Isocoumarins Incorporating Chalcone Moieties Act As Isoform Selective Tumor-associated Carbonic Anhydrase Inhibitors

Overview

Journal Future Med Chem

Specialties Chemistry
Pharmacy

Date 2024 Aug 7

PMID 39109432

Authors

Mehmet Onyilmaz

Murat Koca

Andrea Ammara

Mustafa Degirmenci

Claudiu T Supuran

Affiliations

Soon will be listed here.

Abstract

A series of isocoumarin-chalcone hybrids were prepared and assays for the inhibition of four isoforms of human carbonic anhydrase (hCA; EC 4.2.1.1), hCA I, II, IX and XII. Isocoumarin-chalcone hybrids were synthesized by condensing acetyl-isocoumarin with aromatic aldehydes. They did not significantly inhibit off-target cytosolic isoforms hCA I and II (K >100 μM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors.

References

Emam S, Sonousi A, Osman E, Hwang D, Kim G, Hassan R . Design and synthesis of methoxyphenyl- and coumarin-based chalcone derivatives as anti-inflammatory agents by inhibition of NO production and down-regulation of NF-κB in LPS-induced RAW264.7 macrophage cells. Bioorg Chem. 2021; 107:104630. DOI: 10.1016/j.bioorg.2021.104630. View

Supuran C . Carbonic anhydrase versatility: from pH regulation to CO sensing and metabolism. Front Mol Biosci. 2023; 10:1326633. PMC: 10676200. DOI: 10.3389/fmolb.2023.1326633. View

Wang Y, Zhang W, Dong J, Gao J . Design, synthesis and bioactivity evaluation of coumarin-chalcone hybrids as potential anticancer agents. Bioorg Chem. 2019; 95:103530. DOI: 10.1016/j.bioorg.2019.103530. View

Bonvicini F, Gentilomi G, Bressan F, Gobbi S, Rampa A, Bisi A . Functionalization of the Chalcone Scaffold for the Discovery of Novel Lead Compounds Targeting Fungal Infections. Molecules. 2019; 24(2). PMC: 6359675. DOI: 10.3390/molecules24020372. View

Musatat A, Kiliccioglu I, Kurman Y, Dulger G, Alpay M, Yagci R . Antimicrobial, Antiproliferative Effects and Docking Studies of Methoxy Group Enriched Coumarin-Chalcone Hybrids. Chem Biodivers. 2023; 20(3):e202200973. DOI: 10.1002/cbdv.202200973. View

Supuran C . Emerging role of carbonic anhydrase inhibitors. Clin Sci (Lond). 2021; 135(10):1233-1249. DOI: 10.1042/CS20210040. View

Bonardi A, Bua S, Combs J, Lomelino C, Andring J, Osman S . The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII. J Enzyme Inhib Med Chem. 2022; 37(1):930-939. PMC: 8942523. DOI: 10.1080/14756366.2022.2053526. View

Feng D, Zhang A, Yang Y, Yang P . Coumarin-containing hybrids and their antibacterial activities. Arch Pharm (Weinheim). 2020; 353(6):e1900380. DOI: 10.1002/ardp.201900380. View

Elkanzi N, Hrichi H, Alolayan R, Derafa W, Zahou F, Bakr R . Synthesis of Chalcones Derivatives and Their Biological Activities: A Review. ACS Omega. 2022; 7(32):27769-27786. PMC: 9386807. DOI: 10.1021/acsomega.2c01779. View

10.

Khalifah R . The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. J Biol Chem. 1971; 246(8):2561-73. View

11.

Moya-Alvarado G, Yanez O, Morales N, Gonzalez-Gonzalez A, Areche C, Nunez M . Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies. Molecules. 2021; 26(9). PMC: 8122463. DOI: 10.3390/molecules26092430. View

12.

Aboukhatwa S, Sidhom P, Angeli A, Supuran C, Tawfik H . Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids. ACS Omega. 2023; 8(8):7666-7683. PMC: 9979347. DOI: 10.1021/acsomega.2c07285. View

13.

Tawfik H, Shaldam M, Nocentini A, Salem R, Almahli H, Al-Rashood S . Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity. J Enzyme Inhib Med Chem. 2022; 37(1):1043-1052. PMC: 9037210. DOI: 10.1080/14756366.2022.2056734. View

14.

Supuran C . Coumarin carbonic anhydrase inhibitors from natural sources. J Enzyme Inhib Med Chem. 2020; 35(1):1462-1470. PMC: 7470141. DOI: 10.1080/14756366.2020.1788009. View

15.

Konidala S, Kotra V, Danduga R, Kola P . Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity, and molecular docking. Bioorg Chem. 2020; 104:104207. DOI: 10.1016/j.bioorg.2020.104207. View

16.

Zhang L, Xu Z . Coumarin-containing hybrids and their anticancer activities. Eur J Med Chem. 2019; 181:111587. DOI: 10.1016/j.ejmech.2019.111587. View

17.

Michalkova R, Mirossay L, Kello M, Mojzisova G, Baloghova J, Podracka A . Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence. Int J Mol Sci. 2023; 24(12). PMC: 10299153. DOI: 10.3390/ijms241210354. View

18.

Al-Anazi M, Al-Najjar B, Khairuddean M . Structure-Based Drug Design Studies Toward the Discovery of Novel Chalcone Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors. Molecules. 2018; 23(12). PMC: 6321200. DOI: 10.3390/molecules23123203. View

19.

Bonardi A, Nocentini A, Bua S, Combs J, Lomelino C, Andring J . Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action. J Med Chem. 2020; 63(13):7422-7444. PMC: 8008423. DOI: 10.1021/acs.jmedchem.0c00733. View

20.

Elsayed Z, Almahli H, Nocentini A, Ammara A, Supuran C, Eldehna W . Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors. J Enzyme Inhib Med Chem. 2023; 38(1):2191163. PMC: 10035947. DOI: 10.1080/14756366.2023.2191163. View