基于靶向性抗肿瘤前药策略设计2(1H)-喹啉酮希夫碱-磷酸酯-镧系配合物及其作用机制研究

为了改善金属抗肿瘤配合物的毒副作用大、生物利用度低和耐药性等问题，本项目拟在前期研究基础上，通过靶向性前药设计策略，以具有天然活性成分骨架和潜在抗肿瘤活性的2(1H)-喹啉酮希夫碱衍生物为活性骨架，经过结构修饰后，设计引入靶向性前药基团氨基磷酸酯，并通过抗肿瘤活性筛选活性优良且毒性小的2(1H)-喹啉酮希夫碱-磷酸酯化合物作为配体，再与镧系金属配位，制备出系列2(1H)-喹啉酮希夫碱-磷酸酯-镧系配合物，然后开展抗肿瘤活性筛选和毒理试验，并进一步基于细胞诱导凋亡作用机制、细胞增殖周期的变化、与潜在靶点分子（DNA、酶）的相互作用等对候选配合物的作用机制进行研究，最终筛选出具有较明确的靶点和作用机制的高效、低毒的新型金属基抗肿瘤配合物。

In order to improve the serious side-effect, low bioavailability and resistence of metallic antitumor complex, 2-oxo-quinolinone Schiff base derivatives, which contain a natural active skeleton and have potential antitumor activity, are modified and then connected with functional group amino-phosphate to offer 2-oxo-quinolinone Schiff base-phosphate derivatives, based on targeted prodrug principle and our previous research. In addition, their antitumor activities are tested. Some compounds which show excellent activity and low toxicity are then selected as ligand to coordinate with lanthanide metal to provide 2-oxo-quinolinone Schiff base-phosphate-lanthanide complex. The antitumor activity screening experiment and toxicological test are then performed, while the apoptosis inducing effect, the changes of cell proliferation cycle, as well as the interaction with target molecule (such as DNA and enzymes), are also studied to investigate the action mechanism. Finally, some novel highly active and low toxic novel metallic antitumor complexes with clear targets and action mechanism are obtained.