溴代甲氧基二苯甲酮咪唑类化合物的合成及对过氧化氢致EA. hy 926细胞损伤的保护作用
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摘要
本文旨在引入咪唑环,对溴代甲氧基二苯甲酮类化合物进行结构衍生,以发现对血管内皮细胞具有更高保护活性的化合物。通过以2-甲基-5-溴-苯甲酸为起始原料,经过酰氯化、傅克酰化、溴代、与N-溴代丁二酰亚胺(NBS)自由基取代及与取代咪唑的亲核取代等多步反应,合成了8个新型溴代甲氧基二苯甲酮咪唑类化合物。目标化合物的结构均经质谱(MS)、核磁共振波谱仪(NMR)和高分辨质谱(HRMS)进行确证。并采用噻唑蓝(MTT)法考察了目标化合物对过氧化氢损伤的EA.hy 926细胞的保护活性,结果表明,目标化合物6a、6g、6h具有显著的细胞保护活性,其半抑制浓度(EC50)分别为1.9、4.0和3.2μmol/L,优于阳性对照槲皮素(EC_(50)为18μmol/L),表明该类化合物在心血管疾病的治疗方面有潜在的应用前景。
To introduce the imidazole ring to the bromo-methoxyl benzophenone structures and find the target compounds with high protective activity on vacular endothelium cells, eight novel bromo-methoxyl benzophenone imidazole compounds were synthesized using 5-bromo-2-methylbenzoic acid as starting material via following reactions: acylating chlorination, Friedel acylation, bromination, radical substitution with N-bromosuccinimide( NBS) and nucleophilic substitution with substituted imidazoles. The structures of the target compounds were confirmed by proton and carbon nuclear magnetic resonance spectroscopy(~1H and13 C NMR) and high resolution mass spectrometry( HRMS). Additionally,the protective effects of the target compounds against H_2O_2-induced EA. hy 926 cells injury were evaluated by methylthiazolyldiphenyltetrazolium bromide( MTT) assay and their structure-activity relationships were also preliminarily discussed.The in vitro results show that target compounds 6a,6g and 6h exhibit significant cytoprotective activities and their half maximal inhibitory concentration( EC50) values are 1. 9,4. 0 and 3. 2 μmol/L,respectively,superior to the positive control Quercetin( EC_(50)≈ 18 μmol/L). These results also suggest the potential application prospect of target compounds in the treatment of cardiovascular diseases.
To introduce the imidazole ring to the bromo-methoxyl benzophenone structures and find the target compounds with high protective activity on vacular endothelium cells, eight novel bromo-methoxyl benzophenone imidazole compounds were synthesized using 5-bromo-2-methylbenzoic acid as starting material via following reactions: acylating chlorination, Friedel acylation, bromination, radical substitution with N-bromosuccinimide( NBS) and nucleophilic substitution with substituted imidazoles. The structures of the target compounds were confirmed by proton and carbon nuclear magnetic resonance spectroscopy(~1H and13 C NMR) and high resolution mass spectrometry( HRMS). Additionally,the protective effects of the target compounds against H_2O_2-induced EA. hy 926 cells injury were evaluated by methylthiazolyldiphenyltetrazolium bromide( MTT) assay and their structure-activity relationships were also preliminarily discussed.The in vitro results show that target compounds 6a,6g and 6h exhibit significant cytoprotective activities and their half maximal inhibitory concentration( EC50) values are 1. 9,4. 0 and 3. 2 μmol/L,respectively,superior to the positive control Quercetin( EC_(50)≈ 18 μmol/L). These results also suggest the potential application prospect of target compounds in the treatment of cardiovascular diseases.
引文
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[3]Zheng F L,Ban S R,Feng X E,et al.Synthesis and in Vitro Protein Tyrosine Kinase Inhibitory Activity of Furan-2-yl(Phenyl)Methanone Derivatives[J].Molecules,2011,16(6):4897-4911.
[4]Feng X E,Zhao W Y,Ban S R,et al.Structure Activity Relationship of Halophenols as a New Class of Protein Tyrosine Kinase Inhibitors[J].Int J Mol Sci,2011,12(9):6104-6115.
[5]KONG Liang,FENG Xiu'e,GAO Jie,et al.Synthesis of Novel Phenyl(Thiophen-2-yl)Methanone Derivatives and Their Cytoprotective Activities Against H2O2-Induced Injury in Human Umbilical Vein Endothelial Cells[J].Chinese J Appl Chem,2014,31(10):1185-1190(in Chinese).孔亮,冯秀娥,高洁,等.新型苯基噻吩-2-基甲酮类化合物的合成及其对人脐静脉内皮细胞的保护活性[J].应用化学,2014,31(10):1185-1190.
[6]Yang D,An B,Wei W,et al.Copper-Catalyzed Domino Synthesis of Nitrogen Heterocycle-Fused Benzoimidazole and 1,2,4-Benzothiadiazine 1,1-Dioxide Derivatives[J].ACS Comb Sci,2015,17(2):113-119.
[7]Mumtaz A,Saeed A,Fatima N,et al.Imidazole and Its Derivatives as Potential Candidates for Drug Development[J].Bangl J Pharmacol,2016,11(4):756-764.
[8]Gaba M,Mohan C.Development of Drugs Based on Imidazole and Benzimidazole Bioactive Heterocycles:Recent Advances and Future Directions[J].Med Chem Res,2016,25(2):173-210.
[9]CAI Jiali,LI Shuo,ZHOU Chenghe,et al.Advance in Research of Imidazoles as Anti-Tumoragents[J].Chinese J New Drugs,2009,18(7):598-608(in Chinese).蔡佳利,李硕,周成合,等.咪唑类抗癌药物研究进展[J].中国新药杂志,2009,18(7):598-608.