SYNTHESIS AND ANTITUMOR ACTIVITY OF A NOVEL WATER SOLUBLE MITOMYCIN ANALOG; 7-N-[2-[[2-(γ-L-GLUTAMYLAMINO)ETHYL]DITHIO]ETHYL]MITOMYCIN C

Abstract

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 γ-L-glyuamyl-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 : >500 mg/ml), designated as KW2149, with the γ-L-glutamylcystamino group at the 7th position was finally selected for further evaluation.