Computational Design and Synthesis of Novel Fluoro-Analogs of Combretastatins A-4 and A-1.
Computational Design and Synthesis of Novel Fluoro-Analogs of Combretastatins A-4 and A-1.
复制标题
Combretastatins A-4 和 A-1 新型氟类似物的计算设计和合成。
DOI：
10.1016/j.jfluchem.2017.09.007
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发表时间：
2017
影响因子：
1.9
通讯作者：
Ojima,Iwao
中科院分区：
文献类型：
--
作者：
Zong,Yao;Shea,Christie;Maffucci,Katherine;Ojima,Iwao
Combretastatin A-1（CA-1）和Combretastatin A-4（CA-4）是从非洲灌木丛中分离的高度有效的微管蛋白聚合抑制剂，由于它们的血管破坏特性而具有强的抗肿瘤活性。已对CA-4类似物进行了广泛的SAR研究。由于溶解性差，已经开发了CA-4和CA-1的水溶性前药，目前正在进行人体临床试验。氟因其独特的性质在当前药物发现和开发中起着重要作用。因此，已经研究了CA-4/CA-1的几种含氟类似物。然而，没有研究过在B环中具有CF 3 O-、CF 2 HO-或CF 3-基团而不是4′-甲氧基的类似物。因此，我们着手设计和合成CA-4/CA-1的那些新型氟代类似物。对于新类似物的设计，我们采用基于结构的设计方法，基于秋水仙素-微管蛋白复合物（PDB：4 O2 B）的X射线晶体结构和使用AutoDock维纳程序的计算对接分析。生成CA-4/CA-1的新型氟代类似物的文库，并获得它们的对接能量分数。结果发现，这些新的氟类似物表现出更好的对接能量分数比CA-4/CA-1。此外，所有这些氟类似物的对接姿势几乎是可重叠的，并且非常适合秋水仙碱结合位点。在设计和分析的15个化合物中，我们合成了5个化合物，并评价了它们对药物敏感和多药耐药癌细胞系的细胞毒性。所有氟代类似物即使对多药耐药细胞系也表现出强烈的细胞毒性。然而，这类化合物的关键活性是其血管破坏活性。因此，需要对CA-4/CA-1的这些新型氟代类似物进行进一步的生物学评价。
Combretastatin A-1 (CA-1) and combretastatin A-4 (CA-4) isolated from the African bush willowCombretum caffrumare 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 CF3O-, CF2HO- or CF3- 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.