HETEROATOMIC OLIGONUCLEOSIDE LINKAGES

Abstract: Oligonucleotide-mimicking macromolecules that have improved nuclease resistance are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural oligonucleotides with three or four atom linking groups provide unique oligonucleotide-mimicking macromolecules that are useful in regulating RNA expression and in therapeutics. Methods of synthesis and use also are disclosed.

Description: i HETEROATOMIC OLIGONϋCLEOSIDE LINKAGES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation in part of the PCT Application filed May 21, 1992 entitled "Backbone Modified 5 Oligonucleotide Analogues", which is a continuation-in-part of U.S. Serial No. 703,619 filed May 21, 1991, which is a continu- ation-in-part of U.S. Serial No. 566,836 filed August 13, 1990 and of U.S. Serial No. 558,663 filed July 27, 1990, all of which are assigned to the assignee of this application and all 10 of which are incorporated by reference herein. FIELD OF THE INVENTION This invention relates to the design, synthesis and application of nuclease resistant macromolecules that function as oligonucleotide mimics and are useful for therapeutics, 15 diagnostics and as research reagents. The macromolecules have modified linkages in place of the phosphorodiester inter-sugar linkages found in wild type nucleic acids. The macromolecules are resistant to nuclease degradation and are capable of modulating the activity of DNA and RNA. Methods fo 20 synthesizing the macromolecules and for modulating th production of proteins, utilizing the macromolecules of th invention are also provided. Further provided are intermediat compositions useful in the synthesis of the macromolecules. BACKGROUND OF THE INVENTION 25 It is well known that most of the bodily states i mammals, including most disease states, are effected b proteins. Such proteins, acting either directly or throug their enzymatic functions, contribute in major proportion t many diseases in animals and man. Classical therapeutics has generally focused upo interactions with such proteins in an effort to moderate thei disease causing or disease potentiating functions. Recently, however, attempts have been made to moderate the actua production of such proteins by interactions with the molecules, i.e., intracellular RNA, that direct their synthesis. Thes interactions have involved the hybridization of complementar "antisense" oligonucleotides or certain analogs thereof to RNA. Hybridization is the sequence-specific hydrogen bonding o oligonucleotides or oligonucleotide analogs to RNA or singl stranded DNA. By interfering with the production of proteins, it has been hoped to effect therapeutic results with maximu effect and minimal side effects. In the same way, oligonucleo tide like macromolecules may modulate the production o proteins by an organism. The pharmacological activity of antisense oligonuc leotides and oligonucleotide analogs, like other therapeutics depends on a number of factors that influence the effectiv concentration of these agents at specific intracellula targets. One important factor for oligonucleotides is thei stability in the presence of nucleases. It is unlikely tha unmodified oligonucleotides will be useful therapeutic agent because they are rapidly degraded by nucleases. Modification of oligonucleotides to render them resistant to nucleases i therefore greatly desired. Modifications of oligonucleotides to enhance nucleas resistance have generally taken place on the phosphorus atom o the sugar-phosphate backbone. Phosphorothioates, methy phosphonates, phosphoramidates and phosphorotriesters have bee reported to confer various levels of nuclease resistance However, phosphate modified oligonucleotides have generall suffered from inferior hybridization properties. See Cohen J.S., ed. Oligonucleotides: Antisense Inhibitors of Gen Expression, (CRC Press, Inc., Boca Raton FL, 1989). Another key factor is the ability of antisens compounds to traverse the plasma membrane of specific cell involved in the disease process. Cellular membranes consist o lipid-protein bilayers that are freely permeable to small, non ionic, lipophilic compounds and inherently impermeable to mos natural metabolites and therapeutic agents, see Wilson, D.B Ann . Rev. Biochem . 47:933-965 (1978). The biological an antiviral effects of natural and modified oligonucleotides i cultured mammalian cells have been well documented. Thus, i appears that these agents can penetrate membranes to reac their intracellular targets. Uptake of antisense compound into a variety of mammalian cells, including HL-60, Syria Hamster fibroblast, U937, L929, CV-1 and ATH8 cells has bee studied using natural oligonucleotides and certain nucleas resistant analogs. For alkyl triester analogs, results hav been reported by Miller, P.S., Braiterman, L.T. and Ts'O P.O.P., Biochemistry 16:1988-1996 (1977). For methy phosphonate analogs, results have been reported by Marcus Sekura, CH. , Woerner, A.M., Shinozuka, K. , Zon, G. , an Quinman, G.V. , Nuc . Acids Res . 15:5749-5763 (1987); Miller P.S., McFarland, K.B., Hayerman, K. and Ts'O, P.O.P. Biochemistry 16: 1988-1996 (1977); and Loke, S.K. , Stein, C. Zhang, X.H. Avigan, M. , Cohen, J. and Neckers, L.M. Top Microbiol . Immunol . 141: 282:289 (1988). Often, modified oligonucleotides are less readil internalized than their natural counterparts. As a result, th activity of many previously available, modified antisens oligonucleotides has not been sufficient for practica therapeutic, research or diagnostic purposes. Two othe serious deficiencies of prior modified oligonucleotides ar inferior hybridization to intracellular RNA and the lack of defined chemical or enzyme-mediated event to terminat essential RNA functions. Modifications to enhance the effectiveness o antisense oligonucleotides and overcome these problems ha taken many forms. These modifications include modifications the heterocyclic base, modifications of the sugar, and modifications of sugar-phosphate backbone. Prior sugar- phosphate backbone modifications, particularly on the phosphorus atom, have effected various levels of resistance to nucleases. The ability of an antisense oligonucleotide to bind to specific DNA or RNA with fidelity is fundamental to antisense methodology. However, modified phosphorus oligo¬ nucleotides have generally suffered from inferior hybridization properties. Replacement of the phosphorus atom has been one approach to avoid the problems associated with modified phosphorous oligonucleotides. Certain modifications have been reported in which replacement of the phosphorus atom is effected. Matteucci, M. , Tetrahedron Letters 31:2385-2388 (1990) , reported replacement of the phosphorus atom with a methylene group. However, such replacement is limited by the difficulties associated with uniform insertion of a formacetal linkage throughout an oligonucleotide backbone. Cormier, et al . , Nucleic Acids Research 16:4583-4594 (1988) reported the replacement of the phosphorus moiety with a diisopropylsilyl moiety. Stirchak, et al . , Journal of Organic Chemistry 52:4202-4206 (1987) reported replacement of the phosphorus linkage by short homopolymers containing carbamate or morpholino linkages. Both of these replacements are limited by a lack of suitable synthetic methodology and the low solubility and weak hybridization properties of the resultant molecules. Mazur, et al . , Tetrahedron 40:3949-3956 (1984) reported replacement of the phosphorus linkage with a phosphonic linkage. This replacement has not been developed beyond the synthesis of a homotrimer molecule. Goodchild, J. , Biocon jugate Chemistry 1 : 165-187 (1990) reported replacement b ester linkages. However, ester linkages are enzymaticall degraded by esterases and are therefore unsuitable as replacement for the phosphate bond in antisense applications. A recent publication by Tronchet, J. et. al , J . Carbohydrate Chemistry, 10:723 (1991) reported the use of a oxyimino intergylcosidic linkage between two onosaccharides t form a disaccharide. In forming this linkages, a firs carbonyl sugar, either a hexose or a pentose, was reacted wit a second O-aminohexose sugar. The limitations of the available methods for modifi cation of the phosphorus backbone of oligonucleotides has le to a continuing and long felt need for other modifications tha might provide resistance to nucleases and satisfactor hybridization properties for antisense oligonucleotid diagnostics, therapeutics, and research. OBJECTS OF THE INVENTION It is an object of the invention to provide macro molecules that function as oligonucleotide mimics for use i antisense oligonucleotide diagnostics, research reagents, an therapeutics. It is a further object of the invention to provid oligonucleotide-mimicking macromolecules that possess enhance cellular uptake. Another object of the invention is to provid oligonucleotide-mimicking macromolecules that have greate efficacy than unmodified antisense oligonucleotides. It is yet another object of the invention to provid methods for synthesis and use of such oligonucleotide-mimickin macromolecules. These and other objects shall become apparent t persons skilled in the arts to which this invention pertain given this specification and its appended claims. BRIEF SUMMARY OF THE INVENTION The present invention provides compositions that ar useful for modulating the activity of an RNA or DNA molecul and that generally comprise oligonucleotide-mimickin macromolecules. The macromolecules are constructed from plurality of linked nucleosides. In constructing thes macromolecules, the phosphorodiester linkage of the suga phosphate backbone found in wild type nucleic acids has bee replaced with three and four atom linking groups. Such linkin groups maintain a desired atomic spacing between the 3'-carbo of one nucleoside and the 4'-carbon of an adjacent nucleoside The oligonucleotide-mimicking macromolecules of the inventio comprise a selected linked sequence of nucleosides that ar specifically hybridizable with a preselected nucleotid sequence of single stranded or double stranded DNA or RNA. The oligonucleotide-mimicking macromolecules of th invention are synthesized conveniently, through solid state o solution methodology, to be complementary to or at leas specifically hybridizable with a preselected nucleotid sequence of the RNA or DNA. Solid support synthesis i effected utilizing commercially available nucleic aci synthesizers. The use of such synthesizers is generally under stood by persons of ordinary skill in the art as bein effective in generating nearly any desired oligonucleotide o oligonucleotide mimic of reasonable length. The oligonucleotide-mimicking macromolecules of th invention also can include nearly any modification known in th art to improve the properties of wild type oligonucleotides In particular, the macromolecules can incorporate modification known to increase nuclease resistance or hybridization. In accordance with the present invention, nove macromolecules that function as antisense oligonucleotid mimics are provided to enhance cellular uptake, nucleas resistance, and hybridization properties and to provide defined chemical or enzymatically mediated event to terminat essential RNA functions. It has been found that certain oligonucleotide mimicking macromolecules can be useful in therapeutics and fo other objects of this invention. At least a portion of th macromolecules of the invention has structure 1: STRUCTURE 1 wherein one of L- or L 2 is 0 or S , and the other of L- or L 2 i N-R; and combined 1>~ and L 4 are CH 2 , or L 3 is CH 2 and L 4 i CR'R" ; or one of L j or L 4 is O or S , and the other of L 3 or L 4 i N-R; and combined L- and L 2 are CH 2 , or L 2 is CH 2 and , i CR'R' ' ; or one of L- and L 4 is O, S or N-R, and the other of L and L 4 is CR'R' ' ; and L 2 and L j are CH 2 ; or L-, L 2 , 11 3 and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N O; or L- is O; L 2 is N; L 3 is CH 2 ; and L 4 is C or CH; an together with at least two additional carbon or hetero atoms L 2 , L 3 and L 4 form a 5 or 6 membered ring; or L. is C or CH; L 2 is CH 2 ; L 3 is N; and L 4 is 0; an together with at least two additional carbon or hetero atoms L-, L 2 and L 3 form a 5 or 6 membered ring; and R is H; C- to C 10 straight or branched chain lowe alkyl or substituted lower alkyl; C 2 to C 10 straight or branche chain lower alkenyl or substituted lower alkenyl; C 2 to C 1 straight or branched chain lower alkynyl or substituted lowe alkynyl; a 14C containing lower alkyl, lower alkenyl or lowe alkynyl; C 7 to C 14 substituted or unsubstituted alkaryl o aralkyl; a 14C containing C 7 to C 14 alkaryl or aralkyl alicyclic; heterocyclic; a reporter molecule; an RNA cleavin group; a group for improving the pharmacokinetic properties o an oligonucleotide; or a group for improving the pharmacody¬ namic properties of an oligonucleotide; R' and R" are H; or R' is H and R" is O-R; or combined R' and R'' are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; S0CH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. The remainder of the molecule is composed of chemical functional groups that do not hinder, and preferably enhance, hybridization with RNA or single stranded or double stranded DNA. In certain preferred embodiments, the macromolecules of structure 1 include macromolecules wherein one of L- or L 2 is O or S, and the other of L- or L 2 is N-R; and combined I^ and L 4 are CH 2 ; or one of L j or L 4 is O or S, and the other of L, or L 4 is N-R; and combined L- and L 2 are CH 2 . Other preferred embodiments of the invention include macromolecules of structure 1 wherein one of L- and L 4 is O, S or N-R, and the other of L- and L 4 is CR'R''; and L 2 and 1^ are CH . Further preferred embodiments of the invention includ macromolecules of structure 1 wherein one of L. or L 2 is O o S, and the other of L., or L 2 is N-R; and L 3 is CH 2 and L 4 i CR'R''; or one of I^ or L 4 is 0 or S, and the other of I^ or L is N-R; and L 2 is CH 2 and L- is CR'R". Further preferred embodiments of the invention includ macromolecules of structure 1 wherein L-, L 2 , I^ and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N-0. Further preferred embodiments of the invention includ macromolecules of structure 1 wherein L- is 0; L 2 is N; L 3 i CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , I^ and