基于糖基结构的新型选择性碳酸酐酶Ⅸ抑制剂的设计、合成及生物活性研究

Design,synthesis and biological evaluation of novel carbohydrate-based selective carbonic anhydraseⅨinhibitors

目的为寻找选择性强的碳酸酐酶Ⅸ抑制剂,设计、合成一系列新型的基于糖基结构的香豆素类化合物,并对其酶抑制活性及选择性进行评价。方法以葡萄糖为起始原料,经过全苯甲酰保护、端基溴代、糖苷化和水解反应得到目标化合物(5a~5f)。采用酯酶水解法,以乙酰唑胺为阳性对照,测定了目标化合物对碳酸酐酶Ⅰ、Ⅱ、Ⅸ的抑制活性;以MTT法检测肿瘤细胞增殖抑制活性。结果与结论合成了6个新型含糖基结构的香豆素类衍生物,目标化合物的结构经;H-NMR和MS确证。碳酸酐酶抑制活性测试和MTT法检测细胞增殖抑制活性结果表明,6个目标化合物均有良好的酶抑制活性,实现了对碳酸酐酶Ⅸ的选择性抑制,并展示了一定的抗肿瘤细胞增殖活性和肿瘤细胞外酸化抑制作用。其中化合物5a的碳酸酐酶Ⅸ抑制活性优于阳性对照药乙酰唑胺,对碳酸酐酶Ⅸ的选择性是对碳酸酐酶Ⅰ的2623倍,具有进一步研究的价值。

In order to discover highly selective CAⅨinhibitors,a series of novel carbohydrate-based coumarin derivatives have been designed and synthesized.Subsequently,these target compounds were assayed for the inhibition of three carbonic anhydrase isoforms(CAⅠ,CAⅡand CAⅨ).Intriguingly,all the compounds showed excellent CAⅨinhibitory activity.Among them,compound 5 a showed the most potent CAⅨinhibitory efficacy,being more effective than the reference drug acetazolamide.Notably,compound 5 a showed 2623-fold,1633-fold selectivity relative to CAⅠand CAⅡ,respectively.Meanwhile,representative compounds could reduce tumor cell viability and the extracellular acidification in HT-29 and MDA-MB-231 cancer cell lines.And docking studies were carried out to understand the interactions of our target compounds with the protein target CAⅨ.Collectively,our results suggest that compound 5 a,as a selective CAⅨinhibitor,could be an important lead compound for further optimization and development as an anticancer agent.