David Dukhan

ANTI-HBV SPECIFIC β-L-2′-DEOXYNUCLEOSIDES

A unique series of simple unnatural L-nucleosides that specifically inhibit hepatitis B virus (HBV) replication has been discovered. These molecules have in common a hydroxyl group in the 3′-position (3′-OH) of the β-L-2′-deoxyribose sugar that confers antiviral activity specifically against hepadnaviruses. Replacement of the 3′-OH broadens activity to other viruses. Substitution in the base decreases antiviral potency and selectivity. Human DNA polymerases and mitochondrial function are not effected. Plasma viremia is reduced up to 8 logs in a woodchuck model of chronic HBV infection. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection.

Synthesis of 5-aza-7-deazaguanine nucleoside derivatives as potential anti-flavivirus agents.

Coupling suitable sugars (D- or L-ribofuranose, 2′ or 3′-deoxysugar, branched sugars) with 2-aminoimidazo[1,2-a]-s-triazin-4-one was carried out using the different reaction conditions: 1) condensation in the presence of sodium hydride; or 2) condensation using Vorbruggen′s methods. The 5-aza-7-deazaguanine nucleoside analogues obtained were evaluated in cell culture experiments for the inhibition of the replication of a number of RNA viruses, including BVDV, YFV, and WNV.

4′-Thio-RNA: Synthesis, Base Pairing Properties and Interaction with Dimerization Initiation Site of HIV-1

Abstract in the present paper, we describe the synthesis of a modified 9-mer oligonucleotide, 4′-S-r(UGUGCACCU) containing for the first time 4′-thio-guanosine units. This modified 9-mer was found to inhibit in vitro genomic RNA dimerization as well as the wild type RNA.

Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.

Pharmacokinetics of β-L-thymidine and β-L-2′-deoxycytidine in woodchucks and monkeys

Publisher Summary Pharmacokinetic studies in woodchucks and monkeys indicated that the disposition of β-L-thymidine (L-dT) is comparable to the pharmacokinetic characteristics of other nucleoside analogs after administration to these animals. Woodchuck is a useful animal model for studying anti-hepatitis B virus (HBV) agents because of many similarities between woodchuck hepatitis virus (WHV) and HBV, hence providing important information on the in vivo efficacy of anti-HBV candidates. The compound has good oral bioavailability and is eliminated and unchanged in urine. 3-L-2’-deoxycytidine (L-dC) exhibits lower oral bioavailability in both species. Several prodrugs that improve the oral bioavailability of L-dC are currently under evaluation. Chronic HBV infection is a major global health problem, affecting approximately 5% of the worlds population. Currently, the only approved treatment options include alpha interferon (INF-α) and lamivudine. Potent in vitro and in vivo efficacy coupled with favorable pharmacokinetic disposition make both L-dT and L-dC promising antiviral candidates for the treatment of chronic HBV infection.

Structure-activity relationships of tiazofurin analogs: synthesis and computational studies of 4'-thio derivatives of thiophenfurin and furanfurin

Abstract The synthesis and computational studies of 5-(4-thio-β-D-ribofuranosyl)-furan-3-carboxamide (furanthiofurin) and 5-(4-thio-β-D-ribofuranosyl)thiophene-3-carboxamide (thiophenthiofurin) are reported.

Synthesis and antiviral evaluation of 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives.

Three 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).

Synthesis of 1'-C-fluoromethyladenosine.

In search for new antiviral agents, we have been interested in 1′-C-fluoromethyl branched ribonucleosides. In this paper, we describe the synthesis of 1′-C-fluoromethyladenosine via electrophilic fluorination of exo-glycal.

Synthesis, Physicochemical and Pharmacokinetic Studies of Potential Prodrugs of β-L-2′-Deoxycytidine, a Selective and Specific Anti-HBV Agent

β-L-2′-Deoxycytidine (β-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well as N4-derivatization with an N,N-(dimethyl-amino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, β-L-dC. Presented in part at the 14th International Conference on Antiviral Research, Seattle, Washington, USA, 8–13 April 2001. Antiviral Reseach 2001; 50:A79.

Synthesis of 2'-C-methyl-4'-thio ribonucleosides.

Starting from 2-C-methyl-ribonolactone, 1,2,3,5-tetra-O-acetyl-2-C-methyl-4-thioribofuranose was synthesized and condensed with heterocyclic bases to afford 2′-C-methyl-4′-thioribonucleosides.