PROTACs Precursor Compounds Synthesis Research

The use of protein degradation chimeric molecules(PROTACs)for targeted protein degradation has become an important means of new drug discovery and treatment.Proton protein mediates the degradation and regulation of the selected protein of interest(POls)by hijacking the activity of E3 ubiquitin ligase,so that PO1 is ubiquitinated and degraded by the proteasome.The ubiquitin-proteasome system degrades proteins into Three steps: First,it is used to add a ubiquitin tag to the target protein through a ligase,and then after multiple ubiquitination,there are multiple ubiquitin tags,and the protein after polyubiquitination will become a A specific protease recognizes and is degraded.This hijacking mechanism has been used to degrade various types of disease-related POI.Although there are more than 600 types of 12 ubiquitin ligases found in the human body so far,only a few of the design of PROTACs have been used for targeted protein degradation.According to statistics,there are SCF,MDM2,CIAP1,CRBN,VHL and APC/CCDH1 for E3 ligases that already have small molecule ligands,so exploring more available E3 ubiquitin ligases is the key work in the future.This article focuses on the synthesis of E3 ligase for VHL,CRBN small molecule ligands.A total of 7 compounds were synthesized in this paper,of which(2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide is an E3 ligase of VHL small molecule ligand,which is mainly used for the condensation reaction of ammonium acid and the protection group,Deprotection group and the application of palladium-catalyzed CH bond activation reaction,while the remaining 6 are CRBN small molecule ligand E3 ligase,divided into 2 sub-categories,4 are Pomalidomide derivatives,another 2 This is a lenalidomide derivative.The different groups attached to the derivative can facilitate the development of more links.The different link conditions have a great impact on the final PROTACs drugs.3-(1-carbonyl-5-piperazine-2-isoindolinyl)piperidine-2,6-dione is an important pharmaceutical intermediate,but there are few reports in the existing literature.In this paper,combined with existing literature reports,four synthetic schemes are designed and tested one by one,and finally the fourth synthetic scheme is the simplest and most reasonable,with low cost,high yield,suitable for process amplification,green chemistry and other advantages.The final structures of the seven target compounds are all detected and confirmed by 1H-NMR and LC-MS,and the subsequivuent synthesis of the PROTACs molecule and the biological experiments and pharmacological studies will not be involved in this article.