基于多重设计策略的蒽腙-铂(II)抗肿瘤配合物与作用机制研究

The classic platinum(II)-based and anthracycline antitumor drugs hold important position in the clinical chemotherapy, both of which encountering two problems as the high toxicity and the multiple drug resistance (MDR). Designing and searching for new antitumor drugs with high activity and low toxicity are urgently required. Based on the new concepts and new methods in the modern antitumor drug design, such as targeting and precursor drugs, multi-targeting and multiple action mechanism, the anthracene hydrazone and platinum(II) are combined as the dual-core for antitumor activity, to synthesize a series of antitumor platinum(II) complexes of anthracene hydrazone modulated by different functional groups. The anthracene hydrazone groups are further introduced a classic solubilization group (glucose group or sulfonic acid group) via the imine C=N double bonding mode, to afford the corresponding precursor complexes showing hydrophilicities and low toxicities. And the hydrolytic tendency of the imine bond in weakly acidic tumor micro-environment will help the precursor complexes to hydrolyze more easily to give the original complexes, so that the target antitumor effect can be achieved. The antitumor activity and mechanism of these complexes will be studied and the effectiveness will be evaluated on the molecular/cellular levels and in murines. And the action mechanism for the key metal complexes aiming to the related tumoral drug resistant targets and pathways will be also examined. This research will provide creative thoughts and practical experiences for the researches on new metal-based antitumor drugs.

经典铂类和蒽环类抗肿瘤药物在临床化疗中占有重要地位，但毒副作用和肿瘤多药耐药是两类药物面临的主要问题，因此迫切需求高效低毒、能有效克服肿瘤耐药的新型药物。本项目结合现代抗肿瘤药物研究中的靶向作用与前体药物、多靶点/多重作用机制等新理念、新方法，通过配位化学方法将蒽腙与铂(Ⅱ)两个抗肿瘤活性中心有机结合，以亚胺基联接引入减毒/增溶基团并利用其水解的pH敏感性形成对肿瘤组织弱酸性微环境的靶向性，在不同功能基团和离去基团调控下，设计合成具有高效低毒、肿瘤组织靶向性和复合作用机制特点的蒽腙-铂(Ⅱ)系列抗肿瘤配合物。分别从分子/细胞/动物水平上开展抗肿瘤机制研究；并针对相关肿瘤耐药靶点和通路初步评价配合物克服肿瘤耐药的有效性，为新型金属基抗肿瘤药物研究提供创新思路和实践经验。