bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Polysubstituted Pyrrolizidines from Proline Derivatives and Conjugated Nitroolefins
Authors: Felluga Fulvia , Pitacco Giuliana , Visintin Cristina , Valentin Ennio
Published: December 2004

The stereochemistry of 1,3‐dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and i‐proline alkyl esters with several nitroolefins was investigated. Cyclic and acyclic nitroolefins add to the anti form of the ylide in a highly diastereoselective but poorly regioselective manner to give pyrrolizidine derivatives. In a few cases, the stereochemical results strongly support a stepwise mechanism.
Synthesis of a Novel Tricyclic Dipeptide Template and Its Incorporation into a Cyclic Peptide Mimetic Containing an NPNA Motif
Authors: Pfeifer Marc E. , Linden Anthony , Robinson John A.
Published: December 2004

A novel tricyclic dipeptide template, formally derived by coupling (2S,4S)‐4‐aminoproline (Pro(NH2)) and (S)‐2‐(carboxymethyl)proline (Pro(CH2COOH)) as a diketopiperazine, has been synthesized in a form suitable for solid‐phase peptide synthesis using Fmoc chemistry. This template was incorporated into the cyclic molecule cyclo(‐Ala1‐Asn2‐Pro3‐Asn4‐Ala5‐Ala6‐Temp‐) (Temp = template), whose conformation in H2O was studied by NMR methods. Average solution structures derived by restrained simulated annealing point to a highly populated βI‐turn within the Asn‐Pro‐Asn‐Ala motif and also indicate which conformations are likely to be preferred by the template.
Aza‐Claisen Rearrangement: Synthesis of 5′‐branched 5′‐aminothymidines
Authors: Ammenn Jochen , Altmann Karl‐Heinz , Belluš Daniel
Published: December 2004

The syntheses of both diastereoisomers of 5′‐ethyl‐substituted thymidine dimers, the (5′R)‐ and (5′S)‐configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)‐CH2CONH‐CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b, respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted PdII‐catalysed aza‐Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17, whose structure was confirmed by X‐ray analysis.
Neue Wege zu Pentalen‐Vorstufen
Authors: You Shaochun , Chai Shengyong , Schwarz Nadine , Neuenschwander Markus
Published: December 2004

New Pathways to Precursors of Pentalene

Pentalene dimers 2 and 3 are easily available in moderate yields by CuCl2‐induced oxidative coupling of dilithium‐pentalenediide (5) (Scheme 1). On the other hand, NBS bromination of 1,5‐dihydropentalene (4) or of 1,2‐dihydropentalene (8) gives unstable 1‐bromo‐1,2‐dihydropentalene (9), while subsequent in‐situ elimination with Et3N exclusively gives syn‐cis‐pentalene dimer 2 in moderate yields (Scheme 3). NMR‐Spectroscopic evidence for compounds 2, 3, and 9 is presented, and mechanistic alternatives for the formation of pentalene dimers 2 and 3 are discussed.
Syntheses and Properties of Donor/Acceptor Arylethynyl‐Substituted 1, 6‐Methano[10]annulenes
Authors: Bryant‐Friedrich Amanda C. , Neidlein Richard
Published: December 2004

The stepwise palladium‐catalyzed coupling of dibromo‐1,6‐methano[10]annulene derivatives to a phenyl‐acetylene substituted by an electron‐withdrawing group followed by coupling with a phenylacetylene possessing an electron‐donating group allows the preparation of donor/acceptor systems which contain three aromatic moieties linked by ethynediyl bridges. The same type of cross‐coupling starting from 2‐ethynyl‐1,6‐methano[10]annulene and bromo‐substituted azobenzene derivatives provides easy access to a new class of azo dyes. The properties of these compounds are compared to those of analogous compounds containing only benzene rings.
Dendrimers with Porphyrin Cores: Synthetic models for globular heme proteins
Authors: Dandliker Peter J. , Diederich François , Zingg Adrien , Gisselbrecht Jean‐Paul , Gross Maurice , Louati Alain , Sanford Elizabeth
Published: December 2004

Dendritic iron porphyrins were synthesized as functional mimics of globular electron‐transfer heme proteins. The cascade molecules 1 · Zn−3 Zn of first to third generation were obtained starting from the (meso‐diarylporphyrin) zinc 6 · Zn which contains four carboxylate arms for attachment of the poly(ether‐amide) dendritic branches by peptide‐coupling methodology (Scheme 1). Generation 3 compound 3 · Zn with 108 methyl‐carboxylate end groups has a molecular weight of 19054. D, and computer modeling suggests that its structure is globular and densely‐packed, measuring ca. 4 nm in diameter and, therefore, similar in dimensions to the electron‐transfer protein cytochrome‐c. Starting from the generation 1 poly(carboxylic acid) 11 · Zn and the generation 2 analog 12 · Zn the dendritic ZnII porphyrins 4 · Zn and 5 · Zn, respectively, were obtained by esterification with triethyleneglycol monomethyl ether (Schemes 3 and 4). Demetallation followed by insertion of FeII and in situ oxidation afforded the water‐soluble dendritic iron porphyrins 4 FeCl and 5 FeCl. The electrochemical behavior of esters 1 · Zn−3 · Zn in organic solvents changed smoothly with increasing dendritic generation (Table 1). Progressing from 1 · Zn to 3 · Zn in THF, the first porphyrin‐centered oxidation and reduction potentials become more negative by 320 and 210mV, respectively. These changes were attributed to strong microenvironmental effects imposed on the electroactive core by the densely packed dendritic surroundings. The electrochemical properties of 4 · FeCl and 5 · FeCl were investigated by cyclic voltammetry in both CH2Cl2 and H2O (Tables 2 and 3). Progressing from 4 · FeCl to 5 · FeCl in CH2Cl2, the redox potential of the biologically relevant FeIII/FeII couple remained virtually unchanged, whereas in aqueous solution, 5 FeCl exhibited a potential 420 mV more positive than did 4 FeCl. The large difference between these potentials in H2O was attributed to differences in solvation of the core electrophore. Whereas the relatively open dendritic branches in 4 · Fecl do not impede access of bulk solvent to the central core, the densely packed dendritic superstructure of 5 · FeCl significantly reduces contact between the heme and external solvent. As a result, the more charged FeIII state is destabilized relative to FeII, and the redox potential is strongly shifted to a more positive value.
Determination of the Chemical Structure of novel colored 1H‐pyrrol‐3(2H)‐one derivatives formed by Maillard‐type reactions
Authors: Hofmann Thomas
Published: December 2004

