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.
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