Abstract
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•Inhibitory activity of isatin-based sulfonamides was evaluated toward hCA IX and XII isoforms.•All sulfonamides inhibited hCA IX with KIs spanning in the nanomolar range (6.2–64.8 nM).•hCA XII was highly inhibited by all sulfonamides with KIs in the range of 7.1–55.6 nM.•Anti-proliferative activity against MCF-7 and HCT-116 cancer cell lines was examined.•Sulphonamide 9e induced the intrinsic apoptotic mitochondrial pathway in HCT-116 cells.
Three series of indolinone-based sulfonamides (3a–f, 6a–f and 9a–f) were in vitro evaluated as inhibitors of the tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII, using a stopped-flow CO2 hydrase assay. All the investigated sulfonamides displayed single- or double-digit nanomolar inhibitory activities towards both hCA IX (KIs: 6.2–64.8 nM) and XII (KIs: 7.1–55.6 nM) isoforms. All sulfonamides (3a–f, 6a–f and 9a–f) were in vitro examined for their potential anticancer activity against colorectal cancer HCT-116 and breast cancer MCF-7 cell lines. Sulfonamide 9e was found to be the most potent counterpart against HCT-116 (IC50 = 3.67 ± 0.33 µM). Sulfonamide 9e displayed good selectivity profile for inhibition of the tumor-associated isoforms (CAs IX & XII) over the off-target cytosolic CAs I and II. 9e was screened for cell cycle disturbance and apoptosis induction in HCT-116 cells. It was found to persuade cell cycle arrest at G2-M stage as well as alter the Sub-G1 phase. Also, 9e induced the intrinsic apoptotic mitochondrial pathway in HCT-116 cells via down-regulation of the anti-apoptotic protein Bcl-2 level with concurrent boosting the pro-apoptotic Bax, caspase-9, caspase-3, cytochrome C and p53 levels.