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Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-18 , DOI: 10.1021/acsmedchemlett.0c00094
Wagdy M Eldehna 1, 2 , Alessio Nocentini 3 , Zainab M Elsayed 2 , Tarfah Al-Warhi 4 , Nada Aljaeed 4 , Ohoud J Alotaibi 4 , Mohammad M Al-Sanea 5 , Hatem A Abdel-Aziz 6 , Claudiu T Supuran 3
Affiliation  

Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (9a-f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker. The target carboxylic acids were evaluated for the potential inhibitory action against hCAs I, II, IX, and XII. Superiorly, benzofuran-containing carboxylic acid derivatives 9b, 9e, and 9f acted as submicromolar hCA IX inhibitors with KIs = 0.91, 0.79, and 0.56 μM, respectively, with selective inhibitory profile against the target hCA IX over the off-target isoforms hCA I and II (SIs: 2 to >63 and 4-47, respectively). Compounds 9b, 9e, and 9f were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. In particular, 9e displayed promising antiproliferative (IC50 = 2.52 ± 0.39 μM), cell cycle disturbance, and pro-apoptotic actions in MDA-MB-231 cells.

中文翻译:


基于苯并呋喃的羧酸作为碳酸酐酶抑制剂和抗乳腺癌抗增殖剂。



为了开发癌症相关 hCA IX 异构体的有效抑制剂,我们在此描述了新型苯并呋喃基羧酸衍生物的合成,其特征是苯甲酸 (9a-f) 或马尿酸 (11a,b) 酸部分连接到 2 -甲基苯并呋喃或5-溴苯并呋喃尾部通过脲基连接体。评估了目标羧酸对 hCA I、II、IX 和 XII 的潜在抑制作用。更重要的是,含苯并呋喃的羧酸衍生物 9b、9e 和 9f 分别作为亚微摩尔 hCA IX 抑制剂,KI 分别为 0.91、0.79 和 0.56 μM,对目标 hCA IX 的选择性抑制优于对脱靶异构体 hCA I 的选择性抑制和 II(SI:分别为 2 至 >63 和 4-47)。检查了化合物 9b、9e 和 9f 对人乳腺癌(MCF-7 和 MDA-MB-231)细胞系的抗增殖作用。特别是,9e 在 MDA-MB-231 细胞中表现出有希望的抗增殖 (IC50 = 2.52 ± 0.39 μM)、细胞周期干扰和促凋亡作用。
更新日期:2020-03-18
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