Design,Synthesis And Biological Activity Studies On Thiazolo [3,2-a] Pyrimidine Derivatives As LYP Inhibitors And Anticancer Small Molecules

Thiazolopyrimidine derivatives have drawn more and more attraction as their comprehensive bioactivities.Here,we carry on our research about their LYP inhibitory activity and anticancer activity based on our previous study.Immune regulation is essential for maintaining homeostasis.Disorders will be induced if immune reaction is too weak or strong.LYP,expressing specifically in lymphoid cells,is an important regulator of TCR.Gain-of-function mutant LYP is usually found in patients suffering autoimmune diseases and as a result of that,developing LYP inhibitors is of huge consequence for the treatment of over potent immunity induced diseases,such as type I diabetes,rheumatic arthritis and systemic lupus erythematosus.In 2014,our group reported a thiazolo[3,2-a]pyrimidine based inhibitor A15 which showed good LYP inhibitory activity and selectivity in vitro and in vivo.Herein,we carry out structural modifications on A15.15 compounds were synthesized and their LYP inhibitory activities were evaluated.Four of those were more potent than lead compound A15 and structure and reactivity study shows activity is best when R1 is hydroxyl group,R2 is phenyl group and R3 is 4-COOH-Ph.Our group reported a rodanine-based anticancer compound A which show antiproliferative activity against K562,MDA-MB-231 and PC-3 to some extent.Replacing rodanine group with our thiazolo[3,2-a]pyrimidine scaffold and doing modifications on side chains,we base our design on A.16 compunds were synthesized and their anticancer activities were evaluated by MTT.Compound 12,15 were more potent against specified cell lines than lead compound.32 new compounds were synthesized in two parts of the paper among these are 31 new target compounds and 1 new intermediate.All the structures were identified by'H-NMR.HRMS and/or 13C-NMR.