本文主要研究内容
作者黄晓超（2019）在《靶向微管蛋白的Pt(Ⅳ)抗肿瘤偶合物研究》一文中研究指出：经典的二价铂类药物如顺铂、奥沙利铂和卡铂是常用的DNA损伤抗癌药物,其中顺铂作为一线用药常用于临床治疗多种实体瘤。尽管其在临床上取得了巨大成功,但是铂(Ⅱ)类药物也存在着严重的毒副作用以及固有的或获得的耐药性等缺陷限制了其在临床上的应用。由于铂(Ⅳ)配合物动力学上的惰性且可以被细胞内还原性物质还原成相应的二价铂类母体药物,人们普遍认为铂(Ⅳ)配合物作为铂(Ⅱ)配合物的前药在新一代铂类药物研发中有着广泛的前景。为了克服二价铂类药物的缺陷,我们将具有生物活性小分子引入到铂(Ⅳ)配合物的轴向上,以期望获得具有潜在应用前景的新型铂(Ⅳ)配合物。首先,我们将康普瑞汀类似物和酚尼他汀类似物引入到Pt(Ⅳ)配合物的轴向位置,合成了两个系列的Pt(Ⅳ)配合物。目标化合物对所测试的癌细胞表现出了良好的抗肿瘤活性,且对正常细胞的低毒性,其抗肿瘤活性均优于相应的铂(Ⅱ)配合物。我们对代表性化合物2-22和2-25进行了初步的抗肿瘤作用机制研究。通过HPLC证实了Pt(Ⅳ)配合物2-22和2-25在抗坏血酸(VC)的作用下,能够释放出轴向配体康普瑞汀类似物(2-15)和酚尼他汀类似物(2-21),同时释放出等当量的顺铂。细胞分子生物实验结果表明,化合物2-22和2-25能够诱导细胞发生凋亡并将细胞周期阻滞在G2/M期;同时也能诱导细胞线粒体膜电位下降和ROS在细胞内聚积。Pt(Ⅳ)配合物2-22和2-25能够抑制微管蛋白聚合且能够与秋水仙碱位点结合。此外,化合物2-22能够抑制人肝癌HepG-2细胞裸鼠移植瘤增长,抑瘤率为51.2%(5 mg/kg)和59.4%(10 mg/kg);2-25能够有效地抑制人肺癌NCI-H460细胞裸鼠移植瘤增长,抑瘤率为52.11%(5 mg/kg)和60.23%(12mg/kg)。其次,我们通过戊二酸单甲酯和丁二酸酐作为连接基团将CA-4衍生物引入到顺铂以及奥沙利铂的四价铂轴向位置,合成了两个系列的Pt(Ⅳ)配合物。所有的Pt(Ⅳ)配合物对所测试的人癌细胞如HCT-116(结肠癌)、HepG-2(肝癌)、MGC-803(胃癌)显示出了良好的抗增殖能力,且抗肿瘤活性均优于相应的Pt(Ⅱ)类药物;同时对人正常细胞(如HL-7702和NCM460)的毒性低于相应的母体化合物。此外,Pt(Ⅳ)配合物对顺铂耐药细胞SK-OV-3/CDDP也具有良好的抗肿瘤活性。我们对代表性化合物3-23进行了初步的抗肿瘤活性作用的机制研究。实验结果表明,化合物3-23能够诱导人卵巢癌SK-OV-3细胞早期凋亡并将细胞周期阻滞在G2/M期;且能够显著的诱导人卵巢癌SK-OV-3细胞线粒体膜电位下降和ROS在细胞内聚积;同时还能上调如Bax、Caspase-9和Caspase-3蛋白的表达和下调Bcl-2蛋白的表达。此外,3-23能够有效地抑制人卵巢癌SK-OV-3细胞裸鼠移植瘤增殖,其抑制瘤率为53.1%(5 mg/kg)和60.5%(13 mg/kg),而且对小鼠体重变化没有什么影响相比于顺铂,通过HE组织染色发现,化合物3-23对组织器官也没有造成明显损伤。最后,我们通过连接基团将查尔酮类似物引入到Pt(Ⅳ)配合物的轴向,设计合成了两个系列的Pt(Ⅳ)配合物。所有的Pt(Ⅳ)配合物对所测试的肿瘤细胞表现出了良好的抗肿瘤活性,其抗肿瘤活性均优于相应的铂(Ⅱ)类药物,同时对正常细胞(如HL-7702和BEAS-2B)的毒性低于相应的铂(Ⅱ)类药物;且对顺铂耐药细胞株SK-OV-3/CDDP和A549/CDDP也显示出了良好的细胞毒活性。此外,Pt(Ⅳ)配合物4-49能够有效地诱导人卵巢癌SK-OV-3和人肺癌NCI-H460细胞凋亡并将细胞周期阻滞在G2/M期,且还能抑制微管蛋白聚合和诱导DNA损伤;同时4-49也能诱导SK-OV-3和NCI-H460细胞的线粒体膜电位下降和ROS的产生,且呈现剂量依赖性。4-49能显著地上调促凋亡蛋白Bax、Caspase-9和Caspase-3和下调抗凋亡蛋白Bcl-2的表达,也能显著地下调G2/M期蛋白Cdc2、Cdc25c和Cyclin B1的表达。另外,4-49能够显著地抑制人卵巢癌SK-OV-3细胞裸鼠移植瘤增殖并且呈现剂量依赖性,抑瘤率为60.3%(5 mg/kg)和70.2%(13mg/kg),其高剂量组的抑瘤率优于4-17(50.1%,5 mg/kg)、顺铂(65.7%,5 mg/kg)以及顺铂与化合物4-17联合用药组(68.1%,5+5 mg/kg),而且对小鼠体重变化没有什么影响,另外HE组织染色结果表明化合物4-49对组织器官也没有造成明显损伤。
Abstract
jing dian de er jia bo lei yao wu ru shun bo 、ao sha li bo he ka bo shi chang yong de DNAsun shang kang ai yao wu ,ji zhong shun bo zuo wei yi xian yong yao chang yong yu lin chuang zhi liao duo chong shi ti liu 。jin guan ji zai lin chuang shang qu de le ju da cheng gong ,dan shi bo (Ⅱ)lei yao wu ye cun zai zhao yan chong de du fu zuo yong yi ji gu you de huo huo de de nai yao xing deng que xian xian zhi le ji zai lin chuang shang de ying yong 。you yu bo (Ⅳ)pei ge wu dong li xue shang de duo xing ju ke yi bei xi bao nei hai yuan xing wu zhi hai yuan cheng xiang ying de er jia bo lei mu ti yao wu ,ren men pu bian ren wei bo (Ⅳ)pei ge wu zuo wei bo (Ⅱ)pei ge wu de qian yao zai xin yi dai bo lei yao wu yan fa zhong you zhao an fan de qian jing 。