新型手性邻二胺配体金属（铱（Ⅲ）、铂（Ⅱ））配合物的设计合成及其抗肿瘤活性研究

发布时间：2018-03-10 14:10

  本文选题：铱(Ⅲ)配合物　切入点：铂(Ⅱ)配合物　出处：《复旦大学》2013年硕士论文　论文类型：学位论文

【摘要】：癌症是威胁人类健康的全球头号杀手,以顺铂、卡铂、奥沙利铂为代表的铂(Ⅱ)类金属配合物抗肿瘤药由于其抗癌谱广、作用机制独特、毒性谱特殊,在超过50%的临床联合化疗方案中使用。尽管铂(Ⅱ)配合物在恶心肿瘤的临床治疗中取得了巨大的成功,但其存在毒副作用大、易产生交叉耐药的严重缺陷,进一步研发具有高效低毒、能克服顺铂类交叉耐药的新型金属配合物的抗癌药的需求显得尤为迫切。 本论文基于经典铂(Ⅱ)类抗癌药作用机制和构效关系的研究成果,根据非铂类金属配合物抗肿瘤活性研究的文献调研结果,选择金属配合物抗肿瘤研究中较少涉及到的铱(Ⅲ)作为配合物的中心金属原子,结合本课题组前期工作基础,首次创新引入手性邻二胺作为三价铱配合物的配体,重点设计合成了22个C2对称性手性邻二胺配体铱(Ⅲ)配合物和13个非C2对称性手性邻二胺配体铱(Ⅲ)合物,全部为新化合物。此外,还扩展了配合物配体类型,设计合成了13个具有含氮芳香双齿配体溶剂单齿配体结构的铱(Ⅲ)配合物,其中7个为新化合物。所有配合物结构均经R、MS及(或)NMR确证,其中配合物trans-68d的立体结构还经X-射线单晶衍射得到确认。针对以上三类铱(Ⅲ)配合物进行了系统的抗肿瘤活性及构效关系研究,以期发现高效低毒、完全打破顺铂类结构框架的新型铱(Ⅲ)配合物抗肿瘤新药。此外,完善了本课题组前期研究中关于抗肿瘤(R,R)-非C2对称性邻二胺配体铂(Ⅱ)配合物的工作,补充合成了12个手性邻二胺配体铂(Ⅱ)配合物(9个为新化合物),进行了系统的构效关系研究。 选择A549(非小细胞肺癌)、A2780(卵巢癌)、KB(口腔表皮癌)、MDA-MB-231(乳腺癌)四种人实体瘤细胞株,对所合成的铱(Ⅲ)配合物了进行体外抗肿瘤活性测试。结果显示,三类铱(Ⅲ)配合物中,以Q对称性手性邻二芳胺配体系列的铱(Ⅲ)配合物的活性最好。该系列中有6个配合物对所测四种肿瘤细胞中的至少三种显示出与阳性对照药奥沙利铂相近甚至较之更强的抗肿瘤活性,并且配体的手性碳构型对配合物的抗肿瘤活性有重要影响：以互为对映异构体的两个C2对称性邻二芳胺为配体形成的相应铱(Ⅲ)配合物,(R,R)-构型配体的配合物抗肿瘤活性远大于(S,S)-构型异构体。此外,还对其中活性较好的代表性化合物tran-68d进行了初步的作用机制研究及急性毒性评价,结果显示trans-68d通过p53介导的细胞凋亡通路杀伤A2780细胞,并且经ICR小鼠腹腔注射该配合物LDso值远高于奥沙利铂。 最后,本文分别从三个类型的铱(Ⅲ)配合物中选取了共9个化合物,利用激光共聚焦荧光显微镜对其进行了KB肿瘤细胞内荧光成像研究,结果显示其中7个配合物能发出不同强度的荧光且主要分布于细胞胞浆区,为我们日后探索药靶提供了一定基础。 本论文的研究工作以新型手性邻二胺配体铱(Ⅲ)配合物的抗肿瘤活性研究为重点,涵盖了化学合成,体内外活性测试,毒性评价、作用机制研究等基础研究。该研究内容已获得国家自然科学基金以及上海市科委基金的资助,对开发具有我国自主知识产权的新型铱(Ⅲ)配合物抗肿瘤药物有非常积极的意义。本论文相关内容已发表SCI学术论文一篇,申请专利一项。
[Abstract]:Cancer is a threat to human health in the world's biggest killer, cisplatin, carboplatin, oxaliplatin as the representative of the platinum (II) metal complexes antitumor drugs because of its wide anticancer spectrum, unique mechanism, toxicity profile special use in clinical chemotherapy of more than 50%. As Guan Bo (II) with clinical treatment. The nausea of tumor was a huge success, but it has side effects, serious defects of cross resistance, further research and development of high efficiency and low toxicity of anticancer drugs, the new metal platinum can overcome the cross resistance with the demand is particularly urgent.
This paper is based on the classic platinum (II) type of anticancer drug mechanism and structure-activity relationship research results, according to the literature research results on antitumor activity of non platinum metal complexes, metal complexes are less involved in the anti-tumor research of iridium (III) complexes with metal atoms in the heart as the our previous work, the first innovation introduced two amine as chiral vicinal trivalent iridium complexes with ligands, 22 C2 symmetric chiral vicinal two amine ligand synthesized iridium (III) complexes with the focus on the design of C2 and 13 non symmetry of two adjacent chiral amine ligand iridium (III) complexes, all of them are new compounds. In addition, also extends the ligand type with 13 aromatic nitrogen bidentate ligand solvent monodentate ligand structure of the synthesized iridium (III) complexes, including 7 new compounds. All complexes were confirmed by R, MS and (or) NMR spectra, complexes trans The three-dimensional structure of -68d was confirmed by X- ray diffraction. For the above three types of iridium (III) complexes were the antitumor activity and structure-activity relationship research, in order to find the high efficiency and low toxicity, completely breaking the framework of platinum iridium (III) complexes with antitumor drugs. In addition, perfect a tumor in the previous study (R, R) - C2 non symmetry of two adjacent amine ligands of platinum (II) complexes, 12 chiral vicinal amine ligands were synthesized on two platinum (II) complexes (9 compounds), studied the structure-activity relationship of system.
閫夋嫨A549(闈炲皬缁嗚優鑲虹檶),A2780(鍗靛发鐧，

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