L 4 form a 5 or 6 membered ring; or L- is C or CH; L 2 is CH 2 ; 1^ is N; and L 4 is O; and together with at least two additional carbon or hetero atoms, L.,, L 2 and It- form a 5 or 6 membered ring. In particularly preferred embodiments of the inven¬ tion, Q of structure 1 is O. In accordance with other particularly preferred embodiments of the invention, X of structure 1 is H or OH. In accordance with other preferred embodiments of the invention the Bx group of individual nucleosides incorporated within structure 1 are independently selected from naturally occurring or synthetic purine and pyrimidine heterocyclic bases. Such heterocyclic bases include but are not limited to adenine, guanine, cytosine, thymine, uracil, 5-methylcytosine, hypoxanthine or 2-aminoadenine. Other such heterocyclic bases include 2-methylpurine, 2,6- diaminopurine, 6-mercaptopurine, 2,6-dimercaptopurine, 2-amino- 6-mercaptopurine, 5-methylcytosine, 4-amino-2-mercapto- pyrimidine, 2,4-dimercaptopyrimidine and 5-fluorocytosine. Particularly preferred embodiments of the invention include macromolecules of structure 1 wherein L- is O or S, L 2 is N, I^ is CH 2 and L 4 is CH 2 or CHOR, particularly where R is H. In accordance with other particularly preferred embodiments of the invention, L 4 is O or S, 1^ is N, L 2 is CH 2 and L 1 is CH 2 or CHOR, particularly where R is H. In accordance with even further particularly preferred embodiments of the invention, L 2 and L j both are CH 2 and one of L* or L 4 is N-R and the other is CH 2 . In preferred embodiments of the inventions, the oligonucleotide-mimicking macromolecules include from about 2 to about 50 nucleoside subunits (i.e., n = about 1 - about 49) . The oligonucleotide-mimicking macromolecules of the invention preferably are included in a pharmaceuticall acceptable carrier for therapeutic administration. The substituent groups of the above referenced alkyl, alkenyl, alkynyl, alkaryl and aralkyl R groups include but ar not necessary limited to halogen, hydroxyl, keto, carboxy. nitrates, nitrites, nitro, nitroso, nitrile, trifluoromethyl, O-alkyl, S-alkyl, NH-alkyl, amino, azido, sulfoxide, sulfone, sulfide, silyl, intercalators, conjugates, polyamines, polyamides, polyethylene glycols, polyethers, groups tha enhance the pharmacodynamic properties of oligonucleotides, an groups that enhance the pharmacokinetic properties of oligonuc leotides. One particularly preferred R group is CF 3 . Typica intercalators and conjugates include cholesterols, phospho lipids, biotin, phenanthroline, phenazine, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Halogens include fluorine, chlorine, bromine, an iodine. Groups that enhance the pharmacodynamic properties, i the context of this invention, include groups that improv oligonucleotide uptake, enhance oligonucleotide resistance t degradation, and/or strengthen sequence-specific hybridizatio with RNA. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improv oligonucleotide uptake, distribution, metabolism or excretion. The invention further includes methods of modulatin the production or activity of a protein in a cell system or a organism comprising contacting the cell system or organism wit an oligonucleotide-mimicking macromolecule having structure 1 The invention further includes methods of treating a organism having a disease characterized by the undesire production of a protein comprising contacting the organism wit an oligonucleotide-mimicking macromolecule having structure 1 The invention further includes methods of in vitr assaying a sequence-specific nucleic acid comprising contactin a test solution containing the nucleic acid with a oligonucleotide-mimicking macromolecule having structure 1. The invention further includes nucleosidic precursor of the macromolecules of structure 1, the precursors havin structure 2: STRUCTURE 2 wherein Y- is O; Y 2 is H or R' ' ' ; and Z is aminooxy o phthalimidooxy; or Y- is CH 2 , and Y 2 is aminooxy, alkylamino, amino oxyalkyl, alkenyl or oxoalkyl; and Z is H, OH, 0-R' , , amino, methyleneamino or phthal imido; R' ' ' is a hydroxyl blocking group; X is H or OH; Q is CH 2 or 0; and Bx is a heterocyclic base moiety. In certain preferred embodiments, Y- is CH 2 ; Y 2 i aminooxy, alkylamino, hydroxyalkyl, aminooxyalkyl, alkenyl o aldoalkyl; and Z is H, OH or O-R'''. In other preferre embodiments, Y., is O, Y 2 is H and Z is aminoxy or phthalimido. DETAILED DESCRIPTION OF THE INVENTION The term "nucleoside" refers to a unit composed of heterocyclic base and a sugar, generally a pentose sugar. I naturally occurring nucleosides, the heterocyclic bas typically is guanine, adenine, cytosine, thy ine or uracil. I naturally occurring nucleosides, the sugar is normally deoxyri bose, i.e., erythro-pentofuranosyl, or ribose, i.e., ribo pentofuranosyl. Synthetic sugars also are known, includin arabino, xylo or lyxo pentofuranosyl sugars and hexose sugars Throughout this specification, reference to the sugar portio of a nucleoside or other nucleic acid species shall b understood to refer to either a true sugar or to a specie replacing the traditional sugar moiety of wild type nuclei acids. Additionally, reference to the heterocyclic bas portion of a nucleoside or other nucleic acid species shall b understood to refer to either a natural, modified or syntheti base replacing one or more of the traditional base moiety o wild type nucleic acids. Moreover, reference to inter-suga linkages shall be taken to include moieties serving to join th sugar or sugar substitute moiety together in the fashion o wild type nucleic acids. The term "nucleotide" refers to a nucleoside having a phosphate group esterified to one of its 2', 3' or 5' sugar hydroxyl groups. The phosphate group normally is a monophosphate, a diphosphate or triphosphate. The term "oligonucleotide" refers to a plurality of monophosphate nucleotide units that typically are formed in a specific sequence from naturally occurring bases and pentofuranosyl sugars joined by native phosphodiester bonds. A homo-oligonucleotide is formed from nucleotide units having the same heterocyclic base, i.e. poly(A) . The ter oligonucleotide generally refers to both naturally occurring and synthetic species formed from naturally occurring subunits. The term "oligonucleotide analog" has been used in various published patent application specifications and other literature to refer to molecular species similarly to oligo¬ nucleotides but that have non-naturally occurring portions. This term has been used to identify oligonucleotide-lik molecules that have altered sugar moieties, altered bas moieties or altered inter-sugar linkages. Thus, th terminology oligonucleotide analog has been used to denot structures having altered inter-sugar linkages includin phosphorothioate, methyl phosphonate, phosphotriester o phosphora idate inter-nucleoside linkages used in place o phosphodiester inter-nucleoside linkages; purine and pyrimidin heterocyclic bases other than guanine, adenine, cytosine, thymine or uracil and sugars having other than the pentofuranosyl configuration or sugars having substituen groups at their 2' position or substitutions for one or more o the hydrogen atoms. The term "modified oligonucleotide" als has been used in the literature to denote such structures. "Oligonucleotide mimics" as the term is used i connection with this invention, refers to macromolecula moieties that function similarly to or "mimic" the function o oligonucleotides but have non-naturally occurring inter-suga linkages. Oligonucleotide mimics thus can have natural o altered or non-naturally occurring sugar moieties and natura or altered or non-naturally occurring base moieties i combination with non-naturally occurring inter-sugar linkages. For the purposes of this invention, an oligonu cleotide mimic having non-phosphodiester bonds, i.e. an altere inter-sugar linkage, can alternately be considered a "oligonucleoside" or an "oligonucleotide-mimickin macromolecule." The terms oligonucleoside or oligonucleotide mimicking macromolecule thus refers to a plurality of joine nucleoside units connected by non-phosphate containing linkin groups. Additionally, the term "oligomers" is intended t encompass oligonucleotides, oligonucleotide analogs, oligonucleosides or oligonucleotide-mimicking macromolecules Thus, in speaking of "oligomers" reference is made to a serie of nucleosides or nucleoside analogs that are joined togethe via either natural phosphodiester bonds or via other linkages, including the linkages of this invention. Generally, th linkage is from the 3' carbon of one nucleoside to the 5 carbon of a second nucleoside. However, the term "oligomer can also include other linkages such as a 2' → 5' linkage or 3' → 4' linkage. Antisense therapy is the use of oligonucleotides o other oligomers for the purpose of binding with complementar strands of RNA or DNA. After binding, the oligonucleotide an the RNA or DNA strand can be considered to be "duplexed together in a manner analogous to native, double stranded DNA The oligonucleotide strand and the RNA or DNA strand can b considered to be complementary strands in the same context a native double stranded DNA. In such complementary strands, th individual strands are positioned with respect to one anothe to allow Watson/Crick type hybridization of the heterocycli bases of one strand to the heterocyclic bases of the opposin strand. Antisense therapeutics can be practiced in a plethor of organisms ranging from unicellular prokaryotes and eukaryo tes to multicellular eukaryotes. Any organism that utilize DNA-RNA transcription or RNA-protein translation as fundamental part of its hereditary, metabolic or cellula control is susceptible to antisense therapeutics and/or prophy¬ lactics. Seemingly diverse organisms such as bacteria, yeast, protozoa, algae, all plant and all higher animal forms, including warm-blooded animals, can be treated by antisense therapy. Further, since each of the cells of multicellular eukaryotes includes both DNA-RNA transcription and RNA-protein translation as an integral part of their cellular activity, antisense therapeutics and/or diagnostics can also be practiced on such cellular populations. Furthermore, many of the organelles, e . g. mitochondria and chloroplasts, of eukaryotic cells include transcription and translation mechanisms. Thus, single cells, cellular populations or organelles can also be included within the definition of organisms that are capable of being treated with antisense therapeutics or diagnostics. As used herein, therapeutics is meant to include the eradication of a disease state, killing of an organism, e . g . bacterial, protozoan or other infection, or control of erratic or harmful cellular growth or expression. Prior antisense therapy utilizing "oligonucleotide analogs" is exemplified in the disclosures of the following United States and PCT patent applications: serial number 463,358, filed January 11, 1990, entitled Compositions And Methods For Detecting And Modulating RNA Activity; serial number 566,836, filed August 13, 1990, entitled Novel Nucleoside Analogs; serial number 566,977, filed August 13, 1990, entitled Sugar Modified Oligonucleotides That Detect And Modulate Gene Expression; serial number 558,663, filed July 27, 1990, entitled Novel Polyamine Conjugated Oligonucleotides;, serial number 558,806, filed July 27, 1991, entitled Nuclease Resistant Pyrimidine Modified Oligonucleotides That Detect And Modulate Gene Expression; serial number 703,619, filed May 21, 1991, entitled Backbone Modified Oligonucleotide Analogs; serial number PCT/US91/00243, filed January 11, 1991, entitled Compositions and Methods For Detecting And Modulating RNA Activity; and patent application PCT/US91/01822, filed March 19, 1991, entitled Reagents and Methods For Modulating Gene Expression Through RNA Mimicry; all assigned to the assignee of this invention. The disclosures of each of the above note patent applications are herein incorporated by reference. As is set forth in detail in the above-reference United States and PCT patent applications, oligonucleotides an other oligomers have application in diagnostics, therapeutics, and as research reagents and kits. For therapeutic use, oligonucleotides or other oligomers would be administered to a animal, including humans, suffering from a disease state tha is desirous to treat. This invention is directed to certain macromolecule that function like oligonucleotides yet exhibit other usefu properties. As is illustrated in the Examples and Schemes o this specification, the macromolecules are constructed fro basic nucleoside units. These nucleoside units are joined b a linkage of the invention to form dimeric units. The dimeri units can be further extended to trimeric, tetrameric an other, higher order macromolecules by the addition of furthe nucleosides. The dimeric units (and/or the higher order units) can be linked via linkages other than those of the invention, as for instance, via a normal phosphodiester linkage, phosphorothioate linkage, a phosphoramidate linkage, a phospho triester linkage, a methyl or other alkylphosphonate linkage a phosphorodithioate linkage or other linkage. In certain embodiments, a single linkage is used t join nucleosides to form a macromolecule of the invention. Fo example, in Scheme XVIII below, m and r are 0, q is 1, and and p are greater than 1. In other embodiments, two or mor different linkages are used. For example, in Scheme XVIII, and r are 0, q is 1, and n and p are greater than 1. In other macromolecules of the invention the nucleo side are joined together in groups of two, three or mor nucleoside that together form a unit. An activated phosphity moiety is located at the 3' terminus of this unit and hydroxyl moiety bearing a removable hydroxyl blocking group i located at the 5' terminus. On subsequent removal of th hydroxyl blocking group and reaction of the hydroxyl group wit an activated phosphityl group, the units are then joine together via a normal phosphodiester, phosphorothioate or othe phosphorus linkage. Thus a first unit (a group of two, thre or more nucleosides linked together via a first linkage of th invention) and to a second unit (a group of two, three or mor nucleosides linked together via the first linkage or via second linkage of the invention) are connected together throug a phosphate linkage. The