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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 我们提出了一个系统的多边缘XANES研究，以确定光谱签名的钌基抗癌金属药物，在体外活性相关。这将使从化学结构预测生物功能成为可能，从而有助于药物设计和优化过程。在配体（S和Cl）的K-和金属（Ru）的L-边缘收集的光谱信息将提供深入了解Ru（II）和Ru（III）配合物的电子结构。这些将补充EXAFS分析的金属（Ru）K-边缘光谱的结构不明确的解决方案样品。我们已经合成了一个大的图书馆钌（III）和钌（II）配合物与二甲亚砜，氯化物，咪唑，和吲唑配体。我们已经获得了Cl K-边缘和Ru L-边缘数据的一些配合物和确定的光谱特征，可能是候选人的签名的生物活性。我们计划将这些研究扩展到纯固体，水解，DNA和蛋白质结合形式在中性和酸性（癌细胞）pH条件下的Ru络合物库的10个成员。这些体外模型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，以帮助光谱归属，并为溶液样品获得的结构信息提供依据。

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.