嘧啶羧酸类双光子吸收有机锡氧簇合物的制备及抗癌活性研究

Low cost ans high efficient preparation of novel drugs with anticancer activities play a key scientific role due to their potential applications. Strong two-photon absorption organooxotin cluster in the near infrared region will be designed and synthesized in this project. Two-photon absorption materials can absorb low-energy photons with strong penetrability and highest spatial resolution. In this proposal, the novel pyrimidine ligands will be designed and synthesized based on the theoretical calculation, and then reacted with Ph3Sn(OH) and nBu6Sn2O based on coordination chemistry, thus obtaining a series novel organooxotin cluster with two-photon absorption properties. The interface transport mechanism, energy transfer mechanism, as well as the combination mode between organooxotin cluster and DNA will be discovered in detail utilizing the time-resolved fluorescent spectroscopy, tunable ultra-fast laser technology and quantum chemistry calculation. The binding model of bioactive organooxotin clusters and DNA molecules will be established as well as the mechanism of organooxotin clusters and tumor cells will be researched using two photon confocal technique.The drug delivery systems will be designed for targeting different tumor tissues by modifying directional target molecules. In order to provide new ideas and methods for designing, synthesis and application of the excellent two-photon organooxotin clusters on cancer therapy, the antitumor activity and mechanism of them will be studied.

低成本制备高效抗癌活性新型药物具有重要的科学意义和潜在的应用价值。本项目拟设计合成具有近红外吸收的强双光子吸收有机锡氧簇合物。利用双光子吸收材料能吸收低能量光子，穿透力强，有极高的空间分辨力等优点，设计合成结构新颖的生物相容性嘧啶类小分子有机配体，根据配位选择性和立体结构特点，与有机锡氧化物或氢氧化物反应合成新型双光子嘧啶类锡氧簇合物。项目研究利用时间分辨荧光光谱、可调谐超快速激光光谱等先进技术，结合量子化学计算，探讨簇合物组分之间的能量传递过程、电子跃迁机制及双光子增强效应等光物理性质。建立具有生物活性有机锡氧簇合物分子与DNA的结合模型，利用双光子共聚焦技术研究锡氧簇合物与肿瘤细胞作用的机理。通过修饰不同靶向分子，设计针对不同肿瘤组织的靶向递药系统。研究综合性能优秀的嘧啶类双光子锡氧簇合物的抗癌活性及机理，为新型抗癌活性有机锡氧簇合物材料的设计制备、机理研究及应用提供新思想和新方法。

双光子吸收材料在生命科学和医学领域有着广阔的应用前景。本文以易与金属配位，且易修饰的有机羧酸衍生物为配体，设计合成了一系列有机锡配合物，理论结合实验系统研究配体和配合物的光物理性质和构效关系，基于配合物的双光子性质及生物相容性深入探索了它们在生命科学领域的应用。.1.以单羟基氰基羧酸衍生物为母体设计合成一系列双光子有机锡配合物C1Sn1, C1Sn2，开孔Z扫描测试结果表明C1Sn2具有较大的有效双光子吸收截面，且激发波长在近红外区。C1Sn2具有细胞核选择性，活体肿瘤实验结果表明C1Sn2具有良好的抗肿瘤效果。.2.以双羟基氰基羧酸衍生物为母体设计合成一系列双光子有机锡配合物C2Sn1, C2Sn2, 研究结果表明配合物 C2Sn2显示出较高的有效双光子吸收截面，且激发波长在近红外区。双光子共聚焦显微成像结果表明配合物 C2Sn2可以很好的被细胞摄取，作用在线粒体区域。配合物 C2Sn2诱导细胞凋亡的机理是改变线粒体膜电位并提高细胞内的活性氧含量。.3.通过简单高效的方法设计合成了两种双光子Ir-Sn异核配合物(IrSn1，IrSn2)。IrSn1能够快速、专一的识别酪氨酸。利用双光子共聚焦成像和高分辨显微镜(STED)成像技术，研究IrSn1在细胞内识别酪氨酸，靶向细胞核，半定量检测细胞核内的酪氨酸含量。抗癌测试结果表明IrSn1具有更好的抗肿瘤活性。