Galina V. Gurskaya

An efficient synthesis and physico-chemical properties of 2'-O-D-ribofuranosylnucleosides, minor tRNA components

ABSTRACT A high yield preparation of 9-(2-O-β-D-ribofuranosyl-β-D-ribofuranosyl)adenine, guanine- and the pyrimidine analogs (cytosine, thymine and uracil base moiety) has been achieved, and the conformational properties of the ring systems were investigated using NMR spectroscopy and X-ray.

New syntheses of 2′-C-methylnucleosides starting from d-glucose and d-ribose

Abstract Effective general methods have been developed for the synthesis of 2′-C-methylnucleosides starting from d -glucose and d -ribose. 3-O-benzyl-1,2-O-isopropylidene-3-C-methyl-α- d -allofuranose was prepared in 5 steps from d -glucose and converted into 1,2,3-tri-O-acetyl-2-C-methyl-5-O-p-methylbenzoyl- d -ribofuranose (5), the starting compound for nucleoside synthesis. Compound 5 was also synthesised from 2-C-hydroxymethyl-2,3-O-isopropylidene-5-O-trityl- d -ribofuranose, prepared in 3 steps from d -ribose. Condensation of 5 with the bis-trimethylsilyl derivatives of uracil, N4-benzoylcytosine, and N6-benzoyladenine in the presence of F3CSO3OSiMe3 followed by removal of the protecting acyl groups yielded the corresponding 2′-C-methylnucleosides.

Molecular and crystal properties of ethyl 4,6‐dimethyl‐2‐thioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate from experimental and theoretical electron densities

The electron density and electronic energy densities in ethyl 4,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate have been studied from accurate X-ray diffraction measurements at 110 K and theoretical single-molecule and periodic crystal calculations. The Quantum Theory of Atoms in Molecules and Crystals (QTAMC) was applied to analyze the electron-density and electronic energy-density features to estimate their reproducibility in molecules and crystals. It was found that the local electron-density values at the bond critical points derived by different methods are in reasonable agreement, while the Laplacian of the electron density computed from wavefunctions, and electron densities derived from experimental or theoretical structure factors in terms of the Hansen-Coppens multipole model differ significantly. This disagreement results from insufficient flexibility of the multipole model to describe the longitudinal electron-density curvature in the case of shared atomic interactions. This deficiency runs through all the existing QTAMC bonding descriptors which contain the Laplacian term. The integrated atomic characteristics, however, suffer noticeably less from the aforementioned shortcoming. We conclude that the electron-density and electronic energy QTAMC characteristics derived from wavefunctions, especially the integrated quantities, are nowadays the most suitable candidates for analysis of the transferability of atoms and atomic groups in similar compounds.

1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents

Abstract Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono- and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.

Epimerization during the acetolysis of 3-O-acetyl-5-O-benzoyl-1,2-O-isopropylidene-3-C-methyl-α-d-ribofuranose. Synthesis of 3′-C-methylnucleosides with the β-d-ribo- and α-d-arabino configurations

Abstract Acetolysis of 3-O-acetyl-5-O-benzoyl-1,2-O-isopropylidene-3-C-methyl-α- d -ribofuranose with a high concentration of acetic acid yielded 1,2,3-tri-O-acetyl-5-O-benzoyl-3-C-methyl- d -arabinofuranose, which was used for the preparation of 3-C-methyl-α- d -arabinofuranosyl nucleosides. 3′-C-Methylribonucleosides were also synthesized starting from 1,2,3-tri-O-acetyl-5-O-benzoyl-3-C-methyl- d -ribofuranose.

Synthesis, Conformation of 3′-(Tetrazole-2″-yl)-3′-deoxythymidine and its 5″-Derivatives. Substrate Properties of 3′-(Tetrazole-2″-yl)-3′-deoxythymidine 5′-Triphosphate

Abstract 5′-O-Benzoyl-3′-(tetrazole-2”-yl)-3′-deoxythymidine and its 5”-substituted derivatives were obtained by the reaction of 5′-O-benzoyl-2,3′-anhydrothymidine with triethylammonium salts of either tetrazole or 5-substituted tetrazoles. Debenzoylation of these compounds yielded 3′-(tetrazole-2”-yl)-3′-deoxythymidine and its 5”-derivatives. Structures of two of them were confirmed by X-ray analysis. Both 3′-(tetrazole-2”-yl)-3′-deoxythymidine and 3′-(5”-methyltetrazole-2”-yl)-3′-deoxythymidine have anti-conformation with respect to the glycosidic bond, and 2′-endo-3′-exo-conformation of the sugar residue with gauche + orientation relative to the C4′-C5′ bond. 3′-(Tetrazole-2”-yl)-3′-deoxythymidine 5′-triphosphate exhibited poor termination substrate properties towards avian myeloblastosis virus reverse transcriptase and did not serve as a substrate for other employed DNA polymerases.