macromolecule is elongated by th addition of further units of nucleosides (linked together vi the first, a second or additional linkages of the invention) b joining these additional units to the existing linked units vi further phosphorus linkages. In the examples and flow scheme shown below, units exemplified by compound 58 could be linke together or they could be linked to units of compounds 66, 72, 77, 81 or 85 or various combinations of these compounds coul be linked together in various macromolecule structures. As i exemplified in Scheme XVIII below, in such macromolecules r i 0 or 1, m is a positive number, q is greater than 1, and n an p are positive numbers. Scheme I illustrates certain abbreviations used fo blocking groups in other of the Schemes. Scheme I furthe shows the synthesis of 3'-0-amino and 3'-O-methyleneamin nucleosides via a Mitsunobu reaction utilizing N-hydroxyl phthalimide and methylhydrazine to generate an -0-NH 2 moiety o a sugar hydroxyl. The -0-NH 2 group can then be derivatized t a -O-methyleneamino moiety. These reactions are exemplified i Examples 1, 2, 3, 5 and 15. The reactions of Examples 1, 2, 3 and 5 represent a improved synthesis of 3'-0-NH 2 nucleosides. In forming -0-NH moieties on sugars, it is theoretically possible to displace leaving group, as for instance a tosyl group, wit hydroxylamine. However, Files, L.E., Winn, D.T., Sweger, R.W., Johnson, M.P., and Czarnik, J . Am . Chem . Soc , 14:1493 (1992) have shown that such a displacement leads to a preponderance o -NHOH moieties and not to the desired -0-NH 2 moieties Further, the reaction sequence of Examples 1, 2, 3 and represents an improved synthesis compared to that illustrate in European Patent Application 0 381 335. The syntheti pathway of that patent application requires the use of a xyl nucleoside as the staring material. Xylo nucleosides are les readily obtainable than the ribonucleoside utilized in Example 1, 2, 3 and 5. Scheme II illustrates the conversion of a 4'-ald nucleoside to a 5'-aldo nucleoside. This reaction i exemplified in Example 16. Scheme III illustrates th generation of a 5'-aldo methyl sugar. This is exemplified i Example 14. Scheme IV illustrates the formation of an 5'-iod nucleoside, exemplified in Example 6. Similar methodology i used to generate an active iodo group on a terminal hydroxyl o a dimeric unit in Scheme X and Example 10. In Scheme IV, th iodo nucleoside is further derivatized to a 6'-aldo nucleosid via an allo substituted nucleoside. This is exemplified i Examples 31 and 32. Scheme V illustrates a free radical reaction of a -O methyleneamino nucleoside of Scheme 1 to a 5'-amino 5'-hom nucleoside. This is exemplified in Example 30. Scheme V illustrates use of a Mitsunobu reaction on a 5'-homo nucleosid to synthesize an oxyamine homo nucleoside, i.e. a 6'-0-NH 2 5' homo nucleoside. This is exemplified in Examples 36, 37 an 38. Scheme VII illustrates N-alkylation of the amino moiety o a 6'-amino-5'-deoxy'5-homo nucleoside. This is exemplified i Examples 43, 44 and 45. Such N-alkylation is desirable wher the amino moiety subsequently will be reacted with a thio moiety. The N-alkylated product of such a reaction exhibit greater stability to acid than does the non-alkylated S-N bond This is particularly useful in solid support synthesis wherei acid removal of trityl groups is commonly practiced. However for other synthesis, such as solution synthesis, this may no be a concern. Schemes VIII to XVII illustrate the use of th nucleosides of Schemes I to VII for the assembly of dimeric trimeric and other, higher order oligonucleosides. In Schem VIII, nucleosides 3 and 31 are joined via an acid catalyze coupling reaction to form an -O-nitrilomethylidyne linkag between the respective two nucleosides. This is exemplified i Example 17. Dimeric oligonucleoside 32 can be reduced to a iminomethylene linkage that, in turn, can be alkylated to (methylimino)methylene linkage, as exemplified in Example 18. Scheme IX illustrates the joining of nucleoside 3 t nucleoside 5. This scheme is analogous to Scheme VIII with th exception that in Scheme IX a three atom linkage is create whereas in Scheme VIII a four atom linkage is created. Nucleosides 3 and 5 are joined in Step 1 to form an -O-nitril linkage that is reduced in Step 2 to an -O-imino linkage. Alkylation occurs in Step 3 to a -O-methylimino linkage, wit final deblocking in Step 4. These steps are exemplified i Example 4. The alkylation reaction in Step 3 is accompanied b deblocking the t-butyldimethylsilyl protecting group at the 5' terminus of the dimer. Advantageous use of this deblockin reaction also is utilized in other Schemes. Deblocking of th t-butyldiphenylsilyl group used to protect the 3' terminus o the dimer is effected using tetra-n-butylammonium fluoride. The alkylation step can be used to introduce other, useful, functional molecules on the macromolecule. Such usefu functional molecules include but are not limited to reporte molecules, RNA cleaving groups, groups for improving th pharmacokinetic properties of an oligonucleotide, and group for improving the pharmacodynamic properties of a oligonucleotide. Such molecules can be attached to o conjugated to the macromolecule via attachment to the nitroge atom in the backbone linkage. Alternatively, such molecule can be attached to pendent groups extending from the 2' position of the sugar moiety of one or more of the nucleoside of the marcromolecules. Examples of such other usefu functional groups are provided by United States paten application serial number 782,374, filed Oct. 24, 1991, entitled Derivatized Oligonucleotides Having Improved Uptake Other Properties, assigned to the same assignee as thi application, herein incorporated by reference, and in other o the above-referenced patent applications. Scheme X illustrates a synthetic scheme utilized t prepare di ers, trimers, and other, higher order oligonucleo sides having homogenous linkages between nucleosides. In thi scheme, nucleosides 10 and 12 are linked to form a iminomethylene linkage as exemplified in Example 7. Advantageous use of the alkylating-5' terminus deblocking ste of Scheme IX is effected to remove the blocking group at the 5' terminus of the dimeric oligonucleoside 14, as in Example 8. Using the iodination reaction of Scheme IV, the dimer is the converted to a 5' terminus iodo intermediate, as in Example 10. A further 3'-O-methyleneamino nucleosidic unit 10 then can b added to the dimer to form a trimer, as in Example 11, followe by deblocking and alkylation, as in Example 12. This reactio sequence can be repeated any number of times to form a highe order oligonucleoside. The oligonucleoside is deblocked at th 3' terminus, as is exemplified for the dimer in Example 9 o the tetramer in Example 13. Scheme XI illustrates the use of an 1- -alkyl suga that is first linked to a nucleoside. Reduction followed b alkylation and deblocking yields an -0-(methylimino)methylen linkage joining the 1-O-alkyl sugar and the nucleoside, a exemplified by Example 19. This structure is then blocked a the 5' terminus, as exemplified by Example 20. The full blocked, linked sugar-nucleoside structure is then subjected t glycosylation to add a heterocyclic base to the sugar moiet and thus form a dimeric nucleoside structure, as in Example 21 After glycosylation, removal of the 5' terminus blocking grou and chromatographic separation of α and β anomers, a exemplified by Example 22, yields a dimer. This dimer can b further elongated as per the procedure of Scheme X. Example 23, 34 and 25 exemplify the addition of an adenine, cytosin and guanine base to a thymidine-methyl sugar dimer to form T-A T-C and T-G dimers in addition to the T-T dimer of Scheme X Examples 26, 27 and 28 exemplify the formation of A-T, A-A, A C, A-G, C-T, C-A, C-C, C-G , G-T, G-A, G-C and G-G dimers. Eac may be further elongated as per the procedures of Scheme X. Scheme XII illustrates a radical reaction that form a linkage having a pendant hydroxyl moiety. This i exemplified in Example 33. The pendant OH group can b oxidized to an =0 using Moffatt oxidization conditions. Alternatively, the pendant OH moiety can be cyclized to the nitrogen atom of the linkage to form either a five or a six membered heterocyclic ring. The formation of a linkage incorporating a six atom ring is exemplified in Example 34. A five atom ring would be formed utilizing condition analogous to those of Neumeyer, J.L. & Boyce, C.B., J. Org . Chem . , 38:2291 (1973) to add phosgene in the presence of a base such as triethylamine or diethylphenylamine in toluene at a temperature of about 60 to about 80° C. Scheme XIII illustrates the formation of an imino- oxymethylene linkage. Example 35 describes the preparation of the 5'-0-trityl protected xylo starting nucleoside and Example 39 describes the reaction of compound 50 with compound 54 to form a dimeric unit. Continuing within Scheme XIII, to prepare dimeric units that can be used as solid support building blocks (Example 40) , the backbone nitrogen atom is alkylated, followed by simultaneous removal of both the 5'-0-trityl and the 3'-0- (t-butyldiphenylsilyl) protecting groups with trifluoroacetic acid. The 5'-terminus hydroxyl group is blocked with dimethoxytriryl (Example 41) , followed by forming an active phosphoramidate dimer (Example 42) . Scheme XIV illustrates the preparation of a thiol intermediate and the use of that intermediate with an amino nucleoside to form a S-iminomethylene linkage (Example 45) . As with the reactions of Scheme XIII, a dimeric unit having an active phosphoramidate moiety can be formed. This is exemplified by Examples 46 and 47. Scheme XV illustrates the preparation of a nucleoside intermediate and coupling of that intermediate to a further nucleoside, as exemplified in Example 48, to form a nitrilo- 1,2-ethanediyl linkage. This linkage can be reduced to an imino-1,2-ethanediyl linkage, as exemplified in Example 49. Further, in a manner similar to Schemes XIII and XIV, Scheme X illustrates the preparation of an active phosphoramidate species, as exemplified in Examples 50, 51 and 52. Scheme XVI illustrates the preparation of a 2' substituted nucleoside, as exemplified in Example 53, an conversion of that 2' substituted nucleoside to a furthe nucleoside having an active linkage forming moiety (Exampl 54). Linkage of this 2' substituted nucleoside to a furthe nucleoside (Example 55) is followed by conversion to an activ phosphoramidate (Example 56). Substitution of the 2' positio in a macromolecule of the invention, as noted above, is usefu for the introduction of other molecules, including th introduction of reporter molecules, RNA cleaving groups, group for improving the pharmacokinetic properties of an oligonucleo tide, and groups for improving the pharmacodynamic propertie of an oligonucleotide as well as other groups including but no limited to O, S and NH alkyl, aralkyl, aryl, heteroaryl alkenyl, alkynyl and 14C contai.ni.ng derivatives of these groups F, Cl, Br, CN, CF 3 , OCF 3 , OCN, SOCH 3 , S0 2 CH 3 , ON0 2 , N0 2 , N 3 , NH 2 heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, poly alkylamino and substituted silyl. Further illustrated in Scheme XVI is the preparatio of a carbocyclic nucleoside (Example 57) , joining of tha carbocyclic nucleoside with a further nucleoside via a linkag of the invention (Example 58) , and formation of an activ phosphoramidate (Example 63) . A further sequence of reaction are also illustrated in Scheme XVI, wherein a carbocycli nucleoside is derivatized at its 2' positions (Example 60) an converted to a further nucleoside (Example 61) . As with th other reactions of this scheme, a dimer is first forme (Example 62) , and then derivatized with an activ phosphoramidate (Example 63) . The dimers of this scheme havin a 3' phosphoramidite moiety are used as in schemes XIII, XI and XV to link the oligonucleosides of the invention to othe nucleosides via a phosphodiester, phosphorothioate or othe similar phosphate based linkage. Scheme XVII illustrates a further carbocyclic contain ing, dimeric nucleoside. Internucleoside conversion i exemplified in Examples 64 and 65, and formation of a dimeri structure is exemplified in Example 66. The dimeric structur of Scheme XVII shows a carbocyclic nucleoside as the 5' nucleo side of the dimer, while Scheme XVI shows a carbocyclic nucleoside as the 3' nucleoside of the dimer. Use of carbocyclic nucleosides for both nucleoside intermediates, in the manner as described for other of the reaction schemes, results in a dimer having a carbocyclic nucleoside at both the 3' and 5' locations. Scheme XVIII illustrates generic structures that are prepared from the nucleosides and oligonucleoside of the previous schemes. Exemplary macromolecules of the invention are described for both solid support and solution phase synthesis in Example 68. SCHEME - TBDMSi = TBDPSi TBDMSi-0 TBDMSi 10 Bx = T ymi ne 4 Bx Thym i ne 27 Bx = Aden i ne 24 Bx Aden i ne 28 Bx = Cytos i ne 25 Bx Cytos i ne 29 Bx = Guanine 26 Bx Guan i ne 30 31 SCHEME I I I 21 22 23 SCHEME IV TBDPSi-0- j 11 1122 46 47 SCHEME V TBDMSi SCHEME V SCHEME V 62 SCHEME V I I I Λ .J ' TBDMSi TBDPSi-0 31 TBDMSi TBD 32 SCHEME IX SCHEME X SCHEME XI 23 / T T 35 14, 36, 37, 38 SCHEME X I I H Bx N TBDMSI— 0 Bx TBDPSl-0 j i CH, 10 T SCHEME X I I I 58 SCHEME X IV SCHEME XV x TBDM T 72 71 70 SCHEME XV 73 Q = 0, X = OH 74 Q = o, x = O-CH 3 78 Q = CH 2 , X = H 82 Q = CH 2 , X = 0-Buty I 50 77 Q = o, 85 Q = CH z> X = O-Buty I SCHEME XVI 89 SCHEME XV I I I T. 90, 91 EXAMPLE 1 S'-O-ft-ButyldimethylsilylJ-S'-O-Phthalimidothymidine, 2 To a solution of 5'-0-t-butyldimethylsilylthymidine [1, 21.36g, 60 mmol, prepared according to the procedure of Nair, V., and Buenger, G.S., Org. Prep. Procedures Int . , 22:57 (1990) in dry THF (750 ml)], triphenylphosphine (17.28g, 66 mmol) and N-hydroxyphthalimide (10.74g, 66 mmol) were added. The solution was cooled to 0°C and diisopropylazodicarboxylate (15.15g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH 2 C1 2 (750 ml) , extracted with sat. NaHC0 3 (200 ml) , and water (200 ml) , dried (MgS0 4 ) , filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et 2 0 gradient to 90% Et 2 0) of the residue gave compound 2 as a colorless glass (18.68g, 62%); H NMR (CDC1 3 ) δ 0.05 [2s, 6, (CH 3 ) 2 ], 0.91 [S, 9, (CH 3 ) 3 ], 2.0 (s, 3, CH 3 ) , 2.5 - 2.65 (m, 2, 2'CH 2 ), 4.05 - 4.2 (m, 2, 5'CH 2 ), 4.25 - 4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H), 6.15 (m, 1, l'H), 8.6 (br s, 1, NH) , and aromatic protons. Anal. Calcd. for C 24 H 31 N 3 0 7 Si: C, 57.46;H, 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27. EXAMPLE 2 3'-O-Amino-5'-O-(t-Butyldimethylsilyl)thymidine, 3 Cold methylhydrazine (1.6 ml, 30 mmol) was added to a stirred solution of 5'-0-(t-butyldimethylsilyl)-3 ' -O- phthalimidothymidine (2, 4.6 g, 9.18 mmol) in dry CH 2 C1 2 (60 ml) at 5-10°C. After 10 minutes white precipitation of 1,2- dihydro-4-hydroxy-2-methyl-l-oxophthalizine occurred. The suspension was stirred at room temperature for lh. The suspension was filtered and precipitate washed with CH 2 C1 2 (2x20 ml) . The combined filtrates were concentrated and the residue purified by silica gel column chromatography. Elution with CH 2 Cl 2 :MeOH (100:0 → 97:3, v/v) furnished the title compound (3.40g, 100%) as white solid. Crystallization from CH 2 C1 2 gave white needles, m.p. 171°C; 1 H NMR (CDC1 3 ) δ 0.05 [s, 6, (CH 3 ) 2 ], 0.90 [S, 9, (CH 3 ) 3 ], 2.22-2.58 (2m, 2, 2'CH 2 ), 3.9-4.08 (m, 3, 5'CH 2 , and 3'H) 4.30 (m, 1, 4'H) 5.5 (br s, 2, NH 2 ) 6.2 (m, 1, l'H) 7.45 (s, 1, C^) 8.9 (br s, 1, NH) . Anal. Calcd. for C 16 H 29 N 3 0 5 Si : C , 51 . 