The determination of the chemical structure of a previously unknown Maillard reaction product with an amino acid incorporated in a four‐ring structure is reported. The red compounds 1a and 1b, isolated from a thermally treated aqueous solution of furan‐2‐carbaldehyde and L‐alanine, were identified as (S)‐4{(E)‐1‐formyl ‐2‐(2‐furyl)ethenyl}‐5‐(2‐furyl)‐2‐{(E)‐(2‐furyl)methylidene}‐2, 3‐dihydro‐α‐methyl‐3‐oxo‐1H‐pyrrole‐1‐acetic acid and its 2‐{(Z)‐(2‐furyl)methylidene}isomer, respectively, by several 1D‐ and 2D‐NMR techniques, MS, UV, and IR spectroscopy as well as by synthetic experiments. 2D‐NOESY and 2D‐ROESY experiments performed for conformation analysis indicated the existence of two atropisomers.
New ethylzinc reagents with remarkable properties in palladium‐catalyzed zinc‐ene reactions
Authors: Oppolzer Wolfgang , Schröder Fridtjof , Kahl SÖNke
Published: December 2004

Pd‐Catalyzed Zn‐ene allylic olefinations with the new ethylzinc reagents EtZnOSO2CF3 (4) and EtZnOC(O)CF(MeO)CF3 (5) in CH2Cl2 showed an unexpected trans‐selectivity in the ring closure to cyclopentane derivatives (see Scheme 2 and Table 1). This strong trans‐selectivity is in contrast with the corresponding known Zn‐ene reaction using Et2Zn in Et2O which shows a high cis‐selectivity (Table 1). The probable radical origin of the observed trans‐selectivity is discussed. The Zn‐ene reaction products of the type RZnOSO2CF3 could be derivatized by the known protonation, iodination, and cyanation yielding 8–10 (Scheme 4 and Table 2), these derivatizations could furthermore be extended by allylation and oxidation reaction (→ 13, 15, and 16; see Scheme 5).
Synthese von triafulvalen‐vorstufen durch ‘carben‐dimerisierung’ von 1‐halogeno‐1‐lithiocyclopropanen
Authors: Läng Christoph , Mühlebach Michel , Neuenschwander Markus
Published: December 2004

Synthesis of Triafulvalene Precursors by ‘Carbene‐Dimerization’ of 1‐Halogeno‐1‐lithiocyclopropanes

Bi(cyclopropylidenes) 7a, 7c, and 7e are available in a simple one‐pot reaction by treating 1,1‐dibromocyclo‐propanes 5 at −95° with BuLi and CuCl2. Attempts towards triafulvalene precursors with good leaving groups are reported. The most promising attempt makes use of 2,2′‐bis(phenylthio)‐3,3′‐bis(trimethylsilyl)‐1,1′‐bi(cyclopropylidene) (7c) which has been oxidized to give the bis(phenylsulfonyl) derivative 7g. So far, F−‐induced elimination experiments with 7g failed.
NMR of enaminones. Part 71H‐, 13C‐, and 17O‐NMR and X‐ray structure determinations of 1,2‐disubstituted conjugated 3‐[(tert‐Butyl)amino]enones
Authors: Zhuo Jin‐Cong , Schenk Kurt
Published: December 2004

1H‐, 13C‐, and 17O‐NMR spectra for the 2‐substituted enaminones MeC(O)C(Me)CHNH(t‐Bu) (1), EtC(O)C(Me)CHNH(t‐Bu) (2), PhC(O)C(Me)CHNH(t‐Bu) (3), and MeC(O)C(Me)CHNH(t‐Bu) (4) are reported. These data show that 3 exists mainly in the (E)‐form, 4 in (Z)‐form, and 1 and 2 as mixtures of both forms. Polar solvents favour the (E)‐form. The (Z)‐ and (E)‐forms exist in the 1,2‐syn,3,N‐anti and 1,2‐anti,1,N‐anti conformations A and B, respectively. The structures of the (E)‐ and (Z)‐form are confirmed by X‐ray crystal‐structure determinations of 3 and 4. The shielding of the carbonyl O‐atom in the 17O‐NMR spectrum by intramolecular H‐bonding (ΔλHB) ranging from −28 to −41 ppm, depends on the substituents at C(l) and C(2). Crystals of 3 at 90 K are monoclinic. with a = 9.618(2) Å, b = 15.792(3) Å, c = 16.705(3) Å, and β = 94.44(3)°, and the space group is P21/c with Z = 8 (refinement to R = 0.0701 on 3387 independent reflections). Crystals of 4 at 101 K are monoclinic, with a = 16.625(8) Å, b = 8.637(6) Å, c = 11.024(7) Å, and β = 101.60(5)°, and the space group is Cc with Z = 4 (refinement to R = 0.0595 on 2106 independent reflections).
Enantioselective Alternating Terpolymerization of Styrene and Ethene with Carbon Monoxide. Preliminary communication
Authors: Aeby Anton , Consiglio Giambattista
Published: December 2004

In spite of the higher reactivity of styrene with respect to ethene for the alternating copolymerization with carbon monoxide, catalyzed by chiral (dihydrooxazole)(phosphino)palladium complexes, ethene is preferentially (and randomly) enchained in terpolymerization experiments; enantioface selection for styrene is comparably high in both copolymerization and terpolymerization processes.
8,19‐Dimethyl‐tetraepoxy[22]annulen(2.1.2.1): ein erstes Tetraepoxy‐Verbrücktes aromatisches [22]Annulen
Authors: Märkl Gottfried , Ehrl Robert , Kreitmeier Peter , Burgemeister Thomas
Published: December 2004

8,19‐Dimethyl‐tetraepoxy[22]annulen(2.1.2.1): The First Tetraepoxy‐Bridged Aromatic[22]Annulene

