Novel 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide based thiosemicarbazides as potent and selective inhibitors of tumor-associated human carbonic anhydrase IX and XII: Synthesis, cytotoxicity, and molecular modelling studies.

Autor: Demir-Yazıcı K; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Turkey; Department of Pharmaceutical Chemistry, Institute of Graduate Studies in Health Sciences, Istanbul University, 34126 Istanbul, Turkey., Trawally M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Turkey; Department of Pharmaceutical Chemistry, Institute of Graduate Studies in Health Sciences, Istanbul University, 34126 Istanbul, Turkey., Bua S; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019, Sesto Fiorentino, Florence, Italy., Öztürk-Civelek D; Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Istanbul, Turkey., Akdemir A; Department of Pharmacology, Faculty of Pharmacy, Istinye University, 34408 Istanbul, Turkey., Supuran CT; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019, Sesto Fiorentino, Florence, Italy., Güzel-Akdemir Ö; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Turkey. Electronic address: oguzel@istanbul.edu.tr.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Mar; Vol. 144, pp. 107096. Date of Electronic Publication: 2024 Jan 23.
DOI: 10.1016/j.bioorg.2024.107096
Abstrakt: In the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to ∼340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (K i ) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; K i : 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC 50 : 53.32 ± 7.74 µM for HT-29; IC 50 : 74.64 ± 14.15 µM for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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