylformamide with the corresponding terpenyl bromides can be chosen. In order to avoid side reactions such as the O-alkylation of the sugar hydroxyls as well as of the base protecting groups can be used prior to the alkylation. A suitable protecting group for the sugar moiety is the 1,1,3,3-tetraisopropyldisiloxane group. Scheme 1 and Scheme 2 show in one aspect sugar protected derivatives 2 and 8 which are protected by the so-called Markiewicz silyl clamp. This so-called Markiewicz silyl clamp can be easily introduced and cleaved off with tetra-N-butylammonium fluoride under mild conditions. Subsequent deprotonation of compound 2 and 8 can be performed under various reaction conditions with respect to solvent (DMF, MeCN) and base (NaH, K 2 CO 3 ). 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The unprotected 2′-deoxynucleosides (1 and 7) can be alkylated with geranyl bromide and farnesyl bromide under alkaline conditions, e.g. with K 2 CO 3  in dimethylformamide. For example, in the case of 2′-deoxyinosine (1) a reaction time of 24 h at room temp. was sufficient for a moderate yield (50-75%) of the products 3a,b while for thymidine (7) 48 h and 40° C. can be used to isolate the corresponding products 9a,b in comparable yields. The following table (Table 1) shows the lipophilicity of the thymidine derivatives in form of their calculated log P values and their retention times in RP-18 HPLC. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Calculated logP Values and Retention Times [min] of Thymidine  
               
               
                 Derivatives in RP-18 HPLC (for details, see Exp. Part). 
               
            
           
           
               
               
               
            
               
                   
                   
                 Retention Time 
               
               
                 Compound 
                 logP Value 
                 t R  [min] 
               
               
                   
               
               
                 7 
                 −1.11 ± 0.49  
                 1.89 
               
               
                 9a 
                 4.57 ± 0.61 
                 3.34 
               
               
                 9b 
                 6.60 ± 0.64 
                 7.85 
               
               
                   
               
            
           
         
       
     
     Compounds 3a,b and 9a,b represent synthetic nucleoterpenes of the invention. Dimeric molecules such as 6 and 12 can also be observed as side products. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In a further exemplary embodiment nucleoterpenes, such as nucleoterpene 3b, can be labelled with a fluorescence marker (FA) such as a fluorenyl moiety or Texas Red. An exemplary reaction scheme for labelling compound 3b is shown in Scheme 4. The nucleoterpene 3b can be labelled with different dyes, such as (i) with a fluorenyl moiety (Fmoc) via a glycine spacer and (ii) with Texas Red. For this labelling method compound 3b was reacted at its 5′-hydroxyl with N-[(9H-fluoren-9-yl-methoxy)-carbonyl]-glycine (13) using a Steglich esterification (DCC, DMAP). TLC analysis showed the formation of three products which could be separated by chromatography. 
     All compounds were characterized by  1 H-,  13 C-NMR as well as by UV-VIS spectroscopy. The fastest migrating compound was assigned as the 3′,5′-di-fluorenylated derivative 14, the others as the 5′-(15) and the 3′-(16) labelled compounds. 
     In a further alternative and exemplary synthesis compound 3b can be coupled with sulforhodamin-101-sulfonyl chloride (Texas Red). After extraction and silica gel chromatography the product 17 (Scheme 5) was obtained as a deep black, amorphous material. 
     
       
         
         
             
             
         
       
     
     According to a further aspect of the invention lipophilized oligonecleotides can be prepared via the phosphoramidites of the lipophilized nucleotides. As an example the phosphoramidites 5b and 11a,b were used to prepare a series of lipophilized oligonucleotides and their insertion into artificial lipid bilayers was studied. The following oligonucleotides were synthesized and characterized by MALDI TOF mass spectrometry. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Sequences and MALDI TOF Data of Oligonucleotides. 
               
            
           
           
               
               
               
            
               
                 Oligonucleotide (sequence, formula no, abbreviation) 
                 [M + H] +  (calc.) 
                 [M + H] +  (found) 
               
               
                   
               
               
                 5′-d(3b- Cy3 -TAG GTC AAT ACT)-3′, 18, KK1 
                 4.671.6 
                 4.671.1 
               
               
                   
               
               
                 5′-d(9b- Cy3 -TAG GTC AAT, ACT)-3′, 19, EW1 
                 4.660.6 
                 4.659.5 
               
               
                   
               
               
                 5′-d(9a- Cy3 -TAG GTC AAT, ACT)-3′, 20, EW2 
                 4.592.5 
                 4.590.5 
               
               
                   
               
               
                 5′-d(9b-TAG GTC AAT, ACT)-3′, 21, EW3 
                 4.153.0 
                 4.152.3 
               
               
                   
               
               
                 5′-d(9b-ATC CAG TTA TGA)-3′, 22, EW4 
                 4.153.0 
                 4.152.0 
               
               
                   
               
               
                 5′-d( Cy5 -AGT ATT GAC CTA)-3′, 23, EW5 
                 4.178.1 
                 4.178.4 
               
               
                   
               
            
           
         
       
     
     The oligonucleotides 18-20 contain—besides a nucleoterpene (3b or 9a,b)—an indocarbocyanine dye at the 5′-(n−1) position which was introduced via its phosphoramidite. The oligomers 21 and 22 carry the thymidine terpene 9b at the 5′-end while the oligomer 23 carries a Cy5 fluorophore label and is complementary to the oligonucleotide 21 in an antiparallel strand orientation but not to 22. 
     First, the insertion of the oligonucleotides 18-20 (KK1, EW1 and EW2) was tested at artificial bilayer membranes composed of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC) (8:2, w/w) in n-decane (10 mg/ml) in a set-up shown in  FIGS. 2 a -2 c   . (see E. Werz, et al. Chemistry &amp; Biodiversity, Vol. 9 2012, 272-281 and A Honigmann, PhD Thesis, University of Osnabrück, Germany, 2010 for detailed construction plans). From  FIGS. 3 and 4  it can be clearly seen that all Cy3-labelled lipo-oligonucleotides are inserted into the lipid bilayer, but to a different extent and with different stability towards perfusion. It is obvious that the oligomer carrying the N(3)-geranyl-thymidine nucleoterpene is inserted to the highest extent, but is washed out by one perfusion already to about 50%. The oligomers carrying farnesylated nucleosides at their 5′-end are significantly more stable towards perfusion. 
       FIG. 2 a    shows a schematic drawing of the Laser Scanning Microscope, the optical transparent microfluidic bilayer slide, and the lipid bilayer with incorporated double-tailed nucleolipids. The bilayer slide encloses two microfluidic channels (cis and trans) which are separated by a thin medical grade PTFE foil. This foil hosts a central 100 am aperture which is located 120 am above the coverslip and thus within the working distance of high NA objectives. It is the only connection between the trans and cis channel. When a lipid solution is painted across the aperture a bilayer is formed spontaneously. Electrodes in the cis and trans channels allow an online monitoring of the bilayer integrity as well as electrophysiological recordings. 
       FIG. 2 b    shows a stage unit of the “Ionovation Explorer” from Ionovation GmbH, Osnabrück, Germany, mounted on a standard inverted fluorescence microscope. The computer controlled perfusion unit is a side board and is not shown. 
       FIG. 2 c    shows a “Ionovation Bilayer Slide”; a disposable, optical transparent microfluidic sample carrier with perfusion capabilities. The “Bilayer Port” gives direct access to the lipid bilayer, while both sides of the bilayer can be perfused via the cis and trans channel. Calibration wells allow optical control experiments when needed. 
       FIG. 3 : Protocol of the Insertion of the Oligonucleotides 18-20 into an artificial Bilayer. 
       FIG. 3-1 : z-scan of an empty bilayer; both channels (cis and trans) were perfused (30 s, 1.1 ml/min, each) 
       FIG. 3-2 : Pixel-resolved 3D scan of an empty bilayer 
       FIG. 3-3 : z-scan after addition of 18 (4 al, 50 nM) to the cis channel and 25 min of incubation 
       FIG. 3-4 : z-scan after 1. perfusion of the cis compartment (60 s, 1.1 ml/min) 
       FIG. 3-5 : tilted 3D view onto the bilayer, filled with 18, after 1. perfusion 
       FIG. 3-6 : pixel-resolved 3D scan of the bilayer, filled with 18, after 1. Perfusion 
       FIG. 3-7 : z-scan after 2. perfusion of the cis compartment (60 s, 1.1 ml/min 
       FIG. 3-8 : pixel-resolved 3D scan of the bilayer, filled with 18, after 2. Perfusion 
       FIG. 3-9 : z-scan of the bilayer after addition of 19 (4 al, 50 nM) to the cis compartment and 25 min of incubation 
       FIG. 3-10 : z-scan of the bilayer after 1. perfusion of the cis compartment (60 s, 1.1 ml/min) 
       FIG. 3-11 : z-scan of the bilayer after 2. perfusion of the cis compartment (60 s, 1.1 ml/min) 
       FIG. 3-12 : z-scan of the bilayer after 3. perfusion of the cis compartment (60 s, 1.1 ml/min) 
       FIG. 3-13 : tilted 3D view onto the empty bilayer 
       FIG. 3-14 : z-scan of the bilayer after addition of 20 (4 al, 50 nM) and 25 min of incubation 
       FIG. 3-15 : z-scan of the bilayer, filled with 20, after 1. perfusion of the cis compartment (60 s, 1.1 ml/min) 
       FIG. 3-16 : z-scan of the bilayer after 2. perfusion of the cis compartment (60 s, 1.1 ml/min) 
       FIG. 4 : Relative Bilayer Brightness as a Function of the Perfusion Number. 
     Further, the duplex formation between bilayer-immobilized lipo-oligonucleotides (21 and 22, EW3 and EW4) with a Cy5-labelled oligomer (23, EW5) which is complementary only to 21 (EW3) but not to 22 (EW4) has been analyzed. Fluorescence microscopy ( FIGS. 5 and 6 ) clearly proves duplex formation for 21•23 but not for 22•23. 
       FIG. 5 : Chronological protocol of duplex formation of the oligonucleotide EW3 with the complementary, CY3-labelled oligomer EW5 at an artificial lipid bilayer—aq. buffer boundary, followed by a perfusion 
       FIG. 5-1 : z-scan of an empty bilayer 
       FIG. 5-2 : (2) tilted 3D view on an empty bilayer 
       FIG. 5-3 : (3) pixel-resolved 3D scan of an empty bilayer 
       FIG. 5-4 : z-scan after addition of the oligomer EW3 (6 al, 500 nM) to the cis compartment and 60 min of incubation 
       FIG. 5-5 : z-scan after addition of the Cy-5-labelled oligomer (6 al, 50 nM) to the cis compartment and 60 min of incubation 
       FIG. 5-6 : z-scan after perfusion of the cis compartment (30 s, 1.1 ml/min) 
       FIG. 5-7 : tilted 3D view on the bilayer as in 6. 
       FIG. 5-8 : pixel-resolved 3D scan of the bilayer as in 6. 
       FIG. 6 : Chronological control experiment with the non-complementary oligonucleotides EW4 and EW5. 
       FIG. 6-1 : z-scan of the empty bilayer 
       FIG. 6-2 : tilted 3D view of the empty bilayer 
       FIG. 6-3 : z-scan after addition of the oligomer EW4 (6 al, 500 nM) to the cis compartment and 50 min of incubation and perfusion (30 s, 1.1 ml/min) 
       FIG. 6-4 : z-scan after addition of the CY-5-labelled oligonucleotide (6 μl, 50 nM) to the cis compartment and 40 min of incubation 
       FIG. 6-5 : z-scan after perfusion of the cis compartment (30 s, 1.1 ml/min) 
       FIG. 6-6 : z-scan after further incubation for 20 min and two perfusions of the cis compartment (60 s, 1.1 ml/min, each). 
       FIG. 7 : Relative Bilayer Brightness 
     Furthermore, the diffusion times (T D  in ms) of the duplex 21•23 were measured, both without and in the presence of an artificial bilayer (Table 3). For the determination of the free diffusion times the corresponding oligomer duplex solution (50 nM) was diluted so that there was only a single fluorescent molecule in the confocal measuring volume (˜1 fl). Each measurement was performed ten-times for 30 s. In order to determine the diffusion times of the lipophilized oligonucleotide duplex (21•23) in the presence of a bilayer two measuring positions, one above (in solution but in close proximity to the bilayer), and one within the bilayer, were chosen. Each measurement was performed (i) by recording reference data of a stable, blank bilayer, (ii) after formation of the oligonucleotide duplex and a subsequent 30-min incubation, followed by recording of the data, (iii) recording of further data series after perfusion of the Bilayer Slide. 
     Table 3 summarizes the results and show that the diffusion of oligomer 23 as well as of the duplex 21•23 is fast. However, the broad diffusion time distribution of the duplex 21•23 indicates aggregate formation of heterogeneous size. In the close proximity of a stable bilayer the diffusion time increases approximately by a factor of 10. Probably the molecules aggregate, and the aggregates interact partly with the bilayer. The diffusion time of the bilayer-immobilized DNA duplex increases further by a factor of 10. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Diffusion times [τ D  (ms)] of 21 • 23 without and 
               
               
                 in the presence of a lipid bilayer. Location: 1, bilayer; 
               
               
                 2, solution in close proximity to the bilayer (see FIG. 8) 
               
            
           
           
               
               
               
            
               
                 sample 
                 position 
                 τ D  (ms) 
               
               
                   
               
               
                 23 
                 diffusion (in solution  
                 0.24 ± 0.1 
               
               
                 21 • 23 
                 without bilayer) 
                 0.12 ± 0.1 
               
               
                 21 • 23 
                 1 
                 26.6 ± 2.0 
               
               
                 21 • 23 
                 2 
                 2.39 ± 0.3 
               
               
                   
               
            
           
         
       
     
     In a further aspect of the invention an exemplary synthetic route to compounds of the invention is demonstrated in Scheme 6. According to a preferred embodiment of the invention the compounds of the invention are lipophilized by ketalization of glyconic moiety. Scheme 6 shows as an example the hydrophobization of uridine and methyluridine by long-chain ketal groups. Uridine (24) and methyluridine (29) can be reacted with symmetrical long-chain ketones in acidic medium (DMF) which leads to the O-2′,3′-ketals 25a-e and 30a-c. For this purpose two different synthetic routes may be applied (see Exp. Part). The compounds may directly be converted to their phosphoramidites (26a-e, 31a-c) or first N(3)-farnesylated and then phosphitylated (28a-e, 33a-c). 
     
       
         
         
             
             
         
       
     
       FIG. 9  displays the R f  values of the various uridine- and methyluridine O-2′,3′-ketals as a function of the carbon chain length. 
       FIG. 9 : R f  Values of various O-2′,3′-ketals. 
     Scheme 7 shows several synthetic routes for precursors which can be attached to the nucleotides, especially to the base moiety of the nucleotide. The functionalized lipids shown in Scheme 7 can be used to hydrophobize the nucleosides. Preferably, the compound of the invention comprises double chained lipids. As an example the synthesis of a series of functionalized lipids carrying two octadecanyl chains is described and reflected in Scheme 7. 
     
       
         
         
             
             
         
       
     
     Reaction of dioctadecylamine (34) with methyl bromoacetate (35) in the presence of dibenzo-[18]-crown-6 leads to the pure ester 3 in almost quantitative yield. This was either saponificated to yield the acid 37 or reduced with LiAlH 4  to give the alcohol 38. The latter can be submitted to an Appel reaction with tetrabromomethane and triphenyl phosphine which leads to the bromide 39 in low yield. In order to extend the spacer between the hydroxyl group and the nitrogen carrying the carbon chains the secondary amine 34 can be reacted with methyl acrylate (40). This lead in almost quantitative yield the ester 44 which can further be reduced with LiAlH 4  to give the lipophilic aminopropanol derivative 42. Subsequent Appel bromination to produce the aminobromide 43, however, was unsuccessful. NMR Spectroscopy revealed the formation of the quaternization product 44, an N,N-di-alkylated azetidinium bromide. This implies that the low yield in case of bromide 39 is also due to the formation of a quaternization product, namely an N,N-di-alkylated aziridinium bromide. 
     The amine 34 can be reacted with succinic anhydride (45) to give the acid 46. This was converted to the ester 47 by reaction with dimethyl sulphate in the presence of K 2 CO 3 . Compound 47 can be then reduced with LiAlH 4  yielding the further extended alcohol 48a or with LiAlD 4  giving the deuterated lipophilized 4-aminobutanol derivative 49. It should be noted that this way of labelling of the molecule allow one to introduce four isotope atoms of hydrogen in a single synthetic step which is important for the introduction of low radioactivity labels, such as tritium. Moreover, compound 48a was phosphitylated to the 2-cyanoethylphosphoramidite 48b ready for use for a terminal hydrophobization of nucleic acids. 
     In a further reaction the amine 34 can be alkylated with 1,4-dichlorobut-2-ine (50) in the presence of Na 2 CO 3  in benzene. This leads in 61% yield of the alkine derivative 51, besides the by-products 52-54, each in low yield. 
     Further, single-chained lipids as precursors can be synthesized as reflected in Scheme 8. As an example, the preparation of single-chained lipids with terminal functional groups is shown in Scheme 8. Reaction of octadecylamine (55) with propargylbromide (56) leads in almost quantitative yield the tertiary amine 57. Reaction of the starting amine 55 with succinic anhydride (45) afforded the acid 58 which can further be esterified to the ester 59. Treatment of the latter with LiAlH 4  (under the same conditions as for the reduction of 47 into 48a) yielded surprisingly the N-alkylated pyrrolidine 61 instead of the expected alcohol 60. Reduction of the acid 58 with LiAlH 4  in THF at ambient temperature was attempted, however it has led to a reduction of carboxylic group only, but not of the amide moiety and lead to the amidoalcohol 62 in 82% yield. Increasing of the reaction temperature to 65° C. leads to the desired aminoalkohole 60 but only in moderate yield of 23%. Replacement of THF by Et 2 O leads to compound 60 in a high yield of 84%. Subsequent reaction of compound 60 with propargyl bromide leads to the alkine 63 in 61% yield. 
     
       
         
         
             
             
         
       
     
     In a further aspect a further synthetic route to lipophilize the nucleoside the Mitsunobu reaction can be used to introduce the lipophilic moieties to the nucleosides. The regioselective introduction of lipophilic hydrocarbon chains into a nucleoside, particularly into a nucleoside with biomedical activity, is a difficult synthetic task. Such lipophilic groups can principally positioned either at the heterocyclic base or at the glyconic moiety and can be introduced by various methods, e.g. by base-catalysed alkylation with alkyl halides. 
     Some exemplary alkylation reactions of thymidine (7) with two of the functionalized lipids described above namely with compounds 42 and 51 are shown in Scheme 9. The reaction of unprotected thymidine with the alkine 51 was performed in DMF/K 2 CO 3  (direct alkylation) and leads to the N(3)-alkylated compound 65. This derivative can be further reacted with an azide in a ruthenium-catalysed variant of the azide-alkyne cycloaddition (RuAAC,  Huisgen - Sharpless - Meldal  [3+2] cycloaddition of azides with internal alkynes). Such reactions are underway. After dimethoxytritylation of 65 the derivative 66 was obtained, ready for further 3′-O-phosphitylation. 
     
       
         
         
             
             
         
       
     
     Due to the finding that the direct alkylation of thymidine (7) with compound 51 gave only a moderate yield of 65 (46%), next, the 5′-O-DMT-protected thymidine derivative 69-prepared from 7—was subjected to the alkylation with 51 (Scheme 10). However, the yield of the alkylated product 66 was found to be nearly the same (51%). Therefore, the totally, orthogonal protected derivative 64 was prepared and alkylated. This reaction gave the product 70 in high yield (95%). It could then be deprotected with tetrabutyl-ammonium fluoride in THF to produce the desired compound 66 in high yield (95%). Compound 66 (which can be, therefore, prepared on three different ways: from 69, from 65, and from 70) could be then reacted with 2-cyanoethyl N,N-diisopropylchlorophosphosphite in the presence of Hünig&#39;s base to form the corresponding phosphoramidite 71 which is ready to use for the preparation of oligonucleotides lipophilized at any position within the sequence. 
     
       
         
         
             
             
         
       
     
     In a further aspect alkylation of thymidine (7) can be performed by a Mitsunobu reaction. This type of alkylation is somewhat more versatile because alcohols which are precursors of halides can be used. However, a protection of the nucleoside OH-groups is advantageous. For this purpose 5′-dimethoxytritylated thymidine (68) for a Mitsunobu reaction with the alcohol 42 can be used which, however, may lead to by-products. Therefore, also the 3′-hydroxyl of 5′-DMT-thymidine by a tert-butyl-dimethylsilyl group is protected (˜64). Reaction of compound 64 with the alcohol 42 in the presence of triphenylphosphine and diisopropylazo dicarboxylate (DIAD) gave in 70% yield the product 67 which was subsequently desilylated with tetrabutylammonium fluoride to give compound 68. 
     Nucleolipids are synthesised using the compounds according to the present invention according to known methods. Preferred embodiments of the nucleolipids according to the present invention contain those that were produced with preferred embodiments of reactive lipids according to the invention. An especially preferred embodiment has the lipophilic moiety connected to the 5′ end of the oligo- or poly-nucleotide via the linker, spacer and a phosphoric acid diester group. 
     A further embodiment of the invention is a method for synthesising modified nucleotides, oligonucleotides or polynucleotides and comprising the step of the reaction of the reactive lipids according to the present invention with nucleosides, oligonucleotides or polynucleotides which are protected, except at one OH group. 
     The lipid/sample nucleic acid-conjugates are prepared by preparing the single strands of sample nucleic acids using methods well known to the artisan. Preferably, an automatic solid phase synthesis using the phosphoramidite- or the phosphonate-method is applied. The lipid moiety is the last component used during the routine automatic synthesis using a compound according to the invention and is for example a phosphoramidite derivative or also an appropriate phosphonate derivative. 
     A further embodiment of the present invention is a method for the identification of nucleic acids. This method includes the steps of providing a sample potentially containing nucleic acids, providing nucleolipids according to the present invention which hybridise with the nucleic acid to be determined under hybridising conditions and contacting the nucleolipids with the sample under hybridising conditions, thus, forming a hybridised product of a nucleic acid contained in the sample and the nucleolipid and detecting said hybridisation product. In this context, the term “hybridisation” or “hybridising conditions” means the hybridisation under conventional hybridising conditions, especially under stringent conditions as described for example by Sambrook and Russell (Molecular cloning: a laboratory manual, CSH Press. Cold Spring Harbor, N.Y., USA, 2001). The term “hybridisation” means in an especially preferred embodiment that the hybridisation takes place under the following conditions: Hybridisation buffer: 2.times.SSC; 10 times.Denhardt-solution (Ficoll 400+PEG+BSA; ratio 1:1:1); 0.1% SDS; 5 mMol EDTA; 50 mMol Na 2 HPO 4 ; 250 μg/ml herring-sperm DNA; 50 .mu.g/ml tRNA; or 0.25 mol sodium phosphate buffer, pH 7.2; 1 mMol EDTA, 7% SDS. 
     Hybridising temperature: T=60° C. Washing buffer: 2 times SSC; 0.1% SDS; Washing temperature: T=60° C. 
     In a further preferred embodiment the term “under hybridising conditions” means formation of multiple stranded hybridisation products under the following conditions: Hybridisation buffer: 10 mM Na-Cacodylate, 10 mM MgCl 2 , 100 mM NaCl or 10 mM Na-Cacodylate, 100 mM MgCl 2 , 1 M NaCl (the latter for increase low Tm-values) Hybridisation temperature: room temperature, individually between room temperature and 60° C. depending on the length and the composition of the target and sample sequences to be hybridized washing buffer: see above washing temperature: room temperature (25° C.). 
     In a particular preferred embodiment of the present invention, the sample-sequence only hybridises with the target-sequence under hybridising conditions in which the sample-sequence is complementary to the target-sequence. This is of great importance when single mutations are to be identified like for example in the pharmacogenetic field. 
     A further embodiment of the invention also includes a method for detecting the presence or absence of nucleic acids containing specific sequences within a sample and includes the following steps: bringing the sample in contact with the nucleolipids (compound) according to the present invention having oligo- or polynucleotide moieties. At least one of these oligo- or polynucleotides must show a sequence substantially complementary to a specific sequence of nucleic acids contained in the sample, and detecting the formation of hybridising products of the nucleolipids (compounds) according to the present invention and a specific sequence of nucleic acids within the sample (target-sequence) if contained within the sample. 
     The nucleic acid containing a specific sequence (target sequence) can be marked with a reporter group before using conventional, well known techniques. The skilled person is aware of many of those marker molecules, such as fluorescence dyes, radioactive markers, biotin etc. 
     In a preferred embodiment fluorescence dyes are used as reporter groups, for example fluorescein, a member of the Alexa- or Cy-dye-group. 
     In another embodiment, the method according to the present invention for determining the absence or presence of nucleic acids containing specific sequence within a sample is conducted in a way that the step of bringing into contact is conducted in multiple compartments which are separated from each other, whereby in each of said compartments a nucleic lipid having identical nucleic acid sequences is present, thus, the probe sequences present in a single compartment is identical and, in addition, different sequences are present in each of the separated compartments. Alternatively, in one compartment various nucleic lipids having different predetermined nucleic acid sequences may be present. It allows to analyse multiple samples. 
     During equilibration of the chemical equilibrium hybridization of the target nucleic acid with the corresponding sequence of a multitude of probe sequences occur. Optionally, the kinetics of hybridisation may be optimized by adjusting the temperature of the liquid phase. Optionally, non bonded target sequences may be removed by washing. Stirring of the solution containing the target sequences is preferred. 
     According to the invention, the identification of the hybridising products can be effected by testing for the reporter groups. When using a fluorescence dye as a reporter group, the measurement of the hybridising products is done by measuring the emitted fluorescence of this marker. In a preferred embodiment, the measurement of the reporter group is effected in the area of the liquid-gas boundary only. In another embodiment using two liquid phases (both liquids are only limited miscible or immiscible and they must form a phase boundary) allows the measurement of the reporter group at the liquid-liquid boundary between the two fluids. 
     The nucleolipids (compounds) according to the present invention cannot only be used to identify nucleic acids within a sample but also to isolate nucleic acids from a sample containing nucleic acids. Therefore, this invention also covers a method for the isolation of nucleic acids from samples containing nucleic acids and includes the following steps a) bringing the nucleic acids containing sample into contact with the nucleolipid(s) comprising a lipophilic moiety and an oligo- or polynucleotide moiety, whereby the oligo- or polynucleotides allow the hybridisation with at least a part of the nucleic acids contained within the sample, and b) separation of the hybridising products from the other ingredients contained in the sample and, optionally, washing the hybridising products. 
     Preferably, the bringing into contact occurs in a first liquid phase. By adding a second liquid phase which builds a liquid-liquid boundary with the first liquid phase allowing a spreading of the nucleolipids in a mono-molecular layer in such a way that the lipophilic moiety reaches into the more lipophilic liquid phase, while the other part of the nucleolipid, hybridised with the complementary nucleic acid sequence, extends into the other fluid, the hybridising products can be separated from single stranded nucleic acids from the sample. If desired, the hybridising products can also be separated from the other ingredients contained within the sample and, optionally, be washed. 
     In a preferred embodiment of the present invention the nucleolipids are used for the isolation of RNA-molecules, especially siRNA, miRNA or mRNA. When isolating mRNA-molecules, the nucleotide moiety of the nucleolipid has a polydT-sequence. Of course, the isolation can also be based on other known sequences contained within the target-sequence. 
     In another preferred embodiment of the present invention certain types of nucleic acids, namely aptameres, may be used for the isolation method. In case aptameres are used as the nucleic acid moiety of the nucleolipids, purification of other molecules than nucleic acids, like for example proteins, is possible. 
     This invention also concerns kits for identifying nucleic acids which contain one or more of the nucleolipids according to the present invention. These kits contain instructions for the detection of nucleic acids and, if required, a second liquid phase which builds a liquid-liquid boundary with the liquid sample. 
     The nucleotides according to the present invention may also be used to produce arrays of nucleic acids. This means that the nucleolipids containing a lipid moiety and an oligonucleotide moiety can be utilised in nucleic acid arrays, so called DNA-chips. These DNA-chips can be used for example for the analysis of genes or sections of genes, in particular, in pharmacogenetic analyses. 
     Those microarrays may now be produced with the help of the nucleolipids, according to the present invention, which in contrast to the conventional DNA-chips no longer requires complicated chemical procedures for activation of the solid surface and chemical fixation of the sample sequences on those surfaces. 
     Furthermore, the arrays according to the present invention have another advantage compared to the conventional arrays with permanent, i.e. covalently bound nucleic acid moieties, since they show spacial flexibility. When a hybridising product is formed, they require more space which requires a lateral displacement of the sample sequences. Since the nucleolipids are not connected to the solid plate by covalent bonds and the arrangement of the molecules at the boundary layer of a liquid-liquid system, respectively, the nucleolipids can move laterally thus enabling an optimum density for hybridisation at all times. 
     Therefore, this invention also concerns a system for the analysis of nucleic acids comprising a device like for example a DNA-chip or an array, comprising a lower section which may contain a liquid phase and an upper section which is not permanently attached to the lower part and which is insertable into the lower part, whereby the upper part has at least two compartments separated from each other and these compartments are formed from the upper to the lower side of the upper part. This makes it possible that e.g. the liquid phase in the lower section is able to exchange target nucleic acids contained within the phase of the upper section. 
     Preferably, the upper section has at least 4, 8, 16, 25, 64, 256, 384, etc. separated compartments. In a preferred embodiment of the device, the upper part is designed in such a way that when placed within the lower part the lower section of the lower part contains a joined liquid subphase which is not divided in single compartments. 
     A specific detection of nucleic acids is possible by the use of nucleolipids and the device according to the present invention. In the following an example is given for the analysis of nucleic acids using the system according to the present invention comprising the nucleolipids and the device described above. 
     The highly lipophilic single-stranded oligonucleotides of different nucleic acid sequences according to the present invention are being inserted separately into the compartments of the device e.g. with the help of a spotter, where they form a monolayer with properties of a liquid-analogue phase. The spreading is such that the lipid molecules point towards the gas phase while the oligonucleotides point into the liquid phase. If required, the aqueous phase may also be covered with a thin layer of oil thus creating a liquid-liquid phase boundary, in which the lipid chains point towards the lipophilic phase. 
     Now, the target sequence to be identified—marked with reporter groups such as fluorescence dye using methods known in the art in advance—has been injected into the subphase, common to all sample sequences, and spreaded by gentle mechanical stirring. During the adjustment of the chemical equilibrium, the target-DNA will hybridise with the corresponding sequence. The kinetics of the hybridising process may be optimized by adjusting the temperature of the lower section of the device containing the subphase and/or by flow of a buffer solution through the subphase (washing). In a compartment of the device containing the marked target-sequence and the optimum fitting and known sample sequence will form the hybridisation product which can easily be identified by well known methods, like for example fluorescence detectors. 
     As discussed above, the reactive lipids according to the present invention are particularly useful for the use in conventional DNA-synthesisers where they may be applied as 5′ end building blocks. This allows a simple synthesis of sample sequences and reduces the problems accompanied with the neosynthesis of oligonucleotides on the array itself and the difficult chemical fixation of nucleic acid probes functionalized in advance on the activated surface of the area, respectively. 
     When selecting a sample nucleic acid, various possibilities are given. 
     Not only can nature derived DNA- and RNA-molecules be used. Rather oligomeres which can be modified in multiple ways may be used. For example, a PNA (peptide-nucleic acid), complementary to the target nucleic acid to be examined, can be used for hybridisation. Furthermore, nucleic acids with modifications in their sugar moiety, i.e. hexose or hexitole nucleic acids, have been prepared in recent years which are capable of hybridising with natural nucleic acids. Said sample nucleic acids can be used also in the analytic methods according to the present invention. It has been shown that modifying a nucleobase of a sample oligonucleotide, i.e. incorporation of purin-isosteric 8-Aza-7-deaza-7-halogenopurine-base, significantly increases the stability of a duplex with a common DNA-oligomer which leads to a harmonisation of otherwise differently stable base-pairs guanine-cytosine and adenine-thymine. Also those modified sample nucleic acids can be used in this analytic procedure according to this invention. 
     According to the present invention, the gaseous phase or the gas is air or an inert gas such as nitrogen, argon etc. According to the present invention, using a system of two fluids which are generally immiscible produces a boundary layer, called liquid-liquid boundary layer. The result is a lipophilic phase as well as a hydrophilic phase. Usually, the target sequence will be in the hydrophilic phase which is generally an aqueous phase, like a buffer solution. The lipophilic phase is for example made up of an organic solvent or oil. The skilled person knows many of those systems. 
     Another application of the nucleolipids is using them as marker of different compositions, like crude oil or other processed products. Adding nucleolipids with a known nucleic acid sequence specifically marks the products. This specific marking allows for a later identification of the compound&#39;s origin. This could be an easy way to identify the polluter of an oil spill. These nucleic acids are soluble in oils and other lipophilic fluids due to their lipophilic section. 
     A further object of the present invention is a pharmaceutical composition comprising a compound according to the invention. 
     In a preferred embodiment the pharmaceutical composition comprises a compound of formula (XVI) 
     
