新型二苯甲酮哌嗪类化合物的合成及对H_2O_2损伤的EA.hy 926细胞的保护作用
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摘要
目的合成系列新型氟代/溴代甲氧基二苯甲酮哌嗪类化合物,测定其对H_2O_2损伤的EA.hy 926细胞的保护作用,并初步探讨其构效关系。方法以2-甲基-5-氟苯甲酰氯或2-甲基-5-溴苯甲酸为起始原料,经过傅克酰化、自由基取代以及亲核取代等关键反应合成目标化合物。采用MTT法考察了目标化合物对H_2O_2损伤的EA.hy 926细胞的保护活性。结果与结论合成了12个未见文献报道的新化合物;目标化合物的结构经MS、~1H-NMR谱确证。体外活性筛选结果表明,溴原子取代的目标化合物11a、11b、11d~11f均具有较高的细胞保护活性,且优于阳性对照药槲皮素,其EC50值为4.0~7.4μmol·L~(-1)。
Twelve newhalogenated(bromo-and fuloro-) methoxyl benzophenone piperazine compounds were prepared via following key reactions: Friedel-Crafts acylation,radical-substitution and nucleophilic substitution starting from 5-fluoro-2-methyl benzoylchloride or 5-bromo-2-methylbenzoic acid. The structures of the target compounds were confirmed by MS,~1H-NMR and other analytical methods. Additionally,the protective effects of the target compounds against H_2O_2 induced injury in EA. hy 926 cells were evaluated by MTT assay. Preliminary in vitro results showed that bromo-substituted target compounds 11 a,11b,11d-11 f exhibited protective potency at micromolar level,and were superior to the positive control quercetin,and their EC_(50) values was between 4. 0 μmol·L~(-1) and 7. 4 μmol·L~(-1).
Twelve newhalogenated(bromo-and fuloro-) methoxyl benzophenone piperazine compounds were prepared via following key reactions: Friedel-Crafts acylation,radical-substitution and nucleophilic substitution starting from 5-fluoro-2-methyl benzoylchloride or 5-bromo-2-methylbenzoic acid. The structures of the target compounds were confirmed by MS,~1H-NMR and other analytical methods. Additionally,the protective effects of the target compounds against H_2O_2 induced injury in EA. hy 926 cells were evaluated by MTT assay. Preliminary in vitro results showed that bromo-substituted target compounds 11 a,11b,11d-11 f exhibited protective potency at micromolar level,and were superior to the positive control quercetin,and their EC_(50) values was between 4. 0 μmol·L~(-1) and 7. 4 μmol·L~(-1).
引文
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[2]BALAYDIN H T,SOYUT H,EKINCI D,et al.Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols including natural products[J].J Enzym Inhib M ed Ch,2012,27(1):43-50.
[3]XU X,SONG F,WANG S,et al.Dibenzyl bromophenols w ith diverse dimerization patterns from the brow n alga Leathesia nana[J].J Nat Prod,2004,67(10):1661-1666.
[4]WANG W,OKADA Y,SHI H,et al.Structures and aldose reductase inhibitory effects of bromophenols from the red alga Symphyocladia latiuscula[J].J Nat Prod,2005,68(4):620-622.
[5]SHI D,LI J,GUO S,et al.The antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo[J].Chin J Oceanol Limnol,2009,27(2):277-282.
[6]WANG B G,ZHANG W W,DUAN X J,et al.In vitro antioxidative activities of extract and semi-purified fractions of the marine red alga,Rhodomela confervoides(Rhodomelaceae)[J].Food Chem,2009,113(4):1101-1105.
[7]张圆琳,冯秀娥,高洁,等.新型卤代甲氧基二苯甲酮类化合物的合成及其对H2O2致人脐静脉内皮损伤的保护研究[J].化学通报,2014(5):452-456.
[8]郑飞浪,班树荣,冯秀娥,等.苯基呋喃-2-甲酮类化合物的合成及其抑制血管平滑肌细胞(VSMC)增殖活性[J].中国药物化学杂志,2011,21(4):256-261.
[9]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].M olecules,2011,16(6):4897-4911.
[10]FENG X E,ZHAO W Y,BAN S R,et al.Structureactivity relationship of halophenols as a new class of protein tyrosine kinase inhibitors[J].Int J M ol Sci,2011,12(9):6104-6115.
[11]ZHAO W Y,FENG X E,BAN S R,et al.Synthesis and biological activity of halophenols as potent antioxidant and cytoprotective agents[J].Bioorg M ed Chem Lett,2010,20(14):4132-4134.
[12]TAYLOR R D,MACCOSS M,LAWSON A D G.Rings in drugs:M iniperspective[J].J M ed Chem,2014,57(14):5845-5859.
[13]YE Z,GETTYS K E,DAI M.Opportunities and challenges for direct C—H functionalization of piperazines[J].Beilstein J Org Chem,2016,12(1):702-715.
[14]刘菊娜,班树荣,赵承孝,等.脱氧安息香与二氢异黄酮类化合物的合成及其对血管内皮细胞(VEC)损伤保护作用的初步活性研究[J].中国药物化学杂志,2012,12(4):276-281.
[15]高蒙蒙,孙桂波,斯建勇,等.红车轴草总黄酮对H2O2诱导的血管内皮细胞损伤的保护作用[J].中国药理学通报,2013,29(2):201-207.