Abstract

Coumarins constitute a relatively new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), possessing a unique inhibition mechanism, acting as “prodrug inhibitors.” They undergo the hydrolysis of the lactone ring mediated by the esterase activity of CA. The formed 2-hydroxy-cinnamic acids thereafter bind within a very particular part of the enzyme active site, at its entrance, where a high variability of amino acid residues among the different mammalian CA isoforms is present, and where other inhibitors classes were not seen bound earlier. This explains why coumarins are among the most isoform-selective CA inhibitors known to date among the many chemotypes endowed with such biological activity. As coumarins are widespread secondary metabolites in some bacteria, plants, fungi, and ascidians, many such compounds from various natural sources have been investigated for their CA inhibitory properties and for possible biomedical applications, mainly as anticancer agents targeting hypoxic tumours.

摘要

香豆素构成了相对较新的一类锌酶碳酸酐酶抑制剂（CA，EC 4.2.1.1），具有独特的抑制机制，可作为“前药抑制剂”。它们经历由CA的酯酶活性介导的内酯环的水解。此后，形成的2-羟基肉桂酸在酶活性位点的非常特定的部分结合，在其入口处，在不同的哺乳动物CA同工型之间存在较高的氨基酸残基变异性，并且未见其他抑制剂类型早点绑定。这就解释了为什么香豆素是迄今为止具有这种生物活性的许多化学型中最已知的异构体选择性CA抑制剂之一。由于香豆素是某些细菌，植物，真菌和海鞘中普遍存在的次级代谢产物，