小分子辅助环肽合成研究进展

Progress in the Synthesis of Small Molecule-Assisted Cyclic Peptides

多肽因结构丰富多变且具有广泛的生物活性、合成容易、靶向性强、亲和力高、代谢产物毒副作用小等优点被广泛关注,然而膜透过性差、生物利用度低、半衰期短等缺点极大的限制着多肽类药物的开发。多肽环化是解决这类问题的有效途径,环化的类型主要有多肽自身氨基酸之间成环和小分子辅助成环等,多肽自身成环由于反应活性低、选择性差、产率低、产物稳定性差等缺点,近年来开发了小分子辅助成环策略。小分子辅助成环主要采用一些专属的化学反应如点击化学、亲核取代、碳碳键连接等反应,有效提高了环肽的合成产率和产物稳定性。鉴于该技术在多肽类药物开发中的重要潜力,极大吸引了有机化学和药物研发人员的关注,从而有效推动了该领域新技术的开发。为了系统阐述小分子辅助环肽合成方法的最新进展,本文将对各方法近十年的发展进行梳理与总结。

Peptides have attracted increasing attention as their structural diversity, extensive biological activity, easy synthesis route, good targeting, high affinity as well as low toxic of metabolites. However, the poor membrane permeability, low bioavailability and short half-life greatly impeded the development of peptide drugs. Peptide cyclization is an effective solution of these problems. The main synthesis strategy including cyclization between amino acid in the peptide sequence and small molecule assisted ring lbrmation. As the poor reactivity, selectivity, yield and stability of natural peptides cyclizing strategy, new small molecule assisted synthesis methods have been developed in recent years. Small molecular assisted rings formation use some specific chemical reactions such as clicking chemistry, nucleophilic substitution and carbon-carbon bond lbrmation, which greatly improve the yield and stability of product. The potential of this technology used in peptide drugs development have attracted many scientists fi＇om both organic chemistry and pharmacy, which effectively promoted the development of new technologies in this field.In order to systematically describe the latest synthesis methods of small molecule assisted cyclic peptides, this article will review and summarize the development of each method in the last decade.