噻唑-噁唑串联杂环类RNA剪接抑制剂的发现及构效关系研究

Discovery and Structure-Activity Relationship Studies of Thiazole-Oxazole Tandem Heterocyclic RNA Splicing Inhibitors

剪接是将内含子从前体m RNA(pre-m RNA)中移除,并将侧翼外显子连接在一起形成成熟的m RNA的过程,pre-m RNA剪接过程是高等生物中基因表达和蛋白质组学多样性的重要组成部分,但其发生选择性剪接或剪接因子发生突变,都会导致疾病的发生.利用小分子化合物对剪接过程的调控,或为相关疾病的治疗提供另一种选择.利用circmCherry表达体系进行化合物筛选,发现天然产物LeucamideA的简单衍生物对于剪接过程具有一定的抑制作用,以其为先导化合物,进行了结构改造后,新设计合成了约36个噻唑-噁唑双杂环串联结构的化合物,其中2-[(S)-1-(2-{2-[(S)-1-(4-甲氧基苯甲酰胺)-2-甲基丙基]噻唑-4-基}-5-甲基噁唑-4-甲酰胺基)乙基]噁唑-4-甲酸甲酯(9l)对于剪接过程有较强的抑制作用.

Precursor m RNAs(pre-m RNAs) undergo splicing to remove introns and ligation of their exons to yield mature mRNAs. Pre-mRNA splicing is an essential component of gene expression and proteomic diversity in higher organisms.However, the alternative splicing or mutation of splicing factors have been found in human diseases. By the use of the small molecules modulate the splicing process will provide potential treatment for related diseases. In this paper, circmcherry expression system was used to screen compounds that could affect splicing process. Several simple derivatives of natural product Leucamide A have been found to have inhibitory effects, and 36 compounds with thiazole-oxazole tadem structural core were designed and synthesized, of which methyl 2-((S)-1-(2-(2-((S)-1-(4-methoxybenzamido)-2-methylpropyl)thiazol-4-yl)-5-methyloxazole-4-carboxamido)ethyl)oxazole-4-carboxylate(9l) shows most potent inhibitory activity on splicing.