Role of the C-10 Substituent in Mitomycin C-1−DNA Bonding

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Abstract

The structural requirements for mitomycin C-1 bonding have been investigated by comparing the bonding specificity of mitomycin C (1) with selectively modified porfiromycins (N-methylmitomycin C) at the C-10 position under reductive conditions and then comparing N-methyl-7-methoxyaziridinomitosene (10) with 7-methoxy-10-noraziridinomitosene (11) under nonreductive conditions. Enzymatic and chemical reductive activation of mitomycin C in the presence of the 129-bp fragment from pBR322 led to exclusive guanine (G*) modification with drug bonding that occurred preferentially at 5‘CG* sites, while C-10 chloro (8) and C-10 bromo (9) deoxycarbamoylporfiromycins modified DNA at guanines but with significantly diminished 5‘CG* sequence selectivity. A similar set of bonding profiles were observed with 10 and 11 upon incubation with DNA. Mitosene 10 selectively modified 5‘CG* sites in DNA, while 11 did not. These studies provided support for the hypothesis that a hydrogen bond between the C-10 oxygen in the activated mitomycin species and the guanine N(2)-amino proton on the nonbonding DNA strand in the precovalent complex permits selective modification of 5‘CG* sites in in vitro transformations. We have also found that the kinetics of UVRABC incision of N-methyl-7-methoxyaziridinomitosene (10)−DNA adducts at different sequences are identical. This finding leads us to conclude that drug modification-induced UVRABC incision at different sites represents the sequence selectivity of drug−DNA bonding.

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