72 ; H , 7 . 87 ; N , 11 . 32 . found: C , 51. 87 , H, 7 .81 ; N , 11. 32 . EXAMPLE 3 3'-o-Aminothymidine, 4 3'-O-Amino-(t-butyldimethylsilyl)thymidine was deblocked with (Bu) 4 NF/THF in standard way to furnish compound 4 (72%) . Crystallized from ether/hexanes/ethanol as fine needles, mp 81°C. 1 H NMR (Me 2 SO-d 6 ) δ 1.78 (s, 3, CH 3 ) , 2.17 and 2.45 (2m, 2, 2'CH 2 ), 3.70 (m, 2, 5'CH 2 ), 3.88 (m, 1, 4'H), 4.16 (m, 1, 3'H), 4.8 (br S, 1, 5'OH), 6.05 (dd, 1, l'H), 6.2 (br s, 2 NH 2 ) , 7.48 (s, 1, C^) , and 11.24 (br ε, 1, NH) . Anal. Calcd. for C 10 H 15 N 3 O 5 : C, 46.69; H, 5.87; N, 16.33; found: C, 46.55; H, 5.91; N, 16.21. EXAMPLE 4 3'-0-Dephosphinico-3'-0-(Methylimino)thymidylyl-(3'→ 5')-5'- Deoxythymidine, 9 Step 1. 3'-O-Amino-5'-O-(t-butyldimethylsily1)thymidine (3, 1.85g, 5 mmol), 3'-O-(t-butyldimethylsilyl)thymidine-5'- aldehyde [5, 2.39g, 5 mmol; freshly prepared by following the method of M.J. Camarasa, F.G. De las Heras, and M.J. Perez- Perez, Nucleosides and Nucleotides , 9:533 (1990)] and AcOH (0.25 ml) were stirred together in CH 2 C1 2 (50 ml) solution at room temperature for 2 h. The products were then concentrated under reduced pressure to give the intermediate oxime linked dimer, compound 6. Step 2. The residue obtained from Step 1 was dissolved in AcOH (25 ml). NaCNBH 3 (1.55g, 25 mmol, in 3-portions) was added to the stirred AcOH solution at room temperature. The solution was stirred for 30 min to give the intermediate imine linked dimer, compound 7. Step 3. Aqueous HCHO (20%, 2 ml, 66 mmol) and additional NaCNBH 3 (1.55g, 25 mmol, in 3-portions) was added to the stirred reaction mixture of Step 2 at room temperature. After 2h, the solution was diluted with EtOH (100 ml) , and resulting suspension was evaporated under reduced pressure. The residue was dissolved in CH 2 C1 2 (150 ml) and then washed successively with 0.1 M HCl (100 ml) , saturated aqueous NaHC0 3 (100 ml) , and water (2x 50 ml) . The dried (MgS0 4 ) CH 2 C1 2 solution was evaporated to give crude methylated i ine linked dimer 8. Step 4. The residue from Step 3 was dissolved in the THF (30 ml) and a solution of (Bu) 4 NF (1 M in THF, 10 ml) was added while stirring at room temperature. After 1 h, the reaction mixture was evaporated under reduced pressure and the residue was purified by short column chromatography. The appropriate fractions, which eluted with CH 2 Cl 2 :MeOH (8:2, v/v) were pooled and evaporated to give compound 9 as a foam (0.74 g, 30%). H NMR (Me 2 SO-d 6 ) δ 1.78 (s, 6, 2CH 3 ) , 2.10 (m, 4, 2'CH 2 ), 2.5 (s, 3, N-CH 3 ) , 2.8 (m, 2, 5'-N-CH 2 ), 3.6 - 4.08 (5m, 6, 5' CH 2 , 4' CH, 3' CH) , 4.75 and 5.3 (2 br s, 2, 3' and 5' OH), 6.02 (d, 1, l'H), 6.1 (t, 1, l'H), 7.4 and 7.45 (2s, 2, 20^), 11.3 (br s, 2, NH) . EXAMPLE 5 5'-O-( -Butyldimethylsilyl)-3'-Deoκy-3'-[(Methylenea ino)oxy]- thymidine, 10 A solution of HCHO (20% aqueous, 1 ml) was added dropwise to a stirred solution of 3'-O-amino-S'-O-(t- butyldimethylsilyl)thymidine (3, 7.42 g, 20 mmol) in dry MeOH (400 ml) at room temperature. After 6 h, another portion of HCHO (20% aqueous, 1.5 ml) was added and stirring continued for 16 h. The resulting solution was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give compound 10 (7.25 g, 95%) as clear foam. 1H NMR (CDC1 3 ) δ 0.1 [S, 3, (CH 3 ) 2 ], 0.9 [s, 9, (CH 3 ) 3 ], 1.9 (s, 3, CH 3 ) , 2.25 - 2.72 (m, 2, 2' CH 2 ) , 3.85 - 4.15 (2m, 3, 5' CH 2 , 4' H) , 4.85 (m, 1, 3'H), 6.25 (dd, 1, l'H), 6.5 and 6.95 (2d, 2, N=CH 2 ) , 7.43 (s, 1, (6H) , 9.2 (br s, 1 NH) . EXAMPLE 6 3'-O-(t-Butyldiphβnylsilyl)-5'-Dβoxy-5'-Iodothymidine 12 To a stirred solution of 3'-0-(t-butyldiphenylsilyl)- thymidine [11, 10.Og, 20.83 mmol, prepared according to the procedure of Koster, H. and Sinha, N.D., ret. Letts . , 26:2641 (1982)] in dry DMF (375 ml) was added methyltri- phenoxyphosphonium iodide (12.12g, 30 mmol) under argon at room temperature. The solution was stirred for 16h. The DMF was removed under reduced pressure and the residue was dissolved in CH 2 C1 2 (500 ml) . The organic layer was washed with 20% aqueous Na 2 S 2 0 3 (200 ml) , water (2x200 ml) and dried (MgS0 4 ) . The solvent was evaporated and the residue was purified by silica gel chromatography. Elution with Et 2 0: Hexanes (1:1,v/v), pooling of appropriate fractions and concentration furnished compound 12 as white power (7.87g, 64%, mp 142°C). Anal. Calcd. for C 26 H 31 N 2 0 4 SiI: C, 52.88; H, 5.29; N, 4.74; I, 21.33. Found: C,52.86; H, 5.21; N, 4.66; I, 21.54. EXAMPLE 7 5'-θ-(t-Butyldimethylsilyl)-3'-0-Dephosphinico-3 , -o-(Imino- methylene)thymidylyl-(3'→ 5')-3'-θ-(t-Butyldiphenylsilyl)-5'- Deoxythymidine, 13 A stirred solution of 5'-0-(t-butyldimethylsilyl)-3'- deoxy-3'-[ (methyleneamino)oxy]thymidine (10, 1.62 g, 4.23 mmol) , 3'- -(t-butyldiphenylsilyl)-5'-deoxy-5'-iodothymidine (12, 2.5 g, 4.23 mmol), bis(trimethylstannyl)benzopinacolate [4.84 g, 8.46 mmol, prepared according to the method of Hillgartner, H; Neumann, W.P.; Schroeder, B., Liebigs Ann . Chem . , 586-599 (1975)] in dry benzene (9 ml) was carefully degassed 3-times (flushed with argon) and heated at 80°C for 8 h. The reaction mixture was cooled and concentrated under reduced pressure and the residue was purified by silica gel chromatography. The appropriate fractions, which were eluted with CH 2 Cl 2 :MeOH (97:3, v/v), were pooled and concentrated to give dimeric oligonucleoside, compound 13 (1.25 g, 35%) as white foam. H NMR (CDC1 3 ) δ 0.09 and 0.13 [2s, 6, (CH 3 ) 2 ], 0.89 and 1.06 [2s, 9, (CH 3 ) 3 ], 1.07 and 1.08 [2s, 9, (CH 3 ) 3 ], 1.87, and 1.90 (2s, 6, 2 CH 3 ) , 5.74 (br s, 1, NH) , 6.20 - 6.31 (2m, 2, 2 l'H), 6.88 (S, 1, C^) , 10.33 and 10.36 (2 br s, 2, 2NH) and other protons. EXAMPLE 8 3 , -0-Dephosphinico-3'-()-[ (Mβthyli ino)mβthylene]thymidylyl- (3'→ 5')-3'-0-(t-Butyldiphβnylsilyl)-5 , -Dβoxythymidine, 14 Method A Compound 13 was treated as per the procedure of Step 3 of Example 4 to simultaneously N-alkylate the imino nitrogen and deblock the 5' silyl blocking group of the 5' nucleoside of the dimer to yield compound 14 as a foam. 1 H NMR (CDC1 3 ) δ 1.07 (S, 9, (CH 3 ) 3 ) , 1.85 and 1.88 (2s, 6, 2CH 3 ) , 2.56 (s, 3, N-CH 3 ) , 4.77 (br s, 1, 5' OH) , 6.1 and 6.2 (2m, 2, l'H) , 7.4 and 7.62 (2m, 10, Ph H) , 9.05 (br s, 2, 2 NH) , and other protons. EXAMPLE 9 3'-o-Dephosphinico-3'-0-[ (Methylimino)methylene]thymidylyl- (3'→ 5')-5'-Deoxythymidine, 15 The 3'-0-(t-butyldiphenylsilyl) blocking group of compound 14 is removed as per the procedure of Step 4 of Example 4 to yield the fully deblocked dimeric oligonucleoside, compound 15. EXAMPLE 10 3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene]-5'-Iodo5'- Deoxythymidylyl-(3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'-Deoxy- thymidine, 16 Compound 14 is treated as per the procedure of Example 6 to yield the title dimeric oligonucleoside, compound 16, having a reactive iodo functionality at the terminal 5' position and a blocking group remaining at the 3' position. EXAMPLE 11 S'-O-(t-Butyldimethylsilyl)-3 , -0-Dephosphinico-3'-0-(Imino¬ methylene) thymidylyl- (3'→ 5' ) -3'-O-Dephosphinico-3 '-O- [ (Methyimino)methylene]-5'-Deoxythymidylyl-(3'→ 5')-3'-O-(t- Butyldiphenylsilyl)-5'-Deoxythymidine, 17 Compound 16 is reacted with compound 10 utilizing the conditions of Example 7 to extend the oligonucleoside to yield the trimeric oligonucleoside, compound 17. EXAMPLE 12 3'-O-Dephosphinico-3'-0-[ (Methylimino)methylene]thymidylyl- (3 '→ 5')-3'-O-Dephosphinico-3'-O-[ (Methyimino)methylene]-5'- Deoxythymidylyl-(3'→ 5')-3'-O-(t-Butyldiphenylsilyl)-5'-Deoxy- thymidine, 18 Compound 17 when reacted as per the conditions of Example 8 will undergo N-alkylation to the trimeric oligonucleoside and will be deblock at the 5' position to yield compound 18, wherein n = 2. EXAMPLE 13 3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene]thymidyly1- (3'→ 5')-3'-O-Dephosphinico-3'-0-[ (Methyimino)methylene]-5'- Deoxythymidylyl-(3 '→ 5')-3'-O-Dephosphinico-3'-O-[ (Methyimino)- methylene]-5'-Deoxythymidylyl-(3 '→ 5')-5'-Deoxythymidine, 20 The sequence of Examples 10, 11 and 12 is repeated for the addition of a further nucleoside to extend the oligonuc- leoside to a tetramer, compound 19. The tetrameric oligonucleoside 19 is then treated as per the procedure of Example 9 to remove the terminal 3' silyl blocking group yielding the fully deblocked tetrameric oligonucleoside, compound 20. EXAMPLE 14 Methyl 3-0-(t-Butyldiphenylsilyl)-2,5-Dideoxy-5-C-Pormyl-o/β-D- eryth-ro-Pentofuranoside, 23 2-Deoxy-D-ribose, 21, was modified to methyl 2-deoxy- a/β-D-erythro-pentofuranoside (prepared according to the method of M.S. Motawai and E.B. Pedersen, Liebigs Ann. Chem. 1990, 599-602) , which on selective tosylation followed by 3-0- silylation gave methyl 3-0-(t-butyldimethylsilyl)-2-deoxy-5-0- tosyl-α/β-D-erythro-pentofuranoside in overall 70% yield. The latter compound on iodination followed by cyanation gave the corresponding 5-C-cyano intermediate compound 22, as a syrup. 1 H NMR (CDC1 3 ) δ 1.05 (s, 9, (CH 3 ) 3 ), 1.9-2.38 (m, 4, 2 CH 2 ) , 3.3 and 3.4 (2s, 3, OCH 3 ) , 3.98-4.30 (3m, 2, 3, 4-CH) , 4.95 and 5.05 (2m, 1, 1H) , 7.4 and 7.7 (2m, 10, Ph H) . IR (neat) 2253 cm " (CH 2 CN) ] • Compound 22 (stored at 0°C without any degradation) was reduced(DIBAL-H) freshly every time as and when the title compound 23 was required. EXAMPLE 15 5'-O-(t-Butyldimethylsilyl)-2',3'-Dideoxy-3' [ (Methyleneamino)- oxy]adenosine, 27; S'-O-(t-Butyldimethylsilyl)-2',3'-Dideoxy- 3'-[ (Methyleneamino)oxy]cytidine, 28; and 5'-0-(t-Butyldi- methylsilyl)-2',3'-Dideoxy-3'-[ (Methyleneamino)oxy]guanosine, 29 3'- -Amino-2'-deoxyadenosine, compound 24, 3'-O-amino- 2'-deoxycytidine, compound 25, and 3'-O-amino-2'-deoxyguano- sine, compound 26, prepared as per the procedures of European Patent Application 0 381 335 or in a manner analogous to the preparation of compound 4 by the procedure of Example 3 above, are blocked at their 5' position with a t-butyldimethylsilyl group according to the procedure of Nair, V. , and Buenger, G.S., Org. Prep . Procedures Int . , 22:57 (1990) to give the corresponding 3'-O-amino-5'-(t-butyldimethylsilyl) -2'- deoxyadenosine, 3'-O-amino-5'-(t-butyldimethylsilyl)-2'- deoxycytidine and 3'-O-amino-5'-(t-butyldimethylsilyl)-2'- deoxyguanosine nucleoside intermediates. Treatment of the blocked intermediate as per the procedure of Example 5 or as per the procedure of Preparation example 4 of European Patent Application 0 381335 gives the corresponding 5'-0-(t-butyldi¬ methylsilyl)-2' ,3'-dideoxy-3'-[ (methyleneamino)oxy]adenosine, compound 27; 5'-0-( -butyldimethylsilyl)-2' ,3'-dideoxy-3'- [ (methyleneamino)oxy]cytidine, compound 28; and 5'-0-(t- butyldimethylsilyl) -2 ' , 3 ' -dideoxy-3 ' - [ (methylene¬ amino)oxy]guanosine, compound 29. EXAMPLE 16 3'-O-( -Butyldiphenylsilyl) hymidine-6'-Aldehyde, 31 The title compound is prepared by homologation of the above described 3'-O-(t-butyldimethylsilyl)thymidine-5'- aldehyde (compound 5) utilizing the procedure of Barton, D.H.R. et al . , Tet . Letts . , 30:4969 (1989). The 5'-aldehyde, compound 5, is treated via a itig reaction with (methoxymethylidene)triphenylphosphate. The resulting enol ether, compound 30, is hydrolyzed with Hg(OAc) 2 , KI, H 2 0 and THF according to the procedure of Nicolaou, K.C., et al . , J. Am . Chem . Soc , 102:1404 (1980) to furnish the compound 31. EXAMPLE 17 5'-O-(t-Butyldimethylsilyl)-3'-O-Dephosphinico-3'-O-(Nitrilo- ethylidyne)thymidylyl-(3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'- Deoxythymidine, 32 The title compound is prepared by reaction of compound 31 and compound 3 in the manner of Example 4, Step l to furnish the dimeric oligonucleoside having an oxime backbone. EXAMPLE 18 3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene]thymidyly1- (3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'-Deoxythymidine, 14 Method B Compound 32 when treated as per the procedure of Steps 2 and 3 of Example 4 will also yield compound 14. EXAMPLE 19 Methyl 3'-O-Dephosphinico-3'-θ-[ (Methyimino)methylene]- thymidylyl-(3'→ 5)-3-O-(t-Butyldiphenylsilyl)-2,5-Dideoxy-α/β- D-erytJiro-Pentofuranoside, 33 Compound 23 and compound 3 are linked utilizing the procedure of Example 4, Steps 1 to couple the sugar and the nucleoside via an oxime linkage. The resulting oxime linkage is then reduced utilizing the procedure of Example 4, Step 2 to an iminomethylene linkage and this linkage, in turn, when N- alkylated via the procedure of Example 4, Step 3 will yield compound 33. EXAMPLE 20 Acetyl 5'-O-Benzoy1-3'-O-Dephosphinico-3'-O-[(Methyimino)- methylene]thymidylyl-(3 '→ 5)-3-0-(t-Butyldiphenylsilyl)-2,5- Dideoxy-α/β-D-e-rytixro-Pentofuranoside, 34 Compound 33 will be treated with benzoyl chloride according to the procedure of Jenkins et al . , Synthetic Proce¬ dures in Nucleic Acid Chemistry, Zorbach and Tipson, Ed., Vol. 1, John Wiley & Sons, Pg. 149, to benzoylate the free 5'- hydroxyl of compound 33 which is hydrolyzed and acylated in situ according to the procedure of Baud et. al, Tet . Letts . , 31:4437 (1990) to yield compound 