Salacia属抗糖尿病活性成分的全合成、结构修饰及生物活性研究

Recently, more and more attention has been drawn on a series of potent alpha-glucosidase inhibitors isolated from Salacia genus plant, which have traditionally been used for the treatment of diabetes in Sri Lanka and the south region of India. Their inhibitory activities against maltase, sucrase and isomaltase known as alpha-glucosidases were revealed to be as potent as those of clinically used alpha-glucosidases inhibitory anti-diabetics these days. In addition, the chemical structures of these compounds were found quite unique, bearing specific thiosugar sulfonium moiety, which is believed to mimic the oxacarbenium ion-like transition state of the enzyme-catalyzed hydrolysis of carbohydrates. Thus, this group of small molecules has the potential to become a new type of lead compounds as alpha-glucosidase inhibitors, which could be further developed to a new category of anti-diabetics. Based on our previous research of total synthesis and structure-activity relationship (SAR) studies on this group of sulfonium salts, this proposal describes: newly designed and more economic strategies to synthesize the most potent inhibitor Kotalanol and its de-O-sulfonated analog Neokotalanol, the structures of which are the most complicated ones among this group of natural products; Besides, our recent report on the synthetic route of Neoponkoranol and its epimers will be optimized; furthermore, systematic structure modification will be carried out at 3'-position on side chain of Neoponkoranol and Neokotalanol, aiming at discovering much more potent alpha-glucosidase inhibitors.

近年来，从Salacia属植物的根茎部提取的系列具有alpha-葡萄糖苷酶抑制活性锍糖类天然产物小分子以其独特的化学结构和优良的生物活性，受到了人们普遍的关注。体外活性测试表明，该类化合物对alpha-葡萄糖苷酶的抑制活性不亚于已经成功上市的同类药物。因此它们有望作为一类全新的alpha-葡萄糖苷酶抑制剂先导化合物并由此发展成一类全新的降糖药物。本项目将在我们之前对该类天然产物全合成及其构效关系大量的研究基础之上：以全新、低成本的路线完成这类天然产物中结构复杂而生物活性最为优异的Kotalanol及其脱硫酸盐类似物Neokotalanol的全合成工作；进一步优化天然产物Neoponkoranol及其侧链差向异构体的合成路线；对天然产物Neokotalanol和Neoponkoranol侧链的3'位置进行一系列的结构修饰，希望获得更高抑制活性的分子作为先导化合物，为进一步的药学研究奠定基础。

近年来，从Salacia属植物的根茎部提取的系列具有alpha-葡萄糖苷酶抑制活性锍糖类天然产物小分子以其独特的化学结构和优良的生物活性，受到了人们普遍的关注。体外活性测试表明，该类化合物对alpha-葡萄糖苷酶的抑制活性不亚于已经成功上市的同类药物。因此它们有望作为一类全新的alpha-葡萄糖苷酶抑制剂先导化合物并由此发展成一类全新的降糖药物。本项目将在我们之前对该类天然产物全合成及其构效关系大量的研究基础之上完成了一下工作：1）天然产物neoponkoranol的全合成研究，优化了关键偶合反应的，提高了整体收率；2）完成了天然产物neokotalanol的首次全合成；在工作1）中对偶合反应机理的探讨基础上发展了一种高效的构建单糖分子内3,6-环化反应的方法学，并成功将其运用到具有类似结构的天然产物的全合成当中；4）完成了neoponkoranol侧链的结构修饰工作，筛选出活性更好的类似物，同时通过分子对接和酶动力学研究，发现了新的一种小分子与蛋白酶结合的模式。本项目的研究对建立以及完善该锍糖型天然产物及其类似物的合成方法，深入研究这类活性天然产物构效关系；逐步深入探索小分子和alpha-葡萄糖苷酶相互作用的机理，同时也为进一步的药学研究打下了坚实的基础。