Synthesis and Anti-HIV Evaluation of 2',3'-Dideoxyribo-5-chloropyrimidine Analogues: Reduced Toxicity of 5-Chlorinated 2',3'-Dideoxynucleosides

Article abstract of DOI:10.1021/jm00168a046

In view of the selective anti-HIV activity of 2',3'-dideoxy-3'-fluoro-5-chlorouridine (11), a series of eight 2',3'-dideoxy-5-chloropyrimidines were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus type 1 (HIV-1) replication in MT-4 cells.A marked improvement in selectivity was noted for the 5-chlorouracil derivatives of 2,3-dideoxyribofuranose, 3-azido-2,3-dideoxyribofuranose, and 3-fluoro-2,3-dideoxyribofuranose, mainly due to decreased toxicity of the compounds for the host cells.While chlorination of 2',3'-dideoxycytidine remo ved the anti-HIV activity, introduction of chlorine at the C-5 position of 3'-fluoro-, 3'-azido- or 2',3'-didehydro-2',3'-dideoxycytidine led to reduced cytotoxicity with only slightly reduced anti-HIV activity.X-ray analysis showed compound 11 to have two molecules in the asymmetric unit with κ = -168.8(3) deg and -131.3(3) deg and P = 179(1) deg and 163(1) deg, respectively; thus revealing no close resemblance to 3'-azido-3'-deoxythymidine (AZT).