       
         
         
             
             
         
       
     
     wherein R 2  is H or —Y—X or —Y-L-Y 1 —X; and 
     R 5  and R 6  are independently from each other a C 1 -C 28 -alkyl moiety or a C 1 -C 10  carbon chain which is interrupted by Heteroatom(s), especially O, and functional group(s), especially ester group(s); and 
     R 20  is H or methyl; and 
     R 46  is selected from H, 
     
       
         
         
             
             
         
       
         
         
           
             substituted or unsubstituted cyclic terpene moieties, and 
           
         
       
    
     
       
         
         
             
             
         
       
     
     wherein 
     R 9  and R 9′  are independently selected from C 1  to C 30  alkyl, 
     n is an integer ranging 1 to 4, preferably n is 1 or 2; 
     b is an integer ranging from 1 to 20, preferably 4 to 16; 
     a is an integer ranging from 1 to 20, preferably 2 to 18; and 
     wherein A is CH or N; and 
     wherein Y and Y 1  are independently from each other a single bond or a functional connecting moiety, 
     X is a fluorescence marker (FA) and/or a polynucleotide moiety having up to 50 nucleotide residues, preferably 10 to 25 nucleotides, especially a polynucleotide having an antisense or antigen effect, and 
     L is a linker by means of which Y and X are covalently linked together. 
     It has surprisingly been found that the compounds of the present invention demonstrate a cytoxicity against cancer cells. 
     Therefore, in a further preferred embodiment the pharmaceutical composition according to the invention is for use in the treatment of cancer. 
     Preferably the pharmaceutical composition according to the invention is for use in the treatment of cancer selected from the group consisting of kidney cancer, colon cancer and ovarian cancer. 
     Further preferred is an embodiment of the present invention wherein the pharmaceutical composition comprises the compound according to the invention in a pharmaceutically effective amount. 
     The pharmaceutical composition according to the invention is preferably a liquid composition, more preferably an aqueous composition. 
     In a further preferred embodiment the composition according to the invention is pharmaceutically injectable. Preferably the composition is parenterally administered. 
     In a preferred embodiment the pharmaceutical composition of the invention may comprise further excipients. 
     Further preferred is an embodiment wherein the pharmaceutical composition according to the invention is subjected to humans and/or animals, preferably mammals. 
     EXPERIMENTAL PART 
     General 
     All chemicals were purchased from Sigma-Aldrich (D-Deisenhofen) or from TCI—Europe (B-Zwijndrecht). Solvents were of laboratory grade and were distilled before use. TLC: aluminum sheets, silica gel 60 F 254 , 0.2 mm layer (Merck, Germany). M.p. Biichi SMP-20, uncorrected. UV Spectra: Cary 1E spectrophotometer (Varian, D-Darmstadt). NMR Spectra (incl.  1 H-DOSY spectra): AMX-500 spectrometer (Bruker, D-Rheinstetten);  1 H: 500.14 MHz,  13 C: 125.76 MHz, and  31 P: 101.3 MHz. Chemical shifts are given in ppm relative to TMS as internal standard for  1 H and  13 C nuclei and external 85% H 3 PO 4 ; J values in Hz. ESI MS Spectra were measured on a Bruker Daltronics Esquire HCT instrument (Bruker Daltronics, D-Leipzig); ionization was performed with a 2% aq. formic acid soln. Elemental analyses (C, H, N) of crystallized compounds were performed on a VarioMICRO instrument (Fa. Elementar, D-Hanau). Gel permeation chromatography (GPC) was performed on three columns with a light scattering detector (Dawn Helios) and an RI detector (Optilab rEX, Wyatt). The results were evaluated and displayed with the program ASTRA 5.3.4, version 14. log P Values were calculated using the program suite ChemSketch (version 12.0, provided by Advanced Chemistry Developments Inc.; Toronto, Canada; http://www.acdlabs.com. Oligonucleotides were synthesized, purified, and characterized (MALDI-TOF MS) by Eurogentec (Eurogentec S. A., Liege Science Park, B-Seraing). 
     Oligonucleotide Incorporation into Artificial Bilayers. 
     The incorporation of the oligonucleotides 18-22 into artificial lipid bilayers was performed using a lipid mixture of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC) (8:2, w/w, 10 mg/ml of n-decane). The horizontal bilayers were produced automatically within the “Bilayer Slides” using an “Ionovation Explorer” (Ionovation GmbH, Osnabrück, Germany). After pre-filling with buffer (250 mM KCl, 10 mM MOPS/Tris, pH 7), the “Bilayer Slide” is inserted into the stage unit of the “Ionovation Explorer”. The Ag/AgCl electrodes are mounted, and after addition of 0.2 al of POPE/POPC lipid to the cis-compartment, the automated bilayer production is started. The “Ionovation Explorer” uses a modified painting technique, where the air-water interface paints the lipid across the aperture. The bilayer formation is monitored via capacitance measurements. When a stable bilayer is established (&gt;50 pF) the corresponding oligonucleotide solution was injected into the cis compartment of the “Bilayer Slide”. During the incubation time of 25 min the bilayer integrity was monitored by the “Ionovation Explorer” through continuous capacitance measurements. 
     A confocal laser scanning microscope (Insight Cell 3D, Evotec Technologies GmbH, Hamburg, Germany), equipped with a 635 nm emitting laser diode (LDH-P-635, PicoQuant GmbH, Berlin, Germany), a 40× water-immersion objective (UApo 340, 40×, NA=1.15, Olympus, Tokyo, Japan), and an Avalanche photodiode detector (SPCM-AQR-13-FC, Perkin-Elmer Optoelectronics, Fremont, Calif., USA) was used for the optical measurements. Fluorescence irradiation was obtained with an excitation laser power of 200±5 aW. 2D- and 3D scans were performed by scanning the confocal laser spot in XY direction with a rotating beam scanner and movement of the objective in Z direction. The movement in all directions was piezo-controlled which allows a nano-meter precise positioning. For the 2D pictures (Z-scans,  FIGS. 7, 9, and 10 ) the confocal plane was moved in 100 nm steps. 
     From the fluorescence signals of single molecules which pass the laser spot, the diffusion constants can be calculated by means of fluorescence correlation analysis. In order to determine the diffusion times of the fluorescent oligonucleotides within and in the proximity of the bilayer, they were measured at overall five different positions above, below and within the layer ( FIG. 2 -A). At each point five 30 s—measurements were taken. In summary, each measuring protocol was as follows: (i) a reference scan of the stable (empty) bilayer; (ii) addition of the sample with 30 min of incubation, followed by a scan series; (iii) additional scan series, each after a 1. and 2. perfusion (60 s, each). 
     Subsequently, the cyanine-5-labelled oligonucleotide 23 (50 nM, 6 al) was injected into the cis compartment of the “Bilayer Slides” containing either membrane-bound 21 or membrane-bound 22. After an equilibration time of 60 min the cis channel was perfused repeatedly for 30 sec (1.1 ml/min) and the bilayers were inspected by confocal fluorescence microscopy. 
     RP-18 HPLC. RP-18 HPLC was carried out on a 250×4 mm RP-18 column (Merck, Germany) on a Merck-Hitachi HPLC apparatus with one pump (Model 655A-12) connected with a proportioning valve, a variable wavelength monitor (Model 655 A), a controller (Model L-5000), and an integrator (Model D-2000). Solvent: MeCN/0.1 M Et 3 NH + OAc −  (35:65, v/v, pH 7.0). 
     Synthesis of Inosine Derivatives 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     9-((6aR,8R,9aS)-2,2,4,4-Tetraisopropyltetrahydro-6H-furo[3,2-f]-[1,3,5,2,4]trioxadisilocin-8-yl)-1H-purin-6(9H)one (2) 
     Anhydr. 2′-deoxyinosine (1, 1.01 g, 4 mmol) was suspended in dry pyridine (40 ml), and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (1.39 g/4.4 mmol) was added under moisture exclusion. After stirring for 24 h at ambient temperature the solvent was evaporated, and the residue was partitioned between EtOAc and water (80 ml, 1:1, v/v). The organic layer was washed twice with 1 M hydrochloric acid (80 ml), followed by H 2 O, conc. aq. HaHCO 3  and brine (80 ml, each). After drying (Na 2 SO 4 , 1 h) the solvent was evaporated, and the residue was chromatographed (silica gel, column: 6×10 cm, CHCl 3 -MeOH, 9:1, v/v). From the main zone compound 2 (1.96 g, 99%) was isolated as colourless amorphous material. M.p. 210° C. TLC (silica gel 60, CHCl 3 -MeOH, 9:1, v/v): R f , 0.56. UV (MeOH): λ max =244 nm (ε=12.250 M −1  cm −1 ); ε 260 =7.500 M −1  cm −1 .  1 H-NMR ((D 6 )DMSO): 12.33 (s, NH); 8.19 (s, H—C(2)); 7.97 (s, H—C(8)); 6.27 (t,  3 J(H—C(1′), H—C(2′))=5.5, H—C(1′)); 4.94 (q, H—C(3′)); 3.92 (m, H—C(4′)); 3.81 (H 2 —C(5′)); 2.80 (m, H β —C(2′)); 2.56 (m, H α —C(2′)); 1.08-1.01 (m, 28H, H—C(1″)); i-Pr). 
       13 C-NMR ((D 6 )DMSO): 156.47 (C(6)); 147.41 (C(4)); 145.49 (C(2)); 138.72 (C(8)); 124.74 (C(5)); 84.47 (C(1′)); 82.10 (C(4′)); 71.22 (C(3′)); 62.40 (C(5′)); 38.70 (C(2′)); 17.06 (8×CH 3 ); 12.33 (4×CH). Anal. calc. for C 22 H 38 N 4 O 5 Si 2  (494.732): C, 53.41%, H, 7.74%, N, 11.32%; found: C, 53.21%, H, 7.78%, N, 11.23%. 
     9-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-furan-2-yl)-1-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)-1H-purin-6(9H)-on (3b) 
     Anhydrous 2′-deoxyinosine (1, 1.01 g, 4 mmol) was suspended in anhydr., amine-free DMF and heated on a water bath (55° C.). Then, anhydr. K 2 CO 3  (1.44 g, 10.4 mmol) was added, and the mixture was stirred for 10 min. After cooling to ambient temperature, farnesyl bromide (1.32 g, 4.4 mmol) was added drop-wise under N 2  atmosphere. After stirring for 24 h at room temp., the solvent was evaporated, and the residue dried in high vacuo. Chromatography (silica gel, column: 6×14 cm, CHCl 3 -MeOH, 9:1, v/v) gave one main zone from which after evaporation of the solvent compd. 3b (1.28 g, 74%) was isolated as an amorphous solid. TLC (silica gel 60, CHCl 3 -MeOH, 95:5, v/v): R f  0.42. log P, 3.40±0.94. UV (MeOH): λ max =250 nm (8=10.150 M −1  cm −1 ) ε 260 =7.000 M −1  cm −1 .  1 H-NMR ((D 6 )DMSO): 8.34 (s, H—C(2)); 8.30 (s, H—C(8)); 6.29 (t,  3 J(H—C(1′), H—C(2′)=7.0, H—C(1′)); 5.35 (d,  3 J(HO—C(3′), H—C(3′)=7.5, HO—C(3′)); 5.35 (t,  3 J(H—C(2″), H—C(1″)=7.5, H—C(2″)); 5.10 (H—C(6″)); 5.10 (H—C(10″)); 4.92 (t,  3 J(HO—C(5′), H—C(5′)=6.5, HO—C(5′)); 4.70 (d,  3 J(H—C(1″), H—C(2″)=7.5, H—C(1″)); 4.39 (H—C(3′)); 3.86 (H—C(4′)); 3.55 (H—C(5′)); 2.61 (H β —C(2′)); 2.27 (H α —C(2′)); 2.04 (H—C(8″)); 1.98 (H—C(9″)); 1.93 (H—C(5″)); 1.86 (H—C(4″)); 1.77 (H—C(13″)); 1.60 (H—C(12″)); 1.51 (H—C(14″)); 1.51 (H—C(15″)).  13 C-NMR ((D 6 )DMSO): 155.71 (C(6)); 147.98 (C(4)); 146.99 (C(2)); 140.05 (C(3″)); 138.96 (C(8)); 134.67 (C(7″)); 130.56 (C(11″)); 124.02 (C(6″)); 123.80 (C(5)); 123.44 (C(10″)); 119.43 (C2″)); 87.97 (C(1′)); 83.60 (C(4′)); 70.67 (C(3′)); 61.61 (C(5′)); 43.22 (C(1″)); 39.48 (C(2′)); 39.11 (C(8″)); 38.81 (C(4″); 26.11 (C(5″)); 25.62 (C(12″)); 25.41 (C(9″)); 17.45 (C(15″)); 16.21 (C(14″)); 15.78 (C(13″)). Anal. calc. for C 25 H 36 N 4 O 4  (456.578): C, 65.76%, H, 7.95%, N, 1227%; found: C, 65.42%, H, 8.06%, N, 12.04%. 
     1-((E)-3,7-Dimethylocta-2,6-dienyl)-9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-on (3a) 
     Compound 3a was prepared and worked up from 2′-deoxyinosine (1, 1.01 g, 4 mmol) and geranyl bromide (0.96 g, 4.4 mmol) as described for 3b. Yield: 0.80 g (51%). TLC (silica gel 60, CHCl 3 -MeOH, 95:5, v/v): R f  0.41. UV (MeOH): λ max =250 nm (8=10.450 M −1  cm −1 ) ε 260 =7.800 M −1  cm −1 . log P: 1,37±0.93.  1 H-NMR ((D 6 )DMSO): 8.35 (s, H—C(2)); 8.31 (s, H—C(8)); 6.31 (t,  3 J(H—C(1′), H—C(2′)=7.0, H—C(1′)); 5.30 (HO—C(3′)); 5,28 (t,  3 J(H—C(2″), H—C(1″)=7.0, H—C(2″)); 5.03 (t,  3 J(H—C(6″), H—C(5″)=6.5, H—C(6″)); 4.94 (HO—C(5′)); 4.62 (d,  3 J(H—C(1″), H—C(2″)=6.5, H—C(1″)); 4.39 (H—C(3′)); 3.88 (H—C(4′)); 3.57 (H—C(5′)); 2.63 (H β —C(2′)); 2.30 (H α —C(2′)); 2.04 (H—C(5″)); 2.00 (H—C(4″)); 1.79 (H—C(13″)); 1.59 (H—C(8″)); 1.53 (H—C(14″)).  13 C-NMR ((D 6 )DMSO): 156.19 (C(6)); 148.45 (C(4)); 147.46 (C(2)); 140.56 (C(3″)); 139.49 (C(8)); 131.47 (C(7″)); 124.25 (C(6″)); 124.16 (C(5)); 119.87 (C2″)); 88.42 (C(1′)); 84.07 (C(4′)); 71.12 (C(3′)); 62.07 (C(5′)); 43.71 (C(1″)); 39.65 (C(2′)); 39.32 (C(8″)); 38.98 (C(4″); 26.22 (C(5″)); 25.82 (C(8″)); 17.95 (C(14″)); 16.65 (C(13″)). Anal. calc. for C 20 H 28 N 4 O 4  (388.461): C, 61.84%, H, 7.27%, N, 14.42%; found: C, 61.72%, H, 7.31%, N, 14.31%. 
     9-((2R,4S,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)-methyl)-4-hydroxytetrahydrofuran-2-yl)-1-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)-1H-purin-6(9H)-on (4b) 
     Compound 3b (0.46 g, 1.0 mmol) was co-evaporated twice from dry pyridine (1 ml, each) and then dissolved in anhydr. pyridine (5 ml). After addition of 4,4′-dimethoxytriphenylmethylchlorid (0.40 g, 1.15 mmol) the reaction mixture was stirred for 24 h at ambient temperature under N 2  atmosphere. Then, the reaction was quenched by addition of MeOH (3 ml). After addition of aq. 5% NaHCO 3  (30 ml) the aqueous phase was extracted three times with CH 2 Cl 2  (30 ml, each), and the combined organic layers were dried (Na 2 SO 4 , 1 h) and filtered. Chromatography (silica gel, column: 6×10 cm, CHCl 3 -MeOH: 96:4, v/v) gave one main zone from which compound 4b (0.46 g, 61%) was isolated as a slightly yellowish glass; m.p. 68° C. TLC (silica gel 60, CHCl 3 -MeOH: 96:4, v/v): R f  0.13. UV (MeOH): λ max =235 nm (8=38.200 M −1  cm −1 ); ε 260 =14.150 M −1  cm −1 . log P: 9.81±0.96.  1 H-NMR ((D 6 )DMSO): 8.23 (s, H—C(2)); 8.16 (s, H—C(8)); 7.32 (H—C(10′″)); 7.31 (H—C(8′″)); 7.20 (H—C(3′″)); 7.18 (H—C(9′″)); 6.80 (H—C(4′″)); 6.31 (t,  3 J(H—C(1′), H—C(2′)=6.5, H—C(1′)); 5.33 (HO—C(3′)); 5.24 (t,  3 J(H—C(2″), H—C(1″)=7.0, H—C(2″)); 5.02 (t,  3 J(H—C(10″), H—C(9″)=6.0, H—C(10″)); 4.99 (t,  3 J(H—C(6″), H—C(5″)=6.5, H—C(6″)); 4.59 (H—C(1″)); 4.40 (H—C(3′)); 3.98 (H—C(4′)); 3.71 (H—C(6′″)); 3.15 (H—C(5′)); 2.74 (H β —C(2′)); 2.32 (H a —C(2′)); 2.05 (t,  3 J(H—C(8″), H—C(9″)=6.5, H—C(8″)); 1.99 (H—C(9″)); 1.93 (H—C(5″)); 1.85 (t,  3 J(H—C(4″), H—C(5″)=7.5, H—C(4″)); 1.77 (H—C(13″)); 1.59 (H—C(12″)); 1.50 (H—C(14″)); 1.50 (H—C(15″)).  13 C-NMR ((D 6 )DMSO): 157.93 (C(5′″)); 155.65 (C(6)); 147.65 (C(2)); 146.93 (C(4)); 144.72 (C(7′″)); 140.02 (C(3″)); 139.07 (C(8)); 135.48 (C(2′″)); 134.59 (C(7″)); 130.47 (C(11″)); 129.54 (C3′″)); 129.54 (C(9′″)); 127.57 (C(8′″)); 126.46 (C(10′″)); 123.94 (C(6″)); 123.94 (C(10″)); 123.38 (C(5)); 119.29 (C(2″)); 112.97 (C(4′″); 85.93 (C(1′″)); 85.35 (C(1′)); 83.44 (C(4′)); 70.54 (C(3′)); 64.03 (C(5′)); 54.89 (C(6′″)); 43.09 (C(2′)); 39.02 (C(8″)); 38.85 (C(4″)); 38.75 (C(1″)); 26.02 (C(9″)); 25.56 (C(5″)); 25.32 (C(12″)); 17.36 (C(15″)); 16.12 (C(14″)); 15.67 (C(13″)). Anal. calc. for C 46 H 54 N 4 O 6  (758.944): C, 72.80%, H, 7.17%, N, 7.38%; found: C, 72.53%), H, 7.14%, N, 7.27%. 
     9-((2R,4S,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)-methyl)-4-hydroxytetrahydrofuran-2-yl)-1-((E)-3,7-di-methylocta-2,6-dienyl)-1H-purin-6(9H)-one (4a) 
     Compound 4a was prepared from 3a (0.39 g, 1.0 mmol) and worked up as described for compound 4b. Yield: 0.48 g, 69% of a colourless glass; m.p. 74° C. TLC (silica gel 60, CHCl 3 -MeOH: 96:4, v/v): R f  0.19. UV (MeOH): λ max =235 nm (ε=32.820 M −1  cm −1 ); ε 260 =12.791 M −1  cm −1 . log P: 7.77±0.94.  1 H-NMR ((D 6 )DMSO): 8.25 (s, H—C(2)); 8.18 (s, H—C(8)); 7.33 (H—C(10′″)); 7.31 (H—C(8′″)); 7.20 (H—C(3′″)); 7.19 (H—C(9′″)); 6.81 (H—C(4′″)); 6.32 (t,  3 J(H—C(1′), H—C(2′)=6.5, H—C(1′)); 5.35 (HO—C(3′)); 5.23 (t,  3 J(H—C(2″), H—C(1″)=6.5, H—C(2″)); 5.02 (t,  3 J(H—C(6″), H—C(5″)=6.0, H—C(6″)); 4.60 (H—C(1″)); 4.40 (H—C(3′)); 3.98 (H—C(4′)); 3.72 (H—C(6′″)); 3.16 (H—C(5′)); 2.75 (H β —C(2′)); 2.34 (H α —C(2′)); 2.03 (H—C(5″)); 2.00 (H—C(4″)); 1.77 (H—C(13″)); 1.57 (H—C(8″)); 1.51 (H—C(14″)).  13 C-NMR ((D 6 )DMSO): 157.95 (C(5′″)); 155.67 (C(6)); 147.67 (C(2)); 146.95 (C(4)); 144.72 (C(7′″)); 140.07 (C(3″)); 139.11 (C(8)); 135.48 (C(2′″)); 130.93 (C(11″)); 129.56 (C3′″)); 129.55 (C(9′″)); 127.68 (C(8′″)); 126.48 (C(10′″)); 123.95 (C(6″)); 123.61 (C(5)); 119.27 (C(2″)); 112.98 (C(4′″); 85.92 (C(1′″)); 85.35 (C(1′)); 83.44 (C(4′)); 70.53 (C(3′)); 64.03 (C(5′)); 54.88 (C(6′″)); 43.11 (C(2′)); 38.74 (C(4″)); 38.74 (C(1″)); 25.70 (C(5″)); 25.26 (C(8″)); 17.39 (C(14″)); 16.10 (C(13″)). Anal. calc. for C 41 H 46 N 4 O 6  (690.827): C, 71.28%, H, 6.71%, N, 8.11%); found: C, 70.94%, H, 6.67%, N, 7.93%. 
     (2R,3S,5R)-2-((Bis(4-methoxyphenyl)(phenyl)methoxy)-methyl)-5-(6-oxo-1-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)-1H-purin-9(6H)-yl)tetrahydrofuran-3-yl 2-cyanoethyldiisopropyl phosphoramidite (5b) 
     Compound 4b (100 mg, 0.13 mmol) was co-evaporated twice with CH 2 Cl 2  and then dissolved in CH 2 Cl 2  (5 ml). After addition of N,N-diisopropylethylamine (42 μL, 0.24 mmol) and (chloro)(2-cyanoethoxy)(diisopropylamino)phosphine (52 μL, 0.24 mmol) the reaction mixture was stirred for 15 min (!) at room temp. under N 2  atmosphere. Then, ice-cold 5% aq. NaHCO 3  was added (4 ml), and the mixture was extracted three times with CH 2 Cl 2  (8 ml, each). The combined organic layers were dried (Na 2 SO 4 , 10 min), filtered and the solvent evaporated (&lt;25° C.). Flash chromatography (0.5 bar, silica gel, column: 2×8 cm, CH 2 Cl 2 -acetone: 8:2, v/v) gave compd. 5b (98 mg, 78%) as amorphous material. TLC (silica gel, CH 2 Cl 2 -acetone, 8:2, v/v): R f  0.64, 0.76 (diastereoisomers). log P=12.86±1.11.  31 P-NMR (CDCl 3 ): 148.86, 149.02. 
     (2R,3S,5R)-2-((Bis(4-methoxyphenyl)(phenyl)methoxy)-methyl)-5-(1-((E)-3,7-dimethylocta-2,6-dienyl)-6-oxo-1H-purin-9(6H)-yl)-tetrahydrofuran-3-yl-2-cyanoethyl-diisopropylphosphoramidite (5a) 
     Compound 5a was prepared and worked up from 4a (100 mg, 0.14 mmol) as described for compd. 5b. Yield: 79 mg (61%) of amorphous material. TLC (silica gel, CH 2 Cl 2 -acetone, 8:2, v/v): R f  0.64, 0.76 (diastereoisomers). log P=10.82±1.10.  31 P-NMR (CDCl 3 ): 148.87, 149.02. 
     
