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Abstract：
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 (KIs = 93.4 and 88.6 nM, respectively), hCA IX (KIs = 38.7 and 68.2 nM, respectively), and hCA XII (KIs = 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.
摘要：
天然产物胡椒碱，黑胡椒果实中存在的主要生物活性生物碱，具有调节几种生物靶标的功能活性的能力。在这项研究中,我们利用天然胡椒碱作为尾部部分开发新的SLC-0111类似物（6a-d，8和9）作为潜在的碳酸酐酶抑制剂。此后,不同的功能，游离羧酸(11a-c)，乙酰基（13a）和乙酯（13b-c），被用作氨磺酰基官能团的生物等排物。评估了所有基于胡椒碱的衍生物对四种人（h）CA亚型的抑制作用：hCAI，II,九和十二。对于合成的伯胡椒碱-磺酰胺(6a-d和8),观察到最好的hCA抑制活性。特别是,在这项研究中，对位区域异构体（6c和8）都是最有效的hCA抑制剂，对hCAII具有两位数的纳摩尔活性（KIs=93.4和88.6nM，分别)，hCAIX(KIs=38.7和68.2nM,分别)，和hCAXII（KIs=57.5和45.6nM，分别)。此外，检查了胡椒碱-磺酰胺6c对乳腺MCF-7癌细胞系的抗癌和促凋亡作用。总的来说，基于胡椒碱的磺酰胺可被认为是开发具有有效CA抑制活性的有效抗癌候选物的有前途的支架。
