Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

The mitomycins are a unique family of natural products with a rich history. Hata and co-workers at Kwoya Hakko Kogyo Co. in Japan first isolated mitomycins A and B from Streptomyces caespitosus found in soil samples in 1956. The reductive pathway by which mitomycin C (MMC) is activated to cross-link DNA has now been well established. Researchers focused on the nature of the electron-transfer step to the quinone of MMC, the kinetics and mechanism of ensuing chemical transformations leading to the ultimate DNAFigure. There exist reported modes of involvement of biological dithiols in the modulation of MMC cytotoxicity. Expulsion of the methoxy group gives iminium ion, which quenches itself via deprotonation/tautomerization to afford net elimination of methanol from and yielding intermediate leuco-aziridinomitosene. Electron donation from the hydroquinone indole core opens the aziridine ring to the intermediate quinone methide.