含位阻基团手性二胺为配体的抗肿瘤铂(II)配合物研究

项目名称： 含位阻基团手性二胺为配体的抗肿瘤铂(II)配合物研究

项目编号： No.21271041

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 苟少华

作者单位： 东南大学

项目金额： 80万元

中文摘要： 以手性反式1,2-环己二胺为起始物，在保持原有手性中心构型的情况下，合成两类手性二胺配体，一类是于一个氨基氮原子上选择性地引入一个作为位阻基团的取代基；另一类是于一个氨基氮原子上选择性地引入两个作为位阻基团的取代基(相同或不同)，将如此得到的手性二胺配体结合不同类型的阴离子配体与铂(II)离子配位，制备若干种具有位阻基团的手性铂(II)配合物。对这些铂配合物进行体外抗肿瘤活性评价，确定其抗瘤谱并考察它们与顺铂类药物的交叉耐药情况，探究不同配体、不同位阻、不同手性构型化合物之间抗肿瘤活性的差异，研究活性化合物在肿瘤细胞的积累、诱导细胞凋亡以及与DNA的作用，比较该类含位阻基团铂配合物与现有药物顺铂和奥沙利铂抗肿瘤生物作用机制的异同。对得到的高活性化合物进行体内抗肿瘤活性试验和初步毒性评价，筛选出针对国内高发肿瘤具有有效治疗作用、毒性较低且可能具有抗顺铂耐药的候选药物。

中文关键词： 铂配合物；手性二胺；位阻基团；顺铂耐药；抗肿瘤

英文摘要： The project is concerned with the study on novel antitumor platinum(II) complexes with chiral diamine ligands derived from trans 1,2-cyclohexyldiamine. The ligands are divided into two categories, which are designed and prepared by maintaining the original stereogenic centers of trans 1,2-cyclohexyldiamine. One category is selectively to introduce a substituent to one amino nitrogen atom, while the other is to introduce two identical or different substituents to one amino nitrogen atom as resistance groups. Such obtained chiral ligands will be applied to synthesize several kinds of chiral platinum(II) complexes by combining with different anionic ligands. In vitro biological evaluation of these complexes against a number human tumor cell lines will be carried out in order to understand their antitumor spectra and drug resistance against cisplatin; to explore the distinction of their antutmor activity with different ligands, resistance groups and steric configurations; to study the accumulation in tumor cells, induced cell apopotosis and interaction with DNA of the resuting active compounds; and to compare their antitumor patterns with those of cispatin and oxaliplatin. In vivo antitumor tests and initial toxicity assay will be undertaken with high cytotoxicity compounds. The main purpose of the project is to scr

英文关键词： platinum(II) complex；chiral diamine；hindered group；cisplatin resistance；antitumor