Nucleosides and nucleotides. 97. Synthesis of new broad spectrum antineoplastic nucleosides, 2'-deoxy-2'-methylidenecytidine (DMDC) and its derivatives.
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.
Matsuda
A
A
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Takenuki
K
K
Tanaka
M
M
Sasaki
T
T
Ueda
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003841:Deoxycytidine; C056034:2'-deoxy-2'-methylenecytidine