新型双核铂类配合物的合成、表征及抗肿瘤活性研究

发布时间：2018-02-12 21:37

本文关键词： 双核铂配合物四齿配体 Trans-1R 2R-环己二胺体外抗肿瘤活性　出处：《昆明理工大学》2016年硕士论文　论文类型：学位论文

【摘要】：癌症严重影响人类健康,给人类生命带来极大的挑战。铂类药物因其优越的抗肿瘤活性在各类抗肿瘤药物中占有重要地位。目前上市的铂药以顺铂、卡铂及奥沙利铂为典型的代表,该类药物与其他抗肿瘤药物无交叉耐药性,在临床应用上显示出了优越的抗肿瘤活性。然而,铂类抗肿瘤药物具有严重的毒副作用如耳毒性、肾毒性、神经毒性、胃肠道反应及生物利用度低等缺点。因此,开发新型铂类药物是未来铂类药物发展的一个方向。研究发现,奥沙利铂的手性配Trans-1R,2R-环己二胺是其发挥作用的重要组成部分。同时,双核及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发挥作用。此外,具有平面插入作用的芳香分子可以通过氢键与DNA作用,进而增加药物与DNA的相互作用。姜黄素是从植物姜黄中提取的一种黄色略带酸性且具有二酮结构的酚类色素,也是姜黄属植物姜黄发挥药理作用的主要成分。研究表明,姜黄素的抗肿瘤活性与其结构中的不饱和酮链有关。基于上述考虑,我的毕业论文的设计主要分为两个部分：一、以(1R, 1'R,2R,2'R)-N1, N1'-(1,3-亚苯基双(亚甲基))环己烷-1,2-二胺为载体基团的双核铂配合物的合成、表征及抗肿瘤活性基于奥沙利铂的手性配体Trans-1R,2R-环己二胺、具有插入作用的平面芳香分子间苯二甲醛以及可以改变药物酯水分布的七种离去基团,设计并合成出了七种双核铂配合物并通过MTT法测定了其体外细胞活性。结果表明,七种配合物均具有良好的抗肿瘤活性,其中以3-羟基-环丁烷-1,1-二羧酸为离去基团的双核铂配合物P7显示了优越的活性,其对HepG-2和A549细胞系的活性优于卡铂,对HCT-116细胞系的活性接近于奥沙利铂。因此,P7有望在未来铂药的发展中成为一个非常有希望的先导化合物。二、含有1,6-二乙氧基-1,5-己二烯-3,4-二酮链的四齿配体的合成姜黄素的不饱和酮链是其发挥抗肿瘤作用的重要部分,然而,在某种程度上,该链的稳定性很差。因此,基于姜黄素的不饱和酮链,我们设计并合成了较为稳定的1,6-二乙氧基-1,5-己二烯-3,4-二酮链,在此基础上,以Trans-1R,2R-环己二胺为原料最终设计并合成了一个新的四齿配体。该配体的1,6-二乙氧基-1,5-己二烯-3,4-二酮链与Trans-1R,2R-环己二胺氨基氮原子上的孤对电子形成共轭作用使其更加稳定。此外,与以往四齿配体相比,具有新结构的四齿配体因具有两个氨基和两个酮羰基而显示出良好的水溶性,有望在铂药发展中成为一个非常有潜力的铂药中间体。
[Abstract]:Cancer seriously affects human health and brings great challenges to human life. Platinum drugs play an important role in all kinds of antitumor drugs because of their superior antitumor activity. Carboplatin and oxaliplatin are typical representatives. These drugs have no cross resistance with other antitumor drugs and have superior antitumor activity in clinical application. However, platinum antitumor drugs have serious toxic side effects such as ototoxicity. Kidney toxicity, neurotoxicity, gastrointestinal reaction and low bioavailability. Therefore, the development of new platinum drugs is one of the future development of platinum drugs. The chiral ligand of oxaliplatin, Trans-1RN2R- cyclohexanediamine, is an important component of its action. At the same time, binuclear and polynuclear platinum drugs have different structure-activity relationships from traditional platinum drugs, and can form multi-point bonding with DNA, which is more destructive to DNA. It makes it difficult to repair itself to make it work. In addition, aromatic molecules with planar insertion can interact with DNA through hydrogen bonds. Curcumin is a yellow slightly acidic phenolic pigment with diketone structure extracted from turmeric, which is also the main component of the pharmacological action of turmeric. The antitumor activity of curcumin is related to the unsaturated ketone chain in its structure. Based on the above considerations, the design of my thesis is divided into two parts: first, Synthesis, characterization and Antitumor activity of Dinuclear Platinum complexes based on oxaliplatin Chiral Ligand Trans-1R ~ (2 +) -Cyclohexanediamine. Seven binuclear platinum complexes were designed and synthesized by inserting the planar aromatic molecules of isophthalaldehyde and seven kinds of leaving groups which can change the distribution of the ester water. The results showed that seven binuclear platinum complexes were obtained and their cell activity in vitro was determined by MTT method. Among the seven complexes, the binuclear platinum complex P7, with 3-hydroxy-cyclobutane-1-dicarboxylic acid as the departure group, showed superior activity to HepG-2 and A549 cell line, and the activity of P7 was superior to that of carboplatin. The activity against HCT-116 cell line is close to oxaliplatin. Therefore, P7 is expected to become a very promising lead compound in the development of platinum in the future. Synthesis of tetradentate ligands containing 1O6-diethoxy-1-hexamethoxy-5-hexadiene-4-diketone chain is an important part of its antitumor effect. However, to some extent, the stability of the chain is very poor. Based on the unsaturated ketone chain of curcumin, we have designed and synthesized a relatively stable 1 / 6-diethoxy-1-hexadiene-3-hexadiene-4-dione chain. A new tetradentate ligand was finally designed and synthesized from Trans-1R- 2R- cyclohexanediamine. The conjugation action between the 1 ~ (6) -diethoxy-5-hexadiene-3-hexadiene-4-diketone chain and the amino nitrogen atom of Trans-1R ~ (2 +) -cyclohexanediamine makes the ligand more stable. Compared with the previous tetradentate ligands, the tetradentate ligands with new structures exhibit good water solubility due to their two amino groups and two ketones carbonyl groups, which are expected to become a potential platinum intermediates in the development of platinum drugs.
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O641.4;TQ460.1

【相似文献】