       
         
         
             
             
         
       
     
     Numbering of the terpenyl-, the 4,4′-dimethoxytriphenylmethyl-(DMTr), and of the fluorenylmethoxycarbonyl-(Fmoc) residues throughout the Exp. Part. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Small-Scale Coupling of Compound 3b with (i) N-[(9H-Fluoren-9-ylmethoxy)-carbonyl]-glycine (→14-16) and (ii) Sulforhodamin-sulfonylchloride (→17) 
     (i)N-[(9H-Fluoren-9-ylmethoxy)-carbonyl]-glycine (13, 65.4 mg, 0.22 mmol) was dissolved in CH 2 Cl 2  (20 ml) and 4-(dimethylamino)pyridine (5 mg) and compound 3b (100 mg, 0.22 mmol) were added. The reaction mixture was cooled to 0° C., and dicyclohexylcarbodiimide (45.5 mg, 0.22 mmol) in CH 2 Cl 2  (2 ml) were added drop-wise. After 5 min the mixture was allowed to warm up to room temp., and stirring was continued over night. Then, further portions of N-[(9H-fluoren-9-ylmethoxy)-carbonyl]-glycine, 4-(dimethylamino)pyridine, and dicyclohexylcarbodiimide (30 mole-%, each) were added, and stirring was continued. After a total reaction time of 48 h the suspension was filtered, and the filtrate was evaporated to dryness. Chromatography (silica gel, column: 2×15 cm, CH 2 Cl 2 -acetone, 6:4, v/v) afforded three main zones from which the following fluorene-labelled nucleolipids were obtained upon evaporation of the solvent. 
     (2R,3S,5R)-3-(2-(((9H-Fluoren-9-yl)methoxy)carbonyl-amino)acetoxy)5-(6-oxo-1-((2E,6E)-3,7,11-trimethyl-dodeca-2,6,10-trienyl)-1H-purin-9(6H)-yl)-tetrahydrofuran-2-yl)methyl-2-(((9H-fluoren-9-yl)methoxy)carbonyl-amino)acetate (14) 
     TLC (silica gel, CHCl 3 -MeOH, 96:4, v/v): R f  0.56. UV (MeOH): λ max =263 nm (8=45.200 M −1  cm −1 ); ε 260 =44.200 M −1  cm −1  log P=11.67±1.22.  1 H-NMR ((D 6 )DMSO): 8.29 (s, H—C(2)); 8.27 (s, H—C(8)); 7.87 (H—C(11′″)); 7.68 (H—C(8′″)); 7.40 (H—C(10′″)); 7.31 (H—C(9′″)); 6.28 (t,  3 J(H—C(1′), H—C(2′)=7.0, H—C(1′)); 5.43 (H—C(3′)); 5.25 (H—C(2″)); 5.01 (H—C(6″)); 5.01 (H—C(10″)); 4.60 (H—C(1″)); 4.34 (H—C(5′″)); 4.30 (H—C(4′)); 4.25 (H—C(6′″)); 3.86 (H—C(2′″)); 3.80 (H—C(5′)); 2.99 (H β —C(2′)); 2.03 (H—C(8″)); 1.98 (H—C(9″)); 1.93 (H—C(5″)); 1.85 (H—C(4″)); 1.77 (H—C(13″)); 1.60 (H—C(12″)); 1.50 (H—C(14″)); 1.50 (H—C(15″)).  13 C-NMR ((D 6 )DMSO): 169.88 (C(1′″)); 156.47 (C(4′″)); 155.60 (C(6)); 148.06 (C(2)); 147.06 (C(4)); 143.71 (C(7′″)); 140.66 (C(12′″)); 140.05 (C(3″)); 138.99 (C(8)); 134.61 (C(7″)); 130.49 (C(11″)); 127.53 (C10′″)); 126.96 (C(11′″)); 125.05 (C(9′″)); 123.96 (C(6″)); 123.38 (C(10″)); 119.99 (C(5)); 119.92 (C(8′″)); 119.25 (C(2″)); 83.31 (C(1′); 81.46 (C(4′)); 74.69 (C(3′)); 65.76 (C(5′″)); 55.76 (C(5′)); 47.44 (C(6′″)); 46.53 (C(2′″)); 43.26 (C(1″)); 38.98 (C(2′)); 38.70 (C(8″)); 35.85 (C(4″)); 26.04 (C(5″)); 25.34 (C(12″)); 24.36 (C(9″)); 17.37 (C(15″)); 16.15 (C(14″)); 15.69 (C(13″)). 
     ((2R,3S,5R)-3-Hydroxy-5-(6-oxo-1-((2E,6E)-3,7,11-tri-methyldodeca-2,6,10-trienyl)-1H-purin-9(6H)-yl)tetra-hydrofuran-2-yl)methyl-2-(((9H-fluoren-9-yl)methoxy)-carbonylamino)acetate (15) 
     TLC (silica gel, CHCl 3 -MeOH, 96:4, v/v): R f  0.31. UV (MeOH): λ max =263 nm (8=27.800 M −1  cm −1 ); ε 260 =27.100 M −1  cm −1 . log P: 7.57±1.15.  1 H-NMR ((D 6 )DMSO): 8.33 (s, H—C(2)); 8.25 (s, H—C(8)); 7.88 (H—C(11′″)); 7.69 (H—C(8′″)); 7.41 (H—C(10′″)); 7.32 (H—C(9′″)); 6.29 (t,  3 J(H—C(1′), H—C(2′))=7.5, H—C(1′)); 5.49 (H—C(3′)); 5.26 (H—C(2″)); 5.01 (H—C(6″)); 5.01 (H—C(10″)); 4.60 (H—C(1″)); 4.31 (H—C(5′″)); 4.22 (H—C(4′)); 4.02 (H—C(6′″)); 3.77 (H—C(2′″)); 3.77 (H—C(5′)); 2.72 (H β —C(2′)); 2.34 (H α —C(2′)); 2.03 (H—C(8″)); 1.99 (H—C(9″)); 1.94 (H—C(5″)); 1.86 (H—C(4″)); 1.77 (H—C(13″)); 1.60 (H—C(12″)); 1.51 (H—C(14″)); 1.51 (H—C(15″)).  13 C-NMR ((D 6 )DMSO): 169.95 (C(1′″)); 156.41 (C(4′″)); 155.66 (C(6)); 147.95 (C(2)); 146.99 (C(4)); 143.69 (C(7′″)); 140.64 (C(12′″)); 140.03 (C(3″)); 139.02 (C(8)); 134.61 (C(7″)); 130.49 (C(11″)); 127.52 (C10′″)); 126.96 (C(11′″)); 125.06 (C(9′″)); 123.96 (C(6″)); 123.84 (C(10″)); 123.38 (C(5)); 119.99 (C(8′″)); 119.31 (C(2″)); 84.13 (C(1′); 83.27 (C(4′)); 70.41 (C(3′)); 65.75 (C(5′″)); 64.00 (C(5′)); 46.51 (C(6′″)); 43.18 (C(2′″)); 42.00 (C(1″)); 39.90 (C(2′)); 39.73 (C(8″)); 39.56 (C(4″)); 26.04 (C(5″)); 25.57 (C(9″)); 25.34 (C(12″)); 17.38 (C(15″)); 16.14 (C(14″)); 15.69 (C(13″)). 
     (2R,3S,5R)-2-(hydroxymethyl)-5-(6-oxo-1-((2E,6E)-3,7,11-trimethyl-dodeca-2,6,10-trienyl)-1H-purin-9(6H)-yl)tetra-hydrofuran-3-yl-2-(((9H-fluoren-9-yl)methoxy)carbonyl-amino)acetate (16) 
     TLC (silica gel, CHCl 3 -MeOH, 96:4, v/v): R f  0.20. UV (MeOH): λ max =263 nm (8=27.730 M −1  cm −1 ); ε 260 =27.100 M −1  cm −1 . log P: 7.73±0.98.  1 H-NMR ((D 6 )DMSO): 8.31 (s, H—C(2)); 8.29 (s, H—C(8)); 7.88 (H—C(11′″)); 7.71 (H—C(8′″)); 7.41 (H—C(10′″)); 7.33 (H—C(9′″)); 6.28 (t,  3 J(H—C(1′), H—C(2′))=8.0, H—C(1′)); 5.40 (H—C(3′)); 5.26 (H—C(2″)); 5.12 (H—C(6″)); 5.01 (H—C(10″)); 4.60 (H—C(1″)); 4.34 (H—C(5′″)); 4.25 (H—C(4′)); 4.08 (H—C(6′″)); 3.85 (H—C(2′″)); 3.60 (H—C(5′)); 2.88 (H β —C(2′)); 2.04 (H—C(8″)); 2.00 (H—C(9″)); 1.93 (H—C(5″)); 1.86 (H—C(4″)); 1.78 (H—C(13″)); 1.60 (H—C(12″)); 1.51 (H—C(14″)); 1.51 (H—C(15″)).  13 C-NMR ((D 6 )DMSO): 169.70 (C(1′″)); 156.48 (C(4′″)); 155.61 (C(6)); 148.04 (C(2)); 147.01 (C(4)); 143.72 (C(7′″)); 140.66 (C(12′″)); 140.03 (C(3″)); 138.84 (C(8)); 134.62 (C(7″)); 130.51 (C(11″)); 127.54 (C10″)); 127.19 (C(11′″)); 125.06 (C(9′″)); 123.96 (C(6″)); 123.76 (C(10″)); 121.28 (C(5)); 120.02 (C(8′″)); 119.31 (C(2″)); 85.09 (C(1′); 83.50 (C(4′)); 75.45 (C(3′)); 65.76 (C(5′″)); 61.35 (C(5′)); 46.54 (C(6′″)); 43.25 (C(2′″)); 42.33 (C(1″)); 39.01 (C(2′)); 38.72 (C(8″)); 36.77 (C(4″)); 26.01 (C(5″)); 24.54 (C(9″)); 25.31 (C(12″)); 17.35 (C(15″)); 16.13 (C(14″)); 15.67 (C(13″)). 
     (ii) 9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-furan-2-yl)-1-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)-1H-purin-6(9H)-on-5′-sulforhodaminsulfonic ester (17) 
     Compound 3b (2.74 mg, 6.0 μmol) was dissolved in anhydr. Pyridine (3 ml), and sulforhodaminsulfonyl chloride (2.5 mg, 4.0 μmol) was added. The mixture was stirred under N 2  atmosphere for 48 h. Then, H 2 O (10 ml) was added, and the mixture extracted once with CH 2 Cl 2 . The aqueous layer was separated and evaporated to dryness. Chromatography (silica gel, column: 2×10 cm, CH 2 Cl 2 -MeOH, 1:1, v/v) gave after evaporation of the solvent compound 17 as black, amorphous material. TLC (silica gel 60, CHCl 3 -MeOH, 96:4, v/v): R f  0.56. UV (MeOH): λ max =252 nm (E=18.200 M −1  cm −1 ); ε 260 =16.400 M −1  cm −1 . 
     Thymidine Derivatives 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     5-Methyl-1-((6aR,8R,9aR)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5, 2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione (8) 
     Anhydr. thymidine (7, 0.242 g, 1 mmol) was dissolved in dry pyridine (10 ml), and 1,3-Dichlor-1,1,3,3-tetraisopropyl-disiloxane (0.347 g, 1.1 mmol) was added. The reaction mixture was stirred for 24 h at ambient temp. After evaporation of the solvent the residue was partitioned between EtOAc and H 2 O (80 ml, 1:1, v/v). The organic layer was washed twice with cold 1M aq. HCl and H 2 O (20 ml, each), followed by sat. aq. NaHCO 3  and brine. After drying (anhyd. Na 2 SO 4 ) and filtration, the soln. was evaporated to dryness. Chromatography (silica gel, column: 2×10 cm, CHCl 3 -MeOH, 9:1, v/v) gave, after evaporation of the main zone compd. 8 (0.476 g, 98%) as a colourless solid. M.p. 174° C. TLC (silica gel, CHCl 3 -MeOH, 9:1, v/v): R f , 0.9. UV(MeOH): λ max =265 nm (E=12.040 M −1  cm −1 ).  1 H-NMR ((D6)DMSO): 11.33 (s, NH); 7.40 (d,  3 J(CH 3 , H—C(6))=1.0, H—C(6)); 6.00 (dd,  3 J(H—C(1′), H α —C(2′))=5.0,  3 J(H—C(1′), H β —C(2′))=5.0, C—H(1′)); 4.56 (Ψ,  3 J(H—C(3′), H α —C(2′))=7.5,  3 J(H—C(3′), H β —C(2′))=7.5,  3 J(H—C(3′), H—C(4′)=7.5, C—H(3′)); 3.96 (ddd,  3 J(H b —C(5′), H—C(4′))=5.5,  3 J(H a —C(5′), H—C(4′))=3.25,  2 J(H a —C(5′), H b —C(5′))=−12,  2 J(H b —C(5′), H a —C(5′)=−12.2, H 2 —C(5′)); 3.70 (ddd,  3 J(H—C(4′), H—C(3′))=7.5,  3 J(H—C(4′), H b —C(5′))=5.5,  3 J(H—C(4′), H α —C(5′))=3.25, C—H(4′)); 2.42 (m, H β —C(2′)); 2.30 (m, H α —C(2′)); 1.76 (d,  3 J(CH 3 , H—C(6))=0.5, CH 3 )); 1.04 (m, 28H, i-Pr).  13 C-NMR: ((D 6 )DMSO): 163.65 (C(4)); 150.14 (C(2)); 136.16 (C(6)); 109.25 (C(5)); 84.19 (C(1′)); 83.23 (C(4′)); 70.29 (C(3′)); 61.71 (C(5′)); 38.47 (C(2′)); 17.31, 17.18, 17.16, 17.14, 17.01, 16.86, 16.83, 17.31-16.76 (m, 8×CH 3 , iPr), 12.73-11.95 (4×CH, iPr), 12.11 (CH 3 ). Anal. calc. for C 22 H 40 N 2 O 6 Si 2  (484.73): C, 54.51, H, 8.32, N, 5.78; found: C, 54.54, H, 8.21, N, 5.68. 
     1-((2R,4R,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methyl-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)pyrimidin-2,4(1H,3H)-dione (9b) 
     Anhydr. thymidine (7, 0.97 g, 4 mmol) was dissolved in amine-free, anhydr. DMF (20 ml), and dry K 2 CO 3  (1.2 g, 10.4 mmol) was added. Then, trans,trans-farnesylbromide (0.87 ml, 4.4 mmol) was added drop-wise within 10 min under N 2  atmosphere, and the reaction mixture was stirred for 48 h at 40° C. After filtration the mixture was then partitioned between CH 2 Cl 2  and H 2 O (100 ml, 1:1, v/v), the organic layer was separated and dried (anhydr. Na 2 SO 4 ). After filtration and evaporation of the solvent the residue was dried in high vacuo. Subsequent gradient chromatography (silica gel 60, column: 6×10 cm, (i) CH 2 Cl 2 -MeOH, 95:5, v/v; (ii) CH 2 Cl 2 -MeOH, 9:1, v/v) gave after evaporation of the main zone compd. 9b (0.76 g, 44%). TLC (silica gel, CH 2 Cl 2 -MeOH, 9:1, v/v): R f , 0.5; TLC (silica gel, CH 2 Cl 2 -MeOH, 95:5, v/v): R f , 0.3. UV (MeOH): λ max =266 nm (ε=9.660 M −1  cm −1 ). log P: 6.60+/−0.64.  1 H-NMR (D 6 )DMSO): 7.75 (d,  3 J(CH 3 , H—C(6))=1.26, H—C(6)); 6.20 (i,  3 J(H—C(1′), H α —C(2′))=7.0,  3 J(H—C(1′), H β —C(2′))=7.0, C—H(1′)); 5.20 (d,  3 J(OH—C(3′), H—C(3′))=4.5, OH—C(3′)); 5.10 (Ψt,  3 J(H—C(2″), H 2 —C(1″))=6.5, H—C(2″)); 5.03 (m, (H—C(6″, 10″)); 5.0 (Ψt,  3 J(OH—C(5′), H b —C(5′))=5.2,  3 J(OH—C(5′), H a —C(5′))=5.2, OH—C(5′)); 4.39 (d,  3 J(H 2 —C(1″), H—C(2″))=7.0, H 2 —C(1″)); 4.24 (ddd,  3 J(H—C(4′), H—C(3′))=3.78,  3 J(H—C(4′), H b —C(5′))=4.0,  3 J(H—C(4′), H a —C(5′))=4.0, H—C(4′)); 3.78 (Ψq,  3 J(H—C(3′), H α —C(2′))=3.78,  3 J(H—C(3′), H β —C(2′))=3.78,  3 J(H—C(3′), H—C(4′))=3.78, H—C(3′)); 3.60 (ddd,  3 J(H b —C(5′), H—C(4′))=4.0,  3 J(H b —C(5′), OH—C(5′))=5.2,  2 J(H b —C(5′), H a —C(5′))=−12.0, H b —C(5′)); 3.55 (m,  2 J(H a —C(5′), H b —C(5′))=−12.0, H a —C(5′)); 2.09 (dd,  3 J(H α —C(2′), H—C(1′))=7.0,  3 J(H β —C(2′), H—C(1′))=7.0,  3 J(H α —C(2′), H—C(3′))=4.8,  3 J(H β —C(2′), H—C(3′))=4.8,  2 J(H α —C(2′), H β —C(2′))=−12.0, H 2 —C(2′)); 1.95 (m, (H 2 —C(4″,5″,8″,9″), 4×CH 2 ); 1.82 (d,  3 J(CH 3 , H—C(6)=1.0, CH 3 )); 1.74 (s, H 3 —C(13″)); 1.63 (s, H 3 —C(12″)); 1.55 (s, H 3 —C(14″)); 1.52 (s, H 3 —C(15″)).  13 C-NMR ((D 6 ) DMSO): 162.35 (C(4)); 150.24 (C(2)); 138.72 (C(3″); 134.66 (C(6)); 134.51 (C(7″)); 130.57 (C(11″)); 124.08 (C(6″)); 123.57 (C(10″)); 118.95 (C(2″)); 108.51 (C(5)); 87.36 (C(1′)); 84.75 (C(4′)); 70.31 (C(3′)); 61.24 (C(5′)); 40.06 (C(2′)); 39.17 (C(1″)); 38.88 (C(8″)); 38.58 (C(4″)); 26.15 (C(5″)); 25.67 (C(9″)); 25.41 (C(12″)); 17.48 (C(15″)); 16.11 (C(14″)); 15.75 (C(13″)); 12.84 (CH 3 ). Anal. calc. for C 25 H 38 N 2 O 5  (446.58): C, 67.24, H, 8.59, N, 6.27; found: C, 67.39, H, 8.56, N, 5.90. 
     3-((E)-3,7-Dimethylocta-2,6-dienyl)-1-((2R,4R,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (9a) 
     Anhydr. thymidine (7, 0.97 g, 4 mmol) was reacted and worked up with geranylbromide (0.87 ml, 4.4 mmol) as described for compd. 9b. Chromatography (silica gel, column: 6×10 cm, CH 2 Cl 2 -MeOH, 9:1, v/v) gave after evaporation of the main zone compd. 9a (0.86 g, 2.27 mmol) as a yellowish amorphous solid. TLC (silica gel 60, CH 2 Cl 2 -MeOH 9:1, v/v): R f  0.4. UV (MeOH): λ max =266 nm (ε=7579 M −1  cm −1 ). log P: 4.57+/−0.61.  1 H-NMR ((D 6 )DMSO): 7.75 (d,  3 J(CH 3 , H—C(6))=1.3, H—C(6)); 6.21 (T,  3 J(H—C(1′), H α —C(2′))=7.0,  3 J(H—C(1′), H β —C(2′)=7.0, H—C(1′)); 5.20 (d,  3 J(OH—C(3′), H—C(3′))=4.5, OH—C(3′)); 5.11 (Ψt,  3 J(H—C(2″), H 2 —C(1″)=6.75, H—C(2″)); 5.03 (m, (H—C(6″)); 4.99 (Ψt,  3 J(OH—C(5′), H b —C(5′))=5.2,  3 J(OH—C(5′), H a —C(5′))=5.2, OH—C(5′)); 4.40 (d,  3 J(H 2 —C(1″), H—C(2″))=6.5, H 2 —C(1″)); 4.25 (ddd,  3 J(H—C(4′), H—C(3′))=3.5,  3 J(H—C(4′), H b —C(5′))=4.0,  3 J(H—C(4′), H a —C(5′))=4.0, H—C(4′)); 3.78 (Ψq,  3 J(H—C(3′), H α —C(2′))=3.78,  3 J(H—C(3′), H β —C(2′))=3.78,  3 J(H—C(3′), H—C(4′))=3.78, H—C(3′)); 3.61 (ddd,  3 J(H b —C(5′), H—C(4′))=4.0,  3 J(H b —C(5′), OH—C(5′))=4.0,  2 J(H b —C(5′), H a —C(5′))=−12, H b —C(5′)); 3.55 (ddd,  3 J(H a —C(5′), H—C(4′))=4.0,  3 J(H a —C(5′), OH—C(5′))=5.0,  2 J(H a —C(5′), H b —C(5′))=−12, H a —C(5′)); 2.09 (dd,  3 J(H α —C(2′), H—C(1′))=7.0,  3 J(H β —C(2′), H—C(1′))=7.0,  3 J(H α —C(2′), H—C(3′))=4.8,  3 J(H β —C(2′), H—C(3′))=4.8,  2 J(H α —C(2′), H β —C(2′))=−12.0, H 2 —C(2′)); 1.94 (m, (H 2 —C(4″,5″), 2×CH 2 ); 1.82 (d,  3 J(CH 3 , H—C(6)=1.0, CH 3 )); 1.74 (s, H 3 —C(9″)); 1.61 (s, H 3 —C(8″)); 1.53 (s, H 3 —C(10″)).  13 C-NMR ((D 6 )DMSO): 162.29 (C(4)); 150.17 (C(2)); 138.71 (C(3″)); 134.61 (C(6)); 130.77 (C(7″)); 123.73 (C(6″)); 118.84 (C(2″)); 108.44 (C(5)); 87.28 (C(1′)); 84.67 (C(4′)); 70.21 (C(3′)); 61.16 (C(5′)); 40.08 (C(2′)); 39.41 (C(4″)); 39.07 (C(1″)); 25.79 (C(5″)); 25.32 (C(8″)); 17.41 (C(10″)); 16.05 (C(9″)); 12.79 (CH 3 ). Anal. calc. for C 20 H 30 N 2 O 5  (378,463): C, 63.47, H, 7.99, N, 7.40; found: C, 63.26, H, 7.98, N, 7.19. 
     1-((2R,4R,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-5-methyl-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)pyrimidin-2,4(1H,3H)-dione (10b) 
     Compd. 9b (0.45 g, 1 mmol) was co-evaporated twice with anhydr. pyridine (1 ml, each) and then dissolved in anhydr. pyridine (5 ml). 4,4′-Dimethoxytriphenylmethyl chloride (0.39 g, 1.15 mmol) was added under N 2  atmosphere, and the mixture was stirred for 24 h at ambient temperature. Then, the reaction was quenched by addition of MeOH (3 ml). After 10 min ice-cold 5% aq. NaHCO 3  was added, and the soln. was extracted with CH 2 Cl 2 . The organic layer was dried (Na 2 SO 4 ), filtered, and the solvent evaporated. The residue was dried in high vacuo until a yellowish foam formed. Chromatography (silica gel, column: 6×10 cm, CH 2 Cl 2 -MeOH, 99:1, v/v) gave after evaporation of the main zone compd. 10b (0.48 g, 65%) as a yellowish glass. 
     TLC (silica gel 60, CH 2 Cl 2 -MeOH, 99:1, v/v): R f  0.4. UV (MeOH): λ max  232 nm (8=26.900 M −1  cm −1 ), λ 268 nm (8=13.400). log P: 12.17+/−0.64.  1 H-NMR ((D 6 )DMSO): 7.55 (d,  3 J(CH 3 , H—C(6))=0.9, H—C(6)); 7.38 (d,  3 J(H—C(8′″), H—C(9′″))=7.25, H—C(8′″)); 7.30 (t,  3 J(H—C(10′″), H—C(9′″))=7.41,  3 J(H—C(10′″), H—C(9′″))=7.41; 7.25 (m,  3 J(H—C(3′″,9′″)); 6.88 (d,  3 J(H—C(4′″), H—C(3′″))=8.20, H—C(4′″)); 6.24 (h,  3 J(H—C(1′), H α —C(2′))=6.62,  3 J(H—C(1′), H β —C(2′)=6.62, H—C(1′)); 5.30 (d,  3 J(OH—C(3′), H—C(3′))=4.4, OH—C(3′)); 5.11 (m, (H—C(2″)); 5.03 (m, (H—C(6″), H—C(10′″), 2×CH); 4.40 (d,  3 J(H 2 —C(1″), H—C(2″))=5.0, H 2 —C(1″)); 4.32 (m, (H—C(4′)); 3.90 (m, (H—C(3′)); 3.73 (s, H 3 —C(6″), 2×OCH 3 ); 3.21 (m, (H 2 —C(5′)); 2.21 (m, (H 2 —C(2′)); 2.03 (m, (H 2 —C(5″)); 1.96 (m, H 2 —C(8″), H 2 —C(9″)); 1.89 (m, H 2 —C(4″)); 1.74 (s, H 3 —C(5)); 1.61 (s, H 3 —C(13″)); 1.53 (s, H 3 —C(12″)); 1.52 (s, H 3 —C(14″)); 1.49 (s, H 3 —C(15″)).  13 C-NMR ((D 6 )DMSO): 161.23 (C(4)); 157.11 (C(5′″); 149.10 (C(2)); 143.61 (C(7′″)); 137.74 (C(3″)); 134.37 (C(2′″)); 133.44 (C(6)); 129.50 (C(7″)); 128.64 (C(3′″)); 126.79 (C(9′″)); 126.61 (C(8′″)); 125.70 (C(11′″)); 123.02 (C(6″)); 122.51 (C(10″)); 117.82 (C(2″)); 112.17 (C(4′″)); 107.71 (C(5)); 84.80 (C(1′″)); 84.52 (C(1′)); 83.70 (C(4′)); 69.36 (C(3′)); 62.63 (C(5′)); 53.98 (C(6′″)); 39.10 (C(2′)); 37.81 (C(4″)); 37.59 (C(1″)); 25.07 (C(5″)); 24.61 (C(9″)); 25.34 (C(8″)); 16.42 (C(15″)); 15.07 (C(14″)); 14.69 (C(13″)); 11.26 (CH 3 ). Anal. calc. for C 46 H 56 N 2 O 7  (748.946): C, 73.77, H, 7.54, N, 3.74; found: C, 73.39, H, 7.38, N, 3.74. 
     1-((2R,4R,5R)-5-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-3-((E)-3,7-dimethylocta-2,6-dien-1-yl)-5-methylpyrimidin-2,4(1H,3H)-dione (10a) 
     Compd. 9a (0.38 g, 1 mmol) was dried with anhydr. pyridine, reacted with 4,4′-dimethoxytriphenylmethyl chloride (0.39 g, 1.15 mmol), and worked up as described for compd. 10b. Yield: 0.39 g (57%) of 5b as a yellowish foam. TLC (silica 60, CH 2 Cl 2 -MeOH 99:1, v/v): R f  0.57. UV (MeOH): λ max =231 nm (ε=24.770 M −1  cm −1 ), X=268 nm (ε=12.200 M −1  cm −1 ). log P: 10.14+/−0.61. 
       1 H-NMR (DMSO-d 6 ): 7.55 (d,  3 J(CH 3 , H—C(6))=0.95, H—C(6)); 7.38 (d,  3 J(H—C(8′″), H—C(9′″))=7.57, H—C(8′″)); 7.31 (t,  3 J(H—C(10′″), H—C(9′″))=7.72,  3 J(H—C(10′″), H—C(9′″))=7.72; 7.25 (m,  3 J(H—C(3′″,9′″), 4×CH); 6.89 (d,  3 J(H—C(4′″), H—C(3′″))=8.98, H—C(4′″)); 6.25 (h,  3 J(H—C(1′), H α —C(2′))=6.78,  3 J(H—C(1′), H β —C(2′)=6.78, H—C(1′)); 5.30 (d,  3 J(OH—C(3′), H—C(3′))=4.41, OH—C(3′)); 5.11 (m, (H—C(2″)); 5.02 (m, (H—C(6″)); 4.40 (d,  3 J(H 2 —C(1″), H—C(2″))=5.0, H 2 —C(1″)); 4.32 (m, (H—C(4′)); 3.90 (Ψq,  3 J(H—C(3′), H α —C(2′))=3.90,  3 J(H—C(3′), H β —C(2′))=3.90,  3 J(H—C(3′), H—C(4′))=3.90, H—C(3′)); 3.74 (s, H 3 —C(6″), 2×OCH 3 ); 3.21 (m, (H 2 —C(5′)); 2.22 (m, (H 2 —C(2′)); 2.02 (m, (H 2 —C(5″)); 1.93 (m, H 2 —C(4″)); 1.74 (s, H 3 —C(5)); 1.60 (s, H 3 —C(9″)); 1.53 (s, H 3 —C(8″)); 1.50 (s, H 3 —C(10″)).  13 C-NMR (DMSO-d 6 ): 162.28 (C(4)); 158.12 (C(5′″); 150.13 (C(2)); 144.62 (C(7′″)); 144.62 (C(3″)); 135.39 (C(2′″)); 134.25 (C(6)); 130.82 (C(7″)); 129.67 (C(3′″)); 127.83 (C(9′″)); 127.64 (C(8′″)); 126.74 (C(10′″)); 123.76 (C(6″)); 118.80 (C(2″)); 113.20 (C(4′″)); 108.74 (C(5)); 85.83 (C(1′″)); 85.54 (C(1′)); 84.73 (C(4′)); 70.38 (C(3′)); 63.64 (C(5′)); 55.01 (C(6′″)); 40.14 (C(2′)); 30.87 (C(4″)); 38.62 (C(1″)); 25.80 (C(5″)); 25.34 (C(8″)); 17.43 (C(10″)); 16.09 (C(9″)); 12.29 (CH 3 ). Anal. calc. for C 41 H 48 N 2 O 7  (680.829): C, 72.33, H, 7.11, N, 4.11; found: C, 72.16, H, 7.00, N, 3.84. 
     (2R,3S,5R)-2-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(5-methyl-2,4-dioxo-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite (11b) 
     Compd. 10b (0.32 g, 0.3 mmol) was co-evaporated twice from dry CH 2 Cl 2  and dissolved in CH 2 Cl 2  (15 ml). Then, N,N-diisopropylethylamine (126 μl, 0.72 mmol) and (chloro)(2-cyanoethoxy)(diisopropylamino)phosphine (156 μl, 0.72 mmol) were added under N 2  atmosphere. The reaction was stirred for 20 min at ambient temperature, and the reaction was then quenched by addition of ice-cold 5% aq. NaHCO 3 (12 ml). The raw product was extracted with CH 2 Cl 2 , the solution was dried (Na 2 SO 4 ) for 2 min, filtered and evaporated to dryness (bath temperature: &lt;25° C.), followed by drying in high vacuo for 5 min. Flash chromatography (0.5 bar, silica gel, column: 2×10 cm, CH 2 Cl 2 -acetone, 8:2, v/v, with 8 drops of Et 3 N per 1, total time of chromatography &lt;15 min) afforded the phosphoramidite 11b (0.27 g, 67%) as a colourless foam which was stored at −20° C. TLC (silica gel 60, CH 2 Cl 2 -acetone, 8:2, v/v) R f  0.87, 0.97 (diasteoisomers).  31 P-NMR (CDCl 3 ): 149.055 (P R ), 148.528 (P S ). 
     (2R,3S,5R)-2-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(3-((E)-3,7-dimethylocta-2,6-dien-1-yl)-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite (11a) 
     Compound 11a was prepared from 10a (0.2 g, 0.3 mmol) as described for 11b. Yield: 0.25 g (97%) of a colourless foam. TLC (silica gel 60, CH 2 Cl 2 -acetone, 8:2, v/v) R f  0.84, 0.94 (diastereoisomers).  31 P-NMR (CDCl 3 ): 149.024 (P R ), 148.497 (P S ). 
     Uridine- and Ribothymidine Derivatives 
     
