Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms

Wagdy M Eldehna; Mohammed S Taghour; Tarfah Al-Warhi; Alessio Nocentini; Mostafa M Elbadawi; Hazem A Mahdy; Mohamed A Abdelrahman; Ohoud J Alotaibi; Nada Aljaeed; Diaaeldin M Elimam; Kamyar Afarinkia; Hatem A Abdel-Aziz; Claudiu T Supuran

doi:10.1080/14756366.2021.2024528

Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms

J Enzyme Inhib Med Chem. 2022 Dec;37(1):531-541. doi: 10.1080/14756366.2021.2024528.

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
³ Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
⁴ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
⁶ Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁷ School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
⁸ Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom.
⁹ Department of Applied Organic Chemistry, National Research Center, Giza, Egypt.

Abstract

Different 2,4-thiazolidinedione-tethered coumarins 5a-b, 10a-n and 11a-d were synthesised and evaluated for their inhibitory action against the cancer-associated hCAs IX and XII, as well as the physiologically dominant hCAs I and II to explore their selectivity. Un-substituted phenyl-bearing coumarins 10a, 10 h, and 2-thienyl/furyl-bearing coumarins 11a-c exhibited the best hCA IX (K_Is between 0.48 and 0.93 µM) and hCA XII (K_Is between 0.44 and 1.1 µM) inhibitory actions. Interestingly, none of the coumarins had any inhibitory effect on the off-target hCA I and II isoforms. The sub-micromolar compounds from the biochemical assay, coumarins 10a, 10 h and 11a-c, were assessed in an in vitro antiproliferative assay, and then the most potent antiproliferative agent 11a was tested to explore its impact on the cell cycle phases and apoptosis in MCF-7 breast cancer cells to provide more insights into the anticancer activity of these compounds.

Keywords: 3-acetylcoumarin; Carbonic anhydrase inhibitors; anticancer agents; apoptosis induction; hypoxic tumours.

MeSH terms

Antigens, Neoplasm / metabolism
Apoptosis / drug effects
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Cell Cycle / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
MCF-7 Cells
Molecular Structure
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis
Thiazolidinediones / chemistry
Thiazolidinediones / pharmacology*

Substances

Antigens, Neoplasm
Carbonic Anhydrase Inhibitors
Coumarins
Thiazolidinediones
2,4-thiazolidinedione
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII

Grants and funding

This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, through the Research Groups Program Grant no [RGP-1440 − 0025](2). The work was also financed by the Italian Ministry for Education and Science (MIUR), grant PRIN: rot. 2017XYBP2R, and by Ente Cassa di Risparmio di Firenze (ECRF), grant [CRF2020.1395] to CTS.