基于糖转运蛋白靶向和双重DNA损伤机制的铂(IV)配合物的设计合成及抗肿瘤活性研究

The development of novel platinum chemotherapeutics is a hot topic in anti-tumor field. Platinum (IV) complexes with high potency, low toxicity, good stability, oral administration, and other advantages, are of great potential to be developed as the new generation of platinum drugs. However, platinum (IV) complexes in clinical trials are still unable to be applied in clinic because of their poor targeting and little superior curative effects compared with platinum (II) drugs. Structural modification of platinum (IV) complexes is an effective strategy to overcome the drawbacks above. This project intends to design a series of naphthalimide glycosylated platinum(IV) target complexes. The introduction of sugar transporter targeted glycosyl group would enhance tumor targeting of drugs, meanwhile the incorporation of DNA targeted naphthalimide group would endow platinum(IV) complex with dual DNA damage mechanism which is favorable for overcoming the drug resistance of platinum(II). This project would complete the synthesis and structural characterization of the target complexes, the evaluation of antitumor activity in vitro and in vivo, the test of biotoxicity and the investigation on structure-activity relationships. The sugar transporter targeting and dual DNA damage mechanism would also be elucidated. The results would contribute to the development of novel platinum(IV) lead compounds with high activity and low toxicity, and provide new reference and ideas for future platinum drug exploration. Therefore, this study is of great theoretical and practical significance.

新型铂类化疗药物的开发是抗肿瘤领域的研究热点。铂(IV)配合物具有高效低毒、性质稳定、可口服等优点，有望发展为新一代铂类抗肿瘤药物。但目前进入临床试验的铂(IV)配合物因肿瘤靶向性差、疗效较铂(II)临床药物无明显优势等缺点，仍然无法应用于临床。对铂(IV)配合物进行结构优化是解决上述问题的有效途径。本项目拟设计具有萘酰亚胺糖基铂(IV)结构的目标化合物，通过引入糖转运蛋白靶向糖基增强药物的肿瘤靶向性，通过引入DNA靶向基萘酰亚胺使目标产物具有双重DNA损伤机制并有效克服临床铂类药物的耐药性。该项目拟完成目标化合物的合成表征、体内外抗肿瘤活性和生物毒性测试、构效关系研究，并阐明糖转运蛋白靶向性及双重DNA损伤抗肿瘤机制，以获得高效低毒、肿瘤靶向性强的铂(IV)先导化合物，为新型铂类药物的研发提供借鉴与思路，具有重要的学术研究意义和实际应用价值。

癌症是导致人类死亡的重要疾病，约有90%的癌症患者死于肿瘤转移，然而目前高效的抗肿瘤转移药物依然缺乏。四价铂作为二价铂类药物前药已经成为新型铂类抗肿瘤药物研究的热点领域，对其进行结构修饰，构筑新型多功能四价铂化合物是开发高效抗肿瘤增殖及抗转移药物的有效策略。基于此，本项目分别将具有DNA损伤能力的萘酰亚胺，具有炎症抑制能力的酮洛芬、洛索洛芬、萘普生、香豆素，及具有肿瘤靶向能力的糖基引入四价铂体系制备了系列新型四价铂目标化合物及纳米药物，测定了其抗肿瘤活性，探索了其抗肿瘤机制，并研究了药物在抗肿瘤转移领域的应用。通过构效关系总结，探讨了不同结构修饰对抗肿瘤活性的影响，并对目标化合物结构进行不断优化，筛选出了有发展潜力的新型四价铂先导化合物。先导化合物具有强抗肿瘤增殖及抗肿瘤转移活性，肿瘤靶向性强，且体内毒性较低。该项目的顺利开展，为新型铂类药物的研发提供借鉴与思路，具有重要的学术研究意义和实际应用价值。