       
         
         
             
             
         
       
     
     General 
     Starting compounds and solvents were purchased from the appropriate suppliers and were used as obtained. Chromatography: silica gel 60 (Merck, Germany). TLC: aluminum sheets, silica gel 60 F 254 , 0.2 mm layer (Merck, Germany). NMR Spectra: AMX-500 spectrometer (Bruker, D-Rheinstetten);  1 H: 500.14 MHz,  13 C: 125.76 MHz, and  31 P: 101.3 MHz. Chemical shifts are given in ppm relative to TMS as internal standard for  1 H and  13 C nuclei and external 85% H 3 PO 4 ; J values in Hz. Elemental analyses (C, H, N) of crystallized compounds were performed on a VarioMICRO instrument (Fa. Elementar, D-Hanau). M.p.: Stuart-SMP3 apparatus (Fa. Bibby Scientifis Limited, UK-Staffordshire); uncorrected. UV Spectra: Cary 6000i spectrophotometer (Varian, D-Darmstadt). 
     1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dipentyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidin-2,4(1H,3H)-dione (25a) 
     Uridine (24; 0.76 g, 3.1 mmol) was dissolved in anhydr. DMF (10 ml), and undecan-6-one (0.80 ml, 3.9 mmol) as well as 4 M HCl in 1,4-dioxane (4 ml) and triethylorthoformate (1 ml) were added. The mixture was stirred for 24 h at room temp. Subsequently, the solution was partitioned between CH 2 Cl 2  (75 ml) and a sat. aq. NaHCO 2  soln. (50 ml). The organic phase was washed with dist. H 2 O (100 ml) and separated. After drying over Na 2 SO 4  the solvent was evaporated. Purification was performed by column chromatography (silica gel 60; column: 2×22 cm). A stepwise elution with 750 ml CH 2 Cl 2 /MeOH (99:1, v/v), followed by 250 ml CH 2 Cl 2 /MeOH (95:5, v/v) gave one main zone from which compd. 25a (1.1 g, 2.69 mmol, 87%) was isolated as a colourless foam, obtained upon evaporation and drying in high vacuo. UV(MeOH): λ max =260 nm (E=9.200 M −1  cm −1 ). TLC (silica gel 60; CH 2 Cl 2 /MeOH, 95:5 (v/v)): R f : 0.19. Anal. calc. for C 20 H 32 N 2 O 6  (396.48): C, 60.59; H, 8.14; N, 7.07. Found: C, 60.20; H, 8.11; N, 6.97.  1 H-NMR (500.13 MHz, DMSO-d 6 ): 11.32 (s, H—N(3)); 7.77 (d,  3 J(H—C(6), H—C(5))=8.2, H—C(6)); 5.83 (d,  3 J(H—C(1′), H—C(2′))=2.5, H—C(1′)); 5.62 (dd,  3 J(H—C(5), H—C(6))=8.0,  4 J(H—C(5), H—N(3))=1.7, H—C(5)); 5.01 (t,  3 J (OH—C(5′)), H b —C(5′)=5.04,  3 J (HO—C(5′), H a —C(5′))=5.04, OH—C(5′)); 4.89 (dd,  3 J(H—C(2′), H—C(1′))=2.8,  3 J(H—C(2′), H—C(3′))=6.6, H—C(2′)); 4.74 ((dd,  3 J(H—C(3′), H—C(4′))=3.5,  3 J(H—C(3′), H—C(2′))=6.6, H—C(3′)); 4.06 (q, 2× 3 J(H—C(4′), H 2 —C(5′))=4.4,  3 J(H—C(4′), H—C(3′))=4.4, H—C(4′)); 3.56 (m, H 2 —C(5′)); 1.67 (m, H 2(endo) —C(1a″)); 1.52 (m, H 2(exo) —C(1b″)); 1.44-1.20 (m, 6×H 2(endo) —C(2a″-4a″), 6×H 2(exo) —C(2b″-4b″), 12H); 0.86 (m, 2×H 3 —C(5a″, 5b″), 6H).  13 C-NMR (125.76 MHz, DMSO-d 6 ): δ. 163.06 (C(4)); 150.26 (C(2)); 141.94 (C(6)); 116.631 (C(acetal)); 101.65 (C(5)); 91.20 (C(1′)); 86.66 (C(4′)); 83.79 (C(3′)); 80.73 (C(2′)); 61.34 (C(5′)); 36.34 (C(1″)); 31.34 (C(3a″)); 31.25 (C(3b″)); 23.19 (C(2a″)); 22.51 (C(2b″)); 21.91 (C(4a″)); 21.89 (C(4b″)); 13.76 (C(5″)). 
     1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dinonyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidin-2,4(1H,3H)-dione (25b) 
     Uridine (24; 0.76 g, 3.1 mmol) was dissolved in anhydr. DMF (10 ml), and nonadecan-10-one (1.11 g, 3.9 mmol), 4 M HCl in 1,4-dioxane (4 ml) and triethylortho formate (1 ml) as well as CH 2 Cl 2  (6 ml) were added consecutively. The reaction mixture was stirred for 24 h at room temp. Subsequently, the mixture was partitioned between an aq. sat. NaHCO 3  soln (100 ml) and CH 2 Cl 2  (100 ml). The organic layer was washed with dest. H 2 O (100 ml), separated, dried over Na 2 SO 4 , and then evaporated to dryness. Purification of the raw product was performed by stepped gradient column chromatography (silica gel 60, column: 6.5×10 cm). A stepwise elution with 800 ml CH 2 Cl 2 /MeOH (99:1, v/v), followed by 200 ml of CH 2 Cl 2 /MeOH (95:5, v/v) gave one main zone from which compd. 25b (1.50 g, 2.95 mmol, 95%) was isolated as a colourless foam, obtained upon evaporation and drying in high vacuo. TLC (silica gel 60; CH 2 Cl 2 /MeOH 95:5 (v/v)): R f , 0.21. UV(MeOH): λ max =260 nm (ε=9.600 M −1  cm −1 ). M.p.: 69.8° C. Anal. calc. for C 28 H 48 N 2 O 6  (508.69) C, 66.11; H, 9.51; N, 5.51. Found: C, 65.86; H, 9.50; N, 5.21.  1 H-NMR (500.13 MHz, DMSO-d 6 ): 11.33 (s, H—N(3)); 7.76 (d,  3 J(H—C(6), H—C(5))=8.0, H—C(6)); 5.82 (d,  3 J(H—C(1′), H—C(2′))=2.5, H—C(1′)); 5.62 (d,  3 J(H—C(5), H—C(6))=8.0, H—C(5)); 5.02 (m, HO—C(5′)); 4.89 (dd,  3 J(H—C(2′), H—C(1′))=2.5,  3 J(H—C(2′), H—C(3′))=6.5, H—C(2′)); 4.73 (dd,  3 J(H—C(3′), H—C(4′))=3.5,  3 J(H—C(3′), H—C(2′))=6.5, H—C(3′)); 4.05 (q, 2× 3 J(H—C(4′), H 2 —C(5′))=4.2,  3 J(H—C(4′), H—C(3′))=4.2, H—C(4′)); 3.57 (m, H 2 —C(5′)); 1.66 (m, H 2(endo) —C(1a″)); 1.51 (m, H 2(exo) —C(1b″)); 1.30-1.20 (m, 7×H 2(endo) —C(2a″-8a″), 7×H 2(exo) —C(2b″-8b″), 28H); 0.85 (m, 2×H 3 —C(9a″, 9b″), 6H).  13 C-NMR (125.76 MHz, DMSO-d 6 ): δ. 163.11 (C(4)); 150.28 (C(2)); 141.98 (C(6)); 116.63 (C(acetal)); 101.67 (C(5)); 91.23 (C(1′)); 86.69 (C(4′)); 83.82 (C(3′)); 80.70 (C(2′)); 61.35 (C(5′)); 36.38 (C(1a″)); 36.29 (C(1b″)); 31.21 (C(7a″)); 31.19 (C(7b″)); 29.09 (C(3a″)); 29.04 (C(3b″)); 28.86 (C(4a″)); 28.83 (C(4b″)); 28.80 (C(5″)); 28.59 (C(6a″)); 28.58 (C(6b″)); 23.52 (C(2a″)); 22.88 (C(2b″)); 22.01 (C(8a″)); 22.00 (C(8b″)); 13.85 (C(9″)). 
     1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-ditridecyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidin-2,4(1H,3H)-dione (25c) 
     Heptacosan-14-one (0.40 g, 1 mmol) was added to a soln. of anhydr. THF (14 ml), uridine (24; 1.22 g, 5 mmol), TsOH (0.19 g, 1 mmol) and triethylortho formate (0.85 ml, 5.1 mmol). The reaction mixture was refluxed for 24 h (75° C.), and then triethylamine (0.6 ml) was added. To this mixture ice-cold 4% aq. NaHCO 3  (50 ml) was added and stirred for 15 min at room temp. The mixture was washed with 100 ml of CH 2 Cl 2  and 100 ml of dist. H 2 O. The organic layer was dried (Na 2 SO 4 ), filtered, and the solvent was evaporated. Compound 2c was precipitated by addition of ice-cold MeOH on ice; the material was filtered and dried in high vacuo overnight. Yield: colourless solid (0.41 g, 0.66 mmol, 65.6%). TLC (silica gel 60; CH 2 Cl 2 /MeOH 95:5 (v/v): R f : 0.24. UV(CH 2 Cl 2 ): λ max =260 nm (ε=9.340 M −1  cm −1 ). M.p.: 90.1° C. Anal. calc. for C 36 H 64 N 2 O 6  (620.90): C, 69.64; H, 10.39; N, 4.51. Found: C, 69.77; H, 10.74; N, 3.92.  1 H-NMR (500 MHz, DMSO-d 6 ): 11.32 (d,  4 J(H—N(3), (OH—C(5′))=1.89, H—N(3)); 7.76 (d,  3 J(H—C(6), H—C(5))=8.2, H—C(6)); 5.82 (d,  3 J(H—C(1′), H—C(2′))=2.5, H—C(1′)); 5.61 (dd,  3 J(H—C(5), H—C(6))=8.2,  4 J(H—C(5′), H—N(3))=2.2, H—C(5)); 5.01 (t, 2× 3 J (OH—C(5′), H 2 —C(5′))=5.4, OH—C(5′)); 4.88 (dd,  3 J (H—C(2′), H—C(1′))=2.5,  3 J (H—C(2′), H—C(3′))=6.6, H—C(2′)); 4.73 (dd,  3 J (H—C(3′), H—C(4′))=3.5,  3 J (H—C(3′), H—C(2′))=6.6, H—C(3′)); 4.05 (q, 2× 3 J(H—C(4′), H 2 —C(5′))=4.4,  3 J(H—C(4′), H—C(3′))=4.4, H—C(4′)); 3.55 (m, H 2 —C(5′)); 1.66 (m, H 2(endo) —C(1a″)); 1.51 (m, H 2(exo) —C(1b″)); 1.42-1.19 (m, 11×H 2(endo) —C(2a″-12a″), 11×H 2(exo) —C(2b″-12a″), 44H); 0.85 (m, 2×H 3 —C(13a″, 13b″), 6H).  13 C-NMR (125.76 MHz, DMSO-d 6 ): δ. 163.07 (C(4)); 150.26 (C(2)); 141.94 (C(6)); 116.62 (C(acetal)); 101.66 (C(5)); 91.22 (C(1′)); 86.68 (C(4′)); 83.81 (C(3′)); 80.68 (C(2′)); 61.34 (C(5′)); 36.38 (C(1a″)); 36.22 (C(1b″)); 31.21 (C(11″)); 29.05 (C(3a″)); 28.99 (C(3b″)); 28.96-28.59 (C(4″)-C(10″)); 22.48 (C(2a″)); 22.86 (C(2b″)); 22.00 (C(12″)); 13.84 (C(13″)). 
     1-(6-Hydroxymethyl-2,2-dipentadecyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-1H-pyrimidin-2,4-dione (25d) 
     Hentriacontan-16-one (0.45 g, 1.0 mmol) was added to a soln. of anhydr. THF (14 ml), uridine (24; 1.22 g, 5 mmol), TsOH (0.19 g, 1.0 mmol) and triethylortho formate (0.85 ml, 5.1 mmol). This mixture was refluxed for 24 h (75° C.), and triethylamine (0.6 ml) was added. The resulting mixture was poured into an aq., ice-cold 4% NaHCO 3  soln (50 ml) and stirred for 15 min at room temp. The mixture was washed with CH 2 Cl 2  (100 ml) and dist. H 2 O (100 ml), dried over Na 2 SO 4 , filtered, and the solvent evaporated. The residue was triturated with ice-cold MeOH on ice which gave the solid product 25d (0.36 g, 0.54 mmol, 53.7%) as a slightly yellowish solid which was dried in high vacuo. TLC (silica gel 60; CH 2 Cl 2 /MeOH 95:5 (v/v): R f , 0.26. UV(CH 2 Cl 2 ): λ max =260 nm (E=8.350 M −1  cm −1 ). M.p.: 93° C. Anal. calc. for C 40 H 72 N 2 O 6  (677.01): C, 70.96; H, 10.72; N, 4.14. Found: C, 71.08; H, 11.06; N, 3.74.  1 H-NMR (500 MHz, DMSO-d 6 ): 11.32 (s, H—N(3)); 7.77 (d,  3 J(H—C(6), H—C(5))=8.0, H—C(6)); 5.83 (d,  3 J(H—C(1′), H—C(2′))=2.5, H—C(1′)); 5.62 (d,  3 J(H—C(5), H—C(6))=8.0, H—C(5)); 5.01 (t, 2× 3 J(OH—C(5′), H 2 —C(5′))=5.0, OH—C(5′)); 4.88 (dd,  3 J(H—C(2′), H—C(1′))=2.5,  3 J(H—C(2′), H—C(3′))=6.5, H—C(2′)); 4.73 (dd,  3 J(H—C(3′), H—C(4′))=3.5,  3 J(H—C(3′), H—C(2′))=6.3, H—C(3′)); 4.05 (q, 2× 3 J(H—C(4′), H 2 —C(5′))=4.4,  3 J(H—C(4′), H—C(3′))=4.4, H—C(4′)); 3.55 (m, H 2 —C(5′)); 1.66 (m, H 2(endo) —C(1a″)); 1.51 (m, H 2(exo) —C(1b″)); 1.41-1.16 (m, 13×H 2(endo) —C(2a″-14a″), 13×H 2(exo) —C(2b″-14a″), 52H); 0.85 (m, 2×H 3 —C(15a″, 15b″), 6H).  13 C-NMR (125.76 MHz, DMSO-d 6 ): δ. 162.69 (C(4)); 150.03 (C(2)); 141.49 (C(6)); 116.52 (C(acetal)); 101.45 (C(5)); 91.02 (C(1′)); 86.44 (C(4′)); 83.62 (C(3′)); 80.50 (C(2′)); 61.18 (C(5′)); 36.32 (C(1a″)); 36.06 (C(1b″)); 30.90 (C(13″)); 28.77 (C(3a″)); 28.73 (C(3b″)); 28.66-28.28 (C(4″)-C(12″)); 23.18 (C(2a″)); 22.63 (C(2b″)); 21.66 (C(14″)); 13.46 (C(15″)). 
     1-(2,2-Diheptadecyl-6-hydroxymethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-1H-pyrimidin-2,4-dione (25e) 
     Pentatriacontan-18-one (0.5 g, 0.99 mmol) was added to a soln. of anhydr. THF (14 ml), uridine (24; 1.22 g, 5 mmol), TsOH (0.19 g, 1.0 mmol), and triethylortho formate (0.85 ml, 5.1 mmol). The mixture was refluxed for 24 h at 75° C. Then, triethylamine (0.6 ml) was added, and the resultant mixture was poured into an ice-cold aq. 4% NaHCO 3  soln. (50 ml). This soln. was stirred for 15 min at room temp. The organic layer was washed with CH 2 Cl 2  (100 ml) and dist. H 2 O (100 ml), dried over Na 2 SO 4 , filtered, and the solvent was evaporated. The residue was triturated with ice-cold MeOH on ice which gave the solid product. The colourless product 25e was dried over night in high vacuo. Yield: 0.45 g (0.61 mmol, 61.4%). TLC (silica gel 60; CH 2 Cl 2 /MeOH 95:5 (v/v)): R f : 0.21. UV(CH 2 Cl 2 ): λ max =260 nm (ε=9.320 M −1  cm −1 ). M.p.: 89.7° C. Anal. calc. for C 44 H 8 ON 2 O 6  (733.12) C, 72.09; H, 11.00; N, 3.82. Found: C, 71.70; H, 11.14; N, 3.81.  1 H-NMR (500 MHz, DMSO-d 6 , 60° C.): 11.16 (s, H—N(3)); 7.74 (d,  3 J(H—C(6), H—C(5))=8.0, H—C(6)); 5.84 (d,  3 J(H—C(1′), H—C(2′))=2.5, H—C(1′)); 5.60 (d,  3 J(H—C(5′), H—C(6))=8.2, H—C(5)); 4.88 (m, H—C(2′) &amp; OH—C(5′), 2H); 4.75 (dd,  3 J(H—C(3′), H—C(4′))=3.5,  3 J(H—C(3′), H—C(2′))=6.5, H—C(3′)); 4.07 (q, 2× 3 J(H—C(4′), H 2 —C(5′))=4.3,  3 J(H—C(4′), H—C(3′))=4.3, H—C(4′)); 3.53-3.63 (m, H 2 —C(5′)); 1.68 (m, H 2 —C(1a″)); 1.53 (m, H 2 —C(1b″)); 1.43-1.19 (m, 15×H 2(endo) —C(2a″-16a″), 15×H 2(exo)-C( 2b″-16b″), 60H); 0.86 (m, 2×H 3 —C(17a″, 17b″), 6H).  13 C-NMR (125.76 MHz, DMSO-d 6 ): δ. 162.69 (C(4)); 150.03 (C(2)); 141.50 (C(6)); 116.52 (C(acetal)); 101.45 (C(5)); 91.02 (C(1′)); 86.44 (C(4′)); 83.62 (C(3′)); 80.50 (C(2′)); 61.18 (C(5′)); 36.32 (C(1a″)); 36.05 (C(1b″)); 31.19 (C(15″)); 28.76 (C(3a″)); 28.72 (C(3b″)); 28.79-28.25 (C(4″)-C(14″)); 23.17 (C(2a″)); 22.62 (C(2b″)); 21.66 (C(16″)); 13.46 (C(17″)). 
     (((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-2,2-dipentyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) 2-Cyanoethyl N,N-diisopropylphosphoramidite (26a) 
     Compound 25a (0.214 g, 0.3 mmol) was dissolved in distilled CH 2 Cl 2  (15 ml). Under Ar-atmosphere N,N-diisopropylethylamine (125 al, 0.72 mmol) and 2-cyanoethyldiisopropylchlorophosphoramidite (156 al, 0.6 mmol) were then added, and the mixture was stirred for 17 min at room temp. The reaction was quenched by addition of an ice-cold aq. 5% NaHCO 3  soln. (12 ml), and the mixture was extracted with CH 2 Cl 2  (15 ml). The combined organic layers were dried (1 min, Na 2 SO 4 ), filtered, evaporated to dryness (25° C.), and the raw product was further dried in high vacuo at room temp. Column chromatography (silica gel 60, column: 2×10 cm, CH 2 Cl 2 /acetone 8:2 (v/v)), containing 8 drops of triethylamine per 1) gave one main zone which was pooled, evaporated and dried in high vacuo. Yield: 0.13 g (0.22 mmol, 71%) of a colourless oil which was stored at −20° C. TLC (silica gel 60; CH 2 Cl 2 /acetone 8:2 (v/v)): R f : 0.66.  31 P-NMR (202.45 MHz, CDCl 3 ): δ. 149.40 (P R ), 149.30 (P S ). 
     (((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dinonyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) 2-Cyanoethyl N,N-diisopropylphosphoramidite (26b) 
     Compound 25b (0.153 g, 0.3 mmol) was reacted to the phosphoramidite 26b as described for 25a. Yield: 0.157 g (0.22 mmol, 73%) of a colourless oil which was stored at −20° C. TLC (silica 60; CH 2 Cl 2 /acetone 8:2 (v/v)): R f : 0.89.  31 P-NMR (202.45 MHz, CDCl 3 ): δ. 149.46 (P R ), 149.37 (P S ) 
     (((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-diheptadecyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) 2-Cyanoethyl N,N-diisopropylphosphoramidite (26e) 
     Compound 25e (0.22 g, 0.3 mmol) was reacted to the phosphoramidite 26e as described for 26a. Yield: 0.1 g (0.17 mmol, 57%) of a colourless oil which was stored at −20° C. TLC (silica gel 60; CH 2 Cl 2 /acetone 8:2 (v/v)): R f : 0.81.  31 P-NMR (202.45 MHz, CDCl 3 ): δ. 149.46 (P R ), 149.38 (P S ). 1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dinonyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)pyrimidin-2,4(1H,3H)-dione (27b). Compound 25b (0.5 g, 0.98 mmol) was dissolved in anhydr. DMF (14 ml), and K 2 CO 3  (1 g, 7.24 mmol) was added. Subsequently, under Ar-atmosphere trans-trans-farnesylbromide (0.35 ml, 1.1 mmol) was added dropwise within 10 min. The reaction mixture was stirred for 24 h at room temp. under the exclusion of light. Then, the mixture was filtered and partitioned between dest. H 2 O (225 ml) and CH 2 Cl 2  (150 ml). The organic phase was separated, dried over Na 2 SO 4 , and filtered. The soln. was evaporated to dryness and further dried in high vacuo. Column chromatography (silica gel 60, column: 2×27 cm, CH 2 Cl 2  and MeOH, 99:1 (v/v)) and evaporation of the main fractions gave compd. 27b (0.533 g, 0.75 mmol, 77%) as colourless oil. TLC (silica gel 60; CH 2 Cl 2 /MeOH 95:5 (v/v)): R f , 0.59. UV(MeOH): λ max =260 nm (ε=7010 M −1  cm −1 ). Anal. calc. for C 43 H 72 N 2 O 6  (713.04): C, 72.43; H, 10.18; N, 3.93. Found: C, 72.59; H, 10.58; N, 3.96.  1 H-NMR (500.13 MHz, DMSO-d 6 ): 7.81 (d,  3 J(H—C(6), H—C(5))=8.0, H—C(6)); 5.87 (d,  3 J(H—C(1′), H—C(2′))=2.2, H—C(1′)); 5.74 (d,  3 J(H—C(5), H—C(6))=8.0, H—C(5)); 5.11 (t, 2× 3 J (OH—C(5′), H 2 —C(5′))=6.5, OH—C(5′)); 5.08-5.00 (m, H—C(2′″, 6′″, 10′″), 3H); 4.87 (dd,  3 J(H—C(2′), H—C(1′))=2.5,  3 J(H—C(2′), H—C(3′))=6.6, H—C(2′)); 4.73 (dd,  3 J(H—C(3′), H—C(4′))=3.0,  3 J(H—C(3′), H—C(2′))=6.5, H—C(3′)); 4.41-4.38 (m, H 2 —C(1′″)); 4.09 (q, 2× 3 J(H—C(4′), H 2 —C(5′))=4.2,  3 J(H—C(4′), H—C(3′))=4.2, H—C(4′)); 3.61-3.51 (m, H 2 —C(5′)); 2.03 (m, H 2 —C(5′″)); 2.00-1.92 (m, H 2 —C(8′″, 9′″), 4H); 1.92-1.87 (m, H 2 —C(4′″)); 1.73 (s, H 3 —C(13′″)); 1.69-1.66 (m, H 2 —C(1a″)); 1.63 (s, H 3 —C(12′″)); 1.54 (s, H 3 —C(14′″)); 1.51 (m, H 2 —C(1b″)); 1.42-1.18 (m, 7×H 2(endo) —C(2a″-8a″), 7×H 2(exo) —C(2b″-8b″), 28H); 0.85 (m, 2×H 3 —C(9a″, 9b″), 6H).  13 C-NMR (125.76 MHz, DMSO-d 6 ): δ. 161.55 (C(4)); 150.20 (C(2)); 140.18 (C(6)); 138.81 (C(3′″)); 134.45 (C(7′″)); 130.47 (C(11′″)); 124.01 (C(6′″)); 123.49 (C(10′″)); 118.69 (C(2′″)); 116.56 (C(acetal)); 100.87 (C(5)); 92.09 (C(1′)); 86.79 (C(4′)); 83.99 (C(3′)); 80.72 (C(2′)); 61.28 (C(5′)); 39.04 (C(8′″)); 38.74 (C(4′″)); 38.17 (C(1′″)); 36.36 (C(1a″)); 36.31 (C(1b″)); 31.19 (C(7a″)); 31.16 (C(7b″)); 29.07 (C(3a″)); 29.02 (C(3b″)); 28.83 (C(4a″)); 28.78 (C(4b″)); 28.58 (C(5a″)); 28.56 (C(5b″)); 28.58 (C(6a″); 28.59 (C(6b″)); 26.09 (C(5′″)); 25.62 (C(9′″)); 25.34 (C(12′″)); 23.48 (C(2a″)); 22.83 (C(2b″)); 21.99 (C(8″)); 17.41 (C(15′″)); 16.06 (C(14′″)); 15.66 (C(13′″)); 13.81 (C(9″)). 
     (((3aR,4R,6R,6aR)-6-(2,4-dioxo-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dinonyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) (2,4-dimethylpentan-3-yl) 2-Cyanoethyl N,N-diisopropylphosphoramidite (28b) 
     Compound 27b (0.214 g, 0.3 mmol) was reacted to the phosphoramidite 28b as described for 26a. Yield: 0.253 g (0.26 mmol, 87%) of a colorless oil which was stored at −20° C. TLC (silica gel 60; CH 2 Cl 2 /acetone 8:2 (v/v)): R f : 0.97.  31 P-NMR (202.45 MHz, CDCl 3 ): δ. 149.34 (P R ), 149.31 (P S ). 
     Ribothymidine Derivatives 
     
