Design,Synthesis And Biological Evaluation Of Tying Up Tranylcypromine LSD1 Inhibitors And Indole Carboxamide CB2 Receptor Agonists

This dissertation is divided into two parts:Part One:Design,synthesis and biological evaluation of tying up tranylcypromine LSD 1 inhibitorsLysine specific histone demethylase 1(LSD 1)plays an important role in mediating the expression of genes involved in cancer diseases,especially in acute myelogenous leukemia(AML).Overexpression in the process promotes the development and progression of leukemia.LSD1 inhibitors can inhibit the proliferation of leukemia stem cells,thereby treating human acute myeloid leukemia.Tranylcypromine is a nonselective inhibitor of LSD1,and its configuration and conformation have a great influence on the activity.This dissertation describe the design,synthesis,and biological evaluation of a novel series of tranylcypromine-based LSD1 inhibitors via conformational restriction:1.Using the conformational restriction strategy,28 new tranylcypromine-based derivatives were designed and synthesized.The structures of all compounds were characterized by 1H NMR,13C NMR and HR-MS.2.The inhibitory activity of all compounds on LSD1 was investigated.The preferred compounds were tested for LSD1 homologous histone lysine-specific demethylase 2(LSD2),monoamine oxidase A(MAOA)and monoamine oxidase B(MAOB).The preliminary structure-activity relationships were analysied:(1)All compounds showed good LSD1 inhibitory activity(0.0022-3.4 ?M),and half of the compounds had activity less than 0.10 ?M.Preferred compounds possessing excellent selectivity(60-45000-fold)against LSD2,MAOA and MAOB,and can avoid the central nervous effects that may be caused by inhibition of monoamine oxidase.(2)All 1,1a,6,6a-tetrahydrocyclopropa[a]inden-l-amine-based compounds of the cis configuration have significantly better inhibitory activity against LSD1 than their trans configuration,while 2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-amine-based compounds are different,and its cis configuration and trans configuration have no significant difference in LSD1 inhibitory activity.(3)It was found that the racemic compounds 2-9a,2-9b,2-10a and 2-10b were synthesized in their optically pure monomers,and there was almost no difference in activity between the enantiomers of the cis configuration.However,the enantiomeric differences in the trans configuration showed significant differences in activity,suggesting that differences in conformation have an effect on the inhibitory activity of LSD1.3.A 10-day incubation of MV4-11 cells with compounds 2-9b and 2-10b resulted in the upregulation of CD86 expression,accompanied with the apparent cytotoxicity,and compound 2-9b was significantly inhibited in tumor growth at a dose of 1 mg/kg in the AML animal model.These results have accumulated a research basis for the development of LSD1 small molecule inhibitors in the treatment of human acute myeloid leukemia.Part Two:Design,synthesis and biological evaluation of indole carboxamide CB2 receptor agonistsCannabinoid receptors are mainly classified into two types,CB1R and CB2R.CB1R is mainly distributed in the central nervous system and can cause clinical side effects,CB2R is mainly distributed in peripheral tissues to avoid central nervous system side effects.Based on the previous study,this dissertation modified the indole carboxamide structure by two strategies:introducing N atoms into the indole ring and introducing small polar groups to the benzene ring:1.56 indolecarboxamide-based and azaindolecarboxamide-based derivatives were designed and synthesized.The structures of all compounds were characterized by 1H NMR,13C NMR and HRMS.2.The activity of all compounds on CB1R and CB2R was tested.The preliminary structure-activity relationship showed that the compound was changed from nonselective CB1R and CB2R agonists to selective CB2R antagonist when the introduction of small molecule polar groups at the C-7 position.The benzimidazole structure has good CB2R selectivity and agonistic activity;the indazole structure also has good agonistic activity to CB2R,but lacks of selectivity.3.Aqueous solubility analysis of selective CB2R agonists 5-23 and 5-31,compared with the preferred compound 5-1 of the previous study of this group,the water solubility increased from 23.71 ?M/L to a maximum of 69.43 ?M/L at pH 7.4.The water solubility was raised from 16.77 ?M/L to a maximum of 96.00 ?M/L under pHl.4 conditions.These results provide a basis for the development of CB2R agonists with good aqueous solubility,and further in-depth studies are underway.