34. EXAMPLE 21 5'-Benzoyl-3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene]- thymidylyl-(3'→ 5')-3'-O-(t-Butyldiphenylsilyl)-5'-Deoxy- thymidine, 35 Compound 34 is reacted with silylated thy ine as per the procedure of Baud, et al . , Tetrahedron Letters , 31:4437 (1990) utilizing dibenzo-18-crown-6 and potassium iodide in acetonitrile-toluene to yield 5'-0-benzoyl-3'-O-dephosphinico- 3 ' -O-[ (methyli ino)methylene]thymidylyl-(3 ' → 5' ) -3' -O-(t- butyldiphenylsilyl)-5'-deoxythymidine, compound 35 as an anomeric mixture. EXAMPLE 22 3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene] hymidylyl- (3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'-Deoxythymidine, 14 Method C Compound 35 when treated with methanolic ammonia will also yield compound 14. Further treatment as per the procedure of Example 9 will yield the fully deblocked dimer, from which anomerically pure compound 15 will be isolated by chromatography. EXAMPLE 23 3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene]thymidylyl- (3'→ 5')-3'-O-(t-Butyldiphenylsilyl)-5'-Deoxyadenosine, 36 Compound 34 is reacted with silylated adenine as per the procedure of Baud, et al . , Tetrahedron Letters , 31:4437 (1990) utilizing dibenzo-18-crown-6 and potassium iodide in acetonitrile-toluene. Removal of the benzoyl group with methanolic ammonia and chromatographic separation will yield 3'-O-dephosphinico-3' -O-[ (methylimino)methylene]thymidylyl- (3'→ 5')-3'-0-(t-butyldiphenylsilyl)-5'-deoxyadenosine, 36. EXAMPLE 24 3'-O-Dephosphinico-3'-O-[ (Methylimino)methylene]thymidylyl- (3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'-Deoxycytidine 37 Compound 34 is reacted with silylated cytosine as per the procedure of Baud, et al . , Tetrahedron Letters , 31:4437 (1990) utilizing dibenzo-18-crown-6 and potassium iodide in acetonitrile-toluene. Removal of the benzoyl group with methanolic ammonia and chromatographic separation will yield 3'-O-dephosphinico-3' -O-[ (methylimino)methylene]thymidylyl- (3'→ 5')-3'-O-(t-butyldiphenylsilyl)-5'-deoxycytidine, 37. EXAMPLE 25 3 '-O-Dephosphinico-3'-O-[ (Methylimino)methylene]thymidylyl- (3'→ 5')-3'-O-(t-Butyldiphenylsilyl)-5'-Deoxyguanosine 38 Compound 34 is reacted with silylated guanine as per the procedure of Baud, et al . , Tetrahedron Letters , 31:4437 (1990) utilizing dibenzo-18-crown-6 and potassium iodide in acetonitrile-toluene. Removal of the benzoyl group with methanolic ammonia and chromatographic separation will yield 3 '-O-dephosphinico-3' -O-[ (methylimino)methylene]thymidyly1- (3'→ 5' )-3'-O-(t-butyldiphenylsilyl) -5'-deoxyguanosine, 38. EXAMPLE 26 A-(3'→ 5')-T; A-(3'→ 5')-A; A-(3'→ 5')-C; and A-(3'→ 5' )-G 3'- Dephosphinico-3'-(Methylimino)methylene Linked Dimers in a manner analogous to the procedures of Examples 19 and 20, the 5'-(t-butyldimethylsilyl) -3'- -aminoadenosine intermediate of Example 15 will be reacted with compound 3 to yield a linked nucleoside-sugar compound equivalent to compound 34 wherein Bxi is adenine. The linked nucleoside-sugar intermediate will then be reacted as per the procedures of Examples 21, 23, 24 and 25 to yield the A-T, A-A, A-C and A-G dimers, respectively, of a structure equivalent to that of compound 14 where Bxi is adenine and Bxj is thymine, adenine, cytosine and guanine, respectively. EXAMPLE 27 C-(3'→ 5')-T; C-(3'→ 5')-A; C-(3'→ 5')-C; and C-(3'→ 5')-G 3'-Dephosphinico-3'-(Methylimino) ethylene Linked Dimers In a manner analogous to the procedures of Examples 19 and 20, the 5'-(t-butyldimethylsilyl)-3'- -aminocytidine intermediate of Example 15 will be reacted with compound 3 to yield a linked nucleoside-sugar compound equivalent to compound 34 wherein Bxi is cytidine. The linked nucleoside-sugar intermediate will then be reacted as per the procedures of Examples 21, 23, 24 and 25 to yield the C-T, C-A, C-C and C-G dimers, respectively, of a structure equivalent to that of compound 14 where Bxi is cytosine and Bxj is thymine, adenine, cytosine and guanine, respectively. EXAMPLE 28 G-(3'→ 5')-T; G-(3'→ 5')-A; G-(3'→ 5')-C; and G-(3'→ 5')-G 3'-Dephosphinico-3'-(Methylimino)methylene Linked Dimers In a manner analogous to the procedures of Examples 19 and 20, the 5'-(t-butyldimethylsilyl) -3'-O-aminoguanosine intermediate of Example 15 will be reacted with compound 3 to yield a linked nucleoside-sugar compound equivalent to compound 34 wherein Bxi is guanine. The linked nucleoside-sugar intermediate will then be reacted as per the procedures of Examples 21, 23, 24 and 25 to yield the G-T, G-A, G-C and G-G dimers, respectively, of a structure equivalent to that of compound 14 where Bxi is guanine and Bxj is thymine, adenine, cytosine and guanine, respectively. EXAMPLE 29 Trimeric, Tetrameric, Pentameric, Hexameric And Other Higher Order Oligonucleosides Having a Selected Nucleoside Sequence The dimers of Examples 21, 23, 24, 25, 26, 27 and 28 are extended by reaction with the 5'-(t-butyldimethylsilyl) -3'- deoxy-3'-[ (methyleneamino) oxy] nucleosides, compounds 10, 27, 28 and 29, of Examples 5 and 15 to form trimers utilizing the looping sequence of reactions of Examples 10, 11 and 12. Iteration of this reaction sequence loop adds a further nucleoside to the growing oligonucleoside per each iteration of the reaction sequence loop. The reaction sequence loop of Examples 10, 11 and 12 is- repeated "n" number of times to extend the oligonucleoside to the desired "n+1" length. The final 3'-blocked oligonucleoside when treated as per the procedure of Example 9 to remove the terminal 3'-0-(t- butyldiphenylsilyl) blocking group will yield the fully deblocked oligonucleoside of the selected nucleoside sequence and length. EXAMPLE 30 6'-Amino-6'-Deoxy-5'-Homothymidine, 42; 6'-Amino-2',6'-Dideoxy- 5'-Homoadenosine, 43; 6'-Amino-2',6'-Dideoxy-5'-Homocytidine, 44; and 6'-Amino-2',6'-Dideoxy-5'-Homoguanosine, 45 (Via An Intramolecular Free Radical Reaction) Deblocking of compound 10 is effected by treatment with BuNF in THF. The resulting compound 39 (also reported in Preparation example 4 of European Patent application 0 381 335 Al) will be iodinated upon treatment with methyltri- phenoxyphosphonium iodide as per the procedure of Verheyden, J.P.H. and Moffatt, J.G., J. Org . Chem . , 35:2119 (1970) to furnish 5'-deoxy-5'-iodo-3'-O-methyleneaminothymidine, compound 40. Compound 40 when subjected to an intramolecular free radical reaction according to the procedure of Curran, D.P., Radical Addition Reactions, In Comprehensive Organic Synthesis : Trost, B.M. and Fleming, I., Eds., vol. 4, p 715-832, Pergamon Press, Oxford (1991), will give the corresponding 3'-0- isoxazolidinethymidine, compound 41 which on DIBAL-H reduction will yield 6'-amino-5'-homothymidine, compound 42 [the 3'-(t- butyldimethylsilyl) derivative of this compound is reported in Rawson, T.E. and Webb, T.R. , Nucleosides & Nucleotides , 9:89 (1990) ] . When reacted in a like manner compounds 27, 28 and 29 will give 6'-amino-5'-homoadenosine, compound 43; 6'-amino-5'- homocytidine, compound 44; and 6'-amino-5'-homoguanosine, compound 45. EXAMPLE 31 3'-0-(t-Butyldiphenylsilyl)-5'-Deoxy-5'-C-Allylthymidine 46 A stirred solution of 3'-0-(t-butyldiphenylsilyl)-5'- deoxy-5'-iododthymidine (12, 1.77g, 3 mmol), allytributyltin (2.97g, 9 mmol) and AIBN (0.54g, 3.3 mmol) in dry toluene (30 ml) was degassed completely and heated at 65°C for 6 hr. The solution was cooled and concentrated under vacuo. The residue was purified by silica gel column chromatography and on elution with hexanes:EtOAc (1:1, v/v) furnished the title compound as homogeneous material. Appropriate fractions were pooled and evaporated to furnish 46, 0.75 g of a white foam, 50% yield. The structure was confirmed by H NMR. EXAMPLE 32 3'-O-(t-Butyldiphenylsilyl)-5-Deoxy-7'-C-Aldehydothymidine 47 A solution of 46 (1 mmol), OsO A (0.1 mmol) and n- methylmorpholine oxide (2 mmol) in diethyl ether (4 ml) and water (2 ml) are stirred for 18 hr at room temperature. A solution of NaI0 4 (3 ml) is added and the solution further stirred for 12 hr. The aqueous layer is extracted with diethyl ether. Evaporation of the organic layer will give the crude aldehyde 47. EXAMPLE 33 5 ' -O- ( -Butyldimethylsilyl) -3 '-O-Dephosphinico-3 '-O- (Iminomethylene) hymidylyl-(3'→ 5')-3'-θ-(t-Butyldiphenyl- silyl)-5'-Deoxy-5'-Hydroxythymidine, 48 Utilizing the procedure of Hana oto, T. and Inanaga, J., Tet . Letts . , 32:3555 (1991), Sml 2 (0.1 mmol) in THF (3 ml) is added to a mixture of compound 5 and compound 10 in HMPA (0.5 ml) with stirring. The mixture will be stirred at room temperature for about 15 mins to form the adduct (as detected by the fading color) . The solvent will be removed and the residue purified by column chromatography to give the dimeric oligonucleoside 48. EXAMPLE 34 3 '-O-Dephosphinico-3'-0-[N-(Morpholin-2-yl) ]thymidylyl- (3'→ 4')-3'-O-(t-Butyldiphenylsilyl) -5'-Deoxy-5'-Demeth- ylenethymidine, 49 Utilizing the modification of Lim, M.-I. and Pan, Y.- G., Book of Abstracts, 203 ACS national Meeting, San Francisco, CA. , April 5-10, 1992, of the procedure of Hill, J. and Ramage, G.R. J., J . Chem . Soc , 3709 (1964), the dimeric oligonucleoside of Example 33 (compound 48, 1 equiv.) will be treated with chloroacetyl chloride in acetone to form an adduct with the amino group of the linkage. Further treatment with K 2 C0 3 (1.2 equiv. ) in DMSO at elevated temperature will cyclize the adduct to the hydroxyl group of the linkage to form a 5- oxomorpholino adduct with the linkage. The oxomorpholino adduct is then reduced with BH 3 -THF under reflux to yield the dimer linked via an -0-[N-(morpholin-2-yl) ]- linkage, compound 49. EXAMPLE 35 N3-Benzoyl-l-(5'-O-Dimethoxytrityl-3'-O-Trifluoromethyl- sulfonyl-threo-Pentofuranosyl)thymine, 50 The method of Horwitz, J.P. et al . , J . Org . Chem . , 29:2076 (1964) will be utilized to prepare the title compound with substitution of the trifluoromethanesulfonic an- hydride/pyridine (-50°C to 0°C) reaction conditions of Fleet, G.W. J. et al . , Tetrahedron , 44:625 (1988) for the methylsulfonic anhydride conditions of Horwitz et al . EXAMPLE 36 6'-O-Phthalimido-5'-Homothymidine, 52 To a stirred mixture of 5'-homothymidine [Etzold, G., Kowollik, G. , and Langen, R. , Chemical Communications , pg 422 (1968)] (51, 1.28. g, 5 mmol) , N-hydroxyphthalimide (1.09 g, 6.6 mmol) and triphenylphosphine (1.75 g, 6.6 mmol) in dry DMF (25 ml) will be added diisopropylazodicarboxylate (1.5 ml, 7.5 mmol) over a period of 30 min at 0°C. The stirring is continued for 12 hr at room temperature. The solvent is evaporated under vacuo and the residue is washed with diethyl ether (2x50 ml) . The residue will then be suspended in hot EtOH (50 ml) , cooled and filtered to give the title compound 52. EXAMPLE 37 6'-0-Phthalimido-3'-0-(t-Butyldiphenylsilyl)-Homothymidine 53 Compound 52 will be treated with t-butyldiphenyl- chlorosilane in pyridine and imidazole in a standard manner t afford the title compound 53. EXAMPLE 38 6'-o-Amino-3'-O-(t-Butyldiphenylsilyl)-5'-Homothymidine, 54 To a stirred solution of compound 53 in dry CH 2 C1 2 is added methylhydrazine (3 mmol) under anhydrous conditions at room temperature. The solution is stirred for 12 hr, cooled (0°C) and filtered. The precipitate will be washed with CH 2 C1 2 and the combined filtrates will be concentrated. The residue is purified by flash column chromatography (silica gel, 20 g) . Elution with CH 2 Cl 2 :MeOH, 9:1, v/v) will furnish the title compound 54. EXAMPLE 39 3'-De(oxophosphinico)-3'-(Iminooxymethylene) -5'-Trityl- thymidylyl- (3'→ 5')-3'-θ- (t-Butyldiphenylsilyl) -5 '- Deoxythymidine, 55 6'-O-Amino-3'-O-(t-butyldiphenylsilyl) -5'-homo¬ thymidine, 54, is converted to the corresponding urethane with ethyl chloroformate (CH 2 Cl 2 -saturated NaHC0 3 ) utilizing the stereospecific conditions of Yang, D. , Kim, S.-H. and Kahne, D., J " . Am . Chem . Soc . , 113:4715 (1991). The residue of this reaction will then be stirred in CH 2 C1 2 with compound 50. The products are then concentrated in vacuo to yield the dimeric oligonucleoside, compound 55. EXAMPLE 40 3'-De(oxophosphinico)-3'-[Methyl(iminooxymethylene) ]-5'-Trityl- thymidylyl-(3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'-Deoxy- thymidine, 56 Compound 55 will be N-alkylated as per the conditions of Step 3 of Example 4 to yield the N-alkylate iminooxy¬ methylene linked dimeric oligonucleoside 56. EXAMPLE 41 3'-De(oxophosphinico) -3'-[Methyl (iminooxymethylene) ]-5'- Dimethoxytritylthymidylyl-(3'→ 5')-5'-Deoxythymidine, 57 The δ'-O-trityl and the 3'-0-(t-butyldiphenylsilyl) protecting groups of compound 56 will be removed by treatment with trifluoroacetic acid and the residue dimethoxytritylated as per the procedure of Sproat, B.S. and La ond, A.I., 2 '-0- Methyloligoribonucleotides: synthesis and applications, Oligo¬ nucleotides and Analogs A Practical Approach, F. Eckstein Ed. , IRL Press, pg. 55 (1991) , to give the title compound. EXAMPLE 42 3'-De(oxophosphinico)-3'-[Methyl(iminooxymethylene) ]-5'- Dimethoxytritylthymidylyl-(3'→ 5')-3'-[ (β-Cyanoethoxy)-N-(di- isopropyl)phosphiryl]-5'-Deoxy hymidine, 58 Compound 57 (1.89 mmol) will be dissolved in anhydrous dichloromethane under an argon atmosphere. Diisopropyl- ethylamine (0.82 ml, 4.66 mmol) is added and the reaction mixture cooled to ice temperature. Chloro(diisopropylamino)-β- cyanoethoxyphosphine (0.88 ml, 4.03 mmol) is added to the reaction mixture and the reaction mixture is allowed to warm to 20°C and stirred for 3 hr. Ethylacetate (80 ml) and triethylamine (1 ml) are added and the solution is washed with brine solution three times (3 x 25 ml) . The organic phase is separated and dried over magnesium sulfate. After filtration of the solids the solvent is evaporated in vacuo at 20°C to an oil that will then be purified by column chromatography using silica and a solvent such as hexane-ethyl acetate-triethylamine (50:40:1) as eluent. The fractions are then evaporated in vacuo and the residue will be further evaporated with anhydrous pyridine (20 ml) in vacuo (1 torr) at 26°C in the presence of sodium hydroxide for 24 hr to yield the title compound 58. EXAMPLE 43 5'-Amino-5'-Homothymidine, 60 5'-Amino-3'-O-(t-butyldimethylsilyl)-5'-homothymidine 59 is prepared as per Rawson, T.E.. and Webb, T.R. , Nucleo- sides & Nucleotides , 9:89 (1990). The t-butyldimethylsilyl group will be removed as per the procedure of Step 