新型Valen类多席夫碱有机铋配合物的合成及其生物热动力学研究

The research on the coordination complexes of transition metal elements or rare earths with organic ligands has received much attention in recent years. However, the coordination chemistry of the complexes with main group metal elements as central ions and organic compounds as ligands has been less explored. On the other hand, bismuth resources in Chenzhou is abundant, and its quality and grade are absolutely the best not only in China but also in the world. In order to make full use of this superiority and promote the development and utilization of bismuth resources, this project plans to carry out a series of researches of the coordination complexes with main group metal element- - -bismuth as central ion and Valen multi-shiff base as ligands. The researches mainly include synthesis, characterization, basic thermodynamic properties, the antibacterial and antitumor bioactivities,and their mechanism. Moreover, this project will also focus on exploring the relationship between the bioactivities and structural characteristics of the coordination complexes. In this work, the biothermokinetic methods (e.g. microcalorimetry and thermal analysis, etc.) and the medical molecular biological methods (e.g. microdilution, cell staining, flow cytometry, electron microscope, fluorescence spectrum, gel electrophoresis, etc.) will be employed to be as the main research techniques. It is expected that, by performing this research, a novel ideas and methods for drugs screening and medicine development may be explored from the combination of the biothermokinetic methods and the medical molecular biological methods, which are featured with fast, efficient, low cost, and high reproducibility. These methods may be potentially useful in drugs screening. In addition, this work may promote the intercross between the chemistry and life science, enrich and develop the basic theory of biothermokinetics, and consequently has theoretical instructive significance and application values for the development of nontoxic bismuth-based drug candidates with potent antibacterial, antitumor activities.

有机配体与过渡金属和稀土金属形成配合物的研究相当活跃，而有机配体与主族金属的配位化学研究却很少。另一方面，湖南郴州的铋资源，无论是从储量、品位，不仅在中国而且在世界都是第一。为了充分利用这一奇特资源，加大铋产品的开发利用。本项目拟主要研究Valen类多席夫碱与主族金属铋形成的配合物的合成、表征、基础热力学性质以及抗菌、抗肿瘤活性和作用机制，并对配合物的结构与活性之间的构效关系及其规律性进行深入研究。主要采用生物热动力学方法（微量量热法和热分析法）和医学分子生物学方法（微量稀释法、细胞染色、流式细胞术、电镜、荧光光谱和凝胶电泳等）开展实验研究工作，通过本项目的实施将提出基于生物热动力学方法与医学分子生物学方法相结合的药物筛选研究新思路和新方法。这对促进化学和生命科学的相互交叉渗透，丰富和发展生物热动力学的理论基础以及开发寻找高效无毒抗菌抗肿瘤新型含铋药物具有重要的科学意义和应用价值。

本课题以邻香草醛与乙二胺、甲氧苄啶、邻苯二胺、组氨酸、2,6-二氨基吡啶、胱氨酸、甘氨酸、精氨酸、二氨基硫脲、间苯二胺、2,3-二氨基吡啶、吡啶-2,3-二甲酰胺、4溴吡啶-2,6-二甲酰胺、2-氨基-4，6-二甲基吡啶等含有氨基的化合物反应合成了14种Valen 席夫碱配体；并将这些席夫碱与铋离子和稀土离子合成了十余种席夫碱铋（或稀土）配合物；还利用水杨酸、8-羟基喹啉、烟酸、邻菲罗啉等有机小分子与铋、稀土离子合成了28种铋、稀土配合物；此外，还优化合成了抗肿瘤药物去甲二氢愈创木酸及其衍生物。借助于元素分析、X-射线单晶衍射、核磁共振、质谱、红外光谱、紫外光谱、热重分析、摩尔电导和化学分析等手段对合成的各种物质进行结构和组成的表征。应用溶解量热法或燃烧热法研究了其部分化合物的标准摩尔生成焓。应用荧光法和紫外光谱等光谱方法研究了部分化合物与牛血清白蛋白(BSA)的相互作用。应用TAM air等温量热仪，初步地研究了部分席夫碱、配合物及去甲二氢愈创木酸及其衍生物对酵母细胞、K562细胞、HeLa细胞、幽门螺杆菌（H. pylori）、大肠杆菌、金黄色葡萄球菌、枯草芽孢杆菌等细胞细菌的抑制活性。以SRC-100型溶解-反应量热计为基础, 将其改进成一种精密等温微量燃烧-溶解-反应热量热计。该量热计集燃烧能、溶解能和反应能测定于一体, 水槽温度可控制在（298.15 ± 0.001）K, 温度测量的精度达到±0.0001 K，弹的有效体积约8.5 cm3，样品用量大约5-20 mg。燃烧能的测量不确定度小于0.04%、精度高于0.05%。该项目获得了如下科研成果：授权发明专利1项、申请发明专利2项；撰写了33篇论文，已发表论文30篇（其中19篇被SCI收录、4篇被北大中文核心期刊和CSCD收录、会议论文3篇）、已接受2篇。获湖南省第十五届自然科学优秀学术论文奖贰等奖1项。

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