新型抗肿瘤铂配合物的设计、合成及其活性研究

发布时间：2018-02-02 02:44

本文关键词： 双核铂抗肿瘤药物 trans-1R 2R-环己二胺葫芦[7]脲甲啶铂奈达铂体外抗肿瘤活性药物载体　出处：《昆明理工大学》2017年硕士论文　论文类型：学位论文

【摘要】：近年来,铂类抗肿瘤药物已经成为临床治疗肿瘤的一线药物,它具有独特的抗肿瘤机制、良好的抗肿瘤活性以及广泛的抗肿瘤谱等优势。但是,铂类抗肿瘤药物广泛存在的毒副作用、耐药性或交叉耐药性等问题,严重限制了其临床应用。为了克服铂类药物的临床治疗缺陷,开发高效、低毒的新型铂类抗肿瘤药物或引入新型的药物递送载体是未来铂类药物发展的重要方向。非经典双核铂类抗肿瘤药物具有良好的抗肿瘤活性,其抗肿瘤作用机制与经典单核顺铂类抗肿瘤药物不同。双核铂类抗肿瘤药物能够与DNA之间形成多点键合及链间交联,对DNA的破坏性更大,使DNA难以自我修复从而发挥抗肿瘤作用。在一定程度上规避了经典单核顺铂类抗肿瘤药物所表现出来的临床缺陷。葫芦[n]脲及其衍生化是当今超分子化学的研究热点,其在主客体识别、自组装的应用研究十分广泛。将葫芦[n]脲及其衍生物作为药物递送载体,能够提高药物的水溶性及生物利用度,在一定程度上减少药物的毒副作用。基于上述考虑,本毕业论文主要分为以下两个部分:1、设计并合成一类新型的非经典双核铂抗肿瘤配合物,并对其进行体外抗肿瘤活性研究。基于奥沙利铂的手性配体trans-1R.2R-环己二胺和可以作为嵌入基团的平面芳香分子苯环设计合成了一种手性四齿二胺化合物HL。以HL为配体,制备了六种目标新型手性双核铂配合物A1-A6,通过元素分析、红外(IR)、1H NMR和MS等表征手段确定了其结构。通过水溶性测试及体外抗肿瘤实验,筛选出具有良好体外抗肿瘤活性的双核铂配合物A2,具有一定的深入研究价值。2、采用新型超分子化学主体化合物葫芦[7]脲,研究铂类药物的载药体系特征及其抗肿瘤活性。利用为葫芦[7]脲作为主体,奈达铂和甲啶铂为客体药物制备两种包合物,通过荧光分析法计算Ks值和包合比;运用一维核磁、二维核磁、粉末衍射、扫描电镜等实验方法证实了葫芦[7]脲与两种铂类药物确定形成包合物,并推断出可能的包结模式。
[Abstract]:In recent years, platinum anti-tumor drugs have become the first line of clinical treatment of tumor drugs, it has a unique anti-tumor mechanism, good anti-tumor activity and a wide range of anti-tumor spectrum advantages. Platinum antitumor drugs have many problems, such as side effects, drug resistance or cross resistance, which seriously limit their clinical application. In order to overcome the shortcomings of clinical treatment of platinum drugs, the development of high efficiency. Low toxicity new platinum antitumor drugs or the introduction of new drug delivery vectors are important directions for the development of platinum drugs in the future. Non-classical binuclear platinum antitumor drugs have good antitumor activity. Its antitumor mechanism is different from that of classical mononuclear cisplatin antitumor drugs. Binuclear platinum antitumor drugs can form multi-point bonding and interchain crosslinking with DNA, which is more destructive to DNA. This makes it difficult for DNA to repair itself and play an antitumor role. To some extent, it avoids the clinical defects of classical mononuclear cisplatin antitumor drugs. [Urea and its derivation are the research hotspot of supramolecular chemistry nowadays. The application of urea in host and guest recognition and self assembly is very extensive. [As drug delivery carriers, urea and its derivatives can improve the water solubility and bioavailability of drugs, and reduce the side effects of drugs to a certain extent. This thesis is divided into the following two parts: 1. A novel nonclassical binuclear platinum antitumor complex is designed and synthesized. A chiral tetra was synthesized based on the chiral ligand trans-1R.2R- cyclohexanediamine of oxaliplatin and a planar aromatic molecule benzene ring, which can be used as an intercalation group. The dentate diamine compound HL. with HL as the ligand. Six novel chiral binuclear platinum complexes A1-A6 were prepared by elemental analysis, IR). The structure was confirmed by 1H NMR and MS. The binuclear platinum complex A2 with good antitumor activity in vitro was screened by water solubility test and in vitro antitumor test. It has certain deep research value. 2. The new supramolecular chemical host compound cucurbita is used. [7 Urea, study on the characteristics of platinum drug delivery system and its antitumor activity. [7] Urea as the host, Nedaplatin and methylplatin as the guest drugs to prepare two inclusion complexes, the Ks value and inclusion ratio were calculated by fluorescence analysis. By means of one-dimensional nuclear magnetic field, two-dimensional nuclear magnetic field, powder diffraction, scanning electron microscope and other experimental methods, the gourd has been confirmed. [7] Urea was determined to form inclusion complexes with two platinum drugs, and the possible inclusion patterns were inferred.
【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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