NUCLEOSIDES AND NUCLEOTIDES .122. -CYANO-2'-DEOXY-1-BETA-D-ARABINOFURSANOSYLCYTOSINE AND ITS DERIVATIVES - A NEW CLASS OF NUCLEOSIDE WITH ABROAD ANTITUMOR SPECTRUM

Design, synthesis, and tumor cell growth inhibitory effects of 2'-C-cy ano-2'-deoxy-1-beta-D-arabinofuranosyl derivatives of cytosine (1i, CN DAC), thymine (6a), uracil (6c), and adenine (6d) have been described. The synthesis of the target compounds was achieved from the correspon ding 2'-keto nucleosides 2a-d. Cyanohydrins of 2a-d were converted to thionocarbonates, which were deoxygenated to give the desired 2'-beta- cyano-2'-deoxy derivatives 5a-d, followed by deprotection to furnish t he target nucleosides. Of these nucleosides, CNDAC was the most potent inhibitor of cell growth with an IC50 value of 0.53 mu M against L121 0 cells. In vitro cytotoxicity of CNDAC against human tumor cell lines was also examined; compared with that of 1-beta-D-arabino (ara-C) and 5-fluorouracil (5-FU), CNDAC was more cytotoxic to several cell lines refractory to ara-C. The in vivo effect of CNDAC on M5076 mouse retic ulum cell sarcoma was very strong; 99 % tumor volume inhibition on day 20 was achieved when it was administered orally on days 1, 4, 7, 10, 13, and 16 at a dose of 400 mg/kg/day, while 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-FU caused only 50% inhibition at a dose of 500 mg/kg/d ay and 28% inhibition at a dose of 50 mg/kg/day, respectively, on the same schedule. These results indicated that CNDAC may have potential a s a new antineoplastic agent with a broad antitumor spectrum.