Design,Synthesis And Activity Evaluation Of Novel Indole LSD1 Inhibitors

Histone methylation is the process of transferring methyl groups to the amino terminus of histones.It is an important part of regulating transcriptional regulation.It also regulates many non-transcribed processes,such as DNA repair and recombination.Lysine methylation is regulated by various specific histone methylases,and the enzyme histone lysine specific demethylase 1(LSD1)which can demethylate H3K4 and H3K9 is discovered by first.LSD1 is highly expressed in tumor cells and plays an important role at regulating the occurrence and development of tumors.Inhibiting the expression activity of LSD 1 can inhibit the growth of cancer cells at certain extent.Indole structural unit is a kind of important drug molecules and active small molecule skeletons.Research team discovered the first irreversible LSD1 inhibitor which is non-monoamine oxidase inhibitor analogue.Among them,HM-1 and MN-5 have a strong inhibitory effect on LSD1.IC50 values are 1.230±0.159 ?M and 1.784±0.249 ?M,respective.In this thesis,compounds HM-1 and MN-5 were used as lead compounds to study the structure-activity relationship and structure optimization.1.Effect of modification on the N-1 site benzyl benzene ring of indole on activityKeeping lactone ring,indole structure and N-1 position benzyl benzene ring structure unchanged.19 new compounds(series I compounds)were designed and synthesized based on the benzene ring was substituted and modified on the lead compound MN-1 structure.The structure of the compound was confirmed and characterized by NMR and MS.The evaluation results of LSD1 inhibitory activity showed that imports different substituent groups can basically maintain its LSD1 inhibitory activity.Most of compound's IC50 values are less than 10 ?M.In comparison,electron withdrawing group modification activity is slightly better than the electron donor modification.However,related modifications did not significantly increase their activity.2.Effect of modification on N-1 site benzenesulfonylbenzene ring on activityThe activity of 5-chlorindole-1-N site compound MN-5 which was substituted by p-methylbenzene sulfonyl is similar to HM-1,and the sulfonyl group is SP2 hybrid type and more stable than benzyl group,and no active analogues containing sulfonyl and identical to the MN-5 skeleton were produced.Therefore,taking MN-5 as lead to carry out structural optimization and structure-activity relationship research can potentially improve the inhibitory activity of target compound LSD1.Eleven new compounds(series II derivatives)were synthesized by optimizing the N-1 benzene sulfonyl benzene ring.Their structures were confirmed and characterized by NMR and MS.The results of LSD1 inhibitory activity evaluation showed that compound 10b and 10c have better activity.They were slightly higher than the lead compound LSD1.IC50 value are 0.929±0.135?M and 0.933±0.136pM respective.3.Design of 3-substituted indole derivatives and study of LSD1 inhibitory activityThrough the structure-activity relationship analysis,lactone ring structure plays an important role on LSD1 inhibitory active molecules.It is the key pharmacophore for its activity.It was speculated that LSD1's possible action mode is similar to phenylcyclopropyl amines combined with coenzyme FAD covalently.Therefore,based on structure-activity relationship and above possible molecular mechanism,12 new compounds of series ? and ? were designed and synthesized.The evaluation results of LSD 1 inhibitory activity showed that related mechanisms need farther study for the activities of these two types of compounds completely disappear.4.Design and synthesis of LSD1 fluorescent probeThe design,synthesis and activity evaluation results of series of compounds ?,?,? and ? showed that it is an great significance to clarify the possible mechanism of action for the improvement of LSD1 inhibitory activity.Therefore,the research team designed and synthesized LSD1 fluorescent molecular probe for indole LSD1 inhibitors.Among them,compound 22a uses the characteristics of biotin plays a fluorescent probe.Compounds 22b to 22d themselves show yellow-green visible light.In summary,based on the structure-activity relationship and possible mechanism of action,46 new compounds were designed and synthesized based on the structure-activity relationship and possible mechanism of action,and LSD 1 inhibitory activity was evaluated.At the same time,in order to explore the possible action mechanism of action of this kind of LSD 1 inhibitors,potential LSD1 probe molecules with fluorescent luminescence properties were designed and synthesized,which laid the foundation for further research.