4 of Example 4 to give the title compound. EXAMPLE 44 5'-Methylamino-3'-O-(t-Butyldiphenylsilyl)-5'-Homothymidine, 62 Compound 60 is t-butyldiphenylsilated as per the procedure of 37 to give 5'-Amino-3'-O-(t-butyldiphenylsilyl)- 5'-homothymidine, compound 61, which will then be treated as per the procedure of Step 3 of Example 4 alkylate the 5'-amino group to yield the title compound 62. EXAMPLE 45 3'-Dephosphinico-3'-s-[(Methylimino) ethylene]-5'-Monomethoxy- trityl-3'-Thiothymidylyl-(3'→ 5')-3'-(t-Butyldiphenylsilyl)-5'- Deoxythymidine, 64 5'-Methylamino-3 '-O- (t-butyldiphenylsilyl) -5'- homothymidine 62 (1 mmol) will be added to aqueous sodium hypo- chloride (4 mmol) to furnish a chloramide intermediate. The chloramide intermediate is cooled (0°C) and treated with 5'-0- monomethoxytrity-3'-thiothymidine (0.9 mmol), compound 63, prepared as per Cosstick, R. and Vyle, J.S., Nucleic Acids Res . , 18:829 (1990). The reaction mixture is worked up utilizing the procedure of Barton, D.H.R. et al . , J . Org . Chem . , 56:6702 (1991) and the residue will be purified by chromatography to give the title compound 64. EXAMPLE 46 3'-Dephosphinico-3'-s-[(Methylimino) ethylene]-5'-Monomethoxy- trityl-3'-Thiothymidylyl-(3'→ 5')-5'-Deoxythymidine, 65 Compound 64 will be deblocked at the terminal 3' position utilizing the as per the procedure of Step 4 of Example 4 to give compound 65. EXAMPLE 47 3'-Dephosphinico-3'-S-[(Methylimino) ethylene]-5'-Monomethoxy- trityl-3'-Thiothymidylyl-(3'→ 5')-3'[ (β-Cyanoethoxy)-N-(diiso- propy1) hosphortityl]-5'-Deoxythymidine 66 Compound 65 will be phosphitylated as per the procedure of Example 42 to give the title compound 66. EXAMPLE 48 5'-O-(t-Butyldimethylsilyl)-3'-De(oxyphosphinico)-3'-(Imino- 1,2-Ethanediyl)thymidylyl-(3'→ 5')3'-O-(t-Butyldiphenylsilyl)- 5'-Deoxythymidine, 68 3 '-Amino'-5'-0-(t-butyldimethylsilyl) -3 '-deoxy- thymidine, compound 67, prepared according to Matsuda, A., Satoh, M. and Ueda, T., Nucleoside & Nucleotides , 9:587 (1990) will be reductively coupled with compound 47 in the presence of a catalytic amount of acid as per the procedure of Magid et. al , Tett . Lets . , 31:5595 (1990), to yield the Schiff's base intermediate that is reduced in situ to give the amino linkage of the title compound 68. EXAMPLE 49 3 ' -De (oxyphosphinico) -3 ' - [ (Methylimino) -1 , 2 -Ethanediyl ] - thymidy lyl - ( 3 ' → 5 ' ) - 3 ' -O- ( t-Butyld ipheny l s i ly l ) - 5 ' - Deoxythymidine, 69 Compound 68 will be methylated and deblocked at the 5 ' position as per the procedure of Step 3 of Example 4 to yield the N-alkylated 5 ' -deblocked dimer, compound 69. EXAMPLE 50 3'-De(oxyphosphinico)-5'-Dimethoxytrity1-3'-[(Methylimino)-1,2- Ethanediyl]thymidylyl-(3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'- Deoxythymidine, 70 Compound 69 will be dimethoxytritylated as per the procedure of Sproat, B.S. and Lamond, A.I., 2'-O-Methyloligo- ribonucleotides: synthesis and applications, Oligonucleotides and Analogs A Practical Approach, F. Eckstein Ed., IRL Press, pg. 55 (1991). EXAMPLE 51 3'-De(oxyphosphinico)-5'-Dimethoxytrityl-3'-[ (Methylimino)-1,2- Ethanediyl]thymidylyl-(3 '→ 5')-5'-Deoxythymidine, 71 The dimethoxytritylated intermediate, compound 70 when deblocked at the 3' terminus as per the procedure of Step 4 of Example 4 will give compound 71. EXAMPLE 52 3'-De(oxyphosphinico)-5'-Dimethoxytrityl-3'-[(Methylimino)-1,2- Ethanediyl]thymidylyl-(3 '→ 5')-3'-[ (β-Cyanoethoxy)-N-(diiso- propyl)phosphiryl]-5'-Deoxythymidine, 72 Compound 71 will be phosphitylated as per the procedure of Example 42 to give the title compound 72. EXAMPLE 53 2'-O-Methylhomoadenosine, 74 Homoadenosine, 73, prepared as per the procedure of Kappler, F. and Hampton, A., Nucleic Acid Chemistry, Part 4 , Ed. L.B. Townsend and R. S. Tipson, Wiley-Interscience Publication, pg. 240 (1991), will be blocked across its 3' and 5' hydroxyl groups with a TIPS, i.e. tetraisopropylsilyl, blocking group followed by alkylation as per the procedures described in United States patent applications 566,977, filed Aug. 13, 1990 and PCT/US91/05720, filed Aug. 12, 1991. Removal of the TIPS group with tetra-n-butylammonium fluoride as per the procedure of Step 4 of Example 4 will yield the title compound 74. EXAMPLE 54 6'-O-Amino-3'-O-(t-Butyldiphenylsilyl)-5'-Homoadenosine, 75 Compound 74 will be treated as per the procedures of Examples 36, 37 and 38 to yield the title compound 75. EXAMPLE 55 3'-De(oxophosphinico)-3'-(Iminooxymethylene) -5'-Dimethoxy- tritylthymidylyl-(3'→ 5')-3'-O-(t-Butyldiphenylsilyl)-5'-Deoxy- 2'-0-Methyladenosine, 76 Compound 75 will be treated and reacted with compound 50 as per the procedure of Example 39 to yield the title compound 76. EXAMPLE 56 3 '-De(oxophosphinico) -3 '-[Methyl (iminooxymethylene) ] -5'- Dimethoxytritylthymidylyl-(3'→ 5')-3'-[ (β-Cyanoethoxy) -N-(Di- isopropyl)phosphiryl]-5'-Deoxy-2'-O-Methyladenosine, 77 Compound 76 will be reacted as per the reaction sequence of Examples 40, 41 and 42 to yield the title compound 77. EXAMPLE 57 6'-o-Amino-3'-θ-(t-Butyldiphenylsilyl)-2 '-Deoxy-5'-Homoaris- teromycin, 79 (-) -2'-Deoxy-5'-homoaristeromycin, compound 78, (the carbocyclic analogue of 5'-homo-2'-deoxyadenosine) is prepared as per the procedure of Jones, M.F. and Roberts, S.M., J . Chem . Soc . Perkin Trans . , 1:2927 (1988). Compound 78 will be treated as per the procedure of Examples 36, 37 and 38 to yield the 6'- O-amino-3'-blocked carbocyclic analogue of 5'-homo-2'- deoxyadenosine, compound 79. EXAMPLE 58 3'-De(oxophosphinico) -3'- (Iminooxymethylene) -5 '-Dimethoxy- tritylthymidylyl-(3'→ 5')-3'-0-(t-Butyldiphenylsilyl) -2 ' ,5'- Dideoxyaristeromycin, 80 Compound 79 will be treated and reacted with compound 50 as per the procedure of Example 39 to yield the title compound 80. EXAMPLE 59 3'-De(oxophosphinico) -3 '-[Methyl (iminooxymethylene) ] -5 '- Dimethoxytritylthymidylyl-(3'→ 5')-3'-[ (β-Cyanoethoxy)-N-(Di- isopropyl)phosphiryl]-2' ,5'-Dideoxyaristeromycin, 81 Compound 80 will be reacted as per the reaction sequence of Examples 40, 41 and 42 to yield the title compound 81. EXAMPLE 60 6'-o-Amino-2'-O-Butyl-5'-Homoaristeromycin, 82 (-) -5'-Homoaristeromycin, compound 78, will be blocked with a TIPS group, alkylated and deblocked as per the procedure of Example 57 to yield compound 82. EXAMPLE 61 6'-0-Amino-3'-0-(t-Butyldiphenylsilyl) -2 ' -O-Buty1-5 ' - Homoaristeromycin, 83 Compound 82 will be treated as per the procedures of Examples 36, 37 and 38 to yield the title compound 83. EXAMPLE 62 3'-De(oxophosphinico)-3'- (Iminooxymethylene) -5'-Dimethoxy- tritylthymidylyl-(3'→ 5' )-3'-O-(t-Butyldiphenylsilyl) -2 '-O- Butyl-5'-Deoxyaristeromycin, 84 Compound 83 will be treated and reacted with compound 50 as per the procedure of Example 39 to yield the title compound 84. EXAMPLE 63 3 '-De(oxophosphinico) -3 '-[Methyl (iminooxymethylene) ] -5 '- Dimethoxytritylthymidylyl-(3'→ 5')-3'-[ (β-Cyanoethoxy)-N-(Di- isopropyl)phosphiryl]-2'-O-Buty1-5'-Deoxyaristeromycin, 85 Compound 84 will be reacted as per the reaction sequence of Examples 40, 41 and 42 to yield the title compound 85. EXAMPLE 64 (+)-l-[(lR,3S,4S)-3-Azido-5-Dimethoxytrityl-4-(Hydroxymethyl)- Cyclopentyl]-5-Methyl-2,4-(1H,3H)-Pyrimidindione, 87 (+) -1-[1R,3S,4S) -3-Azido-4-(hydroxymethyl) -cyclo- pentyl]-5-methyl-2,4-(1H,3H) -pyrimidindione, compound 86, prepared as per the procedure of Bodenteich, M. and Grieng, H. , Tetrahedron Letts . , 28:5311 (1987) , will be dimethoxytritylated utilizing dimethoxytrityl chloride in pyridine at room temperature to give the title compound 87. EXAMPLE 65 (+)-l-[ (1R,3S,4S) -3-Amino-4-(Dimethoxytrityloxymethyl)- Cyclopentyl]-5-Methyl-2,4-(1H,3H)-Pyrimidindione, 88 Compound 87 will be reduced with Ph 3 P in pyridine at room temperature as per the procedure of Hronowski, L.J.J. and Szarek, W.A. , J. Chem . Soc , Chem . Commun . , 1547 (1990), to give the carbocyclic analogue of 3'-amino-5'-dimethoxytrityl thymidine, compound 88. EXAMPLE 66 l-{ (lR,3S,4S)-3-[Imino-2-(5'-Deoxythymidylyl-5'-yl) -1,2- Ethanediy1]-4-(Dimethoxtrityloxymethyl)-Cyclopentyl}-5-Methyl- 2,4-(1H,3H)-Pyrimidindione, 89 Compound 88 will be reacted with compound 47 as per the procedure of Example 48 to yield the title compound 89. EXAMPLE 67 Synthesis Of Oligonucleotides Using A DNA Synthesizer Solid support oligonucleotide and "oligonucleotide like" syntheses are performed on an Applied Biosystems 380 B or 394 DNA synthesizer following standard phosphoramidite protocols and cycles using reagents supplied by the manu¬ facture. The oligonucleotides are normally synthesized in either a 10 μmol scale or a 3 x 1 μmol scale in the "Trityl-On" mode. Standard deprotection conditions (30% NH 4 OH, 55°C, 16 hr) are employed. HPLC is performed on a Waters 600E instrument equipped with a model 991 detector. For analytical chromatography, the following reverse phase HPLC conditions are employed: Hamilton PRP-1 column (15 x 2.5 cm); solvent A: 50mm TEAA, pH 7.0; solvent B: 45mm TEAA with 80% CH 3 CN; flow rate: 1.5ml/min; gradient: 5% B for the first 5 minutes, linear (1%) increase in B every minute thereafter. For preparative purposes, the following reverse phase HPLC conditions are employed: Waters Delta Pak Waters Delta-Pak C 15 μm, 300A, 25x100 mm column equipped with a guard column of the same material; column flow rate: 5ml/min; gradient: 5% B for the first 10 minutes, linear 1% increase for every minute thereafter. Following HPLC purification, oligonucleotides are detritylated and further purified by size exclusion using a Sephadex G-25 column. EXAMPLE 68 HIGHER ORDER MIXED OLIGONUCLEOSIDES-OLIGONUCLEOSIDES AND MIXED OLIGONUCLEOSIDES-OLIGONUCLEOTIDES A. Solution Phase Synthesis Of 3'-De(oxophos¬ phinico)-3'-[Methyl(iminooxymethylene)]-Thymidylyl-(3 '→ 5')-5'- Deoxythymidylyl-3'-Phosphorothioate-Thymidylyl-(3'→ 5')-3'- De(oxyphosphinico)-3'-[(Methylimino)-1,2-Ethanediyl]thymidylyl- (3'→ 5')-3'-0-(t-Butyldiphenylsilyl)-5'-Deoxythymidine, 90, A Mixed Oligonucleoside-Oligonucleotide-Oligonucleoside Polymer Incorporating A Nucleotide Linkage Flanked At Its 5' Terminus By A 3'-De(oxophosphinico)-3'-[Methyl(iminooxymethylene) ] Linked Oligonucleoside Dimer and At Its 3' Terminus By A 3'- De(oxyphosphinico)-3'-[ (Methylimino)-1,2-Ethanediyl] Linked Oligonucleoside Dimer A mixed oligonucleoside-oligonucleotide-oligonucleo- side having a 3 ' -de (oxophosphinico) -3 '-[meth- yl(iminooxymethylene) ] linked oligonucleoside dimer and a 3'- de(oxyphosphinico)-3'-[ (methylimino)-1,2-ethanediyl] linked oligonucleoside dimer coupled together via a phosphorothioate nucleotide linkage will be prepared by reacting compound 58, compound 70 and tetrazole in anhydrous acetonitrile under argon. The coupling reaction will be allowed to proceed to completion followed by treatment with Beaucage reagent and ammonium hydroxide removal of the dimethoxytrityl blocking group according to the procedure of Zon, G. and Stec, W.J., Phosphorothioate oligonucleotides , Oligonucleotides and Analogs A Practical Approach , F. Eckstein Ed., IRL Press, pg. 87 (1991). The 3' blocking group will then removed as per the procedure of Step 3 of Example 4 and the product purified by HPLC to yield the title compound 90, wherein utilizing the structure of Scheme XVIII, T 3 and T 5 are OH, D is S, E is OH, X is H, Q is 0, r is 0 and q is 2; and for each q, i . e . q. and q 2 , n and p are 1 in each instance; and for q. is 1; and for - 63 - completely resistant to serum and cytoplasmic nucleases. B. Evaluation of the resistance of oligonucleotide- mimicking macromolecules to specific endo- and exo-nucleases. Evaluation of the resistance of natural oligonucleo¬ tides and oligonucleotide-mimicking macromolecules of the invention to specific nucleases (ie, endonucleases, 3',5'-exo-, and 5' ,3'-exonucleases) can be done to determine the exact effect of the macromolecule linkage on degradation. The oligonucleotide-mimicking macromolecules are incubated in defined reaction buffers specific for various selected nucleases. Following treatment of the products with protease K, urea is added and analysis on 20% polyacrylamide gels containing urea is done. Gel products are visualized by staining with Stains All reagent (Sigma Chemical Co.). Laser densitometry is used to quantitate the extent of degradation. The effects of the macromolecules linkage are determined for specific nucleases and compared with the results obtained from the serum and cytoplasmic systems. As with the serum and cytoplasmic nucleases, it is expected that the oligonucleotide- mimicking macromolecules of the invention will be completely resistant to endo- and exo-nucleases. PROCEDURE 2 - 5-Lipoxygenase Analysis and Assays A. Therapeutics For therapeutic use, an animal suspected of having a disease characterized by excessive or abnormal supply of 5-lipoxygenase is treated by administering the macromolecule of the invention. