Synthesis-Enabled Probing of Mitosene Structural Space Leads to Improved IC_(50) over Mitomycin C

摘要

A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6,a mitomycin C analogue which is twice as potent as mitomycin C againstthe prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis-driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.