       
         
         
             
             
         
       
     
     1-(6-Hydroxymethyl-2,2-dinonyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-5-methyl-1H-pyrimidin-2,4-dione (30a) 
     Anhydrous methyluridine (29; 0.77 g, 3 mmol) was dissolved in dry DMF (10 ml). Then, nonadecan-10-one (1.13 g, 4 mmol), dissolved in CH 2 Cl 2  (10 ml), triethylorthoformate (1 ml), and 4 M HCl in 1,4-dioxane (4 ml) were added. The mixture was stirred at room temp. for 24 h. Subsequently, the mixture was partitioned between an aq. sat. Na 2 CO 3  soln. (100 ml) and CH 2 Cl 2  (100 ml). The organic phase was separated, dried over Na 2 SO 4 , filtered and evaporated to dryness. Traces of DMF were removed by repeated evaporation from CH 2 Cl 2 . The residue was dried in high vacuo overnight. The resulting colourless foam was purified by chromatography (silica gel 60, column: 6.5×10 cm). Elution with CH 2 Cl 2 /MeOH, 95:5 (v/v) gave one main zone which was pooled, the solvent was evaporated, and the residue was dried in high vacuo. Colourless oil (1.3 g, 83%). TLC (silica gel 60, CH 2 Cl 2 /MeOH, 95:5, (v/v)): R f , 0.31. UV(MeOH): λ max =265 nm (E=10600 M −1  cm −1 ). Anal. calc. for C 29 H 50 N 2 O 6  (522.73): C, 66.63; H, 9.64; N, 5.36. Found: C, 66.47; H, 9.272; N, 5.25.  1 H-NMR (DMSO-d 6 ): 11.34 (s, H—N(3)); 7.63 (s, H—C(6)); 5.83 (d,  3 J(H—C(1′), H—C(2′)=2.5, H—C(1′)); 5.02 (t,  3 J(OH—C(5′), H 2 —C(5′))=5.0, (OH—C(5′)); 4.88 (dd,  3 J (H—C(2′), H—C(1′)=3.0,  3 J (H—C(2′), H—C(3′)=6.5, H—C(2′)); 4.75 (dd,  3 J(H—C(3′), H—C(2′)=6.5;  3 J(H—C(3′), H—C(4′)=3.5, H—C(3′)); 4.02 (m,  3 J(H—C(4′), H—C(3′)=3.5;  3 J (H—C(4′), H 2 C(5′)=4.5, H—C(4′)); 3.56 (m, H 2 —C(5′)); 1.76 (s, 3H, CH 3 ); 1.66 (m, H 2(endo) —C(1a″)); 1.52 (m, H 2(exo) —C(1b″)); 1.38 (m, H 2(endo) —C(2a″)); 1.24 (m, 6×H 2(endo) —C(3a″-8a″), 7×H 2(exo) —C(2b″-8b″), 26H); 0.85 (m, 2×H 3 —C(9a″, 9b″), 6H).  13 C-NMR (DMSO-d 6 ): δ. 163.66 (C(4)); 150.27 (C(2)); 137.50 (C(6)); 116.77 (C(acetal)); 109.38 (C(5)); 90.52 (C(1′)); 86.24 (C(4′)); 83.50 (C(3′)); 80.58 (C(2′)); 61.31 (C(5′)); 36.33 (C(1a″)); 36.28 (C(1b″)); 31.17 (C(7a″)); 31.16 (C(7b″)); 29.06 (C(3a″)); 29.01 (C(3b″)); 28.83 (C(4a″)); 28.81 (C(4b″)); 28.80 (C(5″)); 28.77 (C(6a″)); 28.55 (C(6b″)); 23.48 (C(2a″)); 22.86 (C(2b″)); 21.97 (C(8a″)); 21.96 (C(8b″)); 13.82 (C(9a″)); 13.81 (C(9b″)); 11.94 (CH 3 -(base)). 
     1-(6-Hydroxymethyl-2,2-dipentadecyl-tetrahydro-furo[3,4-d][1,3]dioxo-4-yl)-5-methyl-1H-pyrimidin-2,4-dione (30b) 
     Hentriacontan-16-one (0.45 g, 1 mmol) was added to a soln. of methyluridine (29; 1.29 g, 5 mmol), TsOH (0.19 g, 1 mmol), triethylorthoformate (0.83 ml, 5 mmol) in tetrahydrofurane (14 ml). This reaction mixture was heated to 75° C. under reflux for 24 h. Then, triethylamine (0.6 ml) was added and the resultant mixture was poured into an ice-cold aq. 4% NaHCO 3  soln. (50 ml). After stirring for 15 min at room temperature, the reaction mixture was partitioned between CH 2 Cl 2  (100 ml) and H 2 O (100 ml). The organic layer was separated, dried over Na 2 SO 4 , filtered, and the solvent was evaporated. The resulting oil was triturated with ice-cold MeOH on an ice bath, which caused precipitation of compd. 30b as a colourless solid. The latter was filtered off, and the filtrate was evaporated yielding another portion of solid 30b. Total yield: 0.509 g, 74% of a yellowish solid. TLC (silica gel 60, CH 2 Cl 2 /MeOH 95:5 (v/v)): R f , 0.24. UV(CH 2 Cl 2 ): λ max =263 nm (ε=12250 M −1  cm −1 ). M.p.: &lt;70° C. Anal. calc. for C 41 H 74 N 2 O 6  (691.04): C, 71.26; H, 10.79; N, 4.05. Found: C, 72.39; H, 11.48; N, 3.33.  1 H-NMR (DMSO-d 6 ): 11.09 (s, H—N(3)); 7.58 (s, H—C(6)); 5.83 (d,  3 J(H—C(1′), H—C(2′)=2.5, H—C(1′)); 5.01 (t, 2× 3 J (OH—C(5′), H 2 —C(5′))=5.0, (OH—C(5′)); 4.89 (dd,  3 J (H—C(2′), H—C(1′)=2.8,  3 J (H—C(2′), H—C(3′)=6.6, H—C(2′)); 4.77 (dd,  3 J(H—C(3′), H—C(2′)=6.6,  3 J(H—C(3′), H—C(4′)=3.5, H—C(3′)); 4.05 (q, 2× 3 J(H—C(4′), H 2 —C(5′)=4.4,  3 J(H—C(4′), H—C(3′)═4.4, H—C(4′)); 3.60 (m, H 2 —C(5′)); 1.79 (s, H 3 —C(base)); 1.66 (m, H 2(endo) —C(1a″)); 1.52 (m, H 2(exo) —C(1b″)); 1.43-1.19 (m, 13×H 2(endo) —C(2a″-14a″), 13×H 2 (exo-C(2b″-14b″), 52H); 0.85 (m, 2×H 3 —C(15a″, 15b″), 6H).  13 C-NMR (DMSO-d 6 ): δ. 163.14 (C(4)); 149.91 (C(2)); 136.94 (C(6)); 116.59 (C(acetal)); 109.07 (C(5)); 90.50 (C(1′)); 86.03 (C(4′)); 83.31 (C(3′)); 80.38 (C(2′)); 61.12 (C(5′)); 36.32 (C(1a″)); 36.03 (C(1b″)); 30.74 (C(13″)); 28.63 (C(3a″)); 28.61 (C(3b″)); 28.44-28.10 (C(4″)-C(12″)); 23.02 (C(2a″)); 22.52 (C(2b″)); 21.48 (C(14″)); 13.24 (C(15″)); 11.33 (CH 3 -(base)). 
     1-(2,2-Diheptadecyl-6-hydroxymethyl-tetrahydro-furo[3,4-d][1,3]dioxo-4-yl)-5-methyl-1H-pyrimidin-2,4-dione (30c) 
     Pentatriacontan-18-one (0.50 g, 1 mmol) was added to a soln. of methyluridine (29; 1.29 g, 5 mmol), TsOH (0.19 g, 1 mmol), triethylorthoformate (0.83 ml, 5 mmol) in tetrahydrofurane (10 ml). This reaction mixture was heated to 75° C. under reflux for 24 h. Then, triethylamine (0.6 ml) was added and the mixture was poured into an ice-cold aq. 4% NaHCO 3  soln. (50 ml). After stirring for 15 min at room temperature, the reaction mixture was partitioned between CH 2 Cl 2  (100 ml) and H 2 O (100 ml). The organic layer was separated, dried over Na 2 SO 4 , filtered, and the solvent was evaporated. The resulting oil was triturated with cold MeOH which caused precipitation of raw 30c. The product was filtered off, and the filtrate was evaporated to yield a further crop of 30c. Total yield: (0.5 g, 68%). TLC (silica gel 60, CH 2 Cl 2 /MeOH 95:5 (v/v)): R f , 0.19. UV(CH 2 Cl 2 ): λ max =263 nm (ε=14380 M −1  cm −1 ). M.p.: 72° C. Anal. calc. for C 45 H 82 N 2 O 6  (747.14): C, 72.34; H, 11.06; N, 3.75. Found: C, 72.39; H, 11.48; N, 3.33.  1 H-NMR (DMSO-d 6 ): 11.31 (s, H—N(3)); 7.62 (s, H—C(6)); 5.84 (d,  3 J(H—C(1′), H—C(2′)=2.5, H—C(1′)); 5.02 (t, 2× 3 J(OH—C(5′), H 2 —C(5′))=6.5, (OH—C(5′)); 4.88 (dd,  3 J (H—C(2′), H—C(1′)=2.5,  3 J (H—C(2′), H—C(3′)=6.6, H—C(2′)); 4.75 (dd,  3 J(H—C(3′), H—C(2′)=6.6,  3 J(H—C(3′), H—C(4′)=3.5, H—C(3′)); 4.02 (dd, 2× 3 J (H—C(4′), H 2 —C(5′)=4.2,  3 J(H—C(4′), H—C(3′)=4.2, H—C(4′)); 3.57 (m, H 2 —C(5′)); 1.76 (s, H 3 —C(base)); 1.66 (m, H 2(endo) —C(1a″)); 1.51 (m, H 2 (exo-C(1b″)); 1.37 (m, 2H endo —C(2a″)); 1.24 (m, 14×H 2(endo) —C(3a″-16a″), 15×H 2 (exo-C(2b″-16b″), 58H); 0.85 (m, 2×H—C(17a″, 17b″), 6H).  13 C-NMR (DMSO-d 6 ): δ. 163.33 (C(4)); 150.04 (C(2)); 137.14 (C(6)); 116.64 (C(acetal)); 109.18 (C(5)); 90.48 (C(1′)); 86.09 (C(4′)); 83.38 (C(3′)); 80.44 (C(2′)); 61.18 (C(5′)); 36.31 (C(1a″)); 36.06 (C(1b″)); 30.90 (C(15″)); 28.75 (C(3a″)); 28.71 (C(3b″)); 28.59-28.27 (C(4″)-C(14″)); 23.17 (C(2a″)); 22.63 (C(2b″)); 21.66 (C(16″)); 13.46 (C(17″)); 11.56 (CH 3 -(base)). 
     (((3aR,4R,6R,6aR)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-2,2-dinonyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) 2-Cyanoethyl N,N-diisopropyl-phosphoramidite (31a) 
     Compound 30a (0.157 g, 0.3 mmol) was reacted to the phosphoramidite 31a as described for 26a. Yield: 0.155 g (71%) of a colorless oil which was stored at −20° C. TLC (silica gel 60; CH 2 Cl 2 /acetone 8:2 (v/v)): R f : 0.88.  31 P-NMR (202.45 MHz, CDCl 3 ): δ 149.36 (P R ), 149.22 (P S ). 
     (((3aR,4R,6R,6aR)-2,2-diheptadecyl-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) 2-Cyanoethyl N,N-diisopropylphosphoramidite (31c) 
     Compound 30c (0.214 g, 0.3 mmol) was reacted to the phosphoramidite 31c as described for 26a. Yield: 0.20 g (0.21 mmol, 70%) of a colourless oil which was stored at −20° C. TLC (silica 60, CH 2 Cl 2 /acetone 8:2 (v,v)): R f : 0.87.  31 P-NMR (101.25 MHz, CDCl 3 ): δ. 149.31 (P R ), 149.17 (P S ). 
     1-(6-Hydroxymethyl-2,2-dinonyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-5-methyl-3-(3,7,11-trimethyl-dodeca-2,6,10-trienyl)-1H-pyrimidin-2,4-dione (32a) 
     Compound 30a (0.52 g, 1 mmol) was dissolved in dry DMF (14 ml), and anhydr. K 2 CO 3  (1 g, 7.24 mmol) was added. Then, trans-trans-farnesylbromide (0.35 ml, 1.1 mmol) was added drop-wise, and the mixture was stirred under Ar-atmosphere for 24 h under the exclusion of light. Then, the mixture was partitioned between H 2 O (200 ml) and CH 2 Cl 2  (100 ml). The organic layer was separated, dried over Na 2 SO 4 , filtered, and the solvent was evaporated. Traces of DMF were removed by drying in high vacuo overnight. Chromatography (silica gel 60, column: 2×21 cm, CH 2 Cl 2 /MeOH, 99:1 (v/v)) gave one main zone which was pooled and evaporated to dryness. Further drying in high vacuo gave compd. 32a as a colourless oil (0.5 g, 68%). TLC (silica gel 60, CH 2 Cl 2 /MeOH, 95:5, (v/v)): R f , 0.66. UV(MeOH): λ max =266 nm (E=8700 M −1  cm −1 ). Anal. calc. for C 44 H 74 N 2 O 6  (727.07): C, 72.69; H, 10.26; N, 3.85. Found: C, 72.67; H, 9.925; N, 3.76.  1 H-NMR (DMSO-d 6 ): 7.68 (s, H—C(6)); 5.89 (d,  3 J(H—C(1′), H—C(2′)=2.5, H—C(1′))); 5.12 (t,  3 J(OH—C(5′), H 2 —C(5′))=5.0, OH—C(5′)); 5.07-5.00 (m, H—C(2′″, 6′″, 10′″), 3H); 4.85 (dd,  3 J (H—C(2′), H—C(1′)=2.8,  3 J (H—C(2′), H—C(3′)=6.6, H—C(2′)); 4.76 (dd,  3 J(H—C(3′), H—C(2′)=6.6;  3 J(H—C(3′), H—C(4′)=3.5, H—C(3′)); 4.39 (m, H 2 —C(1′″)); 4.06 (m, H—C(4′)); 3.62-3.52 (m, H 2 —C(5′)); 2.03 (m, H 2 —C(5′″)); 1.99-1.92 (m, H 2 —C(8′″, 9′″), 4H); 1.92-1.86 (m, H 2 —C(4′″)); 1.81 (s, H 3 —C(base)); 1.74 (s, H 3 —C(13′″)); 1.69-1.64 (m, H 2(endo) —C(1a″)); 1.63 (s, H 3 —C(12′″)); 1.54 (s, H 3 —C(14′″)); 1.52 (m, H 2(exo) —C(1b″)); 1.43-1.17 (m, 7×H 2(endo) —C(2a″-8a″), 7×H 2(exo) —C(2b″-8b″), 28H); 0.85 (m, 2×H 3 —C(9a″, 9b″), 6H).  13 C-NMR (DMSO-d 6 ): δ. 162.27 (C(4)); 150.09 (C(2)); 138.71 (C(6)); 135.71 (C(3′″)); 134.42 (C(7′″)); 130.45 (C(11′″)); 123.98 (C(6′″)); 123.46 (C(10′″)); 118.75 (C(2′″)); 116.74 (C(acetal)); 108.57 (C(5)); 91.42 (C(1′)); 86.34 (C(4′)); 83.64 (C(3′)); 80.61 (C(2′)); 61.25 (C(5′)); 38.98 (C(8′″)); 38.76 (C(4′″)); 38.52 (C(1′″)); 36.30 (C(1″)); 31.15 (C(7a″)); 31.13 (C(7b″)); 29.03 (C(3a″)); 28.97 (C(3b″)); 28.80 (C(4a″)); 28.74 (C(4b″)); 28.55 (C(5a″)); 28.52 (C(5b″)); 26.06 (C(6a″)); 25.55 (C(6b″)); 25.32 (C(5′″)); 23.44 (C(9′″)); 22.80 (C(12′″)); 21.95 (C(2a″)); 21.93 (C(2b″)); 17.37 (C(8″)); 16.03 (C(15′″)); 15.64 (C(14″)); 13.79 (C(13′″)); 13.78 (C(9″)); 12.59 (H 3 C-(base)). 
     (((3aR,4R,6R,6aR)-6-(5-methyl-2,4-dioxo-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dinonyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl) 2-Cyanoethyl N,N-diisopropylphosphoramidite (33a) 
     Compound 32a (0.22 g, 0.3 mmol) was reacted to the phosphoramidite 33a as described for 26a. Yield: 0.2 g (0.22 mmol, 77.9%) of a colourless oil which was stored at −20° C. TLC (silica gel 60; CH 2 Cl 2 /acetone 8:2 (v/v)): R f : 0.97.  31 P-NMR (202.45 MHz, CDCl 3 ): δ. 149.28 (P R ), 149.26 (P S ). 
     Lipidderivatives and Hydrophobization of Thymidine 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     General 
     Starting compounds and solvents were purchased from the appropriate suppliers and were used as obtained. 1,4-Dichlorobut-2-yne 50 was prepared from but-2-yne-1,4-diol and thionyl chloride in pyridine according to the known procedure. Reactions were carried out under argon atmosphere in a dry Schlenk flask. Chromatography: silica gel 60 (Merck, Germany). NMR Spectra: AMX-500 spectrometer (Bruker, D-Rheinstetten);  1 H: 500.14 MHz,  13 C: 125.76 MHz, and  31 P: 101.3 MHz. Chemical shifts are given in ppm relative to TMS as internal standard for  1 H and  13 C nuclei and external 85% H 3 PO 4 ; J values in Hz. ESI MS Spectra were measured on a Bruker Daltronics Esquire HCT instrument (Bruker Daltronics, D-Leipzig); ionization was performed with a 2% aq. formic acid soln. Elemental analyses (C, H, N) of crystallized compounds were performed on a VarioMICRO instrument (Fa. Elementar, D-Hanau). 
     Methyl N,N-(dioctadecyl)glycinate (36) 
     N,N-Dioctadecylamine 34 (1.90 g, 3.65 mmol), methyl bromoacetate 35 (1.62 g, 10.6 mmol), dibenzo-[18]-crown-6 (10 mg) and Na 2 CO 3  (1.93 g, 18.3 mmol) were suspended in benzene (50 ml) at room temperature and stirred overnight under reflux (20 h). A second portion of methyl bromoacetate 35 (0.56 g, 3.65 mmol) was added and stirring under reflux was continued for further 10 h until the reaction was complete as monitored by  1 H-NMR analysis (amine 34 at 2.95 ppm, product 36 at 3.34 ppm). The white suspension was filtered through a silica gel layer (1 cm) to separate the unreacted amine 34, washed with benzene (2×30 ml) and concentrated in vacuo resulting in the formation of compound 36 (2.10 g, 97%) as a slightly yellow crystalline mass. TLC (hexane-Et 2 O, 1:1 v/v): R f 0.60. M.p. 60-61° C.  1 H-NMR (CDCl 3 ): 3.71 (s, 3H, CH 3 O), 3.34 (s, 2H, CH 2 COO), 2.58-2.55 (m, 4H, 2 CH 2   CH   2 N), 1.48-1.42 (m, 4H, 2  CH   2 CH 2 N), 1.28 (br. s, 60H), 0.90 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 172.09 (C═O), 55.05 (N C H 2 CH 2 ), 54.54 (N C H 2 CO), 51.20, 51.16 (CH 3 O), 31.90 ( C H 2 CH 2 CH 3 ), 29.68, 29.61, 29.55, 29.31 (CH 2 (CH 2 ) 3 N), 27.47 ( C H 2 CH 2 N), 27.37 ( C H 2 (CH 2 ) 2 N), 22.65 ( C H 2 CH 3 ), 14.04, 14.03 (CH 2   C H 3 ). ESI-MS (calculated mass: 593): 594.7 [M+H] + . Anal. calc. for C 39 H 79 NO 2  (594.07): C, 78.85, H, 13.40, N, 2.36; found: C, 78.59, H, 13.50, N, 2.24. 
     N,N-dioctadecylglycine (37) 
     Powder of the amino-ester 36 (2.97 g, 5 mmol) was added at once to a freshly prepared solution of NaOH (0.40 g, 10 mmol) in H 2 O (50 ml) and the resulting suspension was stirred at 95° C. overnight. White precipitate was removed by filtration, washed with Et 2 O (3×5 ml), suspended in H 2 O (20 ml) and carefully made acidic (pH 6) by addition of HCl (5%). Precipitate was collected, washed with H 2 O, pressed down and dried in vacuum resulting in the formation of acid 37 (2.84 g, 98%). TLC (CH 2 Cl 2 -MeOH, v/v 10:1): R f  0.43. M.p. 102-103° C. (Lit. m.p. 102-103° C.).  1 H-NMR (CDCl 3 ): 8.63 (br.s, 0.5H, COOH), 8.15 (br.s, 0.5H, COOH), 3.46 (s, 2H, CH 2 CO), 3.06-3.03 (m, 4H, 2 CH 2 N), 1.70-1.65 (m, 4H, 2 CH 2   CH   2 N), 1.25 (br.s, 60H), 0.88 (t, 6H, J=6.8, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 168.69 (COO), 54.17 (NCH 2 ), 31.94 (CH 3 CH 2 CH 2 ), 29.77, 29.70, 29.52, 29.38, 27.32 ( C H 2 CH 2 N), 26.64 ( C H 2 (CH 2 ) 2 N), 24.89, 22.69 (CH 3   C H 2 ), 14.08 (CH 3 ) (1H and  13 C NMR are in agreement to those reported). 
     2-(Dioctadecylamino)ethanol (38) 
     Methyl N,N-dioctadecylglycinate 36 (2.24 g, 3.77 mmol) was dissolved in THF (150 ml), cooled in an ice-bath and a LiAlH 4  (0.57 g, 15 mmol) was added in portions with stirring within 3 min (gas evolution occurs). The cooling bath was removed, and stirring was continued overnight at room temp. The reaction mixture was cooled in an ice-bath, and MeOH (2.5 ml) was added drop-wise to destroy the excess of LiAlH 4 . The mixture obtained was concentrated in vacuo (25 Torr), suspended in CH 2 Cl 2  (100 ml), and carefully treated with H 2 O (40 ml) until a solid precipitate has been formed. The organic layer was separated, washed with H 2 O (50 ml), dried over anhydr. Na 2 SO 4  and concentrated resulting in the formation of compd. 38 (2.0 g, 94%) as an off-white solid. TLC (silica gel, Et 2 O): R f  0.26. M.p. 43-44° C.  1 H-NMR (CDCl 3 ): 3.52 (t, 2H, J=5.4, CH 2 O), 3.1 (br. S, 1H, OH), 2.57 (t, 2H, J=5.4, OCH 2   CH   2 N), 2.44 (t, 4H, J=7.2, 2 CH 2 CH 2   CH 2   N), 1.43 (m, 4H, CH 2   CH 2   CH 2 N), 1.26 (br. s, 60H), 0.89 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 58.28 (CH 2 O), 55.54 ( C H 2 CH 2 O), 53.90 (N C H 2 (CH 2 ) 16 , 31.93 (CH 3 CH 2   C H 2 ), 29.70, 29.66, 29.60, 29.36 ( C H 2 (CH 2 ) 3 N), 27.45 (CH 2   C H 2 CH 2 N), 27.24 ( C H 2 (CH 2 ) 2 N), 22.68 (CH 3   C H 2 ), 14.08 (CH 3 ). ESI-MS (calculated mass: 565): 566.7 [M+H] + . 
     N-(2-Bromoethyl)-N,N-dioctadecylamine (39) 
     PPh 3  (8.80 g, 33.6 mmol) was dissolved in a pre-cooled solution of compd. 38 (3.80 g, 6.71 mmol) in CH 2 Cl 2  (180 ml) at 5° C. followed by addition of CBr 4  (11.15 g, 33.6 mmol) in portions within 3 min. The resulting orange solution was stirred at ambient temperature for 30 h. The reaction mixture was concentrated, and the bromide 39 was isolated by chromatography on silica gel (100 g, eluted with a gradient mixture of hexane-CH 2 Cl 2 , v/v from 1:1 to 0:1) in low yield (0.43 g, 10%). TLC (silica gel, hexane-CH 2 Cl 2 , 1:1, v/v): R f  0.58. M.p. 69-71° C.  1 H-NMR (CDCl 3 ): 3.38 (t, 2H, J=7.5, CH 2 Br), 2.88 (t, 2H, J=7.5, BrCH 2   CH   2 N), 2.50 (t, 4H, J=7.2, 2 (CH 2 ) 16   CH 2   N), 1.49-1.41 (m, 4H, 2 CH 2   CH 2   CH 2 N), 1.27 (br. s, 60H), 0.90 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 56.16 (BrH 2 C C H 2 ), 54.48 (NCH 2 (CH 2 ) 16 ), 31.91 (CH 3 CH 2   C H 2 ), 29.68, 29.64, 29.61, 29.52 (CH 2 Br), 29.33, 27.35 (NCH 2   C H 2 CH 2 ) 27.21, 22.65 ( C H 2 CH 3 ), 14.05 (CH 3 ). ESI-MS (calculated mass: 627 [ 79 Br]): 548.7 [M−HBr+H] + , 628.7 [M( 79 Br)+H] + , 630.6 [M′( 81 Br)+H] + . Anal. calc. for C 38 H 78 BrN (628.96): C, 72.57, H, 12.50, N, 2.23; found: C, 72.18, H, 12.38, N, 2.04. 
     Methyl N,N-dioctadecyl-2-aminopropionate (41) 
     N,N-Dioctadecylamine (34, 0.93 g, 1.78 mmol) was added to a solution of methyl acrylate (40, 1.75 g, 20.3 mmol) in a mixture of i-PrOH (14 ml) and CH 2 Cl 2  (6 ml), and the resulting white suspension was stirred at 45° C. overnight. The reaction mixture was filtered through a paper filter and concentrated in vacuo (10 Torr) resulting in the formation of the propionate 41 (1.04 g, 96%) as a white solid mass. TLC (silica gel, hexane-Et 2 O, 1:1, v/v): R f  0.58. M.p. 44-45° C.  1 H-NMR (CDCl 3 ): 3.67 (s, 3H, OCH 3 ), 2.78 (t, 2H, J=5.4, CH 2 CO), 2.47-2.36 (m, 6H, 3 CH 2 N), 1.48-1.36 (m, 4H, 2 CH 2   CH   2 CH 2 N), 1.26 (br. s., 60H), 0.89 (t, 6H, J=6.9, 2 CH 3 ) (in a good agreement with those reported).  13 C-NMR (CDCl 3 ): 173.35 (C═O), 54.00 (N C H 2 (CH 2 ) 16 ), 51.42 (OCH 3 ), 49.42 ( C H 2 CH 2 CO), 32.30 ( C H 2 CO), 31.90 (CH 3 CH 2   C H 2 ), 29.68, 29.64, 29.60, 29.33 (N(CH 2 ) 3   C H 2 ), 27.50 (NCH 2   C H 2 CH 2 ), 27.19 (N(CH 2 ) 2   C H 2 ), 22.66 ( C H 3 CH 2 ), 14.07 (CH 3 CH 2 ). ESI-MS (calculated mass: 607): δ08.7 [M+1] + . Anal. calc. for C 40 H 81 NO 2  (608.10): C, 79.01, H, 13.43, N, 2.30; found: C, 78.86, H, 13.39, N, 2.12. 
     3-(Dioctadecylamino)propanol (42) 
     LiAlH 4  (0.26 g, 6.84 mmol) was added in portions within 2 min to a solution of propanoate 41 (1.04 g, 1.71 mmol) in THF (45 ml), cooled in an ice-bath. The bath was removed and stirring was continued overnight. The reaction mixture was carefully treated with a solution of MeOH (0.6 ml) in Et 2 O (2 ml) with cooling in an ice-bath until the gas evolution ceased. Organic solvents were removed in vacuo; the residue was dissolved in CH 2 Cl 2  (70 ml) and washed with H 2 O (3×30 ml), dried (Na 2 SO 4 ) and concentrated resulting in the formation of compd. 42 (0.98 g, 98%) as a white solid mass. TLC (silica gel, Et 2 O): R f  0.23. M.p. 48-49° C.  1 H-NMR (CDCl 3 ): 5.68 (s, 1H, OH), 3.79 (t, 2H, J=5.3,  CH   2 OH), 2.63 (t, 2H, J=5.3,  CH   2 CH 2 CH 2 OH), 2.38-2.43 (m, 4H, 2 (CH 2 ) 16   CH   2 N), 1.67 (quint, 2H, J=5.3, CH 2   CH   2 CH 2 OH), 1.53-1.40 (m, 4H, 2 (CH 2 ) 15   CH   2 CH 2 N), 1.26 (br. s, 60H), 0.89 (t, 6H, J=6.5, 2 CH 3 ).  13 C-NMR (CDCl 3 ): δ4.82 (CH 2 O), 55.36 ( C H 2 (CH 2 ) 2 O), 54.22 (N C H 2 (CH 2 ) 16 ), 31.90 (CH 3 CH 2   C H 2 ), 29.68, 29.64, 29.60, 29.33, 27.83 ( C H 2 CH 2 O), 27.51 (NCH 2   C H 2 (CH 2 ) 15 ), 26.82 (N(CH 2 ) 2   C H 2 (CH 2 ) 14 ), 22.66 ( C H 2 CH 3 ), 14.06 (CH 3 ). ESI-MS (calculated mass: 579): 580.7 [M+H] + . 
     1.1-Dioctadecylazetidinium bromide (44) 
     Crystals of CBr 4  (320 mg, 1 mmol) were added to a pre-cooled (ice-bath) solution of aminopropanole 42 (116 mg, 0.2 mmol) and PPh 3  (260 mg, 1 mmol) in CH 2 Cl 2  (13 ml) and the resulting mixture was stirred at the same temperature overnight. Yellow suspension was filtered through a SiO 2  layer (4 cm) and washed consecutively by CH 2 Cl 2  (100 ml) and Et 2 O (100 ml) to give in the second fraction light-yellow crystalline mass of 44 (16 mg, 13%). TLC (silica gel, CH 2 Cl 2 -Et 2 O v/v 4:1): R f  0.64.  1 H-NMR (CDCl 3 ): 4.52-4.49 (m, NCH 2 ), 3.57-3.54 (m, 2H, NCH 2 ), 3.51-3.48 (m, 2H), 2.87-2.79 (m, 2H), 1.56 (br.s, 2H), 1.34-1.26 (m, 60H), 1.89 (t, J=6.8, 6H, 2 CH 3 ). ESI-MS (calculated mass: 641 [ 79 Br]): 562.7 [M−HBr+H] + , 642.6 [M( 79 Br)+H] + , 644.6 [M′( 81 Br)+H] + . 
