Synthesis and antitumor activity of a novel water soluble mitomycin analog; 7-N-[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]mitomycin C.
Introducing the mercaptoethyl group at the 7-N position of mitomycin C 1 has led to the isolation of 7-N,7'-N'-dithiodiethylenedimitomycin C 2. The compound 2 showed excellent antitumor activity against sarcoma 180 (sc-ip) and leukemia P388 (ip-ip) in mice. As an extension of this study, we synthesized mitomycin dimers with symmetrical disulfide and mitomycin derivatives with unsymmetrical disulfide at the 7-N side chain. Among these compounds, the water soluble conjugate 3 with ethyl gamma-L-glutamyl-L-cysteinylglycinate was far more effective against sarcoma 180 and leukemia P388 than 1. During the subsequent stage of inquiry for the potent congeners of 3, the compound 4 (water solubility: greater than 500 mg/ml), designated as KW2149, with the gamma-L-glutamylcystamino group at the 7th position was finally selected for further evaluation.
Kono
M
M
Saitoh
Y
Y
Kasai
M
M
Sato
A
A
Shirahata
K
K
Morimoto
M
M
Ashizawa
T
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D008937:Mitomycins / Q000138:chemical synthesis* / Q000494:pharmacology; D012510:Sarcoma 180 / Q000188:drug therapy
D000903:Antibiotics, Antineoplastic; D008937:Mitomycins; C057625:KW 2149