Elimam Diaaeldin M, Elgazar Abdullah A, Bonardi Alessandro, Abdelfadil Mohamed, Nocentini Alessio, El-Domany Ramadan A, Abdel-Aziz Hatem A, Badria Farid A, Supuran Claudiu T, Eldehna Wagdy M
Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom.
Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
Eur J Med Chem. 2021 Dec 5;225:113800. doi: 10.1016/j.ejmech.2021.113800. Epub 2021 Aug 25.
The natural product piperine, the major bioactive alkaloid present in black pepper fruits, has the ability to modulate the functional activity of several biological targets. In this study, we have utilized the natural piperine as a tail moiety to develop new SLC-0111 analogues (6a-d, 8 and 9) as potential carbonic anhydrase inhibitors. Thereafter, different functionalities, free carboxylic acid (11a-c), acetyl (13a) and ethyl ester (13b-c), were exploited as bioisosteres of the sulfamoyl functionality. All piperine-based derivatives were assessed for their inhibitory actions against four human (h) CA isoforms: hCA I, II, IX and XII. The best hCA inhibitory activity was observed for the synthesized primary piperine-sulfonamides (6a-d and 8). In particular, both para-regioisomers (6c and 8) emerged as the most potent hCA inhibitors in this study with two-digit nanomolar activity against hCA II (Ks = 93.4 and 88.6 nM, respectively), hCA IX (Ks = 38.7 and 68.2 nM, respectively), and hCA XII (Ks = 57.5 and 45.6 nM, respectively). Moreover, piperine-sulfonamide 6c was examined for its anti-cancer and pro-apoptotic actions towards breast MCF-7 cancer cell line. Collectively, piperine-based sulfonamides could be considered as a promising scaffold for development of efficient anticancer candidates with potent CA inhibitory activities.
天然产物胡椒碱是黑胡椒果实中主要的生物活性生物碱，具有调节多种生物靶点功能活性的能力。在本研究中，我们利用天然胡椒碱作为尾基来开发新的SLC - 0111类似物（6a - d、8和9）作为潜在的碳酸酐酶抑制剂。此后，不同的官能团，即游离羧酸（11a - c）、乙酰基（13a）和乙酯基（13b - c），被用作磺酰胺官能团的生物电子等排体。对所有基于胡椒碱的衍生物针对四种人（h）CA同工型：hCA I、II、IX和XII的抑制作用进行了评估。对于合成的一级胡椒碱 - 磺酰胺（6a - d和8），观察到了最佳的hCA抑制活性。特别是，两种对位区域异构体（6c和8）在本研究中成为最有效的hCA抑制剂，对hCA II（Ks分别为93.4和88.6 nM）、hCA IX（Ks分别为38.7和68.2 nM）和hCA XII（Ks分别为57.5和45.6 nM）具有两位数的纳摩尔活性。此外，还研究了胡椒碱 - 磺酰胺6c对乳腺癌MCF - 7癌细胞系的抗癌和促凋亡作用。总体而言，基于胡椒碱的磺酰胺可被视为开发具有高效CA抑制活性的有效抗癌候选物的有前景的支架。
