EXPLORING AND DEFINING THE ROLE OF LIGAND OXIDATION IN RU(II) ARENE-BASED DRUGS

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。 界定和了解药剂的作用机制是一项持续的研究挑战，需要关于这些药物在生物环境中的反应性的详细信息。对于基于金属的候选药物来说，挑战通常更加复杂，因为它们具有更广泛的反应性，在运输到生物靶标的过程中发生相互作用的可能性也相应更大。我们正在研究一系列具有抗肿瘤活性的基于Ru的药物靶点的基本生化性质。形式为[Ru(Ar)(En)L]X的Ru芳烃配合物已显示出优异的抗癌活性，但L的性质对生物活性有重要但有些不可预测的影响。我们特别注意到硫代配合物(L=RS-)在酸性和氧化条件下具有极高的生物活性。这些络合物的不同氧化形式(例如L=RSO-、RSOH、RSO2-、RSO2H)及其相关的硒类似物的性质目前正在探索中，并显示出不寻常的成键特征，据信这与它们的生物活性非常相关。因此，我们建议使用S K边和Se K边XAS(以及适当的其他配体K边)来评估这些物种和相关物种中Ru-X键的性质。

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. Defining and understanding the mechanisms of action of pharmaceutical agents is an ongoing research challenge that requires detailed information on the reactivity of these drugs within a biological environment. The challenge is generally more complex for metal-based drug candidates due to their broader reactivity and the correspondingly greater possibilities for interactions during transport to the biological target. We are investigating the fundamental biochemical properties of a series of ruthenium-based drug targets with demonstrated antitumor activity. Ru arene complexes of the form [Ru(ar)(en)L]X have shown excellent activity as anticancer agents but the nature of L has an important, yet somewhat unpredictable effect on bioactivity. We note particularly that thiolato complexes (L=RS-) are extremely bioactive under acidic and oxidative conditions. The properties of different oxidized forms of these complexes (e.g. L=RSO-, RSOH, RSO2-, RSO2H) and their related selenium analogs are currently being explored and show unusual bonding characteristics that are believed to be very relevant to their bioactivity. We therefore propose to utilize S K-edge and Se K-edge XAS (as well as other ligand K-edges where appropriate) to evaluate the nature of Ru-X bonding in these and related species.