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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.
Bioorg Chem. 2019 06; 87:838-850.BC

Abstract

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.

Authors+Show Affiliations

Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Istanbul, Turkey. Electronic address: bzengin@bezmialem.edu.tr.Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Istanbul, Turkey.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey. Electronic address: serdar.durdagi@med.bau.edu.tr.Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.Sakarya University of Applied Sciences, Pamukova Vocational Highschool, Pamukova, Turkey.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31003041

Citation

Kurt, Belma Zengin, et al. "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." Bioorganic Chemistry, vol. 87, 2019, pp. 838-850.
Kurt BZ, Dag A, Doğan B, et al. 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. Bioorg Chem. 2019;87:838-850.
Kurt, B. Z., Dag, A., Doğan, B., Durdagi, S., Angeli, A., Nocentini, A., Supuran, C. T., & Sonmez, F. (2019). 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. Bioorganic Chemistry, 87, 838-850. https://doi.org/10.1016/j.bioorg.2019.03.003
Kurt BZ, et al. 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. Bioorg Chem. 2019;87:838-850. PubMed PMID: 31003041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kurt,Belma Zengin, AU - Dag,Aydan, AU - Doğan,Berna, AU - Durdagi,Serdar, AU - Angeli,Andrea, AU - Nocentini,Alessio, AU - Supuran,Claudiu T, AU - Sonmez,Fatih, Y1 - 2019/03/07/ PY - 2019/02/02/received PY - 2019/02/14/revised PY - 2019/03/02/accepted PY - 2019/4/20/pubmed PY - 2020/9/23/medline PY - 2019/4/20/entrez KW - Carbonic anhydrase KW - Coumarin KW - Cytotoxicity KW - Molecular Dynamics (MD) Simulations KW - Molecular docking SP - 838 EP - 850 JF - Bioorganic chemistry JO - Bioorg Chem VL - 87 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/31003041/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(19)30171-3 DB - PRIME DP - Unbound Medicine ER -