A new type of antineoplastic nucleoside, 2'-deoxy-2'-methylidenecytidine (DMDC) has been synthesized from the corresponding 2'-keto pyrimidine nucleosides 3 and 8 by the Wittig reaction. During the course of the reaction, we found that an intermediate betaine could pick a proton from the excess triphenylphosphonium bromide to form the 2'-phosphonium salts 5 and 10, which could be further converted into the 2'-deoxy-2'-methylidene nucleosides 4 and 9 by treatment with sodium hydride. Various 5-substituted DMDC derivatives 19a-e,h and their uracil congeners 16a-h were also synthesized from the corresponding 5-substituted uridines 12a-f,h. Among them, DMDC as well as 2'-deoxy-2'-methylidene-5-fluorocytidine (19a) showed potent antileukemic activity against murine L1210 cells in culture. The activity of DMDC and 19a toward various human tumor cells in culture compared with 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil was also examined. In vivo antitumor activity of DMDC against L1210 was also described.
Communications to the Editor Design, Synthesis, and Antineoplastic Activity of 2/-Deoxy-2'-methylidenecytidine1Sir:l-/3-D-Arabinofuranosylcytosine (ara-C, la) is one of the most potent drugs for the treatment of acute human leukemia.2 However, ara-C has several drawbacks; its half-life is very short because of deamination to chemotherapeutically inactive l-d-D-arabinofuranosyluracil by cytidine deaminase, and it is not effective against solid tumors. In
(2'S and 2'R)-2'-Deoxy-2'-C-methylcytidine (1i and 15) and (2'S)-2'-deoxy-2'-C-ethylcytidine (1j) have been synthesized from the corresponding 2'-C-alkylarabinofuranosyl- or -ribofuranosylpyrimidine derivatives 3 and 4 by radical deoxygenation of the methyl oxalyl esters of the 2'-tert-alcohol, followed by sequential deblocking and amination at the 4-position. (2'S)-2'-Deoxy-2'-C-methyl-5-methyluridine (8) has also been synthesized in a similar manner. Among them, compound 1i exhibits the most potent cytotoxicity to L1210 cells with potency comparable to that of 1-beta-D-arabinofuranosylcytosine (1a). The size of the 2'-substituents and the configuration at the 2'-position are the most important for the cytotoxicity. Cytotoxicity in vitro of 1i against various human cancer cell lines was also examined and compared with that of 1a and 5-fluorouracil.
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