By McMurry reaction of 5,5′‐ethylidenebis[furan‐2‐carbaldehyde] (15), a syn/anti mixture 16 of (E,E)‐ and (Z,Z)‐8,19‐dihydro‐8,19‐dimethyl‐tetraepoxy[22]annulene is obtained. The (E/E)‐isomers 16 are the first rotation‐ ally active noncyclic conjugated macrocycles, where the (E)‐ethenediyl moieties rotate around the connecting single bonds. The dihydro‐tetraepoxy[22]annulenes 16 are dehydrogenated by (Ph3C)BF4 as well as by O2 to give the tetraepoxy[22]annulene 11. The spectroscopic data support the character of 11 as an aromatic, diatropic ring system, which is rather sensitive towards O2. In the oxidation mixture obtained from 11, beside polymeric products, two compounds 19 and 20 can be isolated, carrying one and two CHO groups, respectively, resulting by oxidation of one or both Me‐groups but having retained the aromatic 22π system of 11.
Synthesis and Evaluation of Indolizine‐Type Inhibitors of N‐acetyl‐β‐D‐glucosaminidases
Authors: Panday Narendra , Granier Thierry , Vasella Andrea
Published: December 2004

To check if the strong inhibition of N‐acetyl‐β‐D‐glucosaminidase by the tetrazole 8 and the imidazoles 9 and 10 correlates with the presence of a heteroatom corresponding to the glycosidic O‐atom, we prepared the GlcNAc‐derived pyrroles (tetrahydroindolizines) 18, 19, 27, 28, 34, and 35, lacking such a heteroatom. For this. the glucose‐derived pyrroles 11–13 were treated with a Lewis acid in the presence of trimethylsilyl azide. Conditions of kinetic control favored the formation of the gluco‐azides 14, 23, and 30, while thermodynamic control favoured the manno‐azides 20, 29, and 36. Reduction of the azides 14, 20, 23, 30, and 36 by Pd/C‐catalyzed hydrogenolysis or, better, with propanedithiol and Et3N, followed by acetylation or trifluoroacetylation and hydrogenolytic debenzylation, gave the deprotected acetamido‐ and trifluoroacetamido‐pyrroles 18, 19, 22, 27, 28, 34, 35 40, and 41. As compared to the tetrazole 8 and the imidazole 9, the pyrroles 18, 19, 27, 28, 34, and 35 are only modest inhibitors of N‐acetyl‐β‐D‐glucosaminidase from bovine kidney (Ki values between 10 and 75 μM). indicating the necessity of a heteroatom at the glycosidic position. Ki Values between 100 and 160 μM for the inhibition of N‐acetyl‐β‐D‐glucosaminidase from jack beans were determined for the pyrroles 19, 34, and 35. The trifluoroacetamides inhibited both enzymes about twice as strongly as the corresponding acetamides.
Protonic Quantum Correlations in the H‐Bond Dynamics of Nucleic Acids. Part II. Correlations along the helical axis of protein‐coding DNA of living organisms
Authors: Chatzidimitriou‐Dreismann C. Aris , Seifert Daniel
Published: December 2004

Due to their small mass, adjacent protons (or H‐atoms) of molecular systems may exhibit quantum entanglement (or quantum correlations), even at ambient conditions. The considerable thermal disturbance and/or manybody interactions of condensed matter and the associated decoherence effect, however, cause this protonic entanglement to be restricted in space and time. Some aspects of entanglement and decoherence are mentioned. Extending our previous theoretical work, in the present paper the focus is on the possible existence of entangled protons belonging to the H‐bonds of adjacent base pairs of B‐type DNA. Based on the ‘working hypothesis’ that this effect does really exist, the most probable ‘positions’ for the appearance of protonic entanglement in DNA sequences are qualitatively determined. Furthermore, these ‘positions’ appear to correspond uniquely to dimers of adjacent base pairs of DNA. As a consequence, one can straightforwardly search for an enhanced appearance of such entangled H‐bonds in DNA sequences of living organisms, using the existing DNA databases. A quantitative analysis of protein‐coding DNA sequences of various organisms has been performed, the results of which provide strong evidence for the existence of the considered effect. The most striking finding may be summarized as follows: Quantum entanglement appears preferably between the third base of a codon and the first base of the following one. Quantitative estimates of this and further obtained results are presented. It is also shown that quantum‐chemical considerations of stacking energies cannot account for the results. The new findings provide first evidence for the biological significance of entangled H‐bonds.
Glycosylidene Carbenes part 26. The intramolecular F…︁HO hydrogen bond of 1,3‐diaxial 3‐fluorocyclohexanols
Authors: Biamonte Marco A. , Vasella Andrea
Published: December 2004

According to ab‐initio calculations, the CF…︁HO H‐bond in 1,3‐diaxial 3‐fluorocyclohexanol is characterized by d(F…︁H) = 2.08 Å, and ∠ (F…︁HO) = 138°, and by ΔE between 1.2 and 4.1 kcal/mol, depending upon the reference system. Relative to the OH stretching frequency of axial cyclohexanol, the OH stretching frequency of 1,3‐diaxial 3‐fluorocyclohexanol is shifted by Δω = 7 cm−1. The rigid fluoro diols D‐4 and L‐4 were prepared from tetrahydroxy‐p‐benzoquinone in 11 steps and 1% overall yield. The IR spectrum of 4 in CCl4 soln. is characterized by Δν = 7 cm−1 for the axial and Δν = 44 cm−1 for the equatorial OH group. A relatively strong intramolecular CF…︁HO bond of 4 in CCl4 is evidenced by the large through‐space coupling 5J(F,HO) of 9.3 Hz. Nevertheless, this FHO bond is disrupted in ethereal solvents, while the bifurcated O…︁HO bond subsists. In CCl4, the carbene generated from the glucosylidene‐derived diazirine 5 reacted more rapidly with the axial OH group of D‐4 and L‐4 than with the equatorial one. This regioselectivity is in keeping with the weaker H‐bond of the axial OH group. The regioselectivity is lower in ethers, but its solvent dependence does not parallel solvent basicity. This is not satisfactorily explained by the differential interaction of the ether solvents with the axial and equatorial OH groups, as evidenced by the solvent dependence of their chemical shift, but must also reflect the different interaction of the solvents with the carbene derived from 5, leading to ylides. The lower solvent dependence of the anomeric selectivity for the glycosidation of the equatorial OH group is a consequence of the coordination of the intermediate oxycarbenium ion with OC(1) and OC(3) rather than with the solvent. Under conditions of competitive glycosylation in CCl4, the fluoro alcohol D‐22 reacted more slowly than the alcohol L‐24, evidencing the intramolecular F…︁HO H‐bond.
Reaction of N,N'‐dimethyl‐2‐nitroethene‐1, 1‐diamine with α,ß‐unsaturated acyl isothiocyanates: Preparation of 1,3‐thiazin‐4‐one and 4‐nitro‐1,2‐thiazol‐5(2H)‐imine derivatives
Authors: Trimiño María I. García , Cabrera Castro Arturo Macías Hermán Vélez , Rosado Pérez Arístides , Argilagos Dally Moya , Linden Anthony , Heimgartner Heinz
Published: December 2004

