SYNTHESIS AND MECHNISM OF DNA-CROSSLINKING OF FR900482

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The objective of this program is to synthesize and study the mechanism of action of the recently discovered anti-tumor antibiotic FR-900482. This substance is a natural product isolated from the fermentation extracts of Streptomyces sandaensis No. 6897 at Fujisawa Pharmaceutical Co. in Japan. FR-900482 and its derived triacetate FK973 display potent cytotoxic and anti-tumor activity against murine and human tumors in vitro and in vivo. Structurally related to the well-known mitomycin C anti-tumor antibiotic, these new compounds are exciting due to their unique, demonstrated ability to cross-link double-stranded DNA and also form DNA-protein cross-links. Unlike mitomycin C and most other antitumor drugs, FK 973 does not cause oxidative damage to DNA. FK 973, now in advanced clinical trials in Japan, is significantly less toxic than mitomycin C and is three-fold more potent. The purpose of this investigation is to synthesize FR-900482 and some simple analogs to probe the unique mechanism of DNA-DNA and DNA-protein cross-link formation by this important new drug.