Novel Colchicine-Site Binders with a Cyclohexanedione Scaffold Identified through a Ligand-Based Virtual Screening Approach
Novel Colchicine-Site Binders with a Cyclohexanedione Scaffold Identified through a Ligand-Based Virtual Screening Approach
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DOI：
10.1021/jm401939g
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发表时间：
2014-05-22
影响因子：
7.3
通讯作者：
Priego, Eva-Maria
中科院分区：
文献类型：
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作者：
Canela, Maria-Dolores;Perez-Perez, Maria-Jesus;Priego, Eva-Maria
血管破坏剂（Vascular disrupting agents, VDAs）是一种新型的靶向肿瘤内皮细胞，导致肿瘤坏死的抗癌药物。我们鉴定新的vda的方法依赖于配体三维形状相似虚拟筛选（VS）方法，使用ROCS程序作为VS工具，并查询秋水仙碱和TN-16，它们都结合α， β -微管蛋白二聚体。以TN-16为查询对象，通过对其结构类似物的合成，对鉴定出的其中一个命中点进行了探索，得到了2-（1-（（2-甲氧基苯基）氨基）乙基）-5-苯基环己烷-1,3-二酮（化合物16c），其在HMEC-1和BAEC中的IC50 = 0.09 +/- 0.01 μ M，比初始命中点强100倍。化合物16c在G2/M期引起细胞周期阻滞，并与微管蛋白中的秋水仙碱结合位点相互作用，与N，N'-乙烯双（碘乙酰胺）竞争试验和荧光光谱证实了这一点。此外，16c在1 μ M处破坏了已建立的内皮小管网络，并在0.4 μ M处抑制了人乳腺癌细胞的迁移和侵袭。总之，我们的方法导致了一种新的具有抗有丝分裂和潜在VDA特性的抗增殖化合物的化学类型。
Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the alpha,beta-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 +/- 0.01 mu M in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 mu M and inhibited the migration and invasion of human breast carcinoma cells at 0.4 mu M. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.