European journal of medicinal chemistry · 2018
1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase.
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Lai Mei-Jung, Ojha Ritu, Lin Mei-Hsiang, Liu Yi-Min, Lee Hsueh-Yun, Lin Tony Eight, Hsu Kai-Cheng, Chang Chi-Yen, Chen Mei-Chuan, Nepali Kunal, Chang Jang-Yang, Liou Jing-Ping
Аннотация
We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.