Synthesis And SAR Studies Of 1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-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.LSD1 is overexpressed in human acute myeloid leukemia(AML)cells 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 an important role in inhibiting AML.Therefore,LSD1 has become an effective target for the treatment of AML and the development of novel LSD1 inhibitors is a new approach to treat AML.Tranylcypromine(TCP)is an oral antidepressant known to target the monoamine oxidases A and B(MAO-A and MAO-B),which are structurally related to LSD1.Studies show that TCP is also an active LSD1 inhibitor,and a number of TCP derivatives have been identified as potent LSD1 inhibitors,with ORY-1001 entering clinical phase ?A trail as an orphan drug for the treatment of AML.Cyclopropane conformation of TCP maybe have an effect on LSD1 inhibitory activity and selectivity to MAOs.In this dissertation,in view of the concept of conformational restriction,we designed a series of novel 1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-amine derivatives as potential LSD1 inhibitors baesd on TCP,constraining the phenyl and cyclopropane with a fused 5-membered ring,and then tested its LSD1 and homologous enzyme activities.Conformationally-restricted 1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-amine showed higher LSD1 inhibitory activity and homologous enzyme selectivity than TCP.Futhermore,we performed a chiral seperation of the racemate to obtain enantiomerically pure forms,which were confirmed by X-ray single crystal diffraction and chiral synthesis,and then studied the differences in LSD1 inhibitiory activities of pure forms.Meanwhile,dominant groups were introduced in the amine nitrogen and benzene ring in 1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-amine,such as benzene and pyridine.Most of the compounds increased LSD1 inhibitory activity and had a strong selectivity to homologous enzymes.