SYNTHESIS AND MECHNISM OF DNA-CROSSLINKING OF FR900482

本项目的目标是综合和研究黄曲霉毒素的作用机制。 新近发现的抗肿瘤抗生素FR-900482的作用。这 物质是从发酵提取物中分离出来的一种天然产物 日本藤泽药业株式会社，三大链霉菌6897号。 FR-900482及其衍生的三醋酸酯FK973显示出强大的细胞毒性和 体外和体内对小鼠和人肿瘤的抗肿瘤活性。 在结构上与众所周知的丝裂霉素C抗肿瘤抗生素有关， 这些新化合物因其独特的、被证明的能力而令人兴奋 使双链DNA交联，也形成DNA-蛋白质交联链。 与丝裂霉素C和大多数其他抗肿瘤药物不同，FK 973不会导致 对DNA的氧化损伤。FK 973目前正在日本进行高级临床试验， 比丝裂霉素C毒性小得多，效力是丝裂霉素C的三倍。 本研究的目的是合成FR-900482和一些 用简单类比探讨DNA-DNA和DNA-蛋白质的独特作用机制 由这种重要的新药形成的交联剂。

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.