新型小分子Bcl-2蛋白抑制剂的设计、合成及体外活性研究
Design,synthesis and in vitro activity study of a novel Bcl-2 protein inhibitors
作者：李河川;万剑飞;何谷;范举正;
Author：
收稿日期： 年卷（期）页码：2016,31(04):-332-338
期刊名称：华西药学杂志
Journal Name：WEST CHINA JOURNAL OF PHARMACEUTICAL SCIENCES
关键字：新型小分子抑制剂;Bcl-2;抗肿瘤活性;人肝癌细胞HepG-2;活性小分子;蛋白抑制剂
Key words：
基金项目：
中文摘要
目的设计并合成新型小分子Bcl-2蛋白抑制剂。方法基于已报道的活性小分子,运用Autodock4.2研究其与Bcl-2蛋白的作用模式,并以此设计、合成一系列新型小分子抑制剂,采用MTT法对人肝癌细胞Hep G-2进行体外抗肿瘤活性实验。结果设计合成了11个全新小分子化合物,其结构经~1HNMR和~(13)CNMR确定。结论化合物Ⅱ、Ⅴ、Ⅹ、Ⅺ有明显的体外抗肿瘤活性,化合物Ⅵ显示出比较好的体外抗肿瘤活性,高于阳性对照。
参考文献
[1]Jignesh M,Doshi,Tian DF,et al.Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate(HA-14-1),an antagonist for anti-apoptotic Bcl-2 proteins to overcome drug resistance in cancer[J].J Med Chem,2006,49(26):7731-7739.
[2]MJ Roy,A Vom,PE Czabotar,et al.Cell death and the mitochondria:therapeutic targeting of the BCL-2 family-driven pathway[J].Brit J Pharmacol,2014,171:1973-1987.
[3]张鸣鸣,尤启冬.基于蛋白结构的Bcl-2抑制剂设计与开发[J].药学进展,2010,34(7):289.
[4]Nguyen M,Marcellus RC,Roulston A,et al.Small molecule obatoclax(GX15070)antagonizes MCL-1 and overcomes MCL-1mediated resistance to apoptosis[J].Proc Natl Acad Sci,USA,2007,104(49):19512-19517.
[5]Tang GZ,Ding K.Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the antiapoptotic Bcl-2 proteins[J].J Med Chem,2007,50(14):3163-3166.
[6]Chan SL,Lee MC,Tan KO,et al.Identification of chelerythrine as an inhibitor of Bcl-x L function[J].J Biol Chem,2003,278(23):20453-20456.
[7]Zheng CH,Zhou YJ,Zhu J,et al.Construction of a threedimensional pharmacophore for Bcl-2 inhibitors by flexible docking and the multiple copy simultaneous search method[J].Bioorg Med Chem,2007,15:6407-6417.
[8]Wang JL,Liu DX,Zhang ZJ,et al.Structure-based discovery of an organic compound that binds Bcl-2proteinand induces apoptosis of tumor cells[J].Proc Natl Acad Sci,2000,97:7124-7129.
[9]Enyedy IJ,Ling Y,Nacro,K,et al.Discovery of small molecule inhibitors of Bcl-2 through structure-based computer screening[J].J Med Chem,2001,44(25):4313-43241.
[10]袁霞,王良芥,罗和安.妊娠双烯醇酮醋酸酯的合成[J].精细化工,2003,20(5):307-309.
[11]Manmeet Kumar.Aza-annulation on the 16-dehydropregnenolone,via tandem intermolecular Aldol process and intramolecular Michael addition[J].Bioorg Med Chem Lett,2011,21:2232-2237.
[12]Sujeong K,Eunsook M.Synthesis of pregnane derivatives,their cytotoxicity on LNCap and PC-3 cells,and screening on 5α-reductase inhibitory activity[J].Molecules,2009,14,4655-4668.
[13]David G.Steroidal aminesⅢ16α-amino-substituted pregnanes[J].J Am Chem Soc,1956,78(13):3158-3163.
【关闭】