The reaction of N,N'‐dimethyl‐2‐nitroethene‐1,1‐diamine (8) with α,ß‐unsaturated acyl isothiocyanates 9 affords 3,3‐diamino‐2‐nitroacrylthioamides 10 (Scheme 2) in moderate‐to‐good yields. Cyclization of 10 under acidic conditions gives 1,3‐thiazin‐4‐one derivatives of type 11. Oxidative cyclization of 10 with diethyl azodicaboxylate leads to 4‐nitro‐1,2‐thiazol‐5(2H)‐imine derivatives 12.
An Alternative Synthesis of the Enantiomerically Pure Competitive NMIDA Antagonists SDZ 220‐581 and SDZ EAB 515
Authors: Müller Werner , Bänziger Markus , Kipfer Peter
Published: December 2004

An alternative synthesis of enantiomerically pure SDZ 220–881 (1a) and SDZ EAB 515 (1b) starting from L‐Z‐tyrosine is described.
Absolute rate Constants for the Addition of Malonyl Radicals to Alkenes in Solution
Authors: Weber Matthias , Fischer Hanns
Published: December 2004

Absolute rate constants and their Arrhenius parameters are obtained for the addition of a cyclic malonyl radical derived from Meldrum's acid to 20 mono‐ or 1,1‐disubstituted alkenes in (±)‐propylene oxide and for the addition of the open‐chain di(tert‐butyl)malonyl radical to six mono‐ or 1,1‐disubstituted alkenes in 1,1,2‐trichloro‐1,2,2‐trifluoroethane by time‐resolved electron spin resonance spectroscopy. At room temperature, the radicals add at the unsubstituted C‐atoms with rate constants ranging from 1.1. 105 M−1S−1 (acrolein) to 2.4. 106 M−1S−1 (1,1‐diphenylethene). The frequency factors are in the narrow ranges of log (A/M−1S−1) = 8.7 ± 0.1 for the cyclic and log (A/M−1S−1) = 8.2 ± 0.2 for the open‐chain malonyl species, whereas the activation energies vary from 12.9 kJ/mol (1,1‐diphenylethene) to 21.7 kJ/mol (acrylonitrile). They correlate with the alkene ionization potentials and, more weakly, with the reaction enthalpy. No correlation was found between the activation energies and the alkene electron affinities. Hence, the results confirm and quantify the electrophilic nature of malonyl radicals in addition reactions.
Intramolecular Dynamics of Tetranuclear Iridium Carbonyl Cluster Compounds part VI Derivatives with Bidentate Ligands, Crystal Structures of tetrahedro‐ Decacarbonyl{μ‐[1,1‐bis(methylthio‐χS)ethane]}tetrairidium ([Ir4(CO)10‐(μ2‐(MeS)2CHMe)]), tetrahedro‐Tri‐μ‐carbonylheptacarbonyl{μ‐{ethylidenebis‐ [diphenylphosphine]‐χP:χP'}}tetrairidium ([Ir4(CO)10(μ2‐(Ph2P)2CHMe)]), and tetrahedro‐Tri‐μ‐carbonylheptacarbonyl{μ‐{propane‐1,3‐diylbis[diphenylphosphine]‐χP:χP'}}tetrairidium ([Ir4(CO)10(μ2‐Ph2P(CH2)3PPh2)])
Authors: Lumini Tito , Laurenczy Gábor , Roulet Raymond , Tassan Augusto , Ros Renzo , Schenk Kurt , Gervasio Giuliana
Published: December 2004

The disubstituted clusters[Ir4(CO)10(μ2‐LL)] with one edge‐bridging ligand have a ground‐state geometry with all COs terminal (LL = (MeS)2CHMe, cluster 1) or with three edge‐bridging COs (LL = (Ph2P)2CHMe, cluste 2; LL =Ph2P(CH2)3PPh2, cluster 3) in the solid state and in solution. A comparative 13C‐NMR study of 1–3 shows that their respective ground‐state geometries are merely relative minima of energy in the same kinetic profile of successive fluxional processes consisting of a merry‐go‐round of six COs about a unique trangular face and the rotation of terminal COs about one Ir‐atom. The factors affecting the activation energy of the merry‐go‐round result from the relative bites of the bidentate ligands in the ground‐state geometry, as shown by a comparison of the molecular structures of 2 and 3.
Kinetic Study of the Reaction of Pyridoxal 5′‐Phosphate with Hydrazino Compounds of Pharmacological Activity
Authors: Echevarría‐Gorostidi Gerardo R. , Basagoitia Andrea , Pizarro Eliana , Goldsmid Ruth , Blanco José G. Santos , Blanco Francisco García
Published: December 2004

