A series of novel 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge to retain the cis-orientations of A-ring and B-ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines. Compounds 6a-d exhibited superior potency, with IC50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors.

中文翻译：

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crolibulin和compretastatin A-4的4,6-二苯基-2-（1H-吡咯-1-基）烟腈类似物的合成和生物学评估。

使用2-（1H-吡咯-1-基）发现了一系列新的crolibulin和康维他汀A-4（CA-4）的4,6-二苯基-2-（1H-吡咯-1-基）烟腈类似物。吡啶环作为连接桥，可保留A环和B环的顺式。合成所有目标化合物，并评估其对五种人类癌细胞系的抗增殖活性。化合物6a-d显示出优异的效力，在纳摩尔水平上具有IC 50值。特别地，化合物6a显示出与crolibulin和CA-4相似或更高的抗肿瘤活性。此外，化合物6a对微管组装的抑制作用与CA-4相当。进行了化合物6a的分子建模研究，以阐明其在微管蛋白二聚体中秋水仙碱结合位点的结合方式，