Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt; Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Eur J Med Chem. 2021 Jun 5;218:113360. doi: 10.1016/j.ejmech.2021.113360. Epub 2021 Mar 13.
As a front-runner selective CA IX inhibitor currently in Phase Ib/II clinical trials, SLC-0111 has been herein exploited as a lead molecule for development of new different sets of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides incorporating different functionalities; primary sulfonamide (5a-f), free carboxylic (8a, 8d), ethyl ester (8b, 8e), acetyl (8c, 8f) and nitro (10a, 10b), as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the prepared analogues have been examined for their CA inhibitory activities towards four human (h) isoenzymes, hCA I, II, IX and XII. Interestingly, replacement of SLC-0111 ureido linker with the flexible sulfonyl acetamide linker, as well as linker branching and elongation strategies successfully enhanced the inhibitory action toward hCA IX isoform, such as in sulfones 5a-d and 5f which displayed better activity than SLC-0111. Furthermore, sulfonamide-based sulfone (5f) and carboxylic acid-based sulfones (8a and 8d) demonstrated interesting selectivity toward the tumor-related hCA IX isoform over both hCA I and hCA II, which suggests them as promising candidates for further development as potential anticancer candidates. Thereafter, the anti-proliferative action for sulfones 5f, 8a and 8d was examined against breast (MCF-7) and colon (HCT-116) cancer cell lines. Also, sulfone 5f was further assessed for its impact on the cell cycle progression and apoptosis in HCT-116 cells.
作为目前处于 Ib/II 期临床试验的领先的选择性 CAIX 抑制剂，SLC-0111 已被用作开发新的不同系列 N- 苯基-2-（苯磺酰基）乙酰胺/丙酰胺的先导化合物，其中包含不同的官能团；主要磺酰胺（5a-f）、游离羧酸（8a、8d）、乙酯（8b、8e）、乙酰基（8c、8f）和硝基（10a、10b），作为潜在的碳酸酐酶（CA，EC 4.2.1.1）抑制剂。所有制备的类似物都已针对四种人（h）同工酶 hCA I、II、IX 和 XII 进行了 CA 抑制活性测试。有趣的是，用柔性磺酰基乙酰胺连接基取代 SLC-0111 的脲基连接基，以及连接基分支和延伸策略，成功地增强了对 hCA IX 同工酶的抑制作用，例如在磺酰胺 5a-d 和 5f 中，它们的活性优于 SLC-0111。此外，基于磺酰胺的磺酮（5f）和基于羧酸的磺酮（8a 和 8d）对肿瘤相关的 hCA IX 同工酶表现出比 hCA I 和 hCA II 更有趣的选择性，这表明它们作为进一步开发为潜在抗癌候选药物的有前途的候选物。此后，对磺酰胺 5f、8a 和 8d 的抗增殖作用进行了研究，以评估其对乳腺癌（MCF-7）和结肠癌（HCT-116）癌细胞系的作用。此外，还进一步评估了磺酮 5f 对 HCT-116 细胞中细胞周期进展和凋亡的影响。