The kinetics of the reaction between pyridoxal 5′‐phosphate (PLP) with carbidopa, hydralazine, and isoniazid, in aqueous solution at variable pH and constant ionic strength of 0.1M was studied spectrophotometrically. The rate constants of formation and hydrolysis of the resulting Schiff base, and its stability were determined in a wide range of pH. A comparison is made of the formation rate constants with those of PLP with hydrazine. The reactivity shows the sequence isoniazid > hydrazine > carbidopa > hydralazine in the whole range of pH studied. The Schiff bases studied are more stable than those formed by PLP and hexylamine and as stable as those described for the reactions of PLP with poly(L‐lysine) or copolypeptides containing L‐lysine.
Distamycin‐NA: A DNA analog with an aromatic heterocyclic polyamide backbone. Part 2. Solid‐phase synthesis of distamycin‐NAs containing the nucleobase uracil: Unexpected solvent participation in the coupling step
Authors: Sauter Guido , Leumann Christian
Published: December 2004

The synthesis of the Fmoc‐protected amino acid 2 is presented. First attempts of amide‐bond formation to the homodimer 4 in solution showed only poor coupling yields indicative for the low reactivity of the amino and carboxy groups in the building blocks 1 and 2, respectively (Scheme 1). Best coupling yields were found using dicyclohexylcarbodiimide (DCC) without any additive. The oligomerization of building block 2 adopting the Fmoc ((9H‐fluoren‐9‐ylmethoxy)carbonyl) solid‐phase synthesis yielded a mixture of N‐terminal‐modified distamycin‐NA derivatives. By combined HPLC and MALDI‐TOF‐MS analysis, the N‐terminal functional groups could be identified as acetamide and N,N‐dimethylformamidine functions, arising from coupling of the N‐terminus of the growing chain with residual AcOH or DCC‐activated solvent DMF. An improved preparation of building block 2 and coupling protocol led to the prevention of the N‐terminal acetylation. However, ‘amidination’ could not be circumvented. A thus isolated tetramer of 2, containing a lysine unit at the C‐terminus and a N,N‐dimethylformamidine‐modified N‐terminus, not unexpectedly, showed no complementary base pairing to DNA and RNA, as determined by standard UV‐melting‐curve analysis.
β2‐ and β3‐Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding
Authors: Seebach Dieter , Abele Stefan , Gademann Karl , Guichard Gilles , Hintermann Tobias , Jaun Bernhard , Matthews Jennifer L. , Schreiber Jürg V. , Oberer Lukas , Hommel Ulrich , Widmer Hans
Published: December 2004

Enantiomerically pure β‐amino‐acid derivatives with the side chains of Ala, Val, and Leu in the 2‐ or 3‐position (β2‐ and β3‐amino acids, resp.), as well as with substituents in both the 2‐ and 3‐positions (β2,3‐amino acids, of like‐configuration) have been prepared (compounds 8–17) and incorporated (by stepwise synthesis and fragment coupling, intermediates 24–34) into β‐hexa‐, β‐hepta‐, and β‐dodecapeptides (1–17). The new and some of the previously prepared β‐peptides (35–39) showed NH/ND exchange rates (in MeOH at room temperature) with τ1/2 values of up to 60 days, unrivalled by short chain α‐peptides. All β‐peptides 1–7 were designed to be able to attain the previously described 31‐helical structure (Figs. 1 and 2). CD Measurements (Fig. 4), indicating a new secondary structure of certain β‐peptides constructed of β2‐ and β3‐amino acids, were confirmed by detailed NMR solution‐structure analyses: a β2‐heptapeptide (2c) and a β2,3‐hexapeptide (7c) have the 31‐helical structure (Figs. 6 and 7), while to a β2/β3‐hexapeptide (4) with alternating substitution pattern H‐(β2‐Xaa‐β3‐Xaa)3‐OH a novel, unusual helical structure (in (D5)pyridine, Fig. 8; and in CD3OH, Figs. 9 and 10) was assigned, with a central ten‐membered and two terminal twelve‐membered H‐bonded rings, and with CO and NH bonds pointing alternatively up and down along the axis of the helix (Fig. 11). Thus, for the first time, two types of β‐peptide turns have been identified in solution. Hydrophobic interactions of and hindrance to solvent accessibility by the aliphatic side chains are discussed as possible factors influencing the relative stability of the two types of helices.
Second‐Generation Trifluoromethyl‐Substituted Chiral Dendrimers Containing Triply Branched Building Blocks: CF3 as sensitive NMR probe for ‘remote’ diastereotopicity
Authors: Greiveldinger Guy , Seebach Dieter
Published: December 2004

(S)‐4,4,4‐Trifluoro‐3‐hydroxybutanoic acid was used as a starting material for the synthesis of dendritic branches (16–21, 30–32) which were attached to a chiral triol (6 or ent‐6), derived from (R)‐3‐hydroxybutanoic acid, to give CF3‐substituted dendrimers (33–36, 38–40) and dendritic compounds (37) of 1st and 2nd generation. The key steps in these syntheses are diastereoselective aldol additions of dioxanone enolates (building blocks and intermediates 6–15, 22, 23, and 25–28) and Williamson etherifications of benzylic‐branch bromides with triols (intermediates and products 16–21, 28, and 30–40). The surfaces of the dendrimers are covered with MeO (33–35, 38–40) or allyloxy groups (36 and 37). The new dendrimers are characterized by NMR and mass spectroscopy. 19F‐NMR Signals of the CF3 groups reveal constitutional heterotopicities caused by substituents which are separated from the F‐nuclei by up to 15 bonds (through a 1,1′‐biphenyl‐4,4′‐diyl spacer!) (Fig. 6).
α‐Methylidene‐γ‐butyrolactones: Synthesis and evaluation of quinolin‐2(1H)‐one derivatives
Authors: Wang Tai‐Chi , Chen Yeh‐Long , Tzeng Cherng‐Chyi , Liou Shorong‐Shii , Tzeng Weng‐Feng , Chang Ya‐Ling , Teng Che‐Ming
Published: December 2004

