Synthesis of 3‘- and 5‘-Nitrooxy Pyrimidine Nucleoside Nitrate Esters:  “Nitric Oxide Donor” Agents for Evaluation as Anticancer and Antiviral Agents

A group of 3‘-O-nitro-2‘-deoxyuridines, 3‘-O-nitro-2‘-deoxycytidines, and 5‘-O-nitro-2‘-deoxyuridines possessing a variety of substituents (H, Me, F, I) at the C-5 position were synthesized for evaluation as anticancer/antiviral agents that have the ability to concomitantly release cytotoxic nitric oxide (•NO). Although these compounds generally released a greater percent of •NO than the reference drug isosorbide dinitrate upon incubation in the presence of l-cysteine, or serum, their cytotoxicity (CC50 = 10-3 to 10-6 M range) was comparable to 5-iodo-2‘-deoxyuridine, but weaker than 5-fluoro-2‘-deoxyuridine, against a variety of cancer cell lines. No differences in cytotoxicity against nontransfected (KBALB, 143B), and the corresponding transfected (KBALB−STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+) were observed, indicating that expression of the viral TK enzyme did not provide a gene therapeutic effect. These nitrate esters were inactive antiviral agents except for 5-iodo-3‘-O-nitro-2‘-deoxyuridine that showed modest activity against HSV-1, HSV-2, and vaccinia virus.