wei le ke fu er jia bo lei yao wu de que xian ,wo men jiang ju you sheng wu huo xing xiao fen zi yin ru dao bo (Ⅳ)pei ge wu de zhou xiang shang ,yi ji wang huo de ju you qian zai ying yong qian jing de xin xing bo (Ⅳ)pei ge wu 。shou xian ,wo men jiang kang pu rui ting lei shi wu he fen ni ta ting lei shi wu yin ru dao Pt(Ⅳ)pei ge wu de zhou xiang wei zhi ,ge cheng le liang ge ji lie de Pt(Ⅳ)pei ge wu 。mu biao hua ge wu dui suo ce shi de ai xi bao biao xian chu le liang hao de kang zhong liu huo xing ,ju dui zheng chang xi bao de di du xing ,ji kang zhong liu huo xing jun you yu xiang ying de bo (Ⅱ)pei ge wu 。wo men dui dai biao xing hua ge wu 2-22he 2-25jin hang le chu bu de kang zhong liu zuo yong ji zhi yan jiu 。tong guo HPLCzheng shi le Pt(Ⅳ)pei ge wu 2-22he 2-25zai kang huai xie suan (VC)de zuo yong xia ,neng gou shi fang chu zhou xiang pei ti kang pu rui ting lei shi wu (2-15)he fen ni ta ting lei shi wu (2-21),tong shi shi fang chu deng dang liang de shun bo 。xi bao fen zi sheng wu shi yan jie guo biao ming ,hua ge wu 2-22he 2-25neng gou you dao xi bao fa sheng diao wang bing jiang xi bao zhou ji zu zhi zai G2/Mji ;tong shi ye neng you dao xi bao xian li ti mo dian wei xia jiang he ROSzai xi bao nei ju ji 。Pt(Ⅳ)pei ge wu 2-22he 2-25neng gou yi zhi wei guan dan bai ju ge ju neng gou yu qiu shui xian jian wei dian jie ge 。ci wai ,hua ge wu 2-22neng gou yi zhi ren gan ai HepG-2xi bao luo shu yi zhi liu zeng chang ,yi liu lv wei 51.2%(5 mg/kg)he 59.4%(10 mg/kg);2-25neng gou you xiao de yi zhi ren fei ai NCI-H460xi bao luo shu yi zhi liu zeng chang ,yi liu lv wei 52.11%(5 mg/kg)he 60.23%(12mg/kg)。ji ci ,wo men tong guo wu er suan chan jia zhi he ding er suan gan zuo wei lian jie ji tuan jiang CA-4yan sheng wu yin ru dao shun bo yi ji ao sha li bo de si jia bo zhou xiang wei zhi ,ge cheng le liang ge ji lie de Pt(Ⅳ)pei ge wu 。suo you de Pt(Ⅳ)pei ge wu dui suo ce shi de ren ai xi bao ru HCT-116(jie chang ai )、HepG-2(gan ai )、MGC-803(wei ai )xian shi chu le liang hao de kang zeng shi neng li ,ju kang zhong liu huo xing jun you yu xiang ying de Pt(Ⅱ)lei yao wu ;tong shi dui ren zheng chang xi bao (ru HL-7702he NCM460)de du xing di yu xiang ying de mu ti hua ge wu 。ci wai ,Pt(Ⅳ)pei ge wu dui shun bo nai yao xi bao SK-OV-3/CDDPye ju you liang hao de kang zhong liu huo xing 。wo men dui dai biao xing hua ge wu 3-23jin hang le chu bu de kang zhong liu huo xing zuo yong de ji zhi yan jiu 。