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.

Authors:
Belma Zengin Kurt
Belma Zengin Kurt
Bezmialem Vakif University
Aydan Dag
Aydan Dag
School of Chemistry and School of Chemical Engineering
Serdar Durdagi
Serdar Durdagi
University of Calgary
Canada
Andrea Angeli
Andrea Angeli
Department of Food Quality and Nutrition
Alessio Nocentini
Alessio Nocentini
Università degli Studi di Firenze
Firenze | Italy
Claudiu T Supuran
Claudiu T Supuran
Università degli Studi di Firenze
Firenze | Italy
Fatih Sonmez
Fatih Sonmez
Sakarya University
Turkey

Bioorg Chem 2019 Mar 7;87:838-850. Epub 2019 Mar 7.

Sakarya University of Applied Sciences, Pamukova Vocational Highschool, Pamukova, Turkey.

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 K 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 K 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.

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http://dx.doi.org/10.1016/j.bioorg.2019.03.003DOI Listing
March 2019
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