1. Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors.
- Author
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Shaldam M, Nocentini A, Elsayed ZM, Ibrahim TM, Salem R, El-Domany RA, Capasso C, Supuran CT, and Eldehna WM
- Subjects
- Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents isolation & purification, Antineoplastic Agents therapeutic use, Carbonic Anhydrase IX antagonists & inhibitors, Carbonic Anhydrase IX genetics, Carbonic Anhydrase IX metabolism, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, MCF-7 Cells, Molecular Structure, Neoplasms genetics, Structure-Activity Relationship, Carbonic Anhydrase Inhibitors chemical synthesis, Carbonic Anhydrase Inhibitors isolation & purification, Carbonic Anhydrase Inhibitors therapeutic use, Neoplasms drug therapy, Quinolines chemical synthesis, Quinolines isolation & purification, Quinolines therapeutic use, Sulfonamides chemical synthesis, Sulfonamides isolation & purification, Sulfonamides therapeutic use
- Abstract
A new series of quinoline-based benzenesulfonamides ( QBS ) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group ( QBS 13a - c ); thereafter, the sulphonamide group was switched to ortho - and meta -positions to afford regioisomers 9a - d and 11a - g . Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS 16 . All the described QBS have been synthesized and investigated for their CA inhibitory action against h CA I, II, IX and XII. In general, para -sulphonamide derivatives 13a - c displayed the best inhibitory activity against both cancer-related isoforms h CA IX ( K
I s = 25.8, 5.5 and 18.6 nM, respectively) and h CA XII ( KI s = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent h CA IX inhibitory activity exerted by meta -sulphonamide derivative 11c ( KI = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS.- Published
- 2021
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