Mitomycin C (MMC), a DNA-alkylating agent, is an antitumor drug.  Synthetic MMC-based dimers have been designed with the expectation that enhanced levels of DNA cross-linkage would result in higher potency.  Further, conjugating MMC dimers with target-specific ligands, such as folic acid (FA), might improve selectivity and efficacy of the parent drug.Here we report the synthesis of a series of bis-MMCs, which utilized symmetric tri-amines to separate the two MMC base drugs.  The distance between the two MMC units ranges from five to eleven C-, N-, and/or O-atoms to allow both MMCs the flexibility for best DNA binding and subsequent alkylation.  The third amino group on the core aromatic ring was introduced as attachment site and was tethered to FA via a water-soluble carbohydrate-based spacer unit and a disulfide-base self-immolative linker system. Such molecular architecture will allow for release of intact bis-MMC-based alkylating agent inside of targeted cancer cell.

Design and synthesis of novel bis-mitomycins and their folate conjugates for targeted cancer therapies

244th National Meeting (2012)

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