Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt; School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt.
Eur J Med Chem. 2022 Aug 5;238:114412. doi: 10.1016/j.ejmech.2022.114412. Epub 2022 Apr 27.
In the current work, we adopted the tail/dual tail approaches to design and synthesize the benzenesulfonamide derivatives 6a-b, 8, 10a-b, 12a-b, 14, and 16 as new SLC-0111 analogs endowed with carbonic anhydrase (CA) inhibitory activity. All the prepared benzenesulfonamide derivatives were tested for their inhibitory action towards hCA isoforms; hCA I, II, IX, and XII. The results revealed their ability to affect the examined isoforms in variable degrees with K ranges: 49.3-6459 nM for CA I, 5.1-4171 nM for CA II, 9.4-945.1 nM for CA IX, and 5.2-1159 nM for CA XII. As expected, appending a second hydrophilic tail (ethanolamine) in compound 16 significantly enhanced the inhibitory activities towards hCA IX and hCA XII isoforms by about 5-fold in comparison to its single tail analogue 6c (K = 51.5 and 28.2 nM for 6cvs. 10.2 and 5.2 nM for 16, respectively). Moreover, SAR analysis pointed out the significance of grafting the sulfamoyl functionality at para-position, as well as the incorporation of a bulky hydrophobic tail for CA inhibitory activity. The most potent hCA IX inhibitors (6f and 16) displayed efficient cell growth inhibitory activity against breast cancer cell lines; T-47D (IC = 19 and 10.9 μM, respectively) and MCF-7 (IC = 7.5 and 5.7 μM, respectively).
在当前的工作中，我们采用了尾巴/双尾巴方法来设计和合成苯磺酰胺衍生物 6a-b、8、10a-b、12a-b、14 和 16，作为具有碳酸酐酶（CA）抑制活性的新型 SLC-0111 类似物。所有合成的苯磺酰胺衍生物均测试了对 hCA 同工型的抑制作用；hCA I、II、IX 和 XII。结果表明，它们能够以不同程度影响所研究的同工型，K 值范围为：CA I 为 49.3-6459 nM，CA II 为 5.1-4171 nM，CA IX 为 9.4-945.1 nM，CA XII 为 5.2-1159 nM。正如预期的那样，在化合物 16 中附加第二个亲水尾巴（乙醇胺），与单尾类似物 6c 相比，显著增强了对 hCA IX 和 hCA XII 同工型的抑制活性，约提高了 5 倍（K = 51.5 和 28.2 nM 对 6c，分别为 10.2 和 5.2 nM 对 16）。此外，SAR 分析指出了在对位嫁接磺酰胺官能团以及为 CA 抑制活性引入大体积疏水尾的重要性。最有效的 hCA IX 抑制剂（6f 和 16）对乳腺癌细胞系 T-47D（IC = 19 和 10.9 μM，分别）和 MCF-7（IC = 7.5 和 5.7 μM，分别）表现出有效的细胞生长抑制活性。
