Synthesis and structure-activity relationships of new dimeric mitomycin derivatives; 7-N,7'-N'-bis(omega-thioalkyl)dimitomycins.
The reaction between mitomycin A (1) and cysteamine afforded 7-N,7'-N'-bis(2-thioethyl)dimitomycin C (7), 7-N-[2-[(2-aminoethyl)dithio]ethyl]mitomycin C (8), and 7-methoxy mitosenes (10, 11). The structures of 7 and 8 were elucidated on the basis of spectroscopy and reactions between 1 and 8, and 1 and cystamine. The observation of the time course for the reaction revealed the mechanism of the formation of 7 and 8. The rapid oxidation of cysteamine by the quinone of 1 gave cystamine, which was trapped by 1 to give 8, and 8 was additionally reacted with 1 to give 7. Since 7 showed significant antitumor activities, related 7-N,7'-N'-bis(omega-thioalkyl)dimitomycins were synthesized. They also showed remarkable antitumor activities against HeLa-S3 in vitro, sarcoma 180 (sc-ip), leukemia P388 (ip-ip) in vivo. In these evaluations, compound 7 demonstrated unique potency.
Kono
M
M
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
Saitoh
Y
Y
Kasai
M
M
Shirahata
K
K
Morimoto
M
M
Ashizawa
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D003543:Cysteamine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008937:Mitomycins / Q000737:chemistry* / Q000494:pharmacology; D012510:Sarcoma 180 / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004220:Disulfides; D008937:Mitomycins; D003543:Cysteamine; C046000:mitomycin A