A New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S)-21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I Inhibitors

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• 作者：Zhenyuan Miao ; Lingjian Zhu ; Guoqiang Dong ; Chunlin Zhuang ; Yuelin Wu ; Shengzheng Wang ; Zizao Guo ; Yang Liu ; Shanchao Wu ; Shiping Zhu ; Kun Fang ; Jianzhong Yao ; Jian Li ; Chunquan Sheng ; Wannian Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：7902-7910
• 全文大小：463K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of 伪-fluoro ether as a novel bioisostere of lactone. The effectiveness of the 伪-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure鈥揳ctivity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. 伪-Fluoro ether may have general application in improving the metabolic stability of lactone.