Synthesis And SAR Studies Of 2’,3’-dihydrospiro--[cyclopropane-1,1’-inden]-2-amine And 1,1a,6,6a-tetrahydro--cyclopropa[a]inden-1-amine As LSD1 Inhibitors

Lysine specific demethylase 1(LSD1),the first histone lysine demethylase discovered in 2004,can specifically demethylase H3K4 me1/2 and H3K9 me 1/2.Studies have found that its overexpression is closely related to the occurrence and development of a variety of diseases,such as cancer,neurodegenerative disease,cardiovascular disease,inflammation,viral infection,etc.Therefore,LSD1 may be an important target for the treatment of related diseases.Antiphenycyclopropylamine(TCP)is a non-selective irreversible LSD1 inhibitor.The inhibition of LSD1 homologous monoamine oxidase can cause serious side effects such as orthostatic hypotension,dizziness and drowsiness.Therefore,the research focus of LSD1 inhibitors is to improve the selectivity and activity of LSD1.Making TCP as lead compound and adopting conformation restriction strategy,we get 2 ’,3 ’-dihydrospiro[cyclopropane-1,1’-indene]-2-amine and 1,1 a,6,6 a –tetrahydrocyclopropa[a]inden-1-amine.At the early stage of the project work,we have already proved the feasibility of this strategy.Through the strategy,the LSD1 inhibitory activity of derivatives have been greatly improved.In this dissertation,we regard the compounds 2 ’,3 ’-dihydrospiro [cyclopropane-1,1’-indene]-2-amine and 1,1a,6,6a– tetrahydrocyclopropa[a]inden-1-amine as lead compounds and carry out structural modification on the benzene ring and amino part,so we introduced many different functional groups in the amino part,such as the dominant group in the amino part of GSK2879552,aromatic groups,nitrogen-containing or nitrogen-free ring aliphatic ring etc.The derivatives were evaluated for their LSD1 inhibitory activity and homologous enzyme selectivity at the molecular level,we found their LSD1 inhibitory effect and selectivity were significantly enhanced.Among them,the LSD1 inhibitory activity of 15 derivatives reached the nanomolar level,and the best derivative was 3 n M.Then we selected some compounds with good activity to study the inhibitory effect of LSD1 on MV4-11 AML cells and preliminarily investigated their stability.These provided a certain basis for the study of LSD1 small molecule inhibitors.