Mitomycin C analogs with aryl substituents on the 7-amino group

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Abstract
A series of 30 different N7-phenyl-substituted mitomycin C analogs, including 25 new compounds, was prepared from mitomycin A. Seven of these compounds were clearly superior to mitomycin C in activity against P-388 murine leukemia. The p- and the m-substituted derivatives were subjected to Hansch analysis, which revealed that the lipid-water distribution coefficient .pi. was the only significant factor in determining antitumor potency (MED). The substituent electronegativity factor .sigma. was statistically insignificant in determining potency, despite the good correlation of .sigma.p with the polarographic quinone-reduction potential. Diffusion into the tumor cell or access to the receptor is apparently more important than bioreductive activation in determining antitumor potency for this particular group of mitosanes. Fifteen new mitomycin C analogs with heterocycles on the 7-amino group also were prepared. Two of them, containing pyrazolyl and aminopyridyl substituents, were more active than mitomycin C against P-388 murine leukemia. No broad correlations could be made among the antitumor potencies and physicochemical properties for this type of analog.