α-amanitin类环肽毒素的高效全合成及其ADCs抗癌活性研究

α-amanitin为剧毒的二环八肽毒素，它的抗体-药物偶联物(ADCs)是当前抗癌研究热点。项目研究围绕ADCs抗癌药物前体α-amanitin的高效全合成。解决其化学合成中关键的非天然氨基酸的手性合成、C-S键生成并关环、硫醚选择性磺氧化为手性亚砜等问题，应用高效的MYTsA催化的手性多肽合成新方法，构建α-amanitin的环肽骨架，实现其高效全合成。在此基础上，通过设计合成不同的手性氨基酸，实现9种amatoxins家族、8种phallotoxins家族、6种virotoxins家族环肽毒素的高效全合成，并合成多个α-amanitin环肽毒素类似物。本研究预期实现23个天然α-amanitin类环肽毒素及若干设计的α-amanitin衍生物的高效全合成，为ADCs抗癌药物开发提供原料和基础，并进一步对其ADCs药物前体的合成、制备及抗癌活性进行系统研究。

α-amanitin is a highly toxic bicyclic octapeptide toxin. Its antibody-drug conjugates (ADCs) are the current hotspots in anti-cancer research. The project investigates the highly efficient total synthesis of ADCs anti-cancer drug precursor α-amanitin. To solve the key problems in its chemical synthesis: chiral synthesis of its unnatural amino acids , C-S bond formation with ring closure, and selective oxidation of thioether to chiral sulfoxide, etc., and the application of efficient MYTsA catalyzed chiral peptide synthesis methods to construct α-amanitin cyclic peptide backbone, realizing its highly efficient total synthesis. On this basis, by designing and synthesizing different chiral amino acids, the efficient total syntheses of 9 amatoxins, 8 phallotoxins, and 6 virotoxins will be achieved, and multiple α-amanitin analogs will be synthesized. This study is expected to achieve the efficient total syntheses of 23 natural α-amanitin cyclic peptide toxins and a number of designed α-amanitin derivatives, providing raw materials and foundation for the development of ADCs anticancer drugs, the further synthesis and preparation of ADCs prodrugs, their anticancer activities are systematically studied.