氧化苦参碱及苦参碱Au(Ⅲ)金属配合物对肿瘤细胞增殖的影响及分子机制初探
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摘要
目的合成氧化苦参碱Au(Ⅲ)金属配合物(OMT-Au)和苦参碱Au(Ⅲ)金属配合物(MT-Au),并比较2种配合物体外抑制肿瘤细胞增殖的效果,初步探讨其分子机制及构效关系。方法溶剂热法合成配合物,X射线单晶衍射表征结构,不同剂量配合物分别处理10种肿瘤细胞株,MTT法观察细胞增殖抑制,流式细胞术检测配合物对细胞凋亡和细胞周期的影响,琼脂凝胶电泳探究配合物对拓扑异构酶Ⅰ(TOPO Ⅰ)活性的影响。结果 OMT-Au明显抑制人胃癌MGC803细胞增殖,阻滞MGC803细胞于G2/M期,抑制TOPOI介导的p UC19DNA质粒的解旋反应,呈剂量依赖关系,且抑制作用均强于MT-Au配合物。结论 OMT-Au抗肿瘤活性强于MT-Au,原因可能与配体的分子构象差异有关。
Objective To synthesize metal complexes of Au(Ⅲ) with matrine(MT-Au) and oxymatrine(OMT-Au), compare their inhibitory effect on the proliferation of tumor cells in vitro, and discuss the mechanism and structure-activity relationship. Methods The metal complexes were synthesized by solvothermal method and characterized by X-ray single crystal diffraction. The in vitro cytotoxicity of complexes with different doses towards 10 selected tumor cell lines was evaluated by MTT method. The effects of complex on cell apoptosis and cell cycle were investigated by flow cytometer. Agarose gel electrophoresis was used to study the effects of complex on topoisomerase I(TOPO Ⅰ) activity. Results Complex OMT-Au obviously inhibited the proliferation of MGC803 tumor cells, blocked cell cycle of MGC803 in G2/M phase, and suppressed TOPO Ⅰ mediated untwisting of pUC19 DNA plasmid with a dose-dependence manner. And the inhibited effects of complex OMT-Au were all stronger than MT-Au complex. Conclusion The antitumor activity of complex OMT-Au is stronger than that of MT-Au, which could be attributed to the variation in the molecular conformation of ligand.
Objective To synthesize metal complexes of Au(Ⅲ) with matrine(MT-Au) and oxymatrine(OMT-Au), compare their inhibitory effect on the proliferation of tumor cells in vitro, and discuss the mechanism and structure-activity relationship. Methods The metal complexes were synthesized by solvothermal method and characterized by X-ray single crystal diffraction. The in vitro cytotoxicity of complexes with different doses towards 10 selected tumor cell lines was evaluated by MTT method. The effects of complex on cell apoptosis and cell cycle were investigated by flow cytometer. Agarose gel electrophoresis was used to study the effects of complex on topoisomerase I(TOPO Ⅰ) activity. Results Complex OMT-Au obviously inhibited the proliferation of MGC803 tumor cells, blocked cell cycle of MGC803 in G2/M phase, and suppressed TOPO Ⅰ mediated untwisting of pUC19 DNA plasmid with a dose-dependence manner. And the inhibited effects of complex OMT-Au were all stronger than MT-Au complex. Conclusion The antitumor activity of complex OMT-Au is stronger than that of MT-Au, which could be attributed to the variation in the molecular conformation of ligand.
引文
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[15]Chen Z F,Mao L,Liu L M,et al.Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine(TCM)matrine with Ga(III),Au(III),Sn(IV)ions,and DNA binding studies[J].J Inorg Biochem,2011,105(2):171-180.
[16]Chaudhari R,Tan Z,Huang B,et al.Computational polyphar macology:A new paradigm for drug discovery[J].Expert Opin Drug Discov,2017,12(3):279-291.
[2]赵宝中,荣大奇,王秀军,等.苦参碱和氧化苦参碱电子结构与药性的关系[J].分子科学学报,2000,16(2):88-93.
[3]张庆,茹庆国,刘艳,等.苦参碱与氧化苦参碱对炎症相关结直肠癌的化学预防作用研究[J].中草药,2016,47(9):1548-1553.
[4]李嫚华,许威,张青,等.氧化苦参碱对TGF-β1诱导的PANC-1细胞Smad3/Gli1通路相关因子表达的影响[J].中草药,2017,48(24):5200-5205.
[5]王淑静,任爽,张家宁,等.氧化苦参碱对Hep G-2与A549细胞增殖抑制与促凋亡活性比较研究[J].药物评价研究,2017,40(11):1545-1549.
[6]Rosenberg B,VanCamp L,Trosko J E,et al.Platinum compounds:A new class of potent antitumour agents[J].Nature,1969,222(5191):385-386.
[7]牟永平,吴刚,周立社,等.抗肿瘤金属配合物药物及其药理作用的研究进展[J].中国药理学通报,2007,23(11):1409-1413.
[8]黄晶,洪鸣.三氮螯合单功能三核铂(II)配合物的DNA结合及其抗肿瘤活性研究[J].中国生化药物杂志,2014,34(8):65-69.
[9]施鹏飞,姜琴.三价金配合物抗肿瘤活性研究[J].化学进展,2009,21(4):644-653.
[10]Shi P,Jiang Q,Zhao Y,et al.DNA binding properties of novel cytotoxic gold(III)complexes of terpyridine ligands:The impact of steric and electrostatic effects[J].J Biol Inorg Chem,2006,11(6):745-752.
[11]陈振锋,彭艳,谭明雄,等.基于中药活性成分的金属基抗肿瘤药物前期研究[J].化学进展,2009,21(5):929-933.
[12]胡美薇,傅丽娟,范翠华,等.苦参碱诱导人白血病耐药细胞K562/IM自噬和凋亡的研究[J].中国中西医结合杂志,2018,38(2):213-218.
[13]刘勇华,郭梅珍.氧化苦参碱对SGC-7901胃癌细胞增殖及对血管内皮生长因子表达的影响[J].中国临床药理学杂志,2018,34(4):443-445.
[14]曾克武,屠鹏飞.固相亲和载体应用于中药复杂体系直接作用靶点研究现状与挑战[J].中国中药杂志,2017,42(19):3645-3649.
[15]Chen Z F,Mao L,Liu L M,et al.Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine(TCM)matrine with Ga(III),Au(III),Sn(IV)ions,and DNA binding studies[J].J Inorg Biochem,2011,105(2):171-180.
[16]Chaudhari R,Tan Z,Huang B,et al.Computational polyphar macology:A new paradigm for drug discovery[J].Expert Opin Drug Discov,2017,12(3):279-291.