Elkotamy Mahmoud S, Abdelrahman Mohamed A, Giovannuzzi Simone, Alkabbani Mahmoud Abdelrahman, Nocentini Alessio, Supuran Claudiu T, Eldehna Wagdy M, Abdel-Aziz Hatem A, Abou-Seri Sahar M
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
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.
Int J Biol Macromol. 2025 Apr;303:140462. doi: 10.1016/j.ijbiomac.2025.140462. Epub 2025 Jan 28.
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 9h and 9r exhibited potent inhibitory activity in the low nanomolar range against CA IX (K = 23 and 14 nM, respectively) and CA XII (K = 6 and 17 nM, respectively). In NCI-60 human tumor cell line screening, compounds 9k, 9m, 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 9m showed significant tubulin polymerization inhibition with an IC = 5.28 μM, surpassing the efficacy of colchicine. Cell cycle analysis in MDA-MB-231 breast cancer cells revealed G2/M phase arrest for 9m, 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.
本研究介绍了一系列新型香豆素类化合物（9a - t）作为潜在抗癌药物的设计、合成及评估。这些化合物经策略性设计，旨在抑制与癌症相关的碳酸酐酶（CA）同工型IX和XII以及微管蛋白聚合。采用了两种方法抑制CA：利用香豆素基序封闭CA活性位点入口，并引入锌结合基团（磺酰胺、羧酸和硫醇）与催化锌离子相互作用。目标化合物还通过结合具有优势的香豆素和吡唑并[1,5 - a]嘧啶支架来设计抑制微管蛋白聚合。对目标化合物（9a - t）的生物学评估表明，含磺酰胺的衍生物9h和9r对CA IX（K分别为23和14 nM）和CA XII（K分别为6和17 nM）在低纳摩尔范围内表现出强效抑制活性。在NCI - 60人肿瘤细胞系筛选中，化合物9k、9m和9q在五剂量试验中表现出广谱抗增殖活性，MG - MID值分别为7.31 μM、10.68 μM和5.92 μM。化合物9m显示出显著的微管蛋白聚合抑制作用，IC = 5.28 μM，超过了秋水仙碱的疗效。MDA - MB - 231乳腺癌细胞的细胞周期分析显示，9m使细胞停滞于G2/M期，诱导了显著的凋亡并调节了凋亡标志物。分子对接研究为化合物与CA IX、CA XII和微管蛋白的结合模式提供了见解。进行了ADMET和毒性预测以评估化合物的类药性质。这些发现为进一步优化香豆素支架以开发碳酸酐酶IX/XII和微管蛋白聚合的双重抑制剂铺平了道路。