As a continuation of our previous studies on the synthesis and antiplatelet activity of quinolin‐2(1H)‐ones with an α‐methylidene‐γ‐butyrolactone substituted at O(8), the O(6)‐ and N(1)‐substituted isomers were synthesized and evaluated for antiplatelet activity against thrombin (Thr)‐, arachidonic acid (AA)‐, collagen (Col)‐, and platelet‐activating‐factor (PAF)‐induced aggregation in washed rabbit platelets. These compounds were synthesized from 6‐hydroxyquinolin‐2(1H)‐one via alkylation and Reformatsky‐type condensation (Schemes 1 and 2). All of them were found to inhibit the platelet aggregation perfectly which was induced by AA and Col. 6‐Substituted isomers 5b–g exhibited very strong inhibitory activities against AA‐ and PAF‐ induced aggregation and are approximately ten times more potent than their 8‐substituted counterparts. However, the 1‐substituted (11a and 11b) and the 1,6‐disubstituted (6) counterparts were relatively inactive. Their effects on the Ca2+‐dependent vasoconstriction induced by high K+, and the phasic and tonic vasoconstrictions induced by norepinephrine (NE) in rat aorta were also evaluated. Except 5g, all of them were found to have significant inhibitory activity on the NE‐induced phasic and tonic vasoconstrictions. Compounds 6 and 11b also exhibited strong inhibitory activity on high−K+ medium, Ca2+‐induced vasoconstriction.
Acridine‐Labeled Primers as Tools for the Study of Nonenzymatic RNA Oligomerization
Authors: Kurz Markus , Göbel Karin , Hartel Christian , Göbel Michael W.
Published: December 2004

Short, dye‐labeled oligonucleotides have been used as primers in template‐controlled polymerization reactions of RNA. The synthesis of appropriate acridine derivatives and their attachments to nucleic acids is described. In the nonenzymatic oligomerization of 2‐methyl‐1H‐imidazole‐activated guanosine 5′‐monophosphate, two observations deserve special notice: (1) reaction rates are almost unchanged by variations of the Na+concentration; (2) the conformational type of the primer‐template duplex (Avs.B) has considerable influence on the rates and yields of RNA oligomerization. When the incorporation of cytidine was studied in the presence of 1MNa+or K+, the process was almost inhibited by quadruplex formation of the oligo‐dG template. However, if these cations were omitted, an efficient primer extension could be observed using template concentrations as high as 100 μM. The chances for nonenzymatic self‐replication of RNA thus might be distinctly better than previously assumed.
Synthesis and Spectroscopic Characterization of 4‐Chlorophenyl Isocyanate (= 1‐chloro‐4‐isocyanatobenzene) Adducts with Amino Acids as Potential Dosimeters for the Biomonitoring of Isocyanate Exposure
Authors: Möller Marianne , Henschler Dietrich , Sabbioni Gabriele
Published: December 2004

Blood‐protein adducts are used as dosimeter for modifications of macromolecules in the target organs where the disease develops. The functional groups of cysteine, tyrosine, serine, lysine, tryptophan, histidine and N‐terminal amino acids are potential reaction sites for isocyanates. Especially the N‐terminal amino acids, valine and aspartic acid of hemoglobin and albumin, respectively, are reactive towards electrophilic xenobiotics. To develop methods for the quantification of such blood‐protein adducts, we treated 4‐chlorophenyl isocyanate (1) with the tripeptide L‐valyl‐glycyl‐glycine (2a) and with single amino acids yielding N‐[(4‐chlorophenyl)carbamoyl]valyl‐glycyl‐glycine (3a), N‐[(4‐chlorophenyl)carbamoyl]valine (3b), N‐[(4‐chlorophenyl)carbamoyl]aspartic acid (3c), N‐(4‐chlorophenyl)carbamoyl glutamic acid (3d), N‐acetyl‐S‐[(4‐chlorophenyl)carbamoyl]cysteine (3e), and N‐acetyl‐O‐[(4‐chlorophenyl)carbamoyl]serine (3f), Nα‐acetyl‐Nε‐[(4‐chlorophenyl)carbamoyl]lysine (3g). For several chemicals, it was shown that blood‐protein adducts are good dosimeters of exposure and dosimeters for the target dose. The hydrolysis of the N‐terminal adducts of isocyanates release hydantoins which can be separated from the rest of the protein and analyzed using GC/MS or HPLC. This was achieved with 3a. The released hydantoin could be analyzed using GC/MS. We propose to analyze the N‐terminal adducts of isocyanates with blood protein to distinguish between arenamine and arylisocyanate exposure.
Asymmetric synthesis of pentono‐ and 6‐deoxyhexono‐δ‐lactams via hetero‐Diels‐Alder reactions with nitroso dienophile
Authors: Defoin Albert , Sarazin Hervé , Sifferlen Thierry , Strehler Christiane , Streith Jacques
Published: December 2004

Asymmetric Diels‐Alder reaction of the pentadienoic and hexadienoic acids 2a,b with the chiral chloronitroso derivative 3 gave the primary adducts 4a,b with good‐to‐excellent enantioselectivity. Subsequent as‐ or trans‐dihydroxylation and hydrogenolytic cleavage of the NO bond led to the 5‐amino‐5‐deoxypentono‐δ‐lactams 13a, 14, 15a, and 16 in the D‐ribose, L‐arabinose, D‐xylose, and L‐lyxose series, respectively, and to the 5‐amino‐5,6‐dideoxyhexono‐δ‐lactams 13b and 15b in the D‐allose and D‐glucose series, respectively.
New Enzyme Models of Chloroperoxidase: Improved stability and catalytic efficiency of iron porphyrinates containing a thiolato ligand
Authors: Wagenknecht Hans‐Achim , Claude Cécile , Woggon Wolf‐Dietrich
Published: December 2004

The heme‐thiolate protein chloroperoxidase (CPO) catalyzes the chlorination of activated CH bonds. A reaction mechanism is proposed for this enzymatic transformation (Scheme 1), and a new iron(III) porphyrinate complex 13 is synthesized containing pentafluorophenyl groups at two meso‐positions and a thiophenolato ligand coordinating to the Fe‐atom (Schemes 2 and 3). Due to the presence of the electron‐withdrawing substituents, the catalyst 13 is appreciably resistant to oxidants (HOCl) and chlorinates, e.g., monochlorodimedone (5), with turnover numbers up to 1530. The redox potential of 13, E0 = ‐ 134 mV, and the Soret band (λmax 448 nm) of the CO adduct of the reduced state of 13 are close to the corresponding values of the enzyme CPO.
Stress‐generated potentials in bone: Effects of collagen modifications
Authors: Pollack S. R. , Korostoff E. , Sternberg M. E. , Koh J.
Published: December 2004

