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

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dc.authoridAkdemir, Atilla/0000-0001-8416-0471
dc.authoridTrawally, Muhammed/0000-0002-0041-4612
dc.authorwosidAkdemir, Atilla/G-2595-2015
dc.contributor.authorDemir-Yazici, Kubra
dc.contributor.authorTrawally, Muhammed
dc.contributor.authorBua, Silvia
dc.contributor.authorOzturk-Civelek, Dilek
dc.contributor.authorAkdemir, Atilla
dc.contributor.authorSupuran, Claudiu T.
dc.contributor.authorGuzel-Akdemir, Ozlen
dc.date.accessioned2024-05-20T14:38:44Z
dc.date.available2024-05-20T14:38:44Z
dc.date.issued2024
dc.departmentİstinye Üniversitesien_US
dc.description.abstractIn 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 similar 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 (IC50: 53.32 +/- 7.74 mu M for HT-29; IC50: 74.64 +/- 14.15 mu M 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.en_US
dc.description.sponsorshipIstanbul University Scientific Research Projects Department [TDK-2018-32263]en_US
dc.description.sponsorshipThis work was supported by the Istanbul University Scientific Research Projects Department under project numbers TDK-2018-32263.en_US
dc.identifier.doi10.1016/j.bioorg.2024.107096
dc.identifier.issn0045-2068
dc.identifier.issn1090-2120
dc.identifier.pmid38290186en_US
dc.identifier.scopus2-s2.0-85184244597en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org10.1016/j.bioorg.2024.107096
dc.identifier.urihttps://hdl.handle.net/20.500.12713/4585
dc.identifier.volume144en_US
dc.identifier.wosWOS:001175570900001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherAcademic Press Inc Elsevier Scienceen_US
dc.relation.ispartofBioorganic Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.snmz20240519_kaen_US
dc.subject2-(Hydrazinocarbonyl)-3-Phenyl-1h-Indole-5-Sulfonamideen_US
dc.subjectCarbonic Anhydraseen_US
dc.subjectTumor-Associated Hca Ix/Xiien_US
dc.subjectCytotoxicityen_US
dc.subjectEnsemble Dockingen_US
dc.subjectMolecular Dynamics Simulationsen_US
dc.titleNovel 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 studiesen_US
dc.typeArticleen_US

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