1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase

• Published in: European journal of medicinal chemistry 2019-01, Vol.162, p.612-630
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Benzamide; Cancer; HDAC; Indoline; Tubulin
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.10.066

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. [Display omitted] •A series of 1-Arylsulfonyl Indoline-Benzamides has been synthesized.•Compound 9 remarkably suppressed the growth of cancer cell lines.•The benzamide 9 displayed striking tubulin inhibition.•Compound 9 exhibited significant inhibitory potential against HDAC 1, 2 and 6.•Compound 9 also demonstrated significant in vivo efficacy.