shi yan jie guo biao ming ,hua ge wu 3-23neng gou you dao ren luan chao ai SK-OV-3xi bao zao ji diao wang bing jiang xi bao zhou ji zu zhi zai G2/Mji ;ju neng gou xian zhe de you dao ren luan chao ai SK-OV-3xi bao xian li ti mo dian wei xia jiang he ROSzai xi bao nei ju ji ;tong shi hai neng shang diao ru Bax、Caspase-9he Caspase-3dan bai de biao da he xia diao Bcl-2dan bai de biao da 。ci wai ,3-23neng gou you xiao de yi zhi ren luan chao ai SK-OV-3xi bao luo shu yi zhi liu zeng shi ,ji yi zhi liu lv wei 53.1%(5 mg/kg)he 60.5%(13 mg/kg),er ju dui xiao shu ti chong bian hua mei you shen me ying xiang xiang bi yu shun bo ,tong guo HEzu zhi ran se fa xian ,hua ge wu 3-23dui zu zhi qi guan ye mei you zao cheng ming xian sun shang 。zui hou ,wo men tong guo lian jie ji tuan jiang cha er tong lei shi wu yin ru dao Pt(Ⅳ)pei ge wu de zhou xiang ,she ji ge cheng le liang ge ji lie de Pt(Ⅳ)pei ge wu 。suo you de Pt(Ⅳ)pei ge wu dui suo ce shi de zhong liu xi bao biao xian chu le liang hao de kang zhong liu huo xing ,ji kang zhong liu huo xing jun you yu xiang ying de bo (Ⅱ)lei yao wu ,tong shi dui zheng chang xi bao (ru HL-7702he BEAS-2B)de du xing di yu xiang ying de bo (Ⅱ)lei yao wu ;ju dui shun bo nai yao xi bao zhu SK-OV-3/CDDPhe A549/CDDPye xian shi chu le liang hao de xi bao du huo xing 。ci wai ,Pt(Ⅳ)pei ge wu 4-49neng gou you xiao de you dao ren luan chao ai SK-OV-3he ren fei ai NCI-H460xi bao diao wang bing jiang xi bao zhou ji zu zhi zai G2/Mji ,ju hai neng yi zhi wei guan dan bai ju ge he you dao DNAsun shang ;tong shi 4-49ye neng you dao SK-OV-3he NCI-H460xi bao de xian li ti mo dian wei xia jiang he ROSde chan sheng ,ju cheng xian ji liang yi lai xing 。4-49neng xian zhe de shang diao cu diao wang dan bai Bax、Caspase-9he Caspase-3he xia diao kang diao wang dan bai Bcl-2de biao da ,ye neng xian zhe de xia diao G2/Mji dan bai Cdc2、Cdc25che Cyclin B1de biao da 。ling wai ,4-49neng gou xian zhe de yi zhi ren luan chao ai SK-OV-3xi bao luo shu yi zhi liu zeng shi bing ju cheng xian ji liang yi lai xing ,yi liu lv wei 60.3%(5 mg/kg)he 70.2%(13mg/kg),ji gao ji liang zu de yi liu lv you yu 4-17(50.1%,5 mg/kg)、shun bo (65.7%,5 mg/kg)yi ji shun bo yu hua ge wu 4-17lian ge yong yao zu (68.1%,5+5 mg/kg),er ju dui xiao shu ti chong bian hua mei you shen me ying xiang ,ling wai HEzu zhi ran se jie guo biao ming hua ge wu 4-49dui zu zhi qi guan ye mei you zao cheng ming xian sun shang 。
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论文作者分别是来自东南大学的黄晓超，发表于刊物东南大学2019-10-18论文，是一篇关于铂前药论文,酚尼他汀论文,微管蛋白论文,查尔酮论文,东南大学2019-10-18论文的文章。本文可供学术参考使用，各位学者可以免费参考阅读下载，文章观点不代表本站观点，资料来自东南大学2019-10-18论文网站，若本站收录的文献无意侵犯了您的著作版权，请联系我们删除。
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