Design and synthesis of 3'- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines: biological evaluation as hybrid nitric oxide donor-nucleoside anticancer agents.

A group of 3'-O- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines possessing a variety of substituents (H, Me, I, F, CF(3)) at the C-5 position of the nucleoside moiety were synthesized for evaluation as hybrid anticancer agents that have the ability to simultaneously release cytotoxic nitric oxide (*NO). Incubation of these nitric oxide donor-nucleoside conjugates in the presence of 18 mM L-cysteine released a high percentage of *NO (21-48% at 1 h; 37-86% at 16 h). The release of *NO in the absence of the thiol cofactor was negligible. These hybrid *NO donor-nucleosides exhibited high cellular toxicity (CC(50) = 10(-6)-10(-8) M range) against a battery of tumor cell lines (143B-LTK, 143B, EMT-6, KBALB-STK, and KBALB) and normal human fibroblasts (Hs578Bst). No differences in cytotoxicity between nontransfected (143B, KBALB) and the corresponding transfected (143B-LTK, KBALB-STK) 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.