Arlene Roland

Phosphorothioate Di- and Trinucleotides as a Novel Class of Anti-Hepatitis B Virus Agents

ABSTRACT Several nucleoside analogs are under clinical development for use against hepatitis B virus (HBV). Lamivudine (3TC), a nucleoside analog, and adefovir dipivoxil (ADV), an acyclonucleotide analog, are clinically approved. However, long-term treatment can induce viral resistance, and following the cessation of therapy, viral rebound is frequently observed. There continues to be a need for new antiviral agents with novel mechanisms of action. A library of more than 600 di- and trinucleotide compounds synthesized by parallel synthesis using a combinatorial strategy was screened for potential inhibitors of HBV replication using the chronically HBV-producing cell line 2.2.15. Through an iterative process of synthesis, lead optimization, and screening, three analogs were identified as potent inhibitors of HBV replication: dinucleotides ORI-7246 (drug concentration at which a 10-fold reduction of HBV DNA was observed [EC90], 1.4 μM) and ORI-9020 (EC90, 1.2 μM) and trinucleotide ORI-7170 (EC90, 7.2 μM). These analogs inhibited the replication of both strands of HBV DNA. No suppression of HBV protein synthesis or intracellular core particle formation by these analogs was observed. No inhibition of HBV DNA strand elongation by the analogs or their 5′-triphosphate versions was apparent in in vitro polymerase assays. Although the exact mechanism of action is not yet identified, present data are consistent with an inhibition of the HBV reverse transcriptase-directed priming step prior to elongation of the first viral DNA strand. In transient-transfection assays, these analogs inhibited the replication of 3TC-resistant HBV. Synergistic interactions in combination treatments between the analogs and either 3TC or ADV were observed. These compounds represent a novel class of anti-HBV molecules and warrant further investigation as potential therapeutic agents.

Parallel solid-phase synthesis of nucleoside phosphoramidate libraries.

Combinatorial chemistry is playing an increasingly prominent role in the process of drug discovery. A nucleic acid-based (NAB) scaffold can be engineered to create functional group and topological diversity in a library. Described herein is the parallel solid-phase synthesis of combinatorial libraries of nucleoside phosphoramidates, and the first evaluation of antiviral activity against hepatitis B virus (HBV).

A novel linker for the solid-phase synthesis of a library of 3′-thiophosphorylated dinucleotides

Abstract The preparation of a controlled-pore-glass (CPG) support carrying a novel linker is described. This support was compatible with the established phosphoramidite method of solid-phase oligonucleotide synthesis. The use of this linker for the synthesis of a library of 3′-thiophosphorylated dinucleotides is described.

Total synthesis of ent-15(RS)-2,3-dinor-5,6-dihydro-8-epi-PGF2α

Abstract The first total synthesis of ent -15(RS)-2,3-dinor-5,6-dihydro-8- epi -PGF2α 1 is described using diacetone-D-glucose as starting material. The major urinary metabolite of the isoprostane 8- epi -PGF2α is 2,3-dinor-5,6-dihydro-8- epi -PGF2α, which is a potent lipid peroxidation index to obtain an integrated assessment of oxidative stress in humans.

Radical cyclization of highly functionalized precursors: stereocontrol of ring closure of acyclic 1-substituted-2,4-dihydroxylated hex-5-enyl radicals

Polysubstituted cyclopentane rings can be synthesized with good to high stereocontrol by radical cyclization using tributyltin hydride and a radical initiator, triethylborane–O2 in anhydrous xylene at room temperature. We have demonstrated that the nature (protected or unprotected) of the hydroxy functions in position 2 and 4 is responsible for the stereochemical cyclization outcome of acyclic 1-substituted-2,4-dihydroxylated hex-5-enyl compounds. The presence of a 2,4-diol leads to the all-syn precursor of isoprostanes while the diprotected diol affords the diastereoisomer syn-anti-syn precursor.

Radical cyclization; towards the syntheses of tetranor metabolites of 15-F2t-isoprostane

Abstract Radical cyclization of acyclic 1-substituted-2,4-dihydroxylated 5-hexenyl radicals produced functionalized cyclopentane derivatives. These cyclopentanic precursors after different protection/deprotection reactions followed by Wittig and Horner–Wadsworth–Emmons coupling reactions led to the main urinary tetranor metabolites of 15-F 2t -isoprostane (8- epi -PGF 2α ).