METAL (RU) AND LIGAND K-EDGES (S, CL) AND METAL L-EDGE (RU) INVESTIGATION OF ANT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们提出了一个系统的多边XANES研究来确定与体外活性相关的基于Ru的抗癌金属药物的光谱特征。这将使从化学结构预测生物功能成为可能，从而辅助药物设计和优化过程。在配体(S和氯)K-和金属(Ru)L边收集的光谱信息将提供对Ru(II)和Ru(III)配合物的电子结构的深入了解。此外，还将对结构不明确的溶液样品进行金属(Ru)K边光谱的EXAFS分析。我们合成了大量的Ru(III)和Ru(II)与二甲基亚砜、氯化物、咪唑和吲唑的配合物。我们已经获得了一些配合物的ClK边和Ru L边数据，并确定了可能作为生物活性特征的光谱特征。我们计划将这些研究扩展到我们的Ru复合体文库的10个成员，在中性和酸性(癌细胞)pH条件下，纯固体、水解态、DNA和蛋白质结合形式。这些体外模拟研究有可能为未来的体内研究提供基础。此外，体外测量将补充电子结构计算，以帮助指定光谱，并为获得溶液样品的结构信息提供合理的依据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose a systematic multi-edge XANES study to determine spectroscopic signatures for Ru-based anticancer metallodrugs that correlate with in vitro activity. This would make possible the prediction of biological function from chemical structure and thus aid the drug design and optimization process. Spectral information collected at the ligand (S and Cl) K- and metal (Ru) L-edges will provide insights into the electronic structure of Ru(II) and Ru(III) complexes. These will be supplemented with EXAFS analysis of metal (Ru) K-edge spectra for structurally ill-defined solution samples. We have synthesized a large library of Ru(III) and Ru(II) complexes with dimethylsulfoxide, chloride, imidazole, and indazole ligands. We have already obtained Cl K-edge and Ru L-edge data for some of the complexes and identified spectral features that could be candidates for signatures of biological activity. We plan to extend these studies to ten members of our Ru complex library in pure solid, hydrolyzed, DNA, and protein bound forms at neutral and acidic (cancerous cells) pH conditions. These in vitro modeling studies have the potential to provide the base of future in vivo studies. Also, the in vitro measurements will be supplemented with electronic structure calculations to aid the spectral assignments and provide rational for the structural information obtained for solution samples.