Synthesis, biological activity and multiscale molecular modeling studies of bis-coumarins as selective carbonic anhydrase IX and XII inhibitors with effective cytotoxicity against hepatocellular carcinoma.
A series of novel bis-coumarin derivatives containing triazole moiety as a linker between the alkyl chains was synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms I, II, IX and XII were evaluated. In addition, cytotoxic effects of the synthesized compounds on renal adenocarcinoma (769P), hepatocellular carcinoma (HepG2) and breast adeno carcinoma (MDA-MB-231) cell lines were examined. While the hCA I and II isoforms were inhibited in the micromolar range, the tumor-associated isoform hCA IX and XII were inhibited in the high nanomolar range. 4-methyl-7-((1-(12-((2-oxo-2H-chromen-7-yl)oxy)dodecyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (5p) showed the strongest inhibitory activity against hCA IX with the Ki of 144.6 nM and 4-methyl-7-((1-(10-((2-oxo-2H-chromen-7-yl)oxy)decyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (5n) exhibited the highest hCA XII inhibition with the Ki of 71.5 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modelling approaches were applied. Low energy docking poses of studied molecules at the binding sites of targets have been predicted. In addition, electrostatic potential surfaces (ESP) for binding sites were also generated to understand interactions between proteins and active ligands.
['Kurt|Belma Zengin|BZ|', 'Dag|Aydan|A|', 'Doğan|Berna|B|', 'Durdagi|Serdar|S|', 'Angeli|Andrea|A|', 'Nocentini|Alessio|A|', 'Supuran|Claudiu T|CT|', 'Sonmez|Fatih|F|']
D000951:Antigens, Neoplasm D000970:Antineoplastic Agents D000071231:Carbonic Anhydrase IX D002257:Carbonic Anhydrase Inhibitors D002256:Carbonic Anhydrases D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D049109:Cell Proliferation D003374:Coumarins D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D056945:Hep G2 Cells D006801:Humans D007527:Isoenzymes D008113:Liver Neoplasms D008958:Models, Molecular D015394:Molecular Structure D013329:Structure-Activity Relationship
Carbonic anhydrase Cytotoxicity Coumarin Molecular Dynamics (MD) Simulations Molecular docking