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.

Tumor-associated carbonic anhydrase isoform IX and XII inhibitory properties of certain isatin-bearing sulfonamides endowed with in vitro antitumor activity towards colon cancer / Eldehna, Wagdy M; Nocentini, Alessio; Al-Rashood, Sara T; Hassan, Ghada S; Alkahtani, Hamad M; Almehizia, Abdulrahman A; Reda, Ahmed M; Abdel-Aziz, Hatem A; Supuran, Claudiu T. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - ELETTRONICO. - 81:(2018), pp. 425-432. [10.1016/j.bioorg.2018.09.007]

Tumor-associated carbonic anhydrase isoform IX and XII inhibitory properties of certain isatin-bearing sulfonamides endowed with in vitro antitumor activity towards colon cancer

Nocentini, Alessio;Supuran, Claudiu T
2018

Abstract

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.
2018
81
425
432
Eldehna, Wagdy M; Nocentini, Alessio; Al-Rashood, Sara T; Hassan, Ghada S; Alkahtani, Hamad M; Almehizia, Abdulrahman A; Reda, Ahmed M; Abdel-Aziz, Hatem A; Supuran, Claudiu T
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1289763
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