X-ray diffraction studies of 5-functionalized 1,2,3,4-tetrahydropyrimidin-2-ones(thiones): II. Molecular and crystal structures of 5-benzoyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione and ethyl 6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The structures of two new tetrahydropyrimidine-2-thiones, namely, 5-benzoyl-4,6-dimethyl-1,2,3,4-tetrahydropyrimidine-2-thione and ethyl 6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, which are potential medicinals, are investigated using X-ray diffraction analysis. The conformational features of the molecules studied are analyzed.

X-ray diffraction studies of 5-functionalized substituted 1,2,3,4-tetrahydropyrimidin-2-ones(thiones): I. Molecular structures of 5-acetyl-4-ethyl-6-methyl-1,2,3,4-tetrahydropyrimidine-2-thione, 5-acetyl-6-methyl-4-(4-methylphenyl)-1,2,3,4-tetrahydropyrimidine-2-thione, and 5-acetyl-4-(4-methoxyphenyl)-6-methyl-1,2,3,4-tetrahydropyrimidin-2-one

The structures of three 5-acetyl-1,2,3,4-tetrahydropyrimidin-2-ones(thiones), namely, 5-acetyl-4-ethyl-6-methyl-1,2,3,4-tetrahydropyrimidine-2-thione, 5-acetyl-6-methyl-4-(4-methylphenyl)-1,2,3,4-tetrahy-dropyrimidine-2-thione, and 5-acetyl-4-(4-methoxyphenyl)-6-methyl-1,2,3,4-tetrahydropyrimidin-2-one, which are potential medicinals, are studied by X-ray diffraction. The conformational features of the molecules studied are analyzed. For these compounds, the dependence of the conformation of the tetrahydropyrimidine ring on the orientation of the substituent at the C(4) atom with respect to the heterocycle is found.

Structural Features Of 2′,3′-Riboanhydroadenosine, A Conformationally Restricted Termination Substrate Of DNA Polymerases

Abstract 2′,3′-Riboanhydroadenosine (raA), a conformationally restricted inhibitor of some DNA polymerases, has been studied by X-Ray crystallography. It crystallizes in space group P1 with unit cell parameters: a=4.834(1); b=6.893(1); c=15.942(2)A; α=90.51(1); β=97.16(2); γ=89.27(2)[ddot]; V=527.1α3 and with two independent molecules (A and B) in the cell. The conformation of A and B molecules about the glycosidic bond is different. In the A molecule, the glycosidic torsion angle χA is 56.8[ddot] and corresponds to syn conformation; in the B molecule, χB=−170.8[ddot], which corresponds to the nucleoside in anti conformation. The sugar rings of both molecules are slightly puckered (0.1A), C1′ being exo in A and C4′ -endo-04′-exo in B. The conformation of A and B molecules about the exocyclic bond C4′-C5′ is gauche+. The observed similarities in some structural and biochemical properties of 2′,3′-riboanhydronucleosides and 2′,3′-dideoxy-2′,3′-didehydronucleosides are discussed.

New pyrimidine cyclonucleosides with hydrogenated aglycones: synthesis and X-ray structures.

Abstract Acid catalysed transformations of (6S)-6,5′-anhydro-6-hydroxy-1-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)hexahydropyrimidine-2-thione are studied. (6R)-6,2′-anhydro-6-hydroxy-1-(α-D-ribofuranosyl)hexahydropyrimidine-2-thione was formed as a thermodynamically stable product. Two intermediates, (6S)-6,5′-anhydro-6-hydroxy-1-(β-D-ribofuranosyl)hexahydropyrimidine-2-thione and 6-hydroxy-1-(D-ribosyl)hexahydropyrimidine-2-thione and products of cleavage of glycosidic bond were identified in the reaction mixtures. Results of X-ray structural determination of the synthesised nucleosides are presented.