The effect of collagen modification on the magnitude of stress‐generated potentials has been studied. A whole bone model has been developed for determining the effects of collagen crosslinking on the electrical signals. Increased crosslinking results in larger electrical signals, and such increases result whether in vivo or in vitro changes in the collagen are made.
Characterization of self‐curing acrylic bone cements
Authors: Kusy R. P.
Published: December 2004

Four self‐curing acrylic bone cements were surveyed by infrared, solubility, viscometry, quantitative metallography, microscopy, and physical testing techniques: CMW, Palacos R, Sulfix‐6, and Surgical Simplex P. Results show that these bone cements were primarily composed of poly(methyl methacrylate) and that no cross‐linking was evident. Solubility analysis confirmed this latter observation, as the bone cements dissolved completely except for a small insoluble fraction, which was identified as the radiopaque filler. For each bone cement, the viscosity‐average molecular weights of both the powdered phase and the cured two‐phase product remained unchanged, varying overall from 1 to 5 × 105. Using standard quantitative metallography, porosity ranged from 1 to 8% and the dispersed powder phase decreased 11–46%. Microscopy revealed the nature of the porosity, radiopaque fillers, the powder size and shape, and the fracture morphology. From tensile and fracture toughness tests, five physical properties were determined at ambient conditions and at 37°C after conditioning in distilled water at 37°C for 10 months: the modulus of elasticity, the ultimate tensile strength, the elongation at break, the fracture energy, and the mean inherent flaw size. At ambient conditions, the ultimate tensile strength decreased 33–55% when compared with commercial unmodified poly(methyl methacrylate), Plexiglas G. While the fracture energy remained rather invariant, the mean inherent flaw size increased fivefold over the commercial acrylic tested. This marked increase in the mean inherent flaw size could lower the fatigue resistance of a material, since more and/or larger fracture initiation sites are available. When tested at 37°C after protracted conditioning, the deleterious trends observed at ambient temperature continued. To some degree, porosity, particle‐matrix interfaces, residual stresses, low molecular weight products, inorganic and/or other organic additions, and water contributed to the inherent flaw size at the expense of the working stress. Several modifications are suggested by which the importance of these factors might be minimized.
Compatibility and long‐term stability of glass–ceramic implants
Authors: Blenckè B. A. , Brömer H. , Deutscher K. K.
Published: December 2004

The biocompatible and bioactive glass–ceramic material Ceravital, which has been developed, can be adapted to the physiological conditions of the organism by apropriately monitoring its chemical composition. The material exhibits a remarkable long‐term stability in in vitro solubility tests and when used as implants in animal experiments.
L‐Asparaginase bound to collagen membranes: Effect of glutaraldehyde crosslinking on stabilization of catalytic activity
Authors: Jefferies S. R. , LaPresto P. , Bernath F. R. , Joyeuse R.
Published: December 2004

Reconstituted bovine collagen has been used extensively in our laboratory as a carrier for immobilized E. coli L‐asparaginase. The activity and catalytic stability of these collagen–asparaginase membranes can be altered substantially by conditions used in membrane crosslinking with glutaraldehyde. As the concentration of glutaraldehyde used in tanning is increased, the initial specific activity of collagen–asparaginase membranes decreased asymptotically to a limiting value. Similar results occurred when membranes were subjected to increasing time periods of tanning at a constant glutaraldehyde concentration. These observations point to a time‐concentration relationship for glutaraldehyde tanning and its effect on the specific activity of collagen–asparaginase membranes. Specific activities of membranes tanned at glutaraldehyde concentrations of 5% or higher appear to be very stable over long periods of alternate storage and assay. This result, however, is not observed with membranes tanned at glutaraldehyde concentrations lower than 5% for short periods of time (approximately 30 sec to 1 min). It is not clear whether the instability of membranes tanned at lower concentrations of glutaraldehyde or shorter intervals of tanning is due to enzyme elution from the membrane or denaturation of the bound enzyme.
The effect of surface finish on the anodic polarization of a conventional spherical amalgam
Authors: Boyer D. B. , Chan K. C.
Published: December 2004

The corrosion of carved, burnished, polished, and burnished–polished samples of a conventional spherical amalgam was studied by anodic polarization in Ringer's solution. The effect of the variation of the mercury content from 40 to 60 wt% on the corrosion of burnished or polished samples was also investigated. It was found that burnished and burnished–polished samples corrode the least and carved samples the most. The current‐density peak associated with γ2 was of greater magnitude in polished specimens than in burnished specimens throughout the range of mercury concentrations investigated. It is hypothesized that lower porosity and more ready passivation of the surface due to a high amount of γ2 are the reasons that burnished samples corroded less than polished samples in this anodic polarization test.
Enzyme immobilization on heparin
Authors: Torchilin V. P. , Il'Ina E. V. , Streltsova Z. A. , Smirnov V. N. , Chazov E. I.
Published: December 2004

We describe the preparation and some of the properties of heparin‐bound α‐chymotrypsin that were obtained via activation of heparin with water‐soluble carbodiimide. Immobilized enzyme has unchanged kinetic characteristics toward low‐molecular‐weight and macromolecular substrates. The heparin‐bound enzymes could have a wide range of medical applications.
Mathematical models for the release of drugs from matrix tablets
Authors: Cobby John
Published: December 2004

A previously derived cubic equation describing the release of drugs from matrix tablets is compared with a more complex equation recently presented. Using data obtained from cylindrical hydrocortisone matrix tablets, it is shown that the simpler cubic equation affords an equally acceptable description of drug release. Because the cubic equation contains a release‐rate constant Kr that is independent of tablet shape, a congruency between this equation and other historical models of diffusion may be demonstrated. It is suggested, given the complexity of drug disposition in vivo, that simplicity in modeling is a desirable goal.
Biodegradation behavior of various calcium phosphate materials in bone tissue
Authors: Klein C. P. A. T. , Driessen A. A. , de Groot K. , van den Hooff A.
Published: December 2004

