Nucleosides and nucleotides. 94. Radical deoxygenation of tert-alcohols in 1-(2-C-alkylpentofuranosyl) pyrimidines: synthesis of (2'S)-2'-deoxy-2'-C-methylcytidine, an antileukemic nucleoside.
(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.
Matsuda
A
A
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Takenuki
K
K
Sasaki
T
T
Ueda
T
T
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D007938:Leukemia; D007939:Leukemia L1210; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms; D013329:Structure-Activity Relationship
D000964:Antimetabolites, Antineoplastic; D007202:Indicators and Reagents; D003841:Deoxycytidine; C055031:2'-methyl-2'-deoxycytidine; C067178:2'-deoxy-2'-ethylcytidine