新型手性双核铂配合物的设计、合成及抗肿瘤生物活性研究

Oxaliplatin is now a preferred drug in treating advanced colorectal carcinoma, however, for the structural similarity with other mononuclear platinum-based drugs such as cisplatin and its analogues, the serious resistance/cross resistance exhibited in clinical use. Multinuclear platinum complexes could avoid the resistance/cross resistance of mononuclear platinum-based drugs such as cisplatin and its analogues. Further more, capable of forming multipoint adducts of intrastrand and interstrand crosslinkings, multinuclear platinum complexes show improved cytotoxicities than cisplatin and its analogues. Chiral ligand trans-1R,2R-diaminocyclohexane(DACH) is an important pharmacophore in oxaliplatin. Flexible alkyl skelectons or rigid aromatic rings are used as bridges to link two DACHs and a kind of chiral ligands(L) which could afford four coordination sites are obtained. With L as the carrier group and different anions as the leaving group, novel dinuclear platinum complexes are designed, synthesized and spectrally characterized. Preliminary molecular docking tests between the objective platinum complexes with DNA have been evaluated by CADD. In vitro cytotoxicities of all prepared dinuclear platinum complexes will be evaluated against cisplatin sensitive and tolerant cell lines. Inducing apoptosis and cell cycle phase distribution for the representative platinum complexes will be tested by flow cytometric resection. Agarose gel electrophoresis will be used to test the cleavage of plasmid DNA with the platinum complexes. All the above-mentioned pharmacological experimentations will help us preliminarily exploring the anticancer mechanisms and lay a favourable foundation for finding novel dinuclear platinum leading compounds which would show better antitumor activity, and at the same time, could effectively avoid the resistance/cross resistance of the cisplatin analogs.

奥沙利铂是目前治疗晚期结直肠癌的首选药物，然而结构的相似性使得它与其它单核顺铂类药物存在严重的交叉耐药性。多核铂抗肿瘤配合物能克服顺铂等单核类药物的耐药性或交叉耐药性，并且由于和肿瘤细胞DNA形成多点链间和链内键合物，抗肿瘤活性明显优于顺铂类药物。手性配体trans-1R,2R-环己二胺(DACH)是奥沙利铂的重要药效基团。将具有柔性结构的碳链或刚性结构的芳香环作为桥连接两个DACH，得到一类新型的手性四齿配体L；以L为载体基团，选用不同的阴离子为离去基团，合成一类新型的双核铂配合物。计算机初步模拟目标铂配合物与肿瘤细胞DNA的对接；测试其对顺铂敏感和耐药肿瘤株的体外活性；流式细胞术研究其对肿瘤细胞株的诱导凋亡和对细胞周期的影响；凝胶电泳研究其与质粒DNA的作用模式。对这类铂配合物的抗肿瘤作用机制进行探讨，为发现新型抗肿瘤效果良好为且与单核铂药无交叉耐药性的双核铂先导配合物奠定良好的基础。

铂类药物是化疗或联合化疗治疗恶性肿瘤的主药之一。奥沙利铂则是目前治疗晚期结直肠癌的首选药物，然而结构的相似性使得它与其它单核顺铂类药物仍然存在严重的交叉耐药性。多核铂抗肿瘤配合物能克服顺铂等单核类药物的耐药性或交叉耐药性，并且由于和肿瘤细胞DNA形成多点链间和链内键合物，抗肿瘤活性明显优于顺铂类单核铂药物。手性配体trans-1R,2R-环己二胺(DACH)是奥沙利铂的重要药效基团。本课题将具有柔性结构的碳链或刚性结构的芳香环作为桥连接两个DACH，得到一类新型的手性四齿配体L，项目执行期内共得到新型四齿手性配体26个；以L为载体基团，选用不同的阴离子为离去基团，合成了一类新型的双核铂配合物，项目执行期内共得到新型手性双核铂配合物135个。通过MTT法测试了目标抗肿瘤配合物对顺铂敏感和耐药肿瘤株的体外活性，筛选出6个具有良好生物活性的先导化合物；流式细胞术研究了目标双核铂配合物对肿瘤细胞株的诱导凋亡和对细胞周期的影响；凝胶电泳研究了其与质粒DNA的作用模式。通过构效关系的总结，对这类铂配合物的抗肿瘤作用机制进行了探讨，为发现新型抗肿瘤效果良好为且与单核铂药无交叉耐药性的双核铂先导配合物奠定了良好的基础。

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