Zong Yao, Shea Christie, Maffucci Katherine, Ojima Iwao
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY, 11794-3400, U. S. A.
Institute of Chemical Biology & Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, 11794-3400, U. S. A.
J Fluor Chem. 2017 Nov;203:193-199. doi: 10.1016/j.jfluchem.2017.09.007. Epub 2017 Sep 10.
Combretastatin A-1 (CA-1) and combretastatin A-4 (CA-4) isolated from the African bush willow are highly potent tubulin polymerization inhibitors, possessing strong antitumor activities because of their vascular disrupting properties. Extensive SAR studies have been done for CA-4 analogs. Because of poor solubility, water-soluble prodrugs of CA-4 and CA-1 have been developed, which are currently in human clinical trials. Fluorine plays an important role in the current drug discovery and development due to its unique properties. Thus, several fluorine-containing analogs of CA-4/CA-1 have been studied. However, no analogs, which have a CFO-, CFHO- or CF- group instead of the 4'-methoxy group in the B ring, have been investigated. Therefore, we set out to design and synthesize those novel fluoro-analogs of CA-4/CA-1. For the design of the new analogs, we took a structure-based design approach based on the X-ray crystal structure of colchicine-tubulin complex (PDB: 4O2B) and computational docking analysis using the AutoDock Vina program. A library of novel fluoro-analogs of CA-4/CA-1 was generated and their docking energy scores obtained. It was found that those novel fluoro-analogs exhibited better docking energy scores than CA-4/CA-1. Also, docking poses of all of these fluoro-analogs were virtually superimposable and very good fit to the colchine binding site. Among 15 compounds designed and analyzed, we have synthesized 5 compounds and evaluated their cytotoxicity against drug-sensitive and multidrug-resistant cancer cell lines. All fluoro-analogs exhibited strong cytotoxicity even against multidrug-resistant cell line. However, the critical activity of this class of compounds is its vascular disrupting activity. Thus, further biological evaluations are warranted for those novel fluoro-analogs of CA-4/CA-1.
从非洲柳树中分离得到的康普瑞他汀A-1（CA-1）和康普瑞他汀A-4（CA-4）是高效的微管蛋白聚合抑制剂，因其具有血管破坏特性而拥有强大的抗肿瘤活性。针对CA-4类似物已经开展了广泛的构效关系研究。由于溶解性差，已开发出CA-4和CA-1的水溶性前药，目前正处于人体临床试验阶段。由于氟具有独特的性质，其在当前的药物发现和开发中发挥着重要作用。因此，已经研究了几种CA-4/CA-1的含氟类似物。然而，尚未研究过在B环中具有CFO-、CFHO-或CF-基团而非4'-甲氧基的类似物。因此，我们着手设计并合成那些新型的CA-4/CA-1氟类似物。对于新类似物的设计，我们基于秋水仙碱-微管蛋白复合物的X射线晶体结构（蛋白质数据银行：4O2B）采用基于结构的设计方法，并使用AutoDock Vina程序进行计算对接分析。生成了一个新型CA-4/CA-1氟类似物库，并获得了它们的对接能量分数。发现那些新型氟类似物表现出比CA-4/CA-1更好的对接能量分数。此外，所有这些氟类似物的对接构象实际上是可叠加的，并且与秋水仙碱结合位点非常匹配。在设计和分析的15种化合物中，我们已经合成了5种化合物，并评估了它们对药物敏感和多药耐药癌细胞系的细胞毒性。所有氟类似物甚至对多药耐药细胞系都表现出很强的细胞毒性。然而，这类化合物的关键活性是其血管破坏活性。因此，有必要对那些新型的CA-4/CA-1氟类似物进行进一步的生物学评估。
