Abstract

Carbonic anhydrases (CAs) are one of the promising targets for the development of anticancer agents. CA isoforms are implicated in various physiological processes and are expressed in both normal and cancerous cells. Thus, non-isoform selective inhibitors are associated with several side effects. Consequently, designing selective inhibitors towards cancer-related hCA IX/XII rather than the ubiquitous cytosolic isozymes hCA I and II is the main research objective in the field. Herein, a new series of 3-(6-methylpyridin-2-yl)coumarin derivatives 3 and 5a–o was designed and synthesised. The CA inhibition activities for the synthesised coumarins were analysed on isoforms hCA I, II, IX, and XII. Interestingly, both cancer-linked isoforms hCA IX/XII were inhibited by the prepared coumarins with inhibition constants ranging from sub- to low-micromolar range, whereas hCA I and II isoforms haven’t been inhibited up to 100 µM. Furthermore, the target coumarins were assessed for their antitumor activity on NCI-59 human cancer types.

摘要

碳酸酐酶 (CAs) 是开发抗癌药物的有希望的靶点之一。CA 同种型涉及各种生理过程，并在正常细胞和癌细胞中表达。因此，非同种型选择性抑制剂与几种副作用有关。因此，设计针对癌症相关的h CA IX/XII 而不是普遍存在的细胞溶质同工酶h CA I 和 II 的选择性抑制剂是该领域的主要研究目标。在此，设计并合成了一系列新的 3-(6-methylpyridin-2-yl)coumarin 衍生物3和5a-o 。在异构体h上分析了合成香豆素的 CA 抑制活性CA I、II、IX 和 XII。有趣的是，两种癌症相关的异构体h CA IX/XII 都被制备的香豆素抑制，其抑制常数从亚微摩尔到低微摩尔范围，而h CA I 和 II 异构体在高达 100 µM 时都没有被抑制。此外，还评估了目标香豆素对 NCI-59 人类癌症类型的抗肿瘤活性。