SYNTHESIS AND MECHNISM OF DNA-CROSSLINKING OF FR900482

FR900482的合成及DNA交联机制

• 批准号: 2094419
• 负责人: Robert Michael Williams
• 金额: $ 13.63万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2094419
• 关键词: DNA damage; analog; antineoplastic antibiotics; chemical structure function; crosslink; drug design /synthesis /production; mitomycin C

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.

本程序的目的是综合和研究机制