Synthesis And SAR Studies Of 2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-amine As LSD1 Inhibitors

Lysine-specific demethylase 1(LSD1)is a flavin-dependent demethylase and can specifically remove methyl from mono-and dimethylated Lys4 and Lys9 of histone H3,which regulates gene transcription.LSD1 is overexpressed in human acute myeloid leukemia(AML)and highly relates to AML.The application of small molecule LSD1 inhibitors can inhibit the proliferation potential of leukemia stem cells and promote terminal bone marrow differentiation,thus playing a important role in inhibiting AML.Therefore,LSD1 has become a new target for the treatment of leukemia and the development of new LSD1 inhibitors is a new way to treat leukemia.In this dissertation,in view of the concept of conformational restriction,we designed a series of novel 2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-amine derivatives as potential LSD1 inhibitors baesd on tPCPA,constraining the phenyl with a fused 5-membered ring.Compared to tPCPA,trans-configuration and cis-configuration of 2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-amine obtained by conformational restriction significantly increased the inhibitory activity against LSD 1 and had a strong selectivity to MAO enzymes,which verified the strategy of conformational restriction was feasible.Then dominant groups were introduced in the amine nitrogen and benzene ring2',3'=dihydrospiro[cyclopropane-1,1'-inden]-2-amine.Most of the compounds exhibited a nanomolar inhibitory activity against LSD1 and high selectivity to MAO enzymes.In particular,in terms of the inhibitory activity for LSD1 and selectivity to MAO-A,the trans-configuration of compounds 2-13a-2-16a were superior to cis-configuration of compounds 2-14b-2-16b.It suggested that the relative configuration had an effect on the inhibitory activity of LSD1 and the selectivity to MAO-A.In this dissertation,We designed and synthesized potent and selective LSD1 inhibitors,which would lay a foundation for the drug discovery for the treatment of leukemia.Furthermore,we got a double targets LSD1/MAO-A inhibitor 2-15b for the first time,which may be used as a tool compound for the study.