基于H.Sigel溶液中弱作用的晶体分子构筑与性能研究

The means of solution chemistry and crystal chemistry are firstly used to characterize the π-π stacking. It is mutual penetration, complementary,integrated and is supplemented by new optimization model of quantum chemistry, to comprehensive evaluate the relationship between the strength of weak interactions and the lengths of aliphatic chain, and to achieve the goal of supporting the weak interaction with each other. The quantum calculation molecular packing model is used to study the system of mononuclear MAiBj (M is a metal ion; A is the controlled alkylbenzene malonato ligands; B is fixed as the aromatic nitrogen bases ligands; i, j is the coordination number, the below is same) and dinuclear MM′AiBj (M 'is also a metal ion, M = M' or M ≠ M '; B is the controlled 2,2'-dialkyl malonato ligand) which is based the token constants from H.Sigel, to determine the weak chemical bonds share of compounds in solution. It aim is characterization of the spatial orientation of the weak chemical bonds of crystalstructures, exploring the main factors such as π-π stacking weak interactions, and establish-ing the new relationship between the changes of centroid distance (d), dihedral angle (θ) and the lengths of aliphatic chain. The changes of complex structures can make the differences of inhibitory activity of tumor cells, and affect the action mechanism with targeting DNA, providing the valuable information for the further study of the inorganic drugs.

率先将溶液化学和晶体化学两种表征π-π堆积弱作用的研究手段相互渗透、相互补充，融为一体，并以量子化学优化模型为辅助，系统综合评价弱相互作用强度与调控脂肪链长短之间的相关性，以实现弱作用相互佐证的目标。以单核MAiBj（M为金属离子；A为调控的苯烷基丙二酸类配体，下同；B固定为芳香氮碱类配体；i、j为配位数，下同）和双核MM′AiBj（M′亦为金属离子，M= M′或M≠M′;B为可调控的2,2′-烷基二丙二酸类配体）为研究体系，由量化计算优化出分子堆积模型，基于H.Sigel奠定的标度常数，测定溶液中配合物弱化学键份额。表征晶体分子结构中弱化学键的空间取向，探究以π-π堆积为主要弱作用的影响因素，建立质心距（d）、二面角（θ）数值微变与调控脂肪链长短之间新的构效关系。配合物结构的变化可以导致其对肿瘤细胞的抑制活性的差异，并影响到靶向DNA的作用机制，为无机药物的深入研究提供有价值的信息。

课题组已严格按项目研究计划进行。自己合成或者市购所需配体，通过常温挥发法、溶剂扩散法、水热法和微波反应法等技术，制备出系列配合物30个，并通过元素分析、质谱、红外光谱、核磁共振谱等表征手段对配合物的组成和结构进行表征。通过体外活性，细胞凋亡等实验结果，筛选出对HeLa、KB等肿瘤细胞活性接近或优于顺铂的先导型化合物3个。采用荧光法、紫外光谱法和凝胶电泳法测定了部分化合物与核酸DNA分子的作用，明确不同结构类型的活性配合物与DNA的作用机制，包括非共价结合和共价结合两种模式。以分子对肿瘤细胞的体外酶标比色检测方法为先期活性评价指标，结合流式细胞手段、电泳技术、荧光探针技术和晶体学结构衍射技术等多项检测方法，达到相互补充、相互印证，综合系统评价了化合物的活性和DNA靶向作用的共价和非共价机理。研究更科学、全面，对无机抗肿瘤配合物的设计和生物学功能评价体系具有重要的意义和启示。