新型手性双核铂类配合物的合成、表征及其抗肿瘤活性研究

发布时间：2018-03-05 18:26

本文选题：双核铂配合物　切入点：四齿配体　出处：《昆明理工大学》2017年硕士论文　论文类型：学位论文

【摘要】：癌症是严重威胁着人类的健康的一种疾病,而中国已成世界上癌症发病人数最多的国家。癌症不仅严重威胁着我国人民的生命与健康,而且给家庭、社会、国家造成了沉重的负担,干扰着我国经济建设和社会发展,是一个非常突出的社会公共卫生问题。铂类抗肿瘤药物由于其出色的临床效果,在化疗中有着很高的应用率。目前在世界范围内上市的铂类药物中,顺铂、卡铂和奥沙利铂由于其各自的优点在肿瘤化疗中被广泛应用。然而,铂类抗肿瘤药物在临床中表现出的严重的胃肠道反应、肾毒性、耳毒性、神经毒性等副作用以及铂类药物之间存在着的交叉耐药性限制了其应用。因此,开发新型铂类药物,解决其毒副作用及耐药性是抗肿瘤药物发展的一个方向。研究发现,奥沙利铂的手性配体Trans-1R,2R-环己二胺是其发挥抗肿瘤作用的重要组成部分。同时,多核铂类药物具有不同于传统经典铂药的构效关系,能够与DNA之间形成多点键合,对DNA破坏性更大,使其难以自我修复从而避免经典铂类药物的耐药性问题。此外,一些平面芳香环具有DNA嵌入作用,可以嵌入DNA的沟槽间。考虑到DNA链的双螺旋结构以及目前对双核铂作用机制的研究结果,具有柔性烷基链的双核铂配合物可能在具有与DNA的碱基多点键合的能力之外,其烷基链还可能与DNA链形成纠缠,从而使与DNA结合更紧密,增强细胞毒性,减少耐药性。基于上述考虑,本论文主要分为两个部分:一、以具有DNA嵌入作用的芳香环为桥的手性双核铂配合物的合成、表征及抗肿瘤活性的研究基于奥沙利铂的手性配体Trans-1R,2R-环己二胺、具有DNA嵌入作用的平面芳香分子苯环以及用来调节化合物脂水分配系数的六个离去基团,设计并合成了六种新型双核铂配合物。通过红外光谱、核磁共振氢谱和电喷雾质谱等手段确定了双核铂配合物A1-A6的结构,并通过MTT法测定了其对4种癌细胞的细胞毒性。结果表明,六种双核铂配合物均显示出一定细胞毒性,其中A2对所选4种癌细胞的细胞毒性均超过卡铂与奥沙利铂,对HepG2人肝癌细胞的细胞毒性略强于顺铂,有望在未来抗肿瘤铂类药物的发展中成为一个非常有希望的先导化合物。二、以柔性烷基链为桥的手性双核铂配合物的设计、合成和表征基于奥沙利铂的手性配体Trans-1R,2R-环己二胺,以六个碳链长的柔性烷基链为桥,用来调节化合物脂水分配系数的五个离去基团,我们设计了五种以柔性烷基链为桥的手性双核铂配合物。通过核磁共振和电喷雾质谱等手段确定了双核铂配合物D1-D5的结构。
[Abstract]:Cancer is a serious threat to human health, and China has become the world's largest number of cancer. Cancer not only seriously threaten the lives and health of our people, but also to the family, society, The country has caused a heavy burden and interfered with the economic construction and social development of our country. It is a very prominent social public health problem. Cisplatin, carboplatin and oxaliplatin are widely used in cancer chemotherapy because of their respective advantages. The severe gastrointestinal reaction, nephrotoxicity, ototoxicity, neurotoxicity and other side effects of platinum antitumor drugs in clinic, as well as the cross resistance between platinum drugs, restrict its application. Solving its side effects and drug resistance is one of the directions in the development of antitumor drugs. It has been found that the chiral ligand of oxaliplatin, Trans-1RN2R- cyclohexanediamine, is an important component of its antitumor effect. Polynuclear platinum drugs have a different structure-activity relationship than traditional platinum drugs, and can form multi-point bonding with DNA, which is more destructive to DNA, making it difficult to repair itself and avoid the problem of drug resistance of classical platinum drugs. Some planar aromatic rings have DNA embeddedness, which can be embedded in the grooves of DNA. Considering the double helix structure of DNA chain and the current results of the mechanism of binuclear platinum interaction, The binuclear platinum complexes with flexible alkyl chains may form entanglement with DNA chains in addition to their ability to bond with the bases of DNA, thus making them bind more closely to DNA and enhance their cytotoxicity. Based on the above considerations, this thesis is divided into two parts: first, the synthesis of chiral Dinuclear platinum complexes with aromatic rings with DNA intercalation. Characterization and Antitumor activity Studies based on oxaliplatin's chiral ligand Trans-1RN2R- cyclohexanediamine, a planar aromatic ring with DNA intercalation and six departure groups used to regulate the lipids partition coefficients of the compounds were developed. Six novel binuclear platinum complexes were designed and synthesized. The structures of binuclear platinum complexes A1-A6 were determined by IR, NMR and electrospray mass spectrometry. The cytotoxicity of the six binuclear platinum complexes to four kinds of cancer cells was determined by MTT. The results showed that the cytotoxicity of the six binuclear platinum complexes was higher than that of carboplatin and oxaliplatin. The cytotoxicity of HepG2 human hepatoma cells is slightly stronger than that of cisplatin, which is expected to become a promising lead compound in the future development of antitumor platinum drugs. Second, the design of chiral binuclear platinum complexes with flexible alkyl chains as bridge. Synthesis and characterization of a chiral ligand Trans-1RN2R- cyclohexanediamine based on oxaliplatin, with six carbon chain long flexible alkyl chains as a bridge to regulate the five departure groups of the lipids, Five chiral binuclear platinum complexes with flexible alkyl chains have been designed and the structures of D1-D5 have been determined by NMR and electrospray ionization mass spectrometry.
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O641.4;TQ460.1

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