Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Yang, Cheng-Jie; Song, Zi-Long; Goto, Masuo; Hsu, Pei-Ling; Zhang, Xiao-Shuai; Yang, Qian-Ru; Liu, Ying-Qian; Wang, Mei-Juan; Morris-Natschke, Susan L.; Shang, Xiao-Fei; Lee, Kuo-Hsiung
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 20(2017)
• Page Start: 4694
• Page End: 4697
• Publication Date: 2017-10-15
• Subjects: Camptothecin -- Cytotoxic activity -- Fluorination -- Synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.09.012
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: A novel type of 10-fluorocamptothecin derivatives with excellent cytotoxicity activity were designed and synthesized. Abstract: Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds16b (IC50, 67.0 nM) and19b (IC50, 99.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.