Novel 3'-C/N-substituted 2',3'-beta-D-dideoxynucleosides as potential chemotherapeutic agents .1. Thymidine derivatives: Synthesis, structure, and broad spectrum antiviral properties

A synthetic scheme for the 3'-oxime derivatives 3E, 5E, 5Z, 7E and 7Z of 1-(2,3-dideoxy-beta-D-glycero-pentofuranosyl)thymine and for 1-(2,3-dideoxy-3-nitro-beta-D-erythro-pentofuranosyl)-thymine (10) has been developed starting from appropriately 5'-protected 3'-ketothymidine. X-ray analysis showed that 3'-N-hydroxyimino 3E and 3'-N-methoxyimino 5Z derivatives have close molecular conformations: anti about the N1-C1' bond, and gauche(+) about the C4'-C5' exocyclic bond. Their sugar conformations are C1'-exo-O4'-endo and C1'-exo-C2'-endo, respectively. The antiviral assays in cell cultures demonstrated that 3'-N-hydroxyimino 3E and 3'-N-acetoxyimino 7E + 7Z derivatives are endowed with significant activity against human immunodeficiency virus (HIV) with EC(50) values ranging between 0.02 and 0.40 mu g/mL for both HIV-1 and HIV-2. The other compounds 5E + 5Z and 10 were at least 2 orders of magnitude less active. The 3'-N-hydroxyimino derivative 3E also shows promising activity against hepatitis B virus (HBV) (EC(50) = 0.25 mu g/mL) and against herpes simplex virus type 1 (HSV-1) and HSV-2.