硫代多肽类天然产物Thioviridamide的合成研究

Thioviridamide是一类硫代酰胺键修饰的多肽类天然产物的典型代表之一。Thioviridamide家族化合物具有广谱与高效的抗癌活性，有望成为新型抗癌药物的先导。该类天然产物含有多个硫代酰胺键和AviCys（Aminovinyl-Cysteine）两种特殊的结构片段，其化学合成极具挑战性。化学家对Thioviridamide的全合成研究的多次尝试都失败了，目前其只能从自然界提取和分离获得，大大限制了对其生物合成机制及其抗癌作用机制的深入研究。申请人所在课题组发展了含有多个硫代酰胺键修饰的多肽片段及AviCys结构的合成方法，本课题拟通过课题组开发的合成方法学，实现Thioviridamide的化学全合成。并在此基础上进一步构建Thioviridamide家族化合物及其衍生物化合物库，为深入系统的研究该类化合物构效关系奠定基础，以期发现更加高效、低毒的抗癌药物。

Thioviridamide is one of the typical representatives of a family of thioamidated peptide natural products that are currently of great interest as the basis for their broad and significant anticancer activity. The chemical synthesis of Thioviridamide-like compounds is extremely challenging due to their continuous multi thioamide bonds and a unique AviCys subunit. These compounds are currently produced using biosynthesis technologies, as extensive efforts to the total chemical synthesis of Thioviridamide have failed. Low production yield in fermentation remains a major hindrance to the research of its biosynthesis and anticancer mechanism. Herein, a total synthesis for Thioviridamide is proposed based on the synthetic methodologies developed by applicant's research group for thioamide substituted peptide synthesis and AviCys fragment construction. In addition, this synthetic strategy will be applied to the synthesis and construction of a library of Thioviridamide derivatives to study the structure-activity relationship, with a view to discovering more effective and low-toxic anticancer drugs.