Carbocyclic analogs of 5-fluorouracil nucleosides

Abstract

The carbocyclic analogs of 5-fluoro-2''-deoxyuridine (5-FdUrd, 1), 5-fluorouridine and 5-fluoro-3''-deoxyuridine were prepared by fluorination of the uracil nucleoside analogs with elemental fluorine. The 5-FdUrd analog (C-5-F-2''-dUrd, 6) was enzymatically phosphorylated to the analog of 5-FdUrd 5''-phosphate and inhibited the incorporation of 2''-deoxyuridine into DNA of murine colon 26 tumor cells and [mouse leukemia] L-1210 cells in culture. (6) was a less potent inhibitor of DNA synthesis in tumor cells than was (1). C-5-F-2''-dUrd was cytotoxic (ED50 = 2.5 mcg/mL) to L-1210 cells in culture; the other 2 analogs were less cytotoxic. C-5-F-2''-dUrd was inactive, or at best, borderline active, in tests against [mouse] P-388 leukemia in vivo.