Eldehna Wagdy M, Elbadawi Mostafa M, Elsayed Zainab M, Giovannuzzi Simone, Elkotamy Mahmoud S, Elsawi Ahmed E, Ahmed Saleh A, Rashed Mahmoud, Nocentini Alessio, Supuran Claudiu T, Abdel-Aziz Hatem A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
Int J Biol Macromol. 2025 Sep;322(Pt 4):146776. doi: 10.1016/j.ijbiomac.2025.146776. Epub 2025 Aug 11.
Overexpression of carbonic anhydrases IX and XII due to hypoxia contributes to tumor acidification and progression, suggesting that selective inhibitors may serve as effective anticancer agents. Thirteen piperidine-linked benzenesulfonamides (7a-k, 9, and 11) were synthesized and assessed for their inhibitory activity against hCA I, IX, and XII. Compounds 7h (4-fluoro) and 7b (4-hydroxy) were identified as the most effective inhibitors of hCA IX (K = 1.2 nM) and hCA XII (K = 4.3 nM), respectively. In the context of chemically induced hypoxia, 7h demonstrated an inhibitory effect on MCF-7 breast cancer cell proliferation, with an IC value of 1.20 μM. Molecular docking with PDB codes 5FL4 and 4WW8 demonstrated significant Zn coordination by the sulfonamide group, Thr-mediated hydrogen bonding, and supplementary amide- and aromatic-mediated interactions that elucidate the observed SAR trends. Molecular dynamics simulations of both hCA IX and XII complexes confirmed the stability and favorable binding modes of compounds 7b and 7h over 100 ns trajectories, corroborating their high predicted affinities. The findings indicate that customized sulfonamide-piperidine scaffolds can produce effective and selective CA IX/XII inhibitors with antiproliferative properties, establishing a foundation for further optimization in anticancer therapeutics.
缺氧导致碳酸酐酶IX和XII的过表达，这有助于肿瘤酸化和进展，表明选择性抑制剂可能作为有效的抗癌药物。合成了13种哌啶连接的苯磺酰胺（7a - k、9和11），并评估了它们对hCA I、IX和XII的抑制活性。化合物7h（4 - 氟）和7b（4 - 羟基）分别被确定为hCA IX（K = 1.2 nM）和hCA XII（K = 4.3 nM）最有效的抑制剂。在化学诱导的缺氧环境中，7h对MCF - 7乳腺癌细胞增殖表现出抑制作用，IC值为1.20 μM。与PDB代码5FL4和4WW8的分子对接表明，磺酰胺基团与锌有显著配位作用，苏氨酸介导氢键，以及补充的酰胺和芳香介导的相互作用，阐明了观察到的构效关系趋势。hCA IX和XII复合物的分子动力学模拟证实了化合物7b和7h在100 ns轨迹上的稳定性和良好结合模式，证实了它们的高预测亲和力。研究结果表明，定制的磺酰胺 - 哌啶支架可以产生具有抗增殖特性的有效且选择性的CA IX/XII抑制剂，为抗癌治疗的进一步优化奠定了基础。
