Discovery And Structure-Activity Relationship Studies Of Thiazole-Oxazole Tadem Heterocyclic RNA Splicing Inhibitors

Splicing is the process by which eukaryotic pre-m RNA form mature RNA though removing introns and connecting exons,the process can be divided into linear splicing and back-splicing.Generally,the linear splicing process involves connecting the upstream 5’splice site(splice donor)to the downstream 3’splice site(splice acceptor)across introns to form linear RNA.Pre-m RNA splicing process is an important part of gene expression and proteomic diversity in higher organisms,Once splicing is mutated,disease can follow.Meanwhile,the pre-m RNA will also undergo back-splicing,generating covalently closed circular RNA by connecting the downstream 5’splice site and the upstream 3’splice site.Despite expressed in low levels,increasing evidence reveals that circ RNAs have important function under physiological and pathological conditions,such as influencing immune responses,promoting cancer development,and triggering neuropsychiatric diseases.If back-splicing can be regulated by compounds,or it can provide therapeutic approach for diseases caused by the disorder of circ RNA expression.However,for the regulation of the splicing process,most of small molecules target the canonical splicing to alleviate the development of cancer,no compounds have been reported to act on the back-splicing.In this work,compounds that can affect the splicing process were screened by circmcherry expression system.It was found that the simple derivatives of natural product Leucamide A had certain inhibitory effect on splicing.On the basis of this structure,the inhibitory activity after changing different R~1groups,removing isopropyl side chains,ester hydrolysis and oxazole ring replacement were investigated respectively.A series of compounds with thiazole-oxazole tadem heterocyclic were designed and synthesized,in which 20m had strong inhibitory effect on splicing.In addition,the structure-activity relationship of the thiazole-oxazole tadem heterocyclic splicing inhibitors was also preliminarily summarized according to the activity results.At the same time,we also actively explore other skeletons in splicing.The newly designed and synthesized C-type and heterocyclic tandem compounds have certain inhibitory effects on splicing.This work can provide a reference for the subsequent development of new splicing inhibitors.