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Such treatment is generally continued until either a cure is effected or a diminution in the diseased state is achieved. Long term treatment is likely for some diseases. - 64 - B. Research Reagents The oligonucleotide-mimicking macromolecules of this invention will also be useful as research reagents when used to cleave or otherwise modulate 5-lipoxygenase mRNA in crude cell lysates or in partially purified or wholly purified RNA preparations. This application of the invention is accomplished, for example, by lysing cells by standard methods, optimally extracting the RNA and then treating it with a composition at concentrations ranging, for instance, from about 100 to about 500 ng per 10 Mg of total RNA in a buffer consisting, for example, of 50 mm phosphate, pH ranging from about 4-10 at a temperature from about 30° to about 50° C. The cleaved 5-lipoxygenase RNA can be analyzed by agarose gel electrophoresis and hybridization with radiolabeled DNA probes or by other standard methods. C. Diagnostics The oligonucleotide-mimicking macromolecules of the invention will also be useful in diagnostic applications, particularly for the determination of the expression of specific mRNA species in various tissues or the expression of abnormal or mutant RNA species. In this example, while the macromolecules target a abnormal mRNA by being designed complementary to the abnormal sequence, they would not hybridize to normal mRNA. Tissue samples can be homogenized, and RNA extracted by standard methods. The crude homogenate or extract can be treated for example to effect cleavage of the target RNA. The product can then be hybridized to a solid support which contains a bound oligonucleotide complementary to a region on the 5' side of the cleavage site. Both the normal and abnormal 5' region of the mRNA would bind to the solid support. The 3' region of the abnormal RNA, which is cleaved, would not be bound to the support and therefore would be separated from the normal mRNA. Targeted mRNA species for modulation relates to 5- lipoxygenase; however, persons of ordinary skill in the art will appreciate that the present invention is not so limited - 61 - q 2 , m is 0; and Bxj and Bxi are thymine. B. Solid SupportSynthesis Of 3'-De(oxophosphinico)- 3'-[Methyl (iminooxymethylene) ]-Thymidylyl- (3 ' → 5' ) -5'- Deoxythymidylyl-(3'→ 5')-P-Thymidylyl-3'-De(oxophosphinico)-3'- [Methyl(iminooxymethylene) ]-(3'→ 5')-Thymidylyl-(3'→ 5')-P- Thymidylyl-3 '-De(oxophosphinico) -3 '-[Methyl (iminooxy¬ methylene)]-(3'→ 5')-Thymidylyl-(3'→ 5')-P-2'-Deoxycytidine, 91, AMixed Oligonucleotide-Oligonucleoside Polymer Incorporat¬ ing 3'-De(oxophosphinico)-3'-[Methyl(iminooxymethylene) ] Linked Oligonucleoside Dimers Flanked By Conventional Linked Nucleo¬ tides The dimeric oligonucleoside 58 will be utilized as building block units in a conventional oligonucleotide solid support synthesis as per the procedure of Example 67. For the purpose of illustration a polymer incorporating seven nucleosides is described. A first unit of the dimeric oligonucleoside 58 will be coupled to a first cytidine nucleoside tethered to a solid support via its 3' hydroxyl group and having a free 5' hydroxyl group. After attachment of the first unit of compound 58 to the support, the 5'-dimethoxy- trityl group of that first compound 58 unit will be removed in the normal manner. A second compound 58 unit will then be coupled via its β-cyanoethyl-N-diisopropylphosphiryl group to the first compound 58 unit using normal phosphoramidate chemistry. This forms a conventional phosphodiester bond between the first and second compound 58 units and elongates the polymer by two nucleosides (or one oligonucleoside dimer unit) . The dimethoxytrityl blocking group from the second compound 58 unit will be removed in the normal manner and the polymer elongated by a further dimeric unit of compound 58. As with addition of the first and second dimeric units, the third unit of compound 58 is coupled to the second via conventional phosphoramidite procedures. The addition of the third unit of compound 58 completes the desired length and base sequence. This polymer has a backbone of alternating normal phosphodiester linkages and the methyl(iminooxymethylene) linkages of compound 58. The 5' terminal dimethoxytrityl group - 62 - of the third compound 58 unit will be removed in the normal manner followed by release of the polymer from the solid support, also in the normal manner. Purification of the polymer will be achieved by HPLC to yield compound 91 wherein, utilizing the structure of Scheme XVIII, T 3 and T 5 are OH, D is 0, E is OH, X is H, Q is 0, r is 1 and for the seven nucleoside polymer described, q is 3; and for each q, i.e. q-, q 2 and q 3 , n and p are 1 in each instances; and for q 1 and q 2 , m is 1; and for q 3 , m is 0; and Bxk is cytosine; and each BxJ and Bxi is thymine. EVALUATION PROCEDURE 1 - Nuclease Resistance A. Evaluation of the resistance of oligonucleotide- mimicking macromolecules to serum and cytoplasmic nucleases. Oligonucleotide-mimicking macromolecules of the invention can be assessed for their resistance to serum nucleases by incubation of the oligonucleotide-mimicking macromolecules in media containing various concentrations of fetal calf serum or adult human serum. Labeled oligonucleotide-mimicking macromolecules are incubated for various times, treated with protease K and then analyzed by gel electrophoresis on 20% polyacrylamine-urea denaturing gels and subsequent autoradiography. Autoradiograms are quantitated by laser densitometry. Based upon the location of the modified linkage and the known length of the oligonucleotide-mimicking macromolecules it is possible to determine the effect on nuclease degradation by the particular modification. For the cytoplasmic nucleases, an HL 60 cell line can be used. A post-mitochondrial supernatant is prepared by differential centrifugation and the labelled macromolecules are incubated in this supernatant for various times. Following the incubation, macromolecules are assessed for degradation as outlined above for serum nucleolytic degradation. Autoradiography results are quantitated for evaluation of the macromolecules of the invention. It is expected that the macromolecules will be and it is generally applicable. The inhibition or modulation of production of the enzyme 5-lipoxygenase is expected to have significant therapeutic benefits in the treatment of disease. In order to assess the effectiveness of the compositions, an assay or series of assays is required. D. In Vitro Assays The cellular assays for 5-lipoxygenase preferably use the human promyelocytic leukemia cell line HL-60. These cells can be induced to differentiate into either a monocyte like cell or neutrophil like cell by various known agents. Treatment of the cells with 1.3% dimethyl sulfoxide, DMSO, is known to promote differentiation of the cells into neutrophils. It has now been found that basal HL-60 cells do not synthesize detectable levels of 5-lipoxygenase protein or secrete leukotrienes (a downstream product of 5-lipoxygenase) . Differentiation of the cells with DMSO causes an appearance of 5-lipoxygenase protein and leukotriene biosynthesis 48 hours after addition of DMSO. Thus induction of 5-lipoxygenase protein synthesis can be utilized as a test system for analysis of oligonucleotide-mimicking macromolecules which interfere with 5-lipoxygenase synthesis in these cells. A second test system for oligonucleotide-mimicking macromolecules makes use of the fact that 5-lipoxygenase is a "suicide" enzyme in that it inactivates itself upon reacting with substrate. Treatment of differentiated HL-60 or other cells expressing 5 lipoxygenase, with 10 μM A23187, a calcium ionophore, promotes translocation of 5-lipoxygenase from the cytosol to the membrane with subsequent activation of the enzyme. Following activation and several rounds of catalysis, the enzyme becomes catalytically inactive. Thus, treatment of the cells with calcium ionophore inactivates endogenous 5- lipoxygenase. It takes the cells approximately 24 hours to recover from A23187 treatment as measured by their ability to synthesize leukotriene B 4 . Macromolecules directed against 5- lipoxygenase can be tested for activity in two HL-60 model systems using the following quantitative assays. The assays are described from the most direct measurement of inhibition of 5-lipoxygenase protein synthesis in intact cells to more downstream events such as measurement of 5-lipoxygenase activity in intact cells. A direct effect which oligonucleotide-mimicking macromolecules can exert on intact cells and which can be easily be quantitated is specific inhibition of 5-lipoxygenase protein synthesis. To perform this technique, cells can be labelled with S-methionine (50 μCi/mL) for 2 hours at 37° C to label newly synthesized protein. Cells are extracted to solubilize total cellular proteins and 5-lipoxygenase is immunoprecipitated with 5-lipoxygenase antibody followed by elution from protein A Sepharose beads. The immunoprecipitated proteins are resolved by SDS-polyacrylamide gel electrophoresis and exposed for autoradiography. The amount of immunopre- cipitated 5-lipoxygenase is quantitated by scanning densitometry. A predicted result from these experiments would be as follows. The amount of 5-lipoxygenase protein immuno¬ precipitated from control cells would be normalized to 100%. Treatment of the cells with 1 μM, 10 μM, and 30 μM of the macromolecules of the invention for 48 hours would reduce immunoprecipitated 5-lipoxygenase by 5%, 25% and 75% of control, respectively. Measurement of 5-lipoxygenase enzyme activity in cellular homogenates could also be used to quantitate the amount of enzyme present which is capable of synthesizing leukotrienes. A radiometric assay has now been developed for quantitating 5-lipoxygenase enzyme activity in cell homogenates using reverse phase HPLC. Cells are broken by sonication in a buffer containing protease inhibitors and EDTA. The cell homogenate is centrifuged at 10,000 x g for 30 min and the supernatants analyzed for 5-lipoxygenase activity. Cytosolic proteins are incubated with 10 μM 14C-arachidonic acid, 2mM ATP, 50 μM free calcium, 100 μg/ml phosphatidylcholine, and 50 mM bis-Tris buffer, pH 7.0, for 5 min at 37° C. The reactions are quenched by the addition of an equal volume of acetone and the fatty acids extracted with ethyl acetate. The substrate and reaction products are separated by reverse phase HPLC on a Novapak C18 column (Waters Inc. , Millford, MA) . Radioactive peaks are detected by a Beckman model 171 radiochromatography detector. The amount of arachidonic acid converted into di- HETE's and mono-HETE's is used as a measure of 5-lipoxygenase activity. A predicted result for treatment of DMSO differ¬ entiated HL-60 cells for 72 hours with effective the macromolecules of the invention at 1 μM, 10 μM, and 30 μM would be as follows. Control cells oxidize 200 pmol arachidonic acid/ 5 min/ 10 cells. Cells treated with 1 μM, 10 μM, and 30 μM of an effective oligonucleotide-mimicking macromolecule would oxidize 195 pmol, 140 pmol, and 60 pmol of arachidonic acid/ 5 min/ 10 cells respectively. A quantitative competitive enzyme linked im unosorbant assay (ELISA) for the measurement of total 5-lipoxygenase protein in cells has been developed. Human 5-lipoxygenase expressed in E . coli and purified by extraction, Q-Sepharose, hydroxyapatite, and reverse phase HPLC is used as a standard and as the primary antigen to coat microtiter plates. 25 ng of purified 5-lipoxygenase is bound to the microtiter plates overnight at 4° C. The wells are blocked for 90 min with 5% goat serum diluted in 20 mM Tris«HCL buffer, pH 7.4, in the presence of 150 mM NaCl (TBS). Cell extracts (0.2% Triton X- 100, 12,000 x g for 30 min.) or purified 5-lipoxygenase were incubated with a 1:4000 dilution of 5-lipoxygenase polyclonal antibody in a total volume of 100 μL in the microtiter wells for 90 min. The antibodies are prepared by immunizing rabbits with purified human recombinant 5-lipoxygenase. The wells are washed with TBS containing 0.05% tween 20 (TBST) , then incubated with 100 μL of a 1:1000 dilution of peroxidase conjugated goat anti-rabbit IgG (Cappel Laboratories, Malvern, PA) for 60 min at 25° C. The wells are washed with TBST and the amount of peroxidase labelled second antibody determined by development with tetramethylbenzidine. Predicted results from such an assay using a 30 er oligonucleotide-mimicking macromolecule at 1 μM, 10 μM, and 30 μM would be 30 ng, 18 ng and 5 ng of 5-lipoxygenase per 10 cells, respectively with untreated cells containing about 34 ng 5-lipoxygenase. A net effect of inhibition of 5-lipoxygenase biosyn- thesis is a diminution in the quantities of leukotrienes released from stimulated cells. DMSO-differentiated HL-60 cells release leukotriene B4 upon stimulation with the calcium ionophore A23187. Leukotriene B4 released into the cell medium can be quantitated by radioimmunoassay using commercially available diagnostic kits (New England Nuclear, Boston, MA) . Leukotriene B4 production can be detected in HL-60 cells 48 hours following addition of DMSO to differentiate the cells into a neutrophil-like cell. Cells (2 x 10 cells/mL) will be treated with increasing concentrations of the macromolecule for 48-72 hours in the presence of 1.3% DMSO. The cells are washed and resuspended at a concentration of 2 x 10 6 cell/mL in Dulbecco's phosphate buffered saline containing 1% delipidated bovine serum albumin. Cells are stimulated with 10 μM calcium ionophore A23187 for 15 min and the quantity of LTB4 produced from 5 x 10 cell determined by radioimmunoassay as described by the manufacturer. Using this assay the following results would likely be obtained with an oligonucleotide-mimicking macromolecule directed to the 5-LO mRNA. Cells will be treated for 72 hours with either 1 μM, 10 μM or 30 μM of the macromolecule in the presence of 1.3% DMSO. The quantity of LTB 4 produced from 5 x 10 cells would be expected to be about 75 pg, 50 pg, and 35 pg, respectively with untreated differentiated cells producing 75 pg LTB 4 . E. In Vivo Assay Inhibition of the production of 5-lipoxygenase in the mouse can be demonstrated in accordance with the following protocol. Topical application of arachidonic acid results in the rapid production of leukotriene B 4 , leukotriene C 4 and prostaglandin E 2 in the skin followed by edema and cellular infiltration. Certain inhibitors of 5-lipoxygenase have been known to exhibit activity in this assay. For the assay, 2 mg of arachidonic acid is applied to a mouse ear with the contralateral ear serving as a control. The polymorphonuclear cell infiltrate is assayed by myeloperoxidase activity in homogenates taken from a biopsy 1 hour following the administration of arachidonic acid. The edematous response is quantitated by measurement of ear thickness and wet weight of a punch biopsy. Measurement of leukotriene B 4 produced in biopsy specimens is performed as a direct measurement of 5- lipoxygenase activity in the tissue. Oligonucleotide-mimicking macromolecules will be applied topically to both ears 12 to 24 hours prior to administration of arachidonic acid to allow optimal activity of the compounds. Both ears are pretreated for 24 hours with either 0.1 μmol, 0.3 μmol, or 1.0 μmol of the macromolecule prior to challenge with arachidonic acid. Values are expressed as the mean for three animals per concentration. Inhibition of polymorphonuclear cell infiltration for 0.1 μmol, 0.3 μmol, and 1 μmol is expected to be about 10%, 75% and 92% of control activity, respectively. Inhibition of edema is expected to be about 3%, 58% and 90%, respectively while inhibition of leukotriene B 4 production would be expected to be about 15%, 79% and 99%, respectively.

