| Aberrant hypertension,a complex disease caused by genetic and environmental risk factors,is one of the most serious causes of death and common disease among old people,and has become the main risk of various chronic cardiovascular diseases,including but not limited to,stroke and heart failure.Histone deacetylases(HDACs)are a class of proteases,that play an important role in the structural modification of chromosomes and the regulation of gene expression.Several subtypes of HDACs are closely related to the physiological and pathological processes of hypertension and related vascular diseases,but the related mechanisms need to be further elucidated.In previous studies,our group found that compound BY-4 with biphenyl ring as Cap group,urea-substituted benzene ring as Linker and hydroxamic acid as Zn2+chelating group(ZBG)had strong inhibitory activity against HDAC6(IC50=68 nM)and certain selectivity over other HDACs subtypes(7-27-fold).BY-4 showed dose-dependent vasodilation in response to α-adrenergic receptor agonist phenylephrine(Phe)and 60 mmol/L KCl preconstriction of aorta,and the vasodilation rate reached 100%.The vasodilation effect of BY-4 was significantly stronger than SAHA,suggesting that this compound has potential prospect in regulating blood pressure and treating hypertension.In the present study,based on the structure of BY-4,we have modified the Cap pharmacophore,Linker region and Zn2+chelating group,respectively.Specifically,indole,naphthalene and biphenyl moieties were respectively installed as Cap groups,amide or urea substituted phenyl ring was anchored as Linker part,while methyl ester,carboxylic acid,formamide,hydrazide together with hydroxamic acid were introduced as ZBGs,we designed and synthesized three series of HDAC6 inhibitors of series Ⅰ,Ⅱ and Ⅲ.In the evaluation of HDAC6 inhibitory activity,most of the series Ⅰ compounds showed strong inhibition against HDAC6 at the concentration of 1μM,among which compounds XCY-A2 and XCY-A4 gave 98.8%and 96.6%inhibition rates against HDAC6,respectively,which was similar to the positive control drug SAHA(99.1%inhibition rate).Most of the compounds in series Ⅱ also showed strong inhibition against HDAC6 at 1 μM,and compounds XCY-C2 and XCY-C4 showed 98.5%and 94.3%inhibition rates against HDAC6,respectively.Among the series Ⅲ compounds,when ZBG was hydroxamic acid,the activity was the best,compounds XCY-D5,XCY-D6,XCY-D7,XCY-D8 and XCY-D11 showed 98.4%,97.8%,84.5%,99.1%and 98.1%inhibition rates against HDAC6,respectively,however,when ZBGs were methyl ester,carboxylic acid,formamide and hydrazide,the compounds losed HDAC6 inhibitory activitiesIn the in vitro vasodilation activity test,some compounds had certain vasodilation effect.When mice thoracic aorta vascular rings were exposed to 1×10-6 Vol/L α-adrenergic receptor agonist phenylephrine(Phe)to induce contraction,at a concentration of 3-300μM,in series Ⅰ,the maximum relaxation rates of compounds XCY-A3 on isolated vascular rings of thoracic aorta in C57BL/6 mice were 39.70%.The compound XCY-C1 in series Ⅱ had the best vasodilation effect,and the maximum relaxation rate was 11.20%.While in series Ⅲ,the maximum relaxation rates of compounds XCY-D7,XCY-D8 and XCY-D10 were 23.60%,21.61%and 36.83%,respectively.When mice thoracic aorta vascular rings were exposed to 60 mmol/L KCl to induce contraction,at a concentration of 3-300 μM,compounds XCY-A3,XCY-A4,XCY-C1,XCY-C2,XCY-C4,XCY-D10 and XCY-D13 could relax the vasoconstriction induced by 60 mmol/L KCl to a certain extent.Compounds XCY-A3 and XCY-A4 in series Ⅰ had a maximum relaxation rate of 13.96%and 16.01%,respectively.The maximum relaxation rate of XCY-C1,XCY-C2 and XCY-C4 in series Ⅱ was 23.49%,22.35%and 21.93%,respectively.Compound XCY-D10 and XCY-D13 in series Ⅲ had a maximum relaxation rate of 72.49%and 60.26%,respectively.This study laid a foundation for further developing novel HDAC6 inhibitors and exploring the role of HDAC6 in hypertension and related vascular diseases. |
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