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.
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
Lai, M. J., Ojha, R., Lin, M. H., Liu, Y. M., Lee, H. Y., Lin, T. E., Hsu, K. C., Chang, C. Y., Chen, M. C., Nepali, K., Chang, J. Y., & Liou, J. P. (2019). 1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase. European Journal of Medicinal Chemistry, 162, 612-630. https://doi.org/10.1016/j.ejmech.2018.10.066