Mitomycin C analogues with aryl substituents on the 7-amino group.

A series of 30 different N7-phenyl-substituted mitomycin C analogues, 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 para- and the meta-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. These results suggest that diffusion into the tumor cell or access to the receptor is more important than bioreductive activation in determining antitumor potency for this particular group of mitosanes . Fifteen new mitomycin C analogues 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 analogue.