Design,Synthesis And Activity Testing Of New SSIRT2 Inhibitors

Histone modification is one of the important modification methods of protein post-translational modification,including acetylation,methylation,phosphorylation and so on.Histone acetylation modification is jointly regulated by histone acetylase（HAT）and histone deacetylase（HDAC）,which is crucial to maintain normal physiological functions.Surtuin（SIRT）protein contains seven subtypes,namely SIRT1-SIRT7,which is an atypical deacetylase.The catalytic mechanism of substrate diacylation relied on NAD⁺,which is different from that of typical HDAC.Among them,SIRT2 is an important subtype that exists in the cytoplasm and can shuttle in the nucleus during mitosis.A large number of studies have shown that the abnormality of SIRT2 is closely related to the occurrence and development of cancer,and it can be considered as a potential therapeutic target for related diseases,and SIRT2 inhibitors are expected to be used in the treatment of corresponding diseases.Nowadays,a large number of SIRT2 small molecule inhibitors have been reported one after another,but so far no inhibitor has entered clinical research.In the previous research of our group,through rational design and synthesis,a SIRT2inhibitor with good activity and selectivity was obtained,N-(4-（（3-（2-（（4,6-dimethylpyrimidine-2-（Phenyl）thio）acetamido）benzyl）oxy）phenyl）-1-methyl-1-H-pyrazole-4-carboxamide（24a）,its IC₅₀is 0.815μM,Basis on the previous research,this thesis focus on the structure-activity relationship of 2-（（4,6-dimethylpyrimidin-2-yl）thio）-N-phenylacetamide,which provides new ideas for the development of SIRT2 inhibitors.First,we designed and synthesized 6 new molecules by modiying the two benzene rings A and B of compound 24a.After the activity test,it was found that the synthetic target compound had a significant reduction in the inhibitory activity of SIRT2,which suggested that the substitution of two benzene rings was unfavorable for the SIRT2 inhibitory activity.Next,in view of the foregoing structure-activity relationship,it was observed that the substitution of the 3-position of the benzene ring liked with 2-（（4,6-dimethylpyrimidin-2-yl）thio）acetamide had a higher affinity.Therefore,we cyclized the 3-position with the 2-position of the benzene ring,and designed and synthesized 17 new compounds which1-/2-position and4-position is disubstituted indazoles.After the activity test,it was found that some compounds can inhibit SIRT2 at high concentrations,but the activity is not high and the indazole1-position substitution activity is better than the 2-position substitution activity.Among them,the compound N-（1-benzyl-1H-indazol-4-yl）-2-（naphthalene-1-yloxy）acetamide（14a）has the best activity,and the inhibition rate was 70%at 100μmol·L^-1,through the molecular docking of 14a and SIRT2 that the allosteric sites of 14a and SIRT2 are perfectly matched,forming hydrophobic interactions with Leu206,Pro140,Try139,Leu138,Leu134,Phe131,Leu103,Phe119,Phe234,Phe96 and other residues.In view of this,we finally retain the amide bond bridge of the most active N-（1H-indazol-4-yl）propionamide compound,the substituted fragment is naphthol,and then the indazole 2-After replacing the N atom at the position with a C atom,10 new N-（1H-indol-4-yl）-2-（naphthalene-1-oxyl）acetamides derivatives were designed and synthesized.Finally,these compounds still inhibit SIRT2 at high concentrations,but the activity is not high.Among them,the compound N-（1-（3,5-dibromobenzyl）-1H-indol-4-yl）-2-（naphthalene-1-yloxy）acetamide（38m）has an inhibition rate of 56%at 100μmol·L^-1.In conclusion,this thesis clarifies the structure-activity relationship of 2-（（4,6-dimethylpyrimidin-2-yl）thio）-N-phenylacetamide as SIRT2 inhibitors,synthesises of 1-/2-position and 4-position disubstituted indazoles and N-（1H-indol-4-yl）-2-（naphthalene-1-yloxy）acetamide-based small molecule inhibitors of SIRT2.Although preliminary studies have still not found compounds with higher activity,the further derivatives of these two types skeletons still in progress.The research in this paper laid the foundation for the later research of the project and provided more new SIRT2 frameworks for the development of SIRT2 inhibitors.