School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith South DC, NSW 2751, Australia.
Org Biomol Chem. 2020 Jan 22;18(3):379-390. doi: 10.1039/c9ob02038a.
The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of staphylococcus virulence and has been the focus of tremendous interest in the development of effective therapies for pathogenic bacterial infections. With regards to chemotherapeutic based strategies, the significant proportion of currently reported agr-system modulating molecules are mimics of the native ArgC substrate, which is a thioester-based macrocyclic peptide know as the auto-inducing peptide. Over the past two decades, more than two-hundred synthetic analogues have been reported. This review traces the development of the synthetic strategies employed to synthesise these analogues with a particular focus on macrocyclisation. At present these synthetic approaches can be clustered into five broad categories (1) solution-phase cyclisation, (2) immobilised carbodiimide assisted cyclisation, (3) concomitant on-resin cleavage and macrocyclisation, (4) Boc-compatible chemoselective thioesterification, and (5) Fmoc-compatible chemoselective thioesterification. The advantages and limitation provided by each of the approaches are compared and contrasted with a view towards potential reaction scale-up.
附属基因调控器 (agr) 群体感应系统可以说是调节金黄色葡萄球菌毒力的最重要的调控器，它一直是开发针对致病性细菌感染的有效治疗方法的研究重点。关于化学治疗策略，目前报道的大量 agr 系统调节分子是天然 ArgC 底物的类似物，ArgC 底物是一种基于硫酯的大环肽，称为自诱导肽。在过去的二十年中，已经报道了超过 200 种合成类似物。这篇综述追溯了用于合成这些类似物的合成策略的发展，特别关注大环化。目前，这些合成方法可以分为五类：(1) 溶液相环化，(2) 固定化碳二亚胺辅助环化，(3) 同时进行树脂上切割和大环化，(4) Boc 相容的选择性硫酯化，和 (5) Fmoc 相容的选择性硫酯化。比较了每种方法的优缺点和局限性，并着眼于潜在的反应放大。
