Studies to understand and exploit 10-membered enediyne biosynthesis

摘要 10元烯二炔类化合物[以卡利卡米星(CLM)、埃斯帕米星(ESP)和动力霉素(Dyn)为例] 可以说是迄今为止发现的最著名的天然产品(NPs)之一 前所未有的复杂分子结构，显著的抗癌和抗感染能力，在这种情况下 证明了CLM的临床实用性。目前的研究建立在长期的合作努力的基础上 与10元烯二炔生物合成关键方面相关的成就和发现以及平行 将关键的生物合成催化剂用于合成应用的创新努力。提出的研究将需要 这一雄厚的基础和遗传、生化、化学和蛋白质的强大组合的优势 结构工具，用于阐明剩余的不寻常的生物合成转化并开发精选的催化剂 烯二炔非天然修饰。具体地说，目标1和目标2将侧重于扩展我们对 CLM/DYN/ESP、DYN和DYN生物合成共同的二炔核心生物合成的基本步骤 和一组独特的剪裁反应(CLM/ESP硫糖硫磺安装和氨基戊糖N- 烷基化、ESP C6-羟基化和O-糖基化)。与此同时，目标3将专注于战术结构研究。 对目标1和目标2以及“未知数”的结构研究进行补充，以便于功能注释。其他内容 目标2中的关键催化剂和相应的非天然底物的研究旨在评估这种潜力 用于战略性地安装化学选择性手柄，以实现简便、温和的生物结合的新方法 CLM到肿瘤靶向单抗(与辉瑞公司合作)。

ABSTRACT The 10-membered enediynes [exemplified by calicheamicin (CLM), esperamicin (ESP) and dynemicins (DYN)] are arguably among the most renowned natural products (NPs) discovered to date by virtue of their unprecedented complex molecular architectures, notable anticancer and anti-infective potencies and, in the case of CLM, demonstrated clinical utility. The current study builds on a longstanding collaborative effort of achievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallel innovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will take advantage of this strong foundation and a powerful combination of genetic, biochemical, chemical and protein structural tools to elucidate the remaining unusual biosynthetic transformations and to exploit select catalysts for enediyne non-native modification. Specifically, aims 1 and 2 will focus on extending our understanding of the fundamental steps of enediyne core biosynthesis common to CLM/DYN/ESP, DYN anthraquinone biosynthesis and a selected set of unique tailoring reactions (CLM/ESP thiosugar sulfur installation and aminopentose N- alkylation, ESP C6-hydroxylation and O-glycosylation). In parallel, aim 3 will focus on tactical structural studies to augment both aims 1 and 2 and the structural study of ‘unknowns’ to facilitate functional annotation. Additional studies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess the potential for strategic installation of chemoselective handles to enable novel approaches for facile, mild bioconjugation of CLM to tumor-targeting mAbs (in collaboration with Pfizer).