     4-(Dioctadecylamino)-4-oxobutanoic acid (46) 
     Dioctadecylamine (34) (522 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) were added consecutively to a stirred soln. of succinic anhydride (45) (150 mg, 1.5 mmol) in CH 2 Cl 2  (10 ml), and the white suspension formed was stirred at 35° C. overnight. The clear resulting soln. was concentrated in vacuo and recrystallized from acetone (3 ml) to give the acid 46 (600 mg, 96%) as a white powder. TLC (silica gel, CH 2 Cl 2 —AcOEt, v/v 1:1): R f  0.62. M.p. 68-69° C. (acetone) (Lit. m.p. 63-64° C. (Et 2 O).  1 H-NMR (CDCl 3 ): 3.36-3.33 (m, 2H, NCH 2 ), 3.26-3.23 (m, 2H, NCH 2 ), 2.70 (s, 4H, COCH 2 CH 2 CO), 1.62-1.52 (m, 4H, 2 NCH 2   CH   2 ), 1.28 (br.s, 60H), 0.90 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 173.88 (COO), 172.55 (CON), 48.42, 46.80 (NCH 2 ), 31.90 (CH 3 CH 2   C H 2 ), 30.69 (NCO C H 2 ), 29.67, 29.63, 29.59, 29.57, 29.54, 29.52, 29.49, 29.33, 29.28, 28.81, 28.08, 27.61, 26.99, 26.87 (NCH 2 CH 2   C H 2 ), 22.65 (CH 3 CH 2 ), 14.06 (CH 3 ) (1H and  13 C NMR are in agreement to those partly reported). ESI-MS (calculated mass: 621): δ22.7 [M+H] + . Anal. calc. for C 40 H 79 NO 3  (622.08): C, 77.23, H, 12.80, N, 2.25; found: C, 77.12, H, 12.89, N, 2.08. 
     Methyl 4-(dioctadecylamino)-4-oxobutanoate (47) 
     Dimethyl sulfate (126 mg, 1 mmol) and K 2 CO 3  (198 mg, 1.43 mmol) were added consecutively to a suspension of the acid 46 (311 mg, 0.5 mmol) in acetone (4 ml) and the reaction mixture was stirred at 55° C. overnight. The resulting white suspension was cooled to room temperature, the precipitate was filtered off, washed with acetone (3 ml), and the filtrate was concentrated in vacuo. The residue was taken up in CH 2 Cl 2  (5 ml), washed with aq. NH 3  (2 ml) to destroy the excess of dimethyl sulfate, and H 2 O (2×3 ml), dried (Na 2 SO 4 ) and concentrated resulting in the formation of the methyl ester 47 (291 mg, 91%) in a form of a colorless oil, which solidified upon standing. TLC (silica gel, hexane-Et 2 O, 1:1, v/v): R f  0.55. M.p. 29-30° C.;  1 H-NMR (CDCl 3 ): 3.70 (s, 3H, OCH 3 ), 3.31-3.29 (m, 2H, NCH 2 ), 3.26-3.23 (m, 2H, NCH 2 ), 2.70-2.67 (m, 2H, COCH 2 CH 2 CO), 2.64-2.61 (m, 2H, COCH 2 CH 2 CO), 1.61-1.48 (m, 4H, 2 NCH 2   CH   2 ), 1.27 (br.s, 60H), 0.90 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 173.72 (COO), 170.49 (CON), 51.62 (OCH 3 ), 47.85, 46.18 (NCH 2 ), 31.90, 29.67, 29.63, 29.58, 29.54, 29.42, 29.32, 28.94, 27.99, 27.79, 27.06, 26.92 (NCH 2 CH 2   C H 2 ), 22.65 (CH 3   C H 2 ), 14.06 (CH 3 ). ESI-MS (calculated mass: 635): 1294.2 [2M+Na] + , 658.7 [M+Na] + , 636.7 [M+H] + . 
     4-(Dioctadecylamino)butan-1-ol (48a) 
     Powdered LiAlH 4  (106 mg, 2.8 mmol) was added in portions during 2 min to a pre-cooled (ice-bath) soln. of the ester 47 (222 mg, 0.35 mmol) in THF (4 ml), and the resulting suspension was stirred at room temperature overnight. The reaction mixture was cooled on an ice-bath, and MeOH (1 ml) was added drop-wise to destroy the excess of LiAlH 4 . Stirring was continued until the gas evolution had ceased. The precipitate formed was filtered off, washed with Et 2 O (5×5 ml); the filtrate was concentrated and the crude product was purified by chromatography (preparative TLC, eluted with a mixture of CH 2 Cl 2 -MeOH, 15:1, v/v) resulting in the formation of the alcohol 48a (122 mg, 76%) in a form of a colorless solid mass. TLC (silica gel, CH 2 Cl 2 -MeOH, 15:1, v/v): R f  0.30. M.p. 57-58° C.  1 H-NMR (CDCl 3 ): 3.56 (br.s, 2H, CH 2 O), 2.49-2.43 (m, 6H, (CH 2 ) 2 NCH 2 ), 1.68-1.64 (m, 4H), 1.54-1.43 (m, 4H), 1.26 (br.s, 60H), 0.88 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): δ2.56 (OCH 2 ), 54.58 (NCH 2 ), 53.61 (N C H 2 (CH 2 ) 16 ), 32.54 (br.s,  C H 2 CH 2 OH), 31.30 (CH 3 CH 2   C H 2 ), 29.67, 29.63, 29.60, 29.50, 29.33, 27.62 (NCH 2   C H 2 (CH 2 ) 15 ), 26.05 (br.s, NCH 2   C H 2 ), 25.71 (N(CH 2 ) 2   C H 2 (CH 2 ) 14 ), 22.65 (CH 3   C H 2 ), 14.05 (CH 3 ). ESI-MS (calculated mass: 593): 522.7 [M−C 4 H 8 +H] + , 594.8 [M+H] + . 
     2-Cyanoethyl 4-(dioctadecylamino)butyl N,N-diisopropylphosphoramidite (48b) 
     A solution of dioctadecylaminobutanol (48a, 154 mg, 0.26 mmol) in CH 2 Cl 2  (5 ml) under Argon atmosphere was treated with Hünig&#39;s base (101 mg, 0.78 mmol). The resulting mixture was cooled in an ice-bath, and (chloro)(2-cyanoethoxy)(diisopropylamino)phosphine (123 mg, 0.56 mmol) was added, and the reaction mixture was stirred for 20 min with cooling and then for 1 h at ambient temperature. The resulting colorless clear solution was diluted with CH 2 Cl 2  (40 ml), washed with a, ice-cold aq. NaHCO 3  soln. and brine, dried (Na 2 SO 4 ), and concentrated. The resulting oil was chromatographed (silica gel 60, eluted with benzene-Et 2 O-Et 3 N, 80:10:1, v/v/v); the product (48b) was obtained from the first three fractions upon evaporation as a colorless oil (191 mg, 93%).  1 H NMR (CDCl 3 , 500 MHz) δ: 3.91-3.79 (m, 2H, OCH 2 ), 3.72-3.58 (m, 4H, OCH 2 , 2 N CH ), 2.65 (t, 2H, J=6.55, NCCH 2 ), 2.44-2.41 (m, 2H, NCH 2 ), 2.40-2.37 (m, 4H, 2 NCH 2 ), 1.65-1.60 (m, 2H, OCH 2   CH   2 ), 1.54-1.48 (m, 2H, NCH 2   CH   2 ), 1.45-1.39 (m, 4H, NCH 2   CH   2 ), 1.35-1.1.27 (m, 2H, CH 2 ), 1.27 (br.s, 2H, CH 2 ), 1.20 (d, 6H, J=6.65, CH( CH   3 ) 2 ), 1.19 (d, 6H, J=6.65, CH( CH   3 ) 2 ), 0.90 (t, 6H, J=6.65, 2 CH 2   CH   3 ).  13 C-NMR (CDCl 3 , 125 MHz) δ: 117.53 (C≡N), 63.72 (d,  2 J CP =17.1, CH 2 OP), 58.32 (d,  2 J CP =19.0, CH 2 OP), 54.25 (2 CH 2 N), 53.91 (CH 2 N), 43.51 (d,  2 J CP =12.4, 2 CHNP), 31.90 (2  C H 2 CH 2 CH 3 ), 29.68, 29.37, 29.33, 27.66 (2  C H 2 CH 2 N), 27.16 (2  C H 2 (CH 2 ) 2 N), 24.65 (CHCH 3 ), 24.59 (2 CHCH 3 ), 24.52 (CHCH 3 ), 23.59 ({right arrow over (C)}H 2 CH 2 N), 22.66 (2 {right arrow over (C)}H 2 CH 3 ), 20.34 (d,  3 J CP =6.7, CH 2 CH 2 OP), 14.06 (2 CH 3 ). 
       31 P NMR (CDCl 3 , 202.5 MHz) δ: 147.42. ESI-MS (calculated mass: 793): 711.7 [M−NiPr 2 +OH+H] + , 741.8 [M−O(CH 2 ) 2 CN+OH+H] + , 810.8 [M+O+H] + . 
     [1,1,4,4-D 4 ]-4-(Dioctadecylamino)butan-1-ol (49) 
     Powdered LiAlD 4  (109 mg, 2.6 mmol) was added portions-wise during 2 min to a pre-cooled (ice-bath) soln. of the ester 47 (206 mg, 0.32 mmol) in THF (4 ml), and the resulting suspension was stirred at room temperature overnight. The reaction mixture was cooled in an ice-bath, diluted with Et 2 O (10 ml), and MeOH (1 ml) was added drop-wise to destroy an excess of LiAlD 4 . Stirring was continued until gas evolution had ceased (10 min). The precipitate formed was filtered off, washed with Et 2 O (5×5 ml), the filtrate was concentrated and the crude product was suspended in CH 2 Cl 2 . The resulting precipitate was filtered off and washed with CH 2 Cl 2  (5×1 ml). The filtrate was concentrated resulting in the formation of compd. 49 (145 mg, 75%) as a white solid. TLC (silica gel. CH 2 Cl 2 -MeOH, 8:1, v/v): R f  0.60. M.p. 59-60° C.  1 H-NMR (CDCl 3 ): 2.46-2.42 (m, 4H, (CH 2 ) 2 NCD 2 ), 1.66-1.62 (m, 4H), 1.51-1.46 (m, 4H), 1.27 (br. s, 60H), 0.89 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 61.89 (quint., J C-D =20.5, OCD 2 ), 53.98 (quint., J C-D =21.1, NCD 2 ), 53.71 (NCH 2 ), 32.51 (br. s,  C H 2 CD 2 OH), 31.90 (CH 3 CH 2   C H 2 ), 29.67, 29.63, 29.61, 29.53, 29.33, 27.66 (NCH 2 CH 2 ), 26.13 (br.s, NCD 2   C H 2 ), 25.93 (N(CH 2 ) 2   C H 2 (CH 2 ) 14 ), 22.66 (CH 3   C H 2 ), 14.05 (CH 3 ). ESI-MS (calculated mass: 597): 522.7 [M−C 4 H 4 D 4 +H] + , 598.8 [M+H] + . 
     4-Chloro-N,N-dioctadecylbut-2-yn-1-amine (51) 
     N,N-Dioctadecylamine 34 (2.08 g, 4.0 mmol), the dichloride 50 (1.48 g, 12 mmol), and Na 2 CO 3  (1.69 g, 16 mmol) were suspended in benzene (40 ml) and stirred at 65-70° C. (bath) overnight (16 h) until the reaction was completed (NMR analysis: amine 34 at 2.66 ppm, product 51 at 2.44 ppm). The light brown reaction mixture was concentrated, diluted with Et 2 O, inorganic salts and residual starting amine 34 were filtered off and washed with pre-cooled Et 2 O (+5° C., 20 ml). The filtrate was concentrated resulting in the formation of 2.1 g of a beige solid mass. The product 51 was isolated by chromatography on SiO 2  (100 g, eluted with a mixture CH 2 Cl 2 -Et 2 O (4:1, v/v, 400 ml) as a light beige mass (1.57 g, 60.5%) followed by other products (in order of their elution from the column): N,N,N′,N′-tetraoctadecylbut-2-yne-1,4-diamine (52), 4-chlorobut-2-yn-1-ol (53) and di-N,N-(4-chlorobut-2-ynyl)-N,N-dioctadecylammonium chloride (54). TLC (silica gel, CH 2 Cl 2 ): R f  0.45. M.p. 51-52° C.  1 H-NMR (CDCl 3 ): 4.18 (t, 2H, J=1.83,  CH   2 Cl), 3.44 (t, 2H, J=1.83, N CH   2 C≡), 2.47-2.44 (m, 4H, 2 CH 2   CH   2 N), 1.48-1.41 (m, 4H, 2  CH   2 CH 2 N), 1.28 (br. S, 60H), 0.90 (t, 6H, J=6.9, 2 CH 3 ).  13 C-NMR (CDCl 3 ): 82.45 (ClC— C —), 79.31 (ClC≡C═ C ), 53.83 (N C H 2 CH 2 ), 42.19 (N C H 2 C≡), 31.92 ( C H 2 CH 2 CH 3 ), 30.60 ( C H 2 Cl), 29.70, 29.65, 29.56 ( C H 2 CH 2 CH 2 CH 3 ), 29.35 ( C H 2 (CH 2 ) 3 N), 27.52 ( C H 2 CH 2 N), 27.46 ( C H 2 (CH 2 ) 2 N), 22.66 ( C H 2 CH 3 ), 14.03 (CH 3 ). ESI- MS (calculated mass: 607 [ 35 C 1 ]): δ08.7 [M( 35 Cl)+H] + , 609.7, 610.7 [M′( 37 Cl)+H] + , 611.7. Anal. calc. for C 40 H 78 ClN (608.53): C, 78.95, H, 12.92, N, 2.30; found: C, 78.73, H, 12.97, N, 2.15. 
     N,N,N′,N′-Tetraoctadecylbut-2-yne-1,4-diamine (52) 
     TLC (silica gel, CH 2 Cl 2 : R f  0.40. M.p. 55-56° C.  1 H-NMR (CDCl 3 ): 3.43 (s, 4H, 2 NCH 2 C≡), 2.47-2.44 (m, 8H, 4 CH 2 CH 2 N), 1.48-1.41 (m, 8H, 4  C H 2 CH 2 N), 1.27 (br. s, 120H), 0.90 (t, 12H, J=6.9, 4 CH 3 ).  13 C-NMR (CDCl 3 ): 79.36 (C≡C), 53.95 (N C H 2 CH 2 ), 41.97 (N C H 2 C≡), 31.91 ( C H 2 CH 2 CH 3 ), 29.70, 29.66, 29.64, 29.34, 27.61, 27.52, 22.66 ( C H 2 CH 3 ), 14.06 (CH 3 ). ESI-MS (calculated mass: 1092): 548.7 [M+2H] +2 . 
     4-Chlorobut-2-yn-1-ol (53) 
     [14] TLC (silica gel, CH 2 Cl 2 -Et 2 O, v/v, 1:1): R f  0.31.  1 H-NMR (CDCl 3 ): 4.34 (t, 2H, J=1.75, CH 2 O), 4.19 (t, 2H, J=1.75, CH 2 Cl). 
     Di-N,N-(4-chlorobut-2-ynyl)-N,N-dioctadecylammonium chloride (54) 
       1 H-NMR (CDCl 3 ): 4.97 (s, 4H, 2 ≡CCH 2 N + ), 4.21 (s, 4H, 2 CH 2 Cl), 3.60-3.56 (m, 4H, 2 CH 2 CH 2 N + ), 1.91-1.86 (m, 4H, 2 CH 2 CH 2 N + ), 1.27 (br. s, 120H), 0.90 (t, 12H, J=6.9, 4 CH 3 ). 
     N-Octadecyl-N,N-diprop-2-ynylamine (57) 
     Propargyl bromide (56, 3.57 g, 30 mmol) and K 2 CO 3  (4.14 g, 30 mmol) were added consecutively to a stirred suspension of octadecylamine 55 (2.69 g, 10 mmol) in MeOH (20 ml) in a bottle with a screwed up stopper which was finally closed. The resulting mixture was stirred at room temperature overnight. The brown suspension was filtered through a SiO 2  layer (1 cm), washed with EtOAc (100 ml), and the filtrate was concentrated to give the amine 24 (3.34 g, 96%) as viscose mass which solidified upon standing. The product is pure enough for further synthesis, however it could be easily purified for analytical purpose by filtration through a SiO 2  (5 cm, elution with a mixture hexane-AcOEt, v/v 15:1). TLC (hexane-EtOAct, 2:2, v/v): R f  0.85. M.p. 43-44° C. (MeOH).  1 H-NMR (CDCl 3 ): 3.45 (d, 2H, J=2.3, NCH 2 C≡); 2.54-2.51 (m, 2H, N C H 2 (CH 2 ) 16 ); 2.22 (t, 1H, J=2.3, □C≡); 1.51-1.44 (m, 2H); 1.27 (br. s, 30H); 0.90 (t, 3H, J=6.5, CH 3 ).  13 C-NMR (CDCl 3 ): 78.91 (HC≡ C ); 72.72 (□C≡); 53.05 (N C H 2 (CH 2 ) 16 ); 42.08 (NCH 2 C≡); 31.90, 29.66, 29.59, 29.55, 29.48, 29.32, 27.45, 27.32, 22.65 (CH 3   C H 2 ); 14.05 (CH 3 ). ESI-MS (calculated mass: 345): 384.4 [M+K] + , 346.4 [M+H] + , 318.3 [M−C 2 H 4 +H] + , 270.3 [M−C 6 H 4 +H] + . 
     4-(Octadecylamino)-4-oxobutanoic acid (58) 
     Powdered succinic anhydride (45, 0.440 g, 4.4 mmol) was added in portion to a stirred soln. of octadecylamine 55 (1.076 g, 4 mmol) in CH 2 Cl 2  (20 ml) at r.t. followed by Et 3 N (0.808 g, 8 mmol). The resulting white suspension was stirred for 3 h until the precipitate was dissolved. The clear colorless soln. was concentrated in vacuo, and the residue was crystallized from acetone resulting in the formation of the amide 58 (1.277 g, 87%) as white crystals. Chromatographic separation of the concentrated mother liquid on silica gel (10 g, CH 2 Cl 2 /MeOH, 1:1, v/v) gave a further amount of the amide 58 (0.088 g, 6%). TLC (silica gel, CH 2 Cl 2 -MeOH, 8:1 v/v): R f 0.64. M.p. 124-125° C.  1 H-NMR (CDCl 3 ): 5.69 (br.s, 1H, NH), 3.31-3.27 (m, 2H, NCH 2 ), 2.73-2.71 (m, 2H, NCH 2 ), 2.56-2.54 (m, 2H, O═CCH 2 ), 1.56-1.51 (m, 2H, NCH 2   CH   2 (CH 2 ) 15 ), 1.31 (br.s, 2H), 1.28 (br.s, 28H), 0.90 (t, 3H, J=6.9, CH 3 ),  13 C-NMR: 173.02 (COO), 170.90 (CON), 40.05 (NCH 2 ), 31.90 (CH 3 CH 2   CH   2 ), 30.75, 30.08, 29.66, 29.63, 29.59, 29.54, 29.49, 29.39, 29.32, 29.21, 26.83 (NCH 2 CH 2   C H 2 ), 22.65 (CH 3   C H 2 ), 14.05 (CH 3 ). ESI-MS (calculated mass: 369): 370.4 [M+H] + . 
     Methyl 4-(octadecylamino)-4-oxobutanoate (59) 
     Dimethyl sulfate (0.454 g, 3.6 mmol) and K 2 CO 3  (1.01 g, 7.4 mmol) were added consecutively to a stirred soln. of the acid 58 (0.680 mg, 1.8 mmol) in acetone (4 ml) at room temperature, and the resulting suspension was heated at 55° C. overnight. The reaction mixture was cooled to room temperature, all solids were filtered off, washed with acetone (5 ml); the filtrate was concentrated, and the residue dissolved in CH 2 Cl 2  (5 ml). The soln. was washed with H 2 O (2×5 ml), dried (Na 2 SO 4 ) and concentrated resulting in the formation of the ester 59 (0.502 mg, 72%) in a form of light-cream crystals. TLC (hexane-AcOEt, 1:1 v/v): R f  0.50. M.p. 86-87° C. (Lit. m.p. 86.5-87.5° C.).  1 H-NMR (CDCl 3 ): 5.60 (br. s, 0.8H, NH); 5.35 (br. s, 0.2H, NH); 3.69 (s, 3H, OCH 3 ); 3.23 (q, 2H, J=6.75, NCH 2 ); 2.68 (t, 2H, J=6.75, COCH 2 ); 2.46 (t, 2H, J=6.75, COCH 2 ); 1.59 (br. s, 2H); 1.54-1.44 (m, 2H); 1.26 (br. s, 28H); 0.88 (t, 3H, J=6.8, CH 2   CH   3 ).  13 C-NMR (CDCl 3 ): 173.54 (COO), 171.28 (CON), 51.79 (OCH 3 ), 39.72 (NCH 2 ), 31.92, 31.14 (NCO C H 2 ), 29.69, 29.65, 29.59, 29.54, 29.48, 29.34, 29.28, 26.88 (NCH 2 CH 2   C H 2 ), 22.67 (CH 3 CH 2 ), 14.08 (CH 3 ). ESI-MS (calculated mass: 383): 406.3 [M+Na] + , 384.4 [M+H] + . 
     1-Octadecylpyrrolidine (61) 
     Powdered LiAlH 4  (80 mg, 2.08 mmol) was added portions-wise to a pre-cooled (ice-bath) soln. of the ester 59 (100 mg, 0.26 mmol) in THF (3 ml), and the resulting suspension was stirred at room temperature over a period of 5 h. The resulting grey suspension was cooled on an ice-bath, diluted with Et 2 O (6 ml), and MeOH (1 ml) was added drop-wise. The resulting mixture was stirred for 30 min until the formation of crystalline precipitate was completed. Solids were separated, washed with Et 2 O (2×5 ml), and the filtrate was concentrated in vacuo resulting in the formation of the pyrrolidine derivative 61 (60 mg, 71%) as a yellowish solid mass. TLC (CH 2 Cl 2 -MeOH, 10:1 v/v): R f  0.46. M.p. 25-27° C. (Lit. m.p. 26-27° C.).  1 H-NMR (CDCl 3 ): 2.49 (br. s, 4H, 2 N( CH   2 CH 2 ) 2 ); 2.43-2.40 (m, 2H, N CH   2 (CH 2 ) 16 ); 1.78 (br. s, 4H, N(CH 2   CH   2 ) 2 ); 1.54-1.46 (m, 2H, NCH 2   CH   2 (CH 2 ) 15 ); 1.30-1.26 (m, 30H); 0.89 (t, 3H, J=6.8, CH 3 ).  13 C-NMR (CDCl 3 ): 56.72 (NCH 2 ( C H 2 ) 16 ), 54.21 (N( C H 2 CH 2 ) 2 ), 31.89 (CH 3 CH 2   C H 2 ), 29.66, 29.59, 29.32, 29.02, 27.72, 23.38 (N(CH 2 CH 2 ) 2 ), 22.65 (CH 3   C H 2 ), 14.05 (CH 3 ). ESI-MS (calculated mass: 323): 324.4 [M+H] + , 296.3 [M−C 2 H 4 +H] + . 
     4-Hydroxy-N-octadecylbutanamide (62) 
     Powdered LiAlH 4  (182 mg, 4.8 mmol) was added in portions during 3 min to a pre-cooled (ice-bath) stirred suspension of the acid 58 (222 mg, 0.6 mmol), dissolved in THF (10 ml). After 15 min the cooling bath was removed, and stirring was continued at ambient temperature for another 5 h. The reaction mixture was cooled on an ice-bath, diluted with Et 2 O (20 ml), and MeOH (1 ml), followed by H 2 O (1 ml) were added drop-wise until the gas evolution had ceased, and the violet suspension turned into a white precipitate. It was filtered off, washed with Et 2 O; filtrates were concentrated, and the residue was separated on a TLC plate (silica gel, eluted with a mixture CH 2 Cl 2 /MeOH, 8:1, v/v) to give the amide 62 (175 mg, 82%) as colorless crystals. TLC (CH 2 Cl 2 -MeOH, 9:1 v/v): R f 0.42. M.p. 86-87° C. (Lit. m.p. 86-87° C.).  1 H-NMR (CDCl 3 ): 5.73 (br.s, 1H, NH), 3.72-3.70 (m, 2H, CH 2 O), 3.25 (q, 2H, J=6.7, NCH 2 ), 2.37-2.34 (m, 2H, CH 2 C═O), 1.81 (quint, 2H, J=6.2,  CH   2 CH 2 C═O), 1.51 (quint., 2H, J=6.8, NCH 2   CH   2 ), 1.27 (br.s, 30H), 0.89 (t, 3H, J=6.8, CH 3 ).  13 C-NMR (CDCl 3 ): 173.03 (C═O), 62.37 (COH), 39.71 (N C H 2 ), 34.06 (COCH 2 ), 31.89, 29.66, 29.62, 29.57, 29.52, 29.32, 29.26, 28.17 (NCH 2   C H 2 ), 26.91 (N(CH 2 ) 2   C H 2 ), 22.64 (CH 3   C H 2 ), 14.06 (CH 3 ). ESI-MS (calculated mass: 355): 356.3 [M+H] + . 
     4-(Octadecylamino)butan-1-ol (60) 
     Powdered LiAlH 4  (340 mg, 8 mmol) was added in portions during 10 min to a pre-cooled (ice-bath) stirred suspension of the acid 58 (371 mg, 1 mmol) in Et 2 O (20 ml). After 5 min the cooling bath was removed, and stirring was continued at ambient temperature for another 1 h and than at 35° C. overnight. The reaction mixture was cooled on an ice-bath, diluted with Et 2 O (20 ml), and H 2 O (0.5 ml), was added drop-wise until the gas evolution had ceased, and the gray suspension turned into a white precipitate. It was filtered off and washed with Et 2 O. The filtrates were concentrated, and the white residue was separated on a TLC plate (silica gel, eluted with a mixture CH 2 Cl 2 /MeOH, 8:1, v/v) to give butanol 60 (288 mg, 84%) as colorless crystals followed by the amide 62 (22 mg, 6%). TLC (CH 2 Cl 2 -Et 2 O, 1:1 v/v): R f  0.42. M.p. 68-69° C. (Lit. m.p. 68-70° C.).  1 H-NMR (CDCl 3 ): 3.60-3-58 (m, 2H, CH 2 O); 2.67-2.65 (m, 2H, NCH 2 ); 2.63-2.60 (m, 2H, NCH 2 ); 1.72-1.67 (m, 2H, CH 2 ); 1.65-1.58 (m, 3H, CH 2 , OH); 1.52-1.48 (m, 2H, CH 2 ), 1.26 (br. s, 30H); 0.88 (t, 3H, J=6.8, CH 3 ).  13 C-NMR (CDCl 3 ): 61.53 (COH), 47.90, 47.80 (NCH 2 ), 31.90 (CH 3 CH 2   C H 2 ), 29.68, 29.63, 29.60, 29.53, 29.44, 29.33, 29.07, 26.80, 25.96 (NCH 2 CH 2 ), 23.66 (OCH 2 CH 2   C H 2 ), 22.65 (CH 3   C H 2 ), 14.06 (CH 3 ). ESI-MS (calculated mass: 341): 270.4 [C 18 NH 3 ] + , 314.4 [M−28+H] + , 342.7 [M+H] + . 
     4-[Octadecyl(prop-2-ynyl)amino]butan-1-ol (63) 
     Propargyl bromide (56, 21 mg, 0.18 mmol) was added to a stirred suspension of K 2 CO 3  (25 mg, 0.18 mmol) of a soln. of the amine 60 (30 mg, 0.09 mmol) in MeOH (1 ml) at room temperature. The resulting mixture was stirred overnight. The resulting precipitate was filtered off, washed with EtOAc (3 ml), the filtrate was concentrated in vacuo, and the propargylamine 63 was isolated by chromatography (silica gel, CH 2 Cl 2 /Et 2 O, 1:1, v/v) as colorless crystals (20 mg, 61%). TLC (CH 2 Cl 2 /Et 2 O, 1:1, v/v): R f  0.32. M.p. 33-34° C.  1 H-NMR (CDCl 3 ): 3.59 (br.s, 2H, CH 2 O); 3.48 (br. s, 2H, CH 2 C≡); 2.61-2.59 (m, 2H, NCH 2 ); 2.58-2.55 (m, 2H, NCH 2 (CH 2(15) ; 2.21 (br. s, 1□, □C≡); 1.66 (br.s, 4H,  CH   2   CH   2 CH 2 O); 1.56-1.46 (m, 2H, NCH 2   CH   2 ); 1.26 (br. s, 30H); 0.88 (t, 3H, J=6.7, CH 3 ).  13 C-NMR (CDCl 3 ): 73.80 (HC≡), 62.63 (CH 2 OH), 53.87, 53.61 (NCH 2 ), 40.94 (N C H 2 C≡), 31.90, 30.32 (OCH 2   C H 2 ), 29.66, 29.62, 29.59, 29.53, 29.43, 29.32, 27.40, 26.83, 25.25 (OCH 2 CH 2   C H 2 ), 22.65 (CH 3   C H 2 ), 14.06 (CH 3 ).  13 C-NMR (C 6 D 6 ): 78.88 (HC≡ C ), 73.97 (HC≡), 63.25 (CH 2 OH), 54.65, 54.49 (NCH 2 ), 41.87 (N C H 2 C≡), 32.93, 32.76 (OCH 2   C H 2 ), 32.79, 30.72, 30.58, 30.41, 28.40, 28.29, 26.00, 23.70 (CH 3 CH 2 ), 14.94 (CH 3 ). ESI-MS (calculated mass: 379): 308.4 [M−C 4 H 8 O+H] + , 362.4 [M−H 2 O+H] + , 380.4 [M+H] + . 
     5′-O-(4,4′-Dimethoxytrityl)-2′-deoxythymidine (69) 
