Development of Lipophilic Prodrugs of Mitomycin C. III. Physicochemical and Biological Properties of Newly Synthesized Alkoxycarbonyl Derivatives

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Five alkoxycarbonyl derivatives of mitomycin C possessing various lipophilic pro-moieties including benzyloxycarbonyl, propyloxycarbonyl, pentyloxycarbonyl, nonyloxycarbonyl, and cholesteryloxycarbonyl groups were synthesized and their physicochemical and biological characteristics were examined. All compounds showed increases of octanol/water partition coefficients, lipophilic indexes (k'_o) in HPLC, and lipid solubilities to various degrees depending on their pro-moiety structure. They showed only slight antimicrobial activities against Escherichia coli B, but all the compounds except for cholesteryloxycarbonyl mitomycin C showed significant activity in vivo against a L1210 leukemia system at a relatively low dose range. These derivatives showed enzyme-mediated conversion to the parent compound in rat plasma and liver homogenate, while they were chemically stable in neutral aqueous media. Essentially no bioactivation was observed for cholesteryloxycarbonyl mitomycin C. Species differences were observed in these bioactivation phenomena. These results suggested the potential utility of the derivatives as lipophilic prodrugs.
公益社団法人日本薬学会の論文
1983-11-25