Nucleosides and nucleotides. 122. 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine and its derivatives. A new class of nucleoside with a broad antitumor spectrum.
Design, synthesis, and tumor cell growth inhibitory effects of 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosyl derivatives of cytosine (1i, CNDAC), thymine (6a), uracil (6c), and adenine (6d) have been described. The synthesis of the target compounds was achieved from the corresponding 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 the target nucleosides. Of these nucleosides, CNDAC was the most potent inhibitor of cell growth with an IC50 value of 0.53 microM against L1210 cells. In vitro cytotoxicity of CNDAC against human tumor cell lines was also examined; compared with that of 1-beta-D-arabinofuranosylcytosine (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 reticulum cell sarcoma was very strong; 99% tumor volume inhibition on day 20 was achieved when it was administrated 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/day and 28% inhibition at a dose of 50 mg/kg/day, respectively, on the same schedule. These results indicated that CNDAC may have potential as a new antineoplastic agent with a broad antitumor spectrum.
Azuma
A
A
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Nakajima
Y
Y
Nishizono
N
N
Minakawa
N
N
Suzuki
M
M
Hanaoka
K
K
Kobayashi
T
T
Tanaka
M
M
Sasaki
T
T
Matsuda
A
A
D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D003561:Cytarabine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine; D014498:Uracil; D000225:Adenine; D013941:Thymine; D005472:Fluorouracil