     2′-Deoxythymidine (7, 0.726 g, 3.0 mmol) was added portions-wise at room temperature to a yellowish clear solution of 4,4′-dimethoxytrityl chloride (1.220 g, 3.6 mmol) in pyridine (15 ml), and the resulting orange mixture was stirred overnight. It was diluted with EtOAc (80 ml), washed with H 2 O (3×25 ml), dried (Na 2 SO 4 ) and concentrated in vacuo resulting in the formation of an orange viscose mass (2.0 g). The product was isolated by chromatography on silica gel (120 ml), eluted with a gradient mixture of hexane-EtOAc, 2:1 to 0:1, v/v) as a light-yellow oil (1.52 g, 93.8%), which solidified on standing at room temperature. TLC (silica gel, EtOAc): R f  0.5. M.p. 123-125° C. (Lit. m.p. 122-124° C.).  1 H-NMR (CDCl 3 ): 9.67 (br. s, 1H, NH), 7.60 (s, 1H, C(6)H), 7.41 (d, 2H, J=7.9, C—CH ar ), 7.31-7.28 (m, 6H), 7.21 (t, 1H, J=7.2, CH ar ), 6.83 (d, 4H, J=8.7, 4 CH ar ), 6.45-6.41 (m, 1H, C(1′)H), 4.58-4.56 (m, 1H, C(3′)H), 4.11-4.07 (m, 1H, C(4′)H), 3.77 (s, 6H, 2OCH 3 ), 3.47-3.35 (q AB , 2H, H A =3.46, H B =3.37, J AB =10.5, J AX =J BX =2.6, C(5′)H 2 ), 2.47-2.43 (m, 1H, C(2′)H 2 ), 2.33-2.28 (m, 1H, C(2′)H 2 ), 1.47 (s, 3H, C(7)H 3 ).  13 C-NMR (CDCl 3 ): 164.15 (C4), 158.69 ( C   Ar OCH 3 ), 150.72 (C2), 144.38, 135.78 (C6), 135.48, 135.42, 130.08, 128.14, 127.95, 127.08, 113.27, 111.24 (C5), 86.88 (CH 2 O C ), 86.37 (C4′), 84.85 (C1′), 72.38 (C3′), 63.67 (C5′), 55.21 (OCH 3 ), 40.94 (C2′), 11.78 (C7) ( 1 H and  13 C-NMR spectra are in a good agreement to those reported). ESI-MS (calculated mass: 544): 567.3 [M+Na] + , 583.3 [M+K] + , 1111.5 [2M+Na] + . 
     5′-O-(4,4′-Dimethoxytrityl)-3′-O-(t-butyldimethylsilyl)-2′-deoxythymidine (64) 
     Imidazole (0.52 g, 7.6 mmol) was dissolved in a soln. of 5′-O-(4,4′-dimethoxytrityl)-2′-deoxythymidine (69, 1.36 g, 2.5 mmol) in DMF (20 ml) at room temperature. The resulting mixture was cooled in an ice-bath and a soln. of tert-butyldimethylsilyl chloride (0.57 g, 3.8 mmol) in DMF (3 ml) was added drop-wise during 5 min. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature overnight. Methanol (10 ml) was added to destroy an excess of tert-butyldimethylsilyl chloride, and the resulting mixture was stirred for 30 min, diluted with EtOAc (200 ml), washed consecutively with aq.NaHCO 3 , and H 2 O, dried (Na 2 SO 4 ) and concentrated to give crude 64 (1.95 g) as a colorless viscous oil. It was purified by chromatography on silica gel (200 g), eluted with a gradient mixture of hexane-EtOAc-Et 3 N, (15:15:1, v/v), resulting pure 64 (1.45 g, 88%) as a colorless viscose oil which turned to a solid foam on drying in high vacuum. TLC (silica gel, hexane-EtOAc, 2:1, v/v): R f  0.29. M.p. 87-88° C.  1 H-NMR (CDCl 3 ): 8.46 (s, 1H, NH), 7.64 (s, 1H, C(6)H), 7.43 (d, 2H, J=7.9, CH ar ), 7.33-7.29 (m, 6H, C ar ), 7.27-7.24 (m, 1H, CH ar ), 6.85 (d, 4H, J=8.8, CH ar ), 6.37-6.34 (m, 1H, C(1′)H), 4.54-4.52 (m, 1H, C(3′)H), 3.98-3.95 (m, 1H, C(4′)H), 3.79 (s, 6H, 2OCH 3 ), 3.50-3.24 (q AB , 2H, H A =3.46, H B =3.27, J AB =10.6, J AX =J BX =2.8, C(5′)H 2 ), 2.37-2.32 (m, 1H, C(2′)H 2 ), 2.25-2.21 (m, 1H, C(2′)H 2 ), 1.51 (s, 3H, C(7)H 3 ), 0.84 (s, 9H, SiC(CH 3 ) 3 ), 0.03 (s, 3H, SiCH 3 ), −0.03 (s, 3H, SiCH 3 ).  13 C-NMR (CDCl 3 ): 163.61 (C4), 158.76 (CH 3 O C   ar ), 150.18 (C2), 144.35, 135.58 (C6), 135.50, 135.46, 130.06, 130.04, 128.14, 127.95, 127.11, 113.28, 113.27, 110.98 (C5), 86.84 (CH 2 O C ), 86.80 (C4′), 84.90 (C1′), 72.11 (C3′), 62.94 (C5′), 55.23 (OCH 3 ), 41.54 (C2′), 25.70 (SiC C H 3 ), 17.92 (SiC), 11.86 (C7), −4.69,−4.88 (SiCH 3 ) (1H and  13 C-NMR spectra are in a good agreement to those reported). ESI-MS (calculated mass: 658): δ81.4 [M+Na] + , 697.4 [M+K] + . 
     2′-Deoxy-3-[4-(dioctadecylamino)but-2-ynyl]thymidine (65) 
     2′-Deoxythymidine 31 (32 mg, 0.132 mmol), DMSO (0.1 ml) and K 2 CO 3  (36 mg, 0.264 mmol) were consecutively added to a stirred solution of chloride 51 (80 mg, 0.132 mmol) in THF (0.5 ml) at room temperature in a bottle with a screwed up stopper which was finally closed and the reaction mixture was stirred at 70° C. during 48 h. The resulting brown mixture was cooled to room temperature, treated with H 2 O (4 ml) and Et 2 O (4 ml), organic phase was separated and water phase was extracted with Et 2 O (4 ml). Combined organic phases were washed with H 2 O, dried (Na 2 SO 4 ), concentrated and the product 65 was isolated by preparative TLC (silica gel, eluted with EtOAc) to give 49 mg (46%) of yellow oil. TLC (EtOAc): R f  0.33. M.p. 49-50° C.  1 H-NMR (CDCl 3 ): 7.49 (s, 1H, C(6)H); 6.24 (t, J=6.7, 1H, C(1′)H); 4.72 (s, 2H, CONCH 2 C—), 4.58-4.56 (m, C(3′)H), 4.00-3.98 (m, 1H, C(4′)H), 3.92-3.83 (q AB , 2H, H A =3.91, H B =3.84, J AB =11.8, J AX =J BX =2.8, C(5′)H), 3.33 (s, 2H, CH 2 N CH   2 C≡), 2.47-2.41 (m, 4H, N(CH 2 ) 2 ), 2.34-2.32 (m, 2H; C(2′)H 2 ), 1.99 (s, 3H, C(7)H 3 ), 1.44-1.40 (m, 4H), 1.27 (br. s, 60H); 0.89 (t, 6H, J=6.9, 2 CH 2   CH   3 ).  13 C-NMR (CDCl 3 ): 162.36 (C4), 150.24 (C2), 134.92 (C6), 110.30 (C5), 87.26 (C4′), 86.86 (C1′), 71.43 (C3′), 62.33 (C5′), 53.68 (N C H 2 (CH 2 ) 16 ), 42.25 (N C H 2 C≡), 40.25 (CH C H 2 CH), 31.90 (CH 3 CH 2   C H 2 ), 30.74 (CON C H 2 ), 29.68, 29.63, 29.55, 29.33, 27.48 (NCH 2   C H 2 ), 27.07 (N(CH 2 ) 2   C H 2 ), 22.65 (CH 3   C H 2 ), 14.06 ( C H 3 CH 2 ), 13.22 (C7).  13 C-NMR (CD 3 OD): 164.36 (C4), 151.64 (C2), 136.73 (C6), 110.69 (C5), 89.06 (C4′), 87.28 (C1′), 81.09 (C≡), 77.77 (C≡), 72.11 (C3′), 62.77 (C5′), 54.82 (N C H 2 (CH 2 ) 16 ), 42.76 (N C H 2 C≡), 41.49 (CH C H 2 CH), 33.06 (CH 3 CH 2   C H 2 ), 31.52 (CON C H 2 ), 30.75, 30.66, 30.64, 30.51, 30.44, 28.53 (NCH 2   C H 2 ), 27.81 (N(CH 2 ) 2   C H 2 ), 23.71 (CH 3   C H 2 ), 14.41 ( C H 3 CH 2 ), 13.13 (C7). ESI-MS (calculated mass: 813): 814.7 [M+H] + . 
     5′-O-(4,4′-Dimethoxytrityl)-2′-deoxy-3-[4-(dioctadecylamino)but-2-ynyl]thymidine (66) from 65 
     A solution of 4,4′-dimethoxytrityl chloride (13.4 mg, 0.039 mmol) in pyridine (0.1 ml) was added to a pre-cooled (ice-bath) solution of butynylthymidine 65 (28 mg, 0.034 mmol), and the resulting orange solution was stirred at ambient temperature 48 h. The reaction mixture was diluted with CH 2 Cl 2  (2 ml), concentrated in vacuum (0.05 Torr) and the residue was separated on an analytical TLC plate (20×20 cm, silica gel, eluted with a mixture CH 2 Cl 2 -EtOAc-Et 3 N, 40:9:1, v/v/v) to give in the 3-d fraction protected thymidine 66 (28 mg, 73%) as yellowish oil. TLC (silica gel, CH 2 Cl 2 -EtOAc-Et 3 N, v/v/v, 40:9:1): R f  0.44.  1 H-NMR (CDCl 3 ): 7.55 (s, 1H, C(6)H); 7.42-7.41 (m, 2H, CH ar ), 7.32-7.30 (m, 6H, CH ar ), 7.26-7.24 (m, 1H, CH ar ), 6.86-6.84 (m, 2H, CH ar ), 6.43 (t, J=6.6, 1H, C(1′)H); 4.74 (s, 2H, CONCH 2 C—), 4.58-4.55 (m, C(3′)H), 4.05-4.03 (m, 1H, C(4′)H), 3.81 (s, 6H, 2OCH 3 ), 3.52-3.39 (q AB , 2H, H A =3.45, H B =3.40, J AB =10.5, J AX =3.3, J BX =3.1, C(5′)H 2 ), 3.36 (s, 2H, CH 2 N CH   2 C≡), 2.47-2.41 (m, 4H, N(CH 2 ) 2 ), 2.34-2.29 (m, 2H; NCH CH   2 ), 1.57 (s, 3H, C(7)H 3 ), 1.46-1.40 (m, 4H), 1.27 (br. s, 60H); 0.89 (t, 6H, J=6.9, 2 CH 2   CH   3 ).  13 C-NMR (CDCl 3 ): 162.46 (C4), 158.78 (COCH 3 ), 150.21 (C2), 144.32 (OC C   ar ), 135.40 (OC C   ar ), 133.69 (C6), 130.06 (CH ar ), 128.12 (CH ar ), 127.14 (CH ar ), 113.31 (CH ar ), 110.38 (C5), 86.99 (O C C ar ), 85.84 (C4′), 85.30 (C1′), 72.36 (C3′), 63.43 (C5′), 55.23 (N C H 2 (CH 2 ) 16 ), 53.72 (OCH 3 ), 42.35 (N C H 2 C≡), 41.03 (C2′), 31.90 (CH 3 CH 2 CH 2 ), 30.76 (CON C H 2 ), 29.69, 29.65, 29.60, 29.33, 27.52 (NCH 2   C H 2 ), 27.41, 22.66 (CH 3 CH 2 ), 14.07 ( C H 3 CH 2 ), 12.60 (C7).  13 C-NMR (C 6 D 6 ): 161.89 (C4), 159.03 ( C OCH 3 ), 150.11 (C2), 144.88 (OC C   ar ), 135.63 (OC C   ar ), 133.40 (C6), 130.21 (CH ar ), 128.30 (CH ar ), 126.99 (CH ar ), 113.30 (CH ar ), 109.93 (C5), 86.87 (O C C ar ), 85.89 (C4′), 85.45 (C1′), 79.78 (C≡), 77.59 (C≡), 71.90 (C3′), 63.64 (C5′), 54.48 (N C H 2 (CH 2 ) 16 ), 53.70 (OCH 3 ), 42.12 (N C H 2 C≡), 40.72 (CH C H 2 CH), 31.96 (CH 3 CH 2   C H 2 ), 30.64 (CON C H 2 ), 29.84, 29.75, 29.72, 29.44, 27.75 (NCH 2   C H 2 ), 27.49, 22.72 (CH 3   C H 2 ), 13.96 (CH 3   C H 2 ), 12.56 (C7). ESI-MS (calculated mass: 1115): 1116.9 [M+H] + . 
     5′-O-(4,4′-Dimethoxytrityl)-2′-deoxy-3-[4-(dioctadecylamino)but-2-ynyl]thymidine (66) from 69 
     A clear soln. of compounds 69 (72 mg, 0.132 mmol) and 51 (80 mg, 0.132 mmol) in THF (0.5 ml) was diluted with DMSO (0.2 ml); then, K 2 CO 3  (36 mg, 0.264 mmol) was added, and the resulting mixture was stirred at 70° C. during 2 days. The resulting brownish reaction mixture was cooled and treated with H 2 O (5 ml), extracted with Et 2 O (2×5 ml), washed with H 2 O (2×2 ml), dried (Na 2 SO 4 ) and evaporated. The crude product was purified by column chromatography (silica gel 60, gradient elution with a mixture of CH 2 Cl 2 -MeOH, 500-30:1, v/v) resulting in isolation of the product 66 (75 mg, 51%) and starting thymidine derivative 69 (28 mg, 39%) (in order of their elution from the column). TLC (silica gel, CH 2 Cl 2 —AcOEt-Et 3 N, 40:9:1, v/v/v): R f  0.46.  1 H NMR (CDCl 3 , 500 MHz) δ: 7.55 (s, 1H, C(6)H), 7.41 (d, 2H, J=7.65, CH ar ), 7.32-7.30 (m, 6H, 6 CH ar ), 7.25 (t, 1H, J=7.3, CH ar ), 6.85 (d, 4H, J=8.55, 4 CH ar ), 6.43 (t, 1H, J=6.6, C(1′)H), 4.77-4.70 (m, 2H, ═CCH 2 ), 4.58-4.54 (m, 1H, C(3′)H), 4.05-4.02 (m, 1H, C(4′)H), 3.81 (s, 6H, 2OCH 3 ), 3.52-3.38 (q AB , 2H, H A =3.50, H B =3.40, J AB =10.5, J AX =J BX =3.3, C(5′)H 2 ), 3.43 (s, 1H, OH), 3.36 (s, 2H, ≡CCH 2 ), 2.47-2.40 (m, 5H, CH 2 NCH 2 , C(2′) H H), 2.35-2.28 (m, 1H, C(2′)H H ), 1.57 (s, 3H, C(7)H 3 ), 1.47-1.40 (m, 4H, 2 NCH 2   CH   2 (CH 2 ) 15 ), 1.28 (br.s, 60H), 0.90 (t, 3H, J=6.8, CH 2   CH   3 ). 
     5′-O-(4,4′-Dimethoxytrityl)-3′-O-(t-butyldimethylsilyl)-2′-deoxy-3-[4-(dioctadecylamino)but-2-ynyl]thymidine (70) 
     A solution of compounds 64 (329 mg, 0.50 mmol) and 51 (304 mg, 0.50 mmol) in THF (4.0 ml) was diluted with DMF (5 ml); K 2 CO 3  (276 mg, 2.0 mmol) and dibenzo-[18]-crown-6 (30 mg, 0.08 mmol) were added, and the resulting mixture was stirred at 60° C. for 2 days. Brown cooled reaction mixture was treated with Et 2 O (100 ml), washed with H 2 O (4×15 ml), brine, dried (Na 2 SO 4 ) and concentrated to give the crude product 70 (589 mg, 95%). TLC (silica gel, hexane-CH 2 Cl 2 -acetone-Et 3 N, 20:5:5:1, v/v/v/v): R f  0.75.  1 H NMR (CDCl 3 , 500 MHz) δ: 7.65 (s, 1H, C(6)H), 7.43 (d, 2H, J=7.65, CH as), 7.33-7.29 (m, 6H, 6 CH ar ), 7.25 (t, 1H, J=7.3, CH ar ), 6.85 (d, 4H, J=8.55, 4 CH ar ), 6.40 (t, 1H, J=6.5, C(1′)H), 4.79-4.71 (m, 2H, ═CCH 2 ), 4.53-4.51 (m, 1H, C(3′)H), 4.00-3.98 (m, 1H, C(4′)H), 3.81 (s, 6H, 2O CH   3 ), 3.50-3.27 (q AB , 2H, H A =3.49, H B =3.29, J AB =10.6, J AX =J BX =2.6, C(5′)H 2 ), 3.37 (s, 2H, —CCH 2 ), 2.45-2.42 (m, 4H, CH 2 NCH 2 ), 2.38-2.34 (m, 1H, C(2′)H 2 ), 2.24-2.18 (m, 1H, C(2′)H 2 ), 1.57 (s, 3H, C(7)H 3 ), 1.45-1.39 (m, 4H, 2 NCH 2   CH   2 (CH 2 ) 15 ), 1.28 (br.s, 60H), 0.90 (t, 3H, J=6.5, CH 2   CH   3 ), 0.86 (s, 9H, SiC(CH 3 ) 3 ), 0.04 (s, 3H, SiCH 3 ), −0.02 (s, 3H, SiCH 3 ).  13 C NMR (CDCl 3 , 125 MHz) δ: 162.52 (C(4)), 158.75 (2 OC ar ), 150.21 (C(2)), 144.36 (OC C   ar ), 135.49 (2 OC C   ar ), 133.73 (C(6)), 130.06, 130.05 (4 CH ar ), 128.14 (2 CH ar ), 127.93 (2 CH ar ), 127.09 (CH ar ), 113.27, 113.26 (4 CH ar ), 110.22 (C(5)), 86.83 (O C C ar ), 86.74 (C(1′)), 85.58 (C(4′)), 78.94 (≡C), 77.56 (≡C), 72.06 (C(3′)), 62.92 (C(5′)), 55.22 (2OCH 3 ), 53.74 ( C H 2 N C H 2 ), 42.42 (CH 2 C≡), 41.64 (C(2′)), 31.91 ( C H 2 C≡), 30.71, 29.69, 29.64, 29.33, 27.52, 25.69 (C( C H 3 ) 3 ), 22.66 (2  C H 2 CH 3 ), 17.90 (SiC), 14.07 (2 CH 2   C H 3 ), 12.62 (C(7)), −4.69, −4.89 (2 SiCH 3 ). ESI-MS (calculated mass: 1229): 1230.9 [M+H] + . 
     5′-O-(4,4′-Dimethoxytrityl)-2′-deoxy-3-[4-(dioctadecylamino)but-2-ynyl]thymidine (66) from 70 
     A solution of compd. 70 (192 mg, 0.156 mmol) in THF (0.4 ml) was diluted with H 2 O (0.05 ml), and a soln. of tetrabutylammonium fluoride (0.17 ml, 0.156 mmol) in THF was added in one portion. The resulting clear reaction mixture was stirred at 50° C. overnight. It was cooled, diluted with CH 2 Cl 2  (10 ml), the aqueous phase was separated, the solution was dried (Na 2 SO 4 ) and concentrated. The pure product 66 was isolated by column chromatography on silica gel (eluted with a mixture hexane-CH 2 Cl 2 -acetone-Et 3 N, 40:10:5:1 v/v/v/v) as beige mass (135 mg, 78%). TLC (silica gel, hexane-EtOAc, v/v, 2:1): R f  0.69. 
     5′-O-(4,4′-Dimethoxytrityl)-2′-deoxy-3-[4-(dioctadecylamino)but-2-ynyl]thymidine 2-Cyanoethyl-N,N-diisopropylphosphoramidite (71) 
     Hünig&#39;s base (47 mg, 0.36 mmol) was added to a soln. of compd. 66 (135 mg, 0.12 mmol) in CH 2 Cl 2  (3 ml) under Argon atmosphere; the resulting mixture was cooled in an ice-bath, (chloro)(2-cyanoethoxy)(diisopropylamino)phosphine was added, and the reaction mixture was stirred for 10 min with cooling and 1 h at ambient temperature. The resulting light yellow clear solution was diluted with CH 2 Cl 2  (30 ml), washed with a cold aq. NaHCO 3  solution, brine, dried (Na 2 SO 4 ) and concentrated. The resulting yellowish oil was chromatographed on silica gel (eluted with CH 2 Cl 2 -acetone-Et 3 N, 85:14:1, v/v/v); the product was obtained from the first 4 fractions upon evaporation as a colorless oil (142 mg, 90%) as a mixture of non-assigned R p  and Sp diastereoisomers; m.p.—10-8° C.  1 H NMR (CDCl 3 , 500 MHz, mixture of diastereoisomers X and Y in a ratio of 2.6:1) δ: 7.64 (s, 0.72H, C(6)H, X), 7.59 (s, 0.28H, C(6)H, Y), 7.43-7.41 (m, 2H, CH ar , X, Y), 7.33-7.28 (m, 6H, 6 CH ar , X, Y), 7.27-7.23 (m, 1H, CH, X, Y), 6.86-6.83 (m, 4H, 4 CH a, X, Y), 6.48-6.46 (m, 0.28H, C(1′)H, X), 6.46-6.43 (m, 0.72H, C(1′)H, Y), 4.79-4.71 (m, 2H, ═CCH 2 , X, Y), 4.69-4.63 (m, 1H, C(3′)H, X, Y), 4.20-4.18 (m, 0.72H, C(4′)H, X), 4.17-4.15 (m, 0.28H, C(4′)H, Y), 3.81 (s, 4.3H, 2OCH 3 , X), 3.80 (s, 1.68H, 2 OCH   3 , Y), 3.69-3.55 (m, 4H, POCH 2 , 2 NCH, X, Y), 3.56-3.33 (q AB , 0.72H, H A =3.55, H B =3.34, J AB =10.6, J AX =J BX =2.6, C(5′)H 2 , X), 3.51-3.31 (q AB , 0.28H, H A =3.49, H B =3.33, J AB =10.6, J AX =J BX =2.6, C(5′)H 2 , Y), 3.36 (br.s, 2H, ═CCH 2 , X, Y), 2.65-2.61 (m, 2H, CH 2 CN, X, Y), 2.60-2.55 (m, 0.28H, C(2′)H 2 , Y), 2.53-2.48 (m, 0.72H, C(2′)H 2 , X), 2.45-2.41 (m, 4H, CH 2 NCH 2 , X, Y), 2.35-2.29 (m, 1H, C(2′)H 2 , X, Y), 1.51 (s, 3H, C(7)H 3 , X, Y), 1.45-1.39 (m, 4H, 2 NCH 2   CH   2 (CH 2 ) 5 , X, Y), 1.28 (br.s, 60H), 1.20-1.18 (m, 12H, 2 CH(CH 3 ) 2 , X, Y), 0.91-0.88 (m, 3H, CH 2   CH   3 , X, Y).  31 P NMR (CDCl 3 , 202.5 MHz): 149.17, 148.54. 
     5′-O-(4,4′-Dimethoxytrityl)-3′-O-(t-butyldimethylsilyl)-2′-deoxy-3-[3-(dioctadecylamino)propyl]thymidine (67) 
     Powdered triphenylphosphine (48 mg, 0.182 mmol) was added in one portion to a stirred clear soln. of 64 (80 mg, 0.121 mmol) and alcohol 42 (70 mg, 0.121 mmol) in benzene (2 ml) at room temperature. The mixture was stirred for 5 min until all the precipitate had dissolved. Then, the mixture was cooled on an ice-bath, and diisopropyl azodicarboxylate (37 mg, 0.182 mmol) in benzene (0.5 ml) was added drop-wise within 1 min. After 5 min the cooling bath was removed, and the reaction mixture was stirred at ambient temperature overnight. The solvent was removed under vacuo, and the light-yellow solid residue was chromatographed over silica gel (eluted with a mixture of hexane-EtOAc-Et 3 N, 12:6:1) yielding compd. 67 (71 mg, 48%) as a viscous yellowish mass. TLC (silica gel, hexane-AcOEt-Et 3 N, 120:60:1, v/v/v): R f  0.53.  1 H-NMR (CDCl 3 ): 7.61 (s, 1H, C(6)H), 7.41 (d, 2H, J=7.65, CH ar ), 7.32-7.29 (m, 6H, 6 CH ar ), 7.23 (t, 1H, J=7.3, CH ar ), 6.83 (d, 4H, J=8.55, 4 CH ar ), 6.39-6.37 (m, 1H, C(1′)H), 4.51-4.49 (m, 1H, C(3′)H), 3.97-3.92 (m, 3H, C(4′)H, CON CH   2 ), 3.79 (s, 6H, 2O CH   3 ), 3.48-3.26 (q AB , 2H, H A =3.46, H B =3.27, J AB =10.6, J AX =J BX =2.6, C(5′)H 2 ), 2.54-2.51 (m, 2H, N CH   2 (CH 2 ) 2 N), 2.42-2.39 (m, 4H, 2 N CH   2 (CH 2 ) 16 ), 2.36-2.31 (m, 1H, C(2′)H 2 ), 2.21-2.17 (m, 1H, C(2′)H 2 ), 1.80-1.76 (m, 2H, NCH 2   CH 2   CH 2 N), 1.55 (s, 3H, C(7)H 3 ), 1.45-1.39 (m, 4H, 2 NCH 2   CH   2 (CH 2 ) 15 ), 1.26 (br.s, 60H), 0.88 (t, 3H, J=6.5, CH 2   CH   3 ), 0.84 (s, 9H, SiC(CH 3 ) 3 ), 0.03 (s, 3H, SiCH 3 ), −0.03 (s, 3H, SiCH 3 ).  13 C-NMR (CDCl 3 ): 163.40 (C4), 158.70 (CH 3 OC ar ), 150.79 (C2), 144.36 (OC C   ar ), 135.50 (C6), 133.34 (OC C   ar ), 130.03 (OCC═ C H a r   ), 128.11 (CH ar ), 127.91 (CH ar ), 127.04 (CH ar ), 113.22 (CH 3 OC C H ar ), 110.11 (C5), 86.76 (C4′), 86.62 (C1′), 85.41 (CH 2 O C ), 72.03 (C3′), 62.89 (C5′), 55.18 (OCH 3 ), 53.83 (N C H 2 (CH 2 ) 16 ), 51.55 (N C H 2 (CH 2 ) 2 N), 41.58 (C2′), 40.04 (CON C H 2 ), 31.88 (CH 3 CH 2 CH 2 ), 29.66 ((CH 2 ) 11 ), 29.31 (N(CH 2 ) 3 CH 2 ), 27.58 (N(CH 2 ) 2 CH 2 CH 2 ), 26.95 (NCH 2    C H 2 (CH 2 ) 15 ), 25.66 (SiC C H 3 ), 24.84 (NCH 2   C H 2 CH 2 N), 22.64 (CH 3   C H 2 ), 17.87 (SiC), 14.04 ( C H 3 CH 2 ), 12.67 (C7), −4.72 (SiCH 3 ), −4.94 (SiCH 3 ). ESI-MS (calculated mass: 1219): 522.7 [(C 18 ) 2 NH 2 ] + , 1221.1 [M+H] + . 
     5′-O-(4,4′-Dimethoxytrityl)-2′-deoxy-3-[3-(dioctadecylamino)propyl]thymidine (68) 
     A solution of tetrabutylammonium fluoride (0.05 ml, 1M in THF) was added to a solution of thymidine 67 (65 mg, 0.05 mmol) and H 2 O (20 mg, 1 mmol) in THF (0.1 ml) at room temperature and the resulting mixture was stirred at 50° C. overnight. The solvent was removed, the residue was dissolved in CH 2 Cl 2  (1 ml) and filtered through SiO 2  layer (2 cm), washed consecutively with CH 2 Cl 2  (40 ml), CH 2 Cl 2 —AcOEt (10:1, v/v, 40 ml), EtOAc (40 ml) yielding deprotected thymidine 68 (54 mg, 90%) from the 3-d fraction as a colorless glassy mass. TLC (silica gel, EtOAc): R f 0.4.  1 H-NMR (CDCl 3 ): 7.55 (s, 1H, C(6)H), 7.41 (d, 2H, J=7.65, CH ar ), 7.32-7.29 (m, 6H, 6 CH ar ), 7.24 (t, 1H, J=7.3, CH ar ), 6.84 (d, 4H, J=8.55, 4 CH ar ), 6.45-6.43 (m, 1H, C(1′)H), 4.57-4.54 (m, 1H, C(3′)H), 4.06-4.03 (m, 1H, C(4′)H), 3.98-3.90 (m, 2H, CON CH   2 ), 3.80 (s, 6H, 2 O CH   3 ), 3.50-3.37 (q AB , 2H, H A =3.49, H B =3.39, J AB =10.5, J AX =J BX =2.9, C(5′)H 2 ), 2.53-2.50 (m, 2H, N CH   2 (CH 2 ) 2 N), 2.44-2.39 (m, 5H, 2 N CH   2 (CH 2 ) 16 , C(2′)H 2 ), 2.33-2.27 (m, 1H, C(2′)H 2 ), 1.77 (quint., 2H, J=7.3, NCH 2   CH   2 CH 2 N), 1.54 (s, 3H, C(7)H 3 ), 1.45-1.39 (m, 4H, 2 NCH 2   CH   2 (CH 2 ) 15 ), 1.27 (br.s, 60H), 0.90 (t, 3H, J=6.9, CH 2   CH   3 ).  13 C-NMR (CDCl 3 ): 163.39 (C4), 158.75 (CH 3 OC ar ), 150.84 (C2), 144.38 (OC C   ar ), 135.49 (OC C   ar ), 133.34 (C6), 130.07 (OCC═ C H a r   ), 128.14 (CH ar ), 127.96 (CH ar ), 127.10 (CH ar ), 113.29 (CH 3 OC C H ar ), 110.27 (C5), 86.92 (CH 2 O C ), 85.91 (C4′), 85.25 (C1′), 72.21 (3′), 63.52 (C5′), 55.21 (OCH 3 ), 53.88 (N C H 2 (CH 2 ) 16 ), 51.61 (N C H 2 (CH 2 ) 2 N), 41.06 (C2′), 40.10 (CON C H 2 ), 31.90 (CH 3 CH 2   C H 2 ), 29.69 (CH 2 ), 29.64 (CH 2 ), 29.33 (N(CH 2 ) 3   C H 2 ), 27.62 (N(CH 2 ) 2   C H 2 CH 2 ), 26.92 (NCH 2    C H 2 (CH 2 ) 15 ), 24.90 (NCH 2   C H 2 CH 2 N), 22.66 (CH 3   C H 2 ), 14.07 (CH 3 CH 2 ), 12.65 (C7). ESI-MS (calculated mass: 1105): 1106.9 [M+H] + . 
     6-Azauridine derivatives 
     Ethyl-3-((3aR,4R,6R,6aR)-4-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-6-(hydroxymethyl)-2-methyltetrahydrofuro[3,4-d][1,3]dioxol-2-yl)propanoate (72) 
     Dried 6-azauridine (2 g, 8.15 mmol) was dissolved in 30 ml dry dimethylformamide (DMF). Levulinic acid ester (2.2 ml, 15.58 mmol), triethyl orthoformate (2.0 ml, 12.23 mmol) and 4M HCl in 1,4-dioxane (6.8 ml) were added and the mixture was stirred at room temperature for 25 h. Then, the mixture was distributed between 350 ml dichloromethane (DCM) and 100 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted 3 times with 50 ml DCM, respectively. The collected organic phases were washed with destilled water and dried over sodium sulfate for 1 h. The filtrate was concentrated with the help of rotary evaporator. Next, DCM was added and the solvent evaporated. This was repeated several times. The crude product was dried in high vacuum at 40° C. over night. Column chromatography of the crude product yielded the desired product (72) in 53.9% yield. TLC (silica): R f  0.4. Log P: −0.62. The structure of the desired product (72) is shown below. The number are for reference purposes only. 
     
