Development of pyrazolo[1,5-a]pyrimidine-grafted coumarins as selective carbonic anhydrase inhibitors and tubulin polymerization inhibitors with potent anticancer activity.

Autor: Elkotamy MS; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt., Abdelrahman MA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt; Department of Pharmacy, Kut University College, Al Kut, Wasit, 52001, Iraq., Giovannuzzi S; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Firenze, Italy., Alkabbani MA; Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt., Nocentini A; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Firenze, Italy., Supuran CT; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Firenze, Italy., Eldehna WM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com., Abdel-Aziz HA; Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia Street, Alexandria 21648, Egypt. Electronic address: hatem_741@yahoo.com., Abou-Seri SM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: sahar.shaarawy@pharma.cu.edu.eg.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2025 Jan 28, pp. 140462. Date of Electronic Publication: 2025 Jan 28.
DOI: 10.1016/j.ijbiomac.2025.140462
Abstrakt: This study presents the design, synthesis, and evaluation of a novel series of coumarin-based compounds (9a-t) as potential anticancer agents. The compounds were strategically designed to inhibit cancer-related carbonic anhydrase (CA) isoforms IX and XII and tubulin polymerization. Two approaches were employed for CA inhibition: utilizing the coumarin motif to occlude the CA active site entrance and incorporating zinc-binding groups (sulfonamide, carboxylic acid, and thiol) to interact with the catalytic zinc ion. The target compounds were also designed to inhibit tubulin polymerization by combining the privileged coumarin and pyrazolo[1,5-a]pyrimidine scaffolds. Biological evaluation of the target compounds (9a-t) revealed that sulfonamide-containing derivatives 9 h and 9r exhibited potent inhibitory activity in the low nanomolar range against CA IX (K i  = 23 and 14 nM, respectively) and CA XII (K i  = 6 and 17 nM, respectively). In NCI-60 human tumor cell line screening, compounds 9 k, 9 m, and 9q demonstrated broad-spectrum anti-proliferative activity in the five-dose assay with MG-MID values of 7.31 μM, 10.68 μM, and 5.92 μM, respectively. Compound 9 m showed significant tubulin polymerization inhibition with an IC 50  = 5.28 μM, surpassing the efficacy of colchicine. Cell cycle analysis in MDA-MB-231 breast cancer cells revealed G2/M phase arrest for 9 m, which induced significant apoptosis and modulated apoptotic markers. Molecular docking studies provided insights into the binding modes of the compounds with CA IX, CA XII, and tubulin. ADMET and toxicity predictions were performed to assess the drug-like properties of the compounds. These findings pave the way for further optimization of the coumarin scaffold to develop dual inhibitors of carbonic anhydrase IX/XII and tubulin polymerization.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2025 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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