Design,synthesis And Preliminary Activity Study Of Indoleamine-2,3-dioxygenase 1 Inhibitors

Indoleamine 2,3-dioxygenase 1(IDO1)is a monomer proteinase containing heme.Its main biological function is to catalyze the oxidative cleavage of L-tryptophan(L-Trp)indole ring,which is the first step of L-Trp metabolism along the kynurenine pathway(KP).This pathway plays an important role in tumor immunosuppression.As the first speed limiting enzyme in KP,IDO1 plays an immunosuppressive role mainly through two mechanisms:one is to promote L-Trp consumption,block T cell proliferation,and promote T cell differentiation into regulatory T cells;The other is that due to the accumulation of active metabolites,KYN metabolites can bind to aromatic hydrocarbon receptors(AhR)to activate signaling pathways,enhance immune tolerance,and cause the apoptosis of T cells.In addition,IDO1 can also be involved in immune regulation through non-enzymatic action,which is also an important way for IDO1 to mediate tumor immunosuppression.Therefore,with the advent of tumor immunotherapy,the research and development of IDO1 inhibitors for the treatment of tumors has become more and more popular.Through the efforts of scientific researchers in recent decades,a large number of IDO1 inhibitors have been synthesized.Currently,the major inhibitors at the clinical stage include Indoximod,GDC-0919,INCB024360,BMS-986205 and PF-06840003.In this thesis,INCB024360 was used as the lead compound.Through a careful study on the crystal structure of INCB024360 and IDO1 complex,two series of total ten compounds of IDO1 inhibitors were designed and synthesized using scaffold hopping and bioisosterism based structural modification.All the compounds were characterized using ~1H NMR and MS to confirm their structures.The activity of the inhibitors against IDO1 was measured at the enzyme level and the cell level respectively.The cytotoxic activity of inhibitor compounds against HeLa,MDA-MB-231 and B16F10 cancer cells was determined by MTT assay.The results show that these compounds have a certain degree tumor killing capacity,especially M3 and M9 have strong cytotoxic activity against HeLa,MDA-MB-231 and B16F10cancer cells.In addition,the enzyme activity of compounds M8,M9 and M10 all in the nanomolar level.Among them M8 and M9 have stronger enzyme activities than the positive control GDC0919,which was worthy of further study.These results provide a reference for the further design and synthesis of highly active small molecule based IDO1 inhibitors.