Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives.
Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives.
复制标题
新型10-氟喜树碱衍生物的设计、半合成和有效细胞毒活性
DOI：
10.1016/j.bmcl.2017.09.012
复制
发表时间：
2017-10-15
影响因子：
2.7
通讯作者：
Lee KH
中科院分区：
文献类型：
--
作者：
Yang CJ;Song ZL;Goto M;Hsu PL;Zhang XS;Yang QR;Liu YQ;Wang MJ;Morris-Natschke SL;Shang XF;Lee KH
氟化是在药物发现项目的先导化合物优化阶段提高生物活性分子的生物利用度的众所周知的策略。为了提高喜树碱 (CPT) 的抗肿瘤活性，设计、合成了新型 10-氟-CPT 衍生物，并评估了其对五种人类癌细胞系（A-549、MDA-MB-231、KB、KB-VIN 和 MCF-7）的细胞毒性。所有衍生物对所测试的肿瘤细胞系都表现出比临床喜树碱衍生药物伊立替康更有效的体外细胞毒活性，并且其中大多数表现出与拓扑替康相当或更好的效力。值得注意的是，化合物16b（IC50，67.0 nM）和19b（IC50，99.2 nM）对多重耐药（MDR）KB-VIN细胞系表现出最高的细胞毒性，值得进一步开发作为治疗癌症（包括MDR表型）的临床前候选药物。我们的研究表明，将氟原子掺入 CPT 的 10 位是发现新的有效 CPT 衍生物的有效方法。设计并合成了一类具有优异细胞毒活性的新型10-氟喜树碱衍生物。
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, compounds 16b (IC50, 67.0 nM) and 19b (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. A novel type of 10-fluorocamptothecin derivatives with excellent cytotoxicity activity were designed and synthesized.
登录
查看更多内容
影响因子：
7.3
作者：
Wilcken, Rainer;Zimmermann, Markus O.;Boeckler, Frank M.
通讯作者：
Boeckler, Frank M.
影响因子：
7.3
作者：
Dallavalle, S;Ferrari, A;Zunino, F
通讯作者：
Zunino, F
影响因子：
7.3
作者：
Gillis, Eric P.;Eastman, Kyle J.;Meanwell, Nicholas A.
通讯作者：
Meanwell, Nicholas A.
影响因子：
2.7
作者：
Dallavalle, S;Ferrari, A;Zunino, F
通讯作者：
Zunino, F
影响因子：
7.3
作者：
Dallavalle, S;Delsoldato, T;Zunino, F
通讯作者：
Zunino, F