       
         
         
             
             
         
       
     
       1 H-NMR (500.13 MHz, DMSO-d 6 ):(1R): 12.24 (s, H—N(5)); 7.54 (s, H—C(3)); 6.07 (s, H—C(1′)); 5.06 (d,  3 J(H—C(2′), H—C(1′))=6.00, H-(2′)); 4.81 (t,  3 J(OH—C(5′), H α —C(5′))=5.50, (OH—C(5′), H β —C(5′))=5.50, OH—C(5′); 4.73 (dd,  3 J(H—C(3′), H—C(4′))=2.5, (H—C(3′), H—C(2′))=2.5, H—C(3′); 4.08-4.04 (m, 3H, H 2 —C(5″), H—C(4′)); 3.41 (ψt, 2H,  2 J(H α —C(5′), H β —C(5′))=−6.0, (H β —C(5′), H α —C(5′))=6.5, H 2 —C(5′); 2.39 (qt, 2H,  3 J(H α —C(2″), H 2 —C(1″))=7.0, (H β —C(2″), H 2 —C(1″))=8.0, H 2 —C(2″); 2.04-2.00 (m, 2H, H 2 —C(1″)); 1.27 (s, 3H, H—C(Me-(ketal))); 1.21-1.15 (m, 3H, H 3 —C(6″)).  13 C-NMR (125.76 MHz, DMSO-d 6 ): 172.50 (C(3″)); 156.48 (C(4)); 147.83 (C(6)); 136.25 (d, J=10.81, C(3); 112.95 (C-(ketal)); 90.72 (C(1′)); 87.83 (C(4′)); 83.01 (C(3′)); 81.59 (C(2′)); 61.82 (C(5′)); 59.78 (C(5″)); 33.12 (C(2″)); 27.88 (C(1″)); 23.38 (Me-(ketal)); 13.95 (C(6″). 
       1 H-NMR (500.13 MHz, DMSO-d 6 ):(1S): 12.24 (s, H—N(5)); 7.54 (s, H—C(3)); 6.07 (s, H—C(1′)); 5.06 (d,  3 J(H—C(2′), H—C(1′))=6.00, H-(2′)); 4.81 (t,  3 J(OH—C(5′), H α —C(5′))=5.50, (OH—C(5′), H β —C(5′))=5.50, OH—C(5′); 4.73 (dd,  3 J(H—C(3′), H—C(4′))=2.5, (H—C(3′), H—C(2′))=2.5, H—C(3′); 4.08-4.04 (m, 3H, H 2 —C(5″), H—C(4′)); 3.41 (ψt, 2H,  2 J(H α —C(5′), H β —C(5′))=−6.0, (H β —C(5′), H α —C(5′))=6.5, H 2 —C(5′); 2.29 (t, 2H,  3 J(H α —C(2″), H 2 —C(1″))=7.5, (H β —C(2″), H 2 —C(1″))=7.5, H 2 —C(2″); 1.87 (t, 2H,  3 J(H α —C(1″), H 2 —C(2″))=7.5, (H β —C(1″), H 2 —C(2″))=7.5, H 2 —C(1″); 1.45 (s, 3H, H—C(Me-(ketal))); 1.21-1.15 (m, 3H, H 3 C-(6″)). 
       13 C-NMR (125.76 MHz, DMSO-d 6 ): 172.39 (C(3″)); 156.48 (C(4)); 147.83 (C(6)); 136.25 (d, J=10.81, C(3); 113.36 (C-(ketal)); 90.85 (C(1′)); 88.04 (C(4′)); 83.47 (C(3′)); 82.16 (C(2′)); 61.82 (C(5′)); 59.78 (C(5″)); 33.25 (C(2″)); 28.84 (C(1″)); 24.73 (Me-(ketal)); 13.95 (C(6″)). Anal. calc. for C 15 H 21 N 3 O 8 *0.05 H 2 O*0.05 CH 2 Cl 2  (371.342): C, 48.01, H, 5.68, N, 11.16; found: C, 48.27, H, 5.67, N, 11.20. 
     Ethyl-3-((3aR,4R,6R,6aR)-4-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-6-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2-methyltetrahydrofuro[3,4-d][1,3]dioxol-2-yl)propanoate (73) 
     Compound (72) (1 g, 2.69 mmol) was evaporated 3 times with 2.18 ml dry pyridine, respectively, and then dissolved in 11.1 ml of pyridine. Monomethoxytrityl chloride (0.987 g, 3.10 mmol) was added under N 2 -atmosphere and the mixture was stirred for 21.5 h at room temperature. The reaction was stopped by adding 6.7 ml of methanol. After 10 minutes, the reaction mixture was distributed between 68 ml of an ice-cold 5% sodium bicarbonate and 77 ml DCM and additionally extracted with DCM (1×39 ml, 1×19 ml). The collected organic phases were dried for 1 h over sodium sulfate, filtered off, concentrated, evaporated with DCM several times and then dried in high vacuum. Column chromatography of the crude product yielded the desired product (73) in 73.5% yield. TLC (silica): R f  0.5. Log P: 4.67. The desired structure (73) is shown below, wherein the numbers are references only. 
     
       
         
         
             
             
         
       
     
       1 H-NMR (500.13 MHz, DMSO-d 6 ):(1R): 12.27 (s, H—N(5)); 7.38-7.21 (m, 12H, 2×H—C(3′″), 4×H—C(9′″), 4×H—C(10′″); 2×H—C(11′″)); 7.14 (s, H—C(3)); 6.876 (d, 2H,  3 J(H—C(4′″), H—C(3′″))=9.00, H—C(4′″)); 6.12 (s, H—C(1′)); 4.97 (d,  3 J(H—C(2′), H—C(1′))=6.50, H-(2′)); 4.62 (dd,  3 J(H—C(3′), H—C(4′))=2.0, (H—C(3′), H—C(2′))=2.0, H—C(3′); 4.33-4.31 (m, H—C(4′)); 4.10-4.00 (m, 2H, H α —C(5′), H β —C(5′)); 3.75 (s, 3H, H 3 C(7′″)); 2.42 (qt, 2H,  3 J(H α —C(2″), H 2 —C(1′″))=7.0, (H β —C(2″), H 2 —C(1″))=7.5, H 2 —C(2″); 1.87 (pt, 2H,  3 J(H α —C(1′″), H 2 —C(2″))=7.5, (H β —C(1″), H 2 —C(2″))=7.0, H 2 —C(1″); 1.25 (s, 3H, H—C(Me-(ketal))); 1.22 (ψt, 3H,  3 J(H 3 —C(6″), H a —C(5″))=7.5, (H—C(6″), H β —C(5″))=7.0, H 3 —C(6″). 
       13 C-NMR (125.76 MHz, DMSO-d 6 ): 172.55 (C(3″)); 158.14 (C(5′″), 156.24 (C(4)); 147.66 (C(6)); 144.07 (d, J=20.0, C(8′″); 135.85 (d, J=37.22, C(3); 134.78 (C(2′″)); 129.83-126.43 (m, C(3′″), C(9′″), C(10′″), C(11′″)), 113.08 (C-(ketal)); 112.75 (C(4′″)); 90.60 (C(1′)); 86.57 (C(4′)); 83.13 (C(3′)); 81.56 (C(2′)); 64.57 (C(5′)); 59.77 (C(5″)); 54.94 (C(7′″)); 33.05 (C(2″)); 27.83 (C(1″)); 23.41 (Me-(ketal)); 13.97 (C(6″). 
       1 H-NMR (500.13 MHz, DMSO-d 6 ):(1S): 12.27 (s, H—N(5)); 7.38-7.21 (m, 12H, 2×H—C(3′″), 4×H—C(9′″), 4×H—C(10′″); 2×H—C(11′″)); 7.14 (s, H—C(3)); 6.876 (d, 2H,  3 J(H—C(4′″), H—C(3′″))=9.00, H—C(4′″)); 6.12 (s, H—C(1′)); 4.91 (d,  3 J(H—C(2′), H—C(1′))=6.00, H-(2′)); 4.62 (dd,  3 J(H—C(3′), H—C(4′))=2.0, (H—C(3′), H—C(2′))=2.0, H—C(3′); 4.33-4.31 (m, H—C(4′)); 4.10-4.00 (m, 2H, H α —C(5′), H β —C(5′)); 3.75 (s, 3H, H 3 C(7′″)); 2.28 (qt, 2H,  3 J(H α —C(2″), H 2 —C(1″))=7.0, (H β —C(2″), H 2 —C(1″))=7.5, H 2 —C(2″); 1.86 (t, 2H,  3 J(H α —C(1″), H 2 —C(2″))=7.5, (H β —C(1″), H 2 —C(2″))=7.5, H 2 —C(1″); 1.45 (s, 3H, H—C(Me-(ketal))); 1.14 (t, 3H,  3 J(H 3 —C(6″), H a —C(5″))=7.0, (H—C(6″), H β —C(5″))=7.0, H 3 —C(6″). 
       13 C-NMR (125.76 MHz, DMSO-d 6 ): 172.37 (C(3″)); 158.14 (C(5′″), 156.24 (C(4)); 147.99 (C(6)); 144.07 (d, J=20.0, C(8′″); 135.85 (d, J=10.81, C(3); 134.78 (C(2′″)); 129.83-126.43 (m, C(3′″), C(9′″), C(10′″), C(11′″)), 112.98 (C-(ketal)); 112.75 (C(4′″)); 90.69 (C(1′)); 86.57 (C(4′)); 83.58 (C(3′)); 82.04 (C(2′)); 64.57 (C(5′)); 59.77 (C(5″)); 54.94 (C(7′″)); 33.22 (C(2″)); 28.81 (C(1″)); 24.79 (Me-(ketal)); 13.97 (C(6″)). Anal. calc. for C 35 H 37 N 3 O 9  (643.68): C, 65.31, H, 5.79, N, 6.53; found C, 65.12, H, 5.79, N, 6.52. 
     Ethyl-3-((3aR,4R,6R,6aR)-4-(3,5-dioxo-4-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-4,5-dihydro-1,2,4-triazin-2 (3H)-yl)-6-(hydroxymethyl)-2-methyltetrahydrofuro[3,4-d][1,3]dioxol-2-yl)propanoate (74) 
     Compound (73) (0.2 g, 0.5386 mmol) was dissolved in amine-free and water-free DMF and heated to 55° C. Then, dry potassium carbonate (0.193 g, 1.4003 mmol) was added and it was stirred for 10 minutes. After the reaction mixture was cooled to room temperature, farnesyl bromide (0.17 ml, 0.5924 mmol) was added dropwise under N 2 -atmosphere. After 20 minutes, the potassium carbonate was filtered off and the crude product was evaporated together with DCM several times. Column chromatography of the crude product yielded the desired product (74) in 72% yield. 
     Oncological Tests 
     It was surprisingly found that the compounds according to the invention showed pharmaceutical activity in the treatment of tumor cells, i.e. in the treatment of various forms of cancer. 
     Several oncological tests were conducted with exemplary compounds according to the invention as well as several comparable examples, the results of which are shown in  FIGS. 10 to 17 . Table 4 shows the structure of the compounds tested as well as the abbreviations to which they are referred to in  FIGS. 10 to 17 . 
     
       
         
           
               
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 Entry 
                 Structure 
                 Reference 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ESP_2.2 
               
               
                   
               
               
                 2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ESP_2.5 
               
               
                   
               
               
                 3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ESP_31 or ESP 3.1 
               
               
                   
               
               
                 4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ESP_2 (comparative) 
               
               
                   
               
               
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ESP_3 (comparative) 
               
               
                   
               
            
           
         
       
     
       FIGS. 10 to 17  show the activity of compounds ESP_2.2, ESP_2.5 and ESP_31 according to the invention as well as the comparative examples ESP_2 and ESP_3 (Table 4) in relation to the concentration employed against various different cancer cells. The y-axis shows the cell growth in percent, wherein the range from +125 to 0 represents an inhibition of the growth of the cancer cells and the range from 0 to −125 represents a cytotoxic effect. The x-axis depicts the molar concentration of the respective compound on a logarithmical scale. 
     As can be seen from the data shown in  FIG. 10 , compound ESP_2.2 leads to an inhibition of cell growth of the cells of OVCAR-5 when employed in high dosages. Compound ESP_2.5 which is lipophilized at the nitrogen at the 3 position of the 6-azauridine derivative shows a high cytotoxicity against cells of OVCAR-5. The unmodified nucleoside 6-azauridine (ESP_2) which serves as a comparative example shows no activity. OVCAR-5 is a human epithelial carcinoma cell line of the ovary, established from the ascetic fluid of a patient with progressive ovarian adenocarcinoma without prior cytotoxic treatment. The unique growth pattern of ovarian carcinoma makes it an ideal model for examining the anticancer drug activity. With epithelial-like morphology, OVCAR-5 has abundant activity in both the Boyden chamber chemotaxis and invasion assay. The OVCAR-5 cell line is able to grow in soft agar, an indicator of transformation and tumorigenicity, and displays a relatively high colony forming efficiency. In vivo, OVCAR-5 cells can form moderately well-differentiated adenocarcinoma consistent with ovarian primary cells. 
       FIG. 11  shows the results of the oncological tests of compounds ESP_3 and ESP_3.1 (Table 4, entries 3 and 5) against cell line OVCAR-5. Again, the comparative example ESP_3, the unmodified nucleoside uridine, shows no activity. The introductions of lipophilic substituents at the sugar moiety surprisingly lead to a cytotoxicity of compound ESP_3.1. 
       FIG. 12  shows the results of oncological tests of compounds ESP_2 (comparative) and ESP_2.2 and ESP_2.5 (both according to the invention) against IGR-OV1. Maintained in monolayer cultures, IGR-OV1 cells exhibited a 20-h doubling time and highly tumorigenic properties. The epithelial morphology of IGR-OV1 cells was retained during in vitro and in vivo passages. Two cytogenetic markers characterize IGR-OV1 cells: a paracentric inversion of chromosome 3, and a translocation between chromosomes 2 and 5. These characteristics make the IGR-OV1 cell line a suitable experimental model for the treatment of human ovarian carcinomas and for biological studies of human solid tumors. 
     IGR-OV1 is one of the cell lines of the NCI-60 panel which represents different cancer types and has been widely utilized for drug screening and molecular target identification. As can be depicted from the data shown, the unmodified nucleoside ESP_2 only causes a slight inhibition of the respective cancer cells. The activity of the compound could be increased by the introduction of a triphenylmethyl substituent at the sugar moiety (ESP_2.2). Compound ESP_2.5, carrying a terpene radical at the azauridine moiety, also showed an improved inhibition effect against cells of IGR-OV1. 
       FIG. 13  shows the test results of the unmodified nucleoside uridine (ESP_3) and the modified uridine derivative ESP_31 which is lipophilized at the sugar moiety against IGR-OV1. Again, the introduction of long alkyl chains lead to vast improvement with respect to the cytotoxic activity in comparison to compound ESP_3 which did not even cause a growth inhibition of the employed cancer cells. 
       FIG. 14  shows the results of the oncological tests of compounds ESP_2, ESP_2.2 and ESP_2.5 against HCT-15 cells. The human colorectal adenocarcinoma cell line HCT15, Dukes&#39; type C, possesses a epithelioid morphotype and is one of the cell lines of the NCI-60 panel and has been widely utilized for drug screening and molecular target identification. The unmodified nucleoside ESP_2, which serves as a comparative example, only lead to slight inhibition of the growth of the cells, whereas both, compound ESP_2.2 as well as compound ESP_2.5, showed an increased activity. ESP_2.5, being lipophilized at the base moiety of the azauridine derivative even showed a remarkable cytotoxic effect, resulting in the death of over 50% of the cells, when employed in high dosage. 
       FIG. 15  depicts the data obtained in the oncological tests of compounds ESP_3 (comparative) and ESP_31 (according to the invention) when tested against HCT-15. The introduction of lipophilic radicals at the sugar moiety of uridine surprisingly lead to a high cytotoxic activity of the respective compound ESP_31, resulting in almost no surviving cancer cells. 
       FIG. 16  shows the pharmaceutical activity of compounds ESP_2 (comparative), ESP_2.2 and ESP_2.5 (both according to the invention) when tested against 786-0. This cell line is derived from a primary clear renal cell adenocarcinoma. The cells display both microvilli and desmosomes, and can be grown in soft agar. The cells produce a PTH like peptides that is identical to peptides produced by breast and lung tumors. The peptide has an N terminal sequence similar to PTH, has PTH like activity, and has a molecular weight of 6000 daltons. 
     Although the incorporation of a triphenylmethyl radical into the azauridine derivative only lead to slightly stronger inhibition of cell growth, the introduction of a terpene radical at the basic moiety resulted in the highly active compound ESP_2.5, which had a high cytotoxic effect. 
       FIG. 17  shows that compound ESP_31, carrying lipophilc substituents at the sugar moiety, possesses a cytotoxic effect when tested against 786-0 cells, whereas the unmodified uridine (ESP_3, comparative) did not show any activity at all. 
     As can be seen from  FIGS. 10 to 17 , the compounds of the invention show a high activity against various forms of cancer, especially against ovarian cancer, colon cancer and kidney cancer. As has been surprisingly found, especially compounds of the invention carrying a farnesyl moiety at the nitrogen at the 3 position of the 6-azauridin moiety and a levulinic acid ethyl ester moiety at the sugar show a particular high cytotoxicity against various cancer cells (see compound ESP_2.5).