In order to study the biodegradation behavior of calcium phosphate materials, cylinders of standard size were implanted in the tibiae of rabbits. Material parameters were stoichiometry (hydroxyapatite with a Ca/P ratio of 1.67 versus tricalcium phosphate with a Ca/P ratio of 1.50), crystallographic structure (apatite versus β‐whitlockite), microporosity, and macroporosity. The extent of biodegradation was evaluated by radiography, light and fluorescence microscopy, microradiography, and porosity measurements. All calcium phosphate materials were biocompatible in bone tissue. Hydroxyapatite ceramics had a higher osteogenic potential than β‐whitlockite materials. Depending on their porosities, sintered tricalciumphosphate (β‐whitlockite) materials were more or less biodegradable, in contrast to sintered hydroxyapatite materials, which showed no detectable resorption over a period of 9 months of implantation.
Osteoinduction within porous polysulfone implants at extraosseous sites using demineralized allogeneic bone matrix
Authors: Vandersteenhoven J. J. , Spector M.
Published: December 2004

The objective of this study was to determine if bone induction could occur in implants of porous polysulfone (PPSF) impregnated with particles of demineralized allogeneic bone matrix (DABM). DABM–PPSF composites were fabricated by inserting DABM particles into PPSF specimens. The porous implants were produced by sintering polysulfone particles (850–1180 μm in diameter). DABM particles were prepared by demineralizing rat cortical bone in 0.6N HCl at 4°C for 18–24 h. A composite DABM–PPSF specimen and three “controls” were implanted subcutaneously at abdominal sites in 30 adult Sprague–Dawley rats. The three controls were whole DABM (4 × 4 × 1 mm), particulate DABM (1 × 1 × 1 mm), and porous polysulfone (5 × 5 × 1 mm). Microradiographic and histological evaluation of DABM–PPSF composites revealed chondrogenesis within the pores of the specimens at 10 days, followed by ossification and fatty marrow production at 21 and 43 days. This histological sequence was similar to that seen with DABM controls. The tissue response to porous polysulfone did not prevent the osteoinductive process. These results suggest that an osteoinductive material such as DABM may be useful in augmenting the implantation of porous implants at osseous sites in which the potential for bone regeneration is limited.
Cement strain measurement surrounding loose and well‐fixed femoral component stems
Authors: Crowninshield Roy D. , Tolbert James R.
Published: December 2004

Strain measurement within the cement surrounding stemmed total hip femoral components was accomplished using PMMA encapsulated and embedded strain gauges. Cement strain measurement associated with a well‐bonded stem–cement interface and an unbonded stem–cement interface (i.e., loose prosthesis) was performed. The presence of a stem–cement bond was found to reduce proximal cement strain magnitudes while having little effect on distal cement strain magnitudes. The assurance of a stem–cement bond on only the proximal third of the interface was found to have an effect similar to that of a complete stem–cement bond. The results of this experimental investigation confirm the theoretical prediction that the stem–cement bond is important in maintaining the integrity of the cement mantle surrounding a stemmed femoral component.
Retrieval analysis of total knee prostheses: A method and its application to 48 total condylar prostheses
Authors: Hood Roger W. , Wright Timothy M. , Burstein Albert H.
Published: December 2004

A technique for the classification and quantification of damage in retrieved total knee prostheses is presented and applied to the examination of 48 removed total condylar‐type knee replacements. The technique involves inspection of all metallic and polyethylene components for evidence of gross deformation, fracture, and damage to articulating surfaces. A grading system was developed to quantitate surface damage on polyethylene components. Results of the examinations are combined with patient variables (weight, activity level, radiographic findings, time of implantation, and results of histology performed on surrounding tissue) to determine correlations between clinical variables and the mechanical damage experienced by the prostheses. For the 48 total condylar‐type prostheses, significant positive correlations were found for the surface damage correlated with the patient's weight and the time the prosthesis was implanted.
Macroporous hydrogel membranes for a hybrid artificial pancreas. II. Biocompatibility
Authors: Klomp Gregory F. , Hashiguchi Hiroshi , Ursell Philip C. , Takeda Yoshi , Taguchi Tadahiro , Dobelle William H.
Published: December 2004

A histological evaluation of the biocompatibility of a new porous hydrogel membrane made of 2‐hydroxyethyl methacrylate (2‐HEMA) was performed. Isolated membranes and diffusion chambers made of this material and filled with rabbit pancreas were implanted in diabetic rats for periods of up to 8 1/2 months. Histologic evaluation showed that this polymer elicits minimal tissue reaction within the first 7 weeks but some increase in granulation tissue and fibrosis thereafter. A component of this tissue reaction is neovascularization, and many blood vessels were noted immediately adjacent to the membrane's surface. Calcification of the membrane was also progressive but could be minimized by formulations resulting in the incorporation of acid groups throughout the hydrogel and on its surface. Diffusion chambers made of this new material show promise for use in a “hybrid” artificial pancreas for the treatment of diabetes.
Creep of conventional and microfilled dental composites
Authors: Papadogianis Yannis , Boyer Daniel B. , Lakes Roderic S.
Published: December 2004

The creep of microspecimens of two conventional and two microfilled composites was studied using a torsional creep apparatus. Small stresses below the materials' proportional limits were maintained for 3 h and recovery was monitored for 30 h. Creep curves were obtained at 21.5,37, and 50°C, and three torque levels. The composites exhibited linear viscoelastic behavior at low deformations. The magnitude of creep depended on the amount and type of resin in the composites. The materials did not recover their original shape after 30 h after the stress was removed. No transitions were observed in the temperature range employed. The shear moduli decreased with temperature and are in reasonable agreement with literature values obtained with other tests.
Long‐term compressive creep deformation and damage in acrylic bone cements
Authors: Chwirut Daniel J.
Published: December 2004

Compressive creep tests were performed on five commercially available acrylic bone cements under conditions simulating in vivo usage. Measured creep strains are quite large, generally exceeding elastic strains. Large variations in creep response were noted among the various cements, with a carbon‐reinforced cement by far the most resistant to creep. The empirical model ϵ = a exp(bσ)tn was found to predict creep strains within about 10% of the measured values. Microscopic examination of some specimens after testing revealed significant cracking, resulting from long‐term loading, that could be a contributing cause of time‐dependent failure.