Synthesis of several pyrimidine l-nucleoside analogues as potential antiviral agents

Abstract

β-l-5-Iodo-2′-deoxyuridine (β-l-IUdR, 7) and 1-[(β-l-arabinofuranosyl)-E-5-(2-bromovinyl)]uracil (β-l-BV-ara-U, 10) have been synthesized via a multi-step synthesis from l-arabinose. 2′,3′-Dideoxy-β-l-5-azacytidine (18), 2′,3′-dideoxy-β-l-2-thiocytidine (20) and their respective α-anomers, compounds 19 and 21, also were synthesized by direct coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-l-ribofuranose (13) with the corresponding silylated bases, in the presence of EtAlCl2 in CH2Cl2, followed by separation of the α- and β-isomers and deblocking of the 5′-protecting groups. In addition, 2′,3′-dideoxy-β-l-5-fluorocytidine (34), a potent anti-HIV and anti-HBV agent, was synthesized by an alternative methodology from 2′,3′-dideoxy-β-l-5-fluorouridine (31) via a 4-triazolylpyrimidinone intermediate. These l-nucleoside analogues were tested in vitro against HIV, HBV, HSV-1, and HSV-2. Among these compounds, 2′,3′-dideoxy-β-l-5-azacytidine (18) was found to show significant activity against HBV in vitro at approximately the same level as 2′,3′-dideoxy-β-d-cytidine (ddC), which is a known potent anti-HBV agent.