Claims: WE CLAIM: 1. A macromolecule, at least a portion of which is of the structure: wherein one of L- or L 2 is O or S, and the other of L- or L 2 is N-R; and L j and L 4 , combined, are CH 2 , or j is CH 2 and L 4 is CR'R"; or one of L j or L 4 is O or S, and the other of L 3 or L 4 is N-R; and L 1 and L 2 , combined, are CH 2 , or L 2 is CH 2 and L- is CR'R"; or one of L- and L 4 is O, S or N-R, and the other of 1>_ and L 4 is CR'R"; and L 2 and I^ are CH 2 ; or L-, L 2 , 1^ and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N- O; or L- is O; L 2 is N; 1^ is CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , L j and L 4 form a 5 or 6 membered ring; or L- is C or CH; L 2 is CH 2 ; L j is N; and L 4 is 0; and together with at least two additional carbon or hetero atoms, L-, L 2 and j form a 5 or 6 membered ring; R is H; C, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C 7 to C 14 alkaryl or aralkyl; a 14C. containing C~ to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; R' and R" are H; or R' is H and R' ' is O-R; or R' and R' ' , combined, are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkyla ino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 2. The macromolecule of claim 1 wherein R is H. 3. The macromolecule of claim 1 wherein R is C, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; or C 7 to c 14 alkaryl or aralkyl. 4. The macromolecule of claim 1 wherein R is a 14C containing lower alkyl, lower alkenyl or lower alkynyl; or a 14C containing C 7 to C 14 alkaryl or aralkyl. 5. The macromolecule of claim 1 wherein R is a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide. 6. The macromolecule of claim 1 wherein Q is O. 7. The macromolecule of claim 1 wherein X is H or OH. 8. A macromolecule, at least a portion of which is of the structure: wherein one of L- or L 2 is O or S, and the other of L- or L 2 is N-R; and L~ and L 4 , combined, are CH 2 ; or one of L j or L 4 is 0 or S, and the other of L 3 or L 4 is N-R; and L* and L 2 , combined, are CH 2 ; and R is H; C, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C, to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C 7 to C 14 alkaryl or aralkyl; a 14C containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; SOCH 3' S0 2 CH 3 ; ONO 2' NO -, 2 , N-t 3 ,, N«Hn, 2 , heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkyla ino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 9. The macromolecule of claim 8 wherein 1>~ and L 4 , combined, are CH 2 . 10. The macromolecule of claim 9 wherein L- is O and L 2 is N-R. 11. A macromolecule, at least a portion of which is of the structure: wherein one of L- and L 4 is O, S or N-R, and the other of L- and L 4 is CR'R''; and L 2 and L j are CH 2 ; R is H; C- to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C- to C 14 alkaryl or aralkyl; a 14C containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; R' and R" are H; or R' is H and R" is O-R; or R' and R" , combined, are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 12, The macromolecule of claim 11 wherein R' and R' ' are H. 13. The macromolecule of claim 11 wherein R' is H; R" is O-R; and R is H. 14. A macromolecule, at least a portion of which is of the structure: wherein one of L or L 2 is CH 2 , 0 or S , and the other of L 1 or L 2 is N-R; and L~ is CH 2 and L 4 is CR'R" ; or one of L j or L 4 is CH 2 , O or S , and the other of L 3 or L 4 is N-R; and L 2 is CH 2 and L- is CR'R"; and R is H; C- to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C 7 to C 14 alkaryl or aralkyl; a C containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; R' and R" are H; or R' is H and R" is O-R; or R' and R" , combined, are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; 0CF 3 ; OCN; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 15. The macromolecule of claim 14 wherein L~ and L 4 are CH 2 . 16. The macromolecule of claim 15 wherein L- is 0 or S and L 2 is N-R. 17. The macromolecule of claim 16 wherein L- is 0. 18. The macromolecule of claim 16 wherein L 1 is S. 19. The macromolecule of claim 14 wherein L 1 is N-R. 20. The macromolecule of claim 19 wherein L 2 is CH 2 , O or S. 21. The macromolecule of claim 19 wherein L 2 is CH 2 . 22. The macromolecule of claim 19 wherein L 2 is O or S. 23. The macromolecule of claim 22 wherein L 2 is O. 24. The macromolecule of claim 14 wherein one of L. or L 4 is CR'R", R' is H, and R" is O-R. 25. The macromolecule of claim 24 wherein R is H. 26. The macromolecule of claim 14 wherein L 4 is CR'R", R' is H, and R" is O-R. 27. The macromolecule of claim 26 wherein R is H. 28. The macromolecule of claim 27 wherein L- is O or S and L 2 is N-R. 29. A macromolecule, at least a portion of which is of the structure: wherein L-, L 2 , j and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N- O; is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; SOCH 3' S0 2 CH 3 ; ONO 2' NO 2' N 3' NH 2' heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 30. A macromolecule, at least a portion of which is of the structure: wherein L- is O; L 2 is N; ~ -~_ is CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , L j and L 4 form a 5 or 6 membered ring; or L 1 is C or CH; L 2 is CH 2 ; j is N; and L 4 is O; and together with at least two additional carbon or hetero atoms, L-, L 2 and L j form a 5 or 6 membered ring; and X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; NO 2' N 3' NH 2' heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 31. A nucleoside of the structure: wherein Y- is O; Y 2 is H or R' '' ; and Z is aminooxy or phthalimidooxy; or Y 1 is CH 2 ; and Y 2 is aminooxy, alkylamino, aminohydroxyalkyl, alkenyl or oxoalkyl; and Z is H, OH, O-R'", amino, methyleneamino or phthal- imido; R' " is a hydroxyl blocking group; X is H or OH; Q is CH 2 or O; and Bx is a heterocyclic base moiety. 32. The nucleoside of claim 31 wherein Y- is O, Y 2 is H or R" ' , and Z is aminooxy or phthalimidooxy. 33. The nucleoside of claim 32 whereinY 2 is H and Z is aminooxy. 34. The nucleoside of claim 31 wherein: Y- is CH 2 ; Y 2 is aminooxy, alkylamino, aminoalkyl, hydroxyalkyl, aminohydroxyalkyl, alkenyl or aldoalkyl; and Z is H, OH, O-R'", amino, methyleneamino or phthal- imido. 35. The nucleoside of claim 34 whereinZ is OH. 36. A method of modulating the production or activity of a protein in an organism, comprising contacting the organism with a macromolecule, wherein at least a portion of said macromolecule is of the structure: wherein one of L 1 or L 2 is 0 or S, and the other of L 1 or L 2 is N-R; and L j and L 4 , combined, are CH 2 , or L j is CH 2 and L 4 is CR'R"; or one of L j or L 4 is 0 or S, and the other of L j or L 4 is N-R; and L- and L 2 , combined, are CH 2 , or L 2 is CH 2 and L 1 is CR'R' ' ; or one of L- and L 4 is O, S or N-R, and the other of L., and L 4 is CR'R"; and L 2 and L j are CH 2 ; or L 1 , L 2 , L j and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N- O; or L- is O; L 2 is N; L j is CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , L j and L 4 form a 5 or 6 membered ring; or L- is Cor CH; L 2 is CH 2 ; L j is N; and L 4 is O; and together with at least two additional carbon or hetero atoms, L-, L 2 and L j form a 5 or 6 membered ring; R is H; C, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower 14 alkynyl; C 7 to C 14 alkaryl or aralkyl; a C containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; R' and R" are H; or R' is H and R' ' is O-R; or R' and R' ' , combined, are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; 0CF 3 ; OCN; SOCH 3' S0 2 CH 3 ; ON0 2 ; NO 2' N 3' NH 2' heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 37. A method of treating an organism having a disease characterized by the undesired production of a protein, comprising contacting the organism with a macromolecule, wherein at least a portion of said macromolecule is of the structure : wherein one of L- or L 2 is O or S, and the other of L- or L 2 is N-R; and I^ and L 4 , combined, are CH 2 , or 1^ is CH 2 and L is CR'R"; or one of L j or L 4 is O or S, and the other of 1>~ or L 4 is N-R; and L- and L 2 , combined, are CH 2 , or L 2 is CH 2 and L- is CR'R"; or one of L 1 and L 4 is O, S or N-R, and the other of L- and L 4 is CR'R"; and L 2 and L j are CH 2 ; or L-, L 2 , L j and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N- O; or L- is O; L 2 is N; L j is CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , L j and L 4 form a 5 or 6 membered ring; or L- is C or CH; L 2 is CH 2 ; !>- is N; and L 4 is O; and together with at least two additional carbon or hetero atoms, L., L 2 and !>_, form a 5 or 6 membered ring; R is H; c, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C 7 to C 14 alkaryl or aralkyl; a 14C containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; R' and R" are H; or R' is H and R" is O-R; or R' and R" , combined, are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; S0CH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 38. A method of assaying a sequence-specific nucleic acid, comprising contacting a test solution containing said nucleic acid with a macromolecule, wherein at least a portion of said macromolecule is of the structure: wherein one of L., or L 2 is O or S, and the other of L, or L 2 is N-R; and 1>~ and L 4 , combined, are CH 2 , or L 3 is CH 2 and L 4 is CR'R"; or one of L j or L 4 is O or S, and the other of L j or L 4 is N-R; and L- and L 2 , combined, are CH 2 , or L 2 is CH 2 and L 1 is CR'R"; or one of L. and L 4 is O, S or N-R, and the other of L., and L 4 is CR'R"; and L 2 and L j are CH 2 ; or L-, L 2 , L 3 and L , together, are 0-N=CH-CH 2 or CH 2 -CH=N- O; or L. is 0; L 2 is N; L j is CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , L j and L 4 form a 5 or 6 membered ring; or h_ is C or CH; L 2 is CH 2 ; L j is N; and L 4 is O; and together with at least two additional carbon or hetero atoms, L-, L 2 and L j form a 5 or 6 membered ring; R is H; C, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C 7 to C 14 alkaryl or aralkyl; a 14C- containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; R' and R" are H; or R' is H and R" is O-R; or R' and R'' , combined, are =0; X is H; O-R; S-R; NH-R; F, Cl; Br; CN; CF 3 ; OCF 3 ; OCN; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; Q is O or CH 2 ; n is an integer greater than 0; and Bx is a variable heterocyclic base moiety. 39. A compound comprising a first nucleoside and a second nucleoside joined through a 3' position of the first nucleoside and a 4' position of the second nucleoside by a linkage -L--L 2 -L j -L 4 - wherein: one of L. or L 2 is O or S, and the other of L 1 or L 2 is N-R; and L j and L 4 , combined, are CH 2 , or I^ is CH 2 and L 4 is CR'R' ' ; or one of L j or L 4 is 0 or S, and the other of L j or L 4 is N-R; and L- and L 2 , combined, are CH 2 , or L 2 is CH 2 and L- is CR'R' ' ; or one of L., and L 4 is O, S or N-R, and the other of L- and L 4 is CR'R"; and L 2 and L j are CH 2 ; or L-, L 2 , L j and L 4 , together, are 0-N=CH-CH 2 or CH 2 -CH=N- 0; or L 1 is 0; L 2 is N; L j is CH 2 ; and L 4 is C or CH; and together with at least two additional carbon or hetero atoms, L 2 , L j and L 4 form a 5 or 6 membered ring; or L, is C or CH; L 2 is CH 2 ; L j is N; and L 4 is 0; and together with at least two additional carbon or hetero atoms, L.,, L 2 and I^ form a 5 or 6 membered ring; R is H; C, to C 10 straight or branched chain lower alkyl or substituted lower alkyl; C 2 to C 10 straight or branched chain lower alkenyl or substituted lower alkenyl; C 2 to C 10 straight or branched chain lower alkynyl or substituted lower alkynyl; a 14C containing lower alkyl, lower alkenyl or lower alkynyl; C 7 to C 14 alkaryl or aralkyl; a C containing C 7 to C 14 alkaryl or aralkyl; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; and R' and R" are H; or R' is H and R" is O-R; or R' and R" , combined, are =0. 40. The compound of claim 39 wherein at least one of L-, L 2 , L j or L 4 is O or S and at least a further of L 1( L 2 , I^ or L 4 is N-R.

Inventors: COOK PHILLIP DAN, SANGHVI YOGESH S, COOK, PHILLIP, DAN, SANGHVI, YOGESH, SHANTILAL
Applicants: ISIS PHARMACEUTICALS INC, ISIS PHARMACEUTICALS, INC.
Application year: 1993
Main classification: C07H17
IPC codes: A01N43, A61K31, A61P31, A61P35, C07D405, C07F7, C07H19, C07H21, C12N15, C12Q1