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

探索和定义配体氧化在 RU(II) 芳烃类药物中的作用

• 批准号: 8170118
• 负责人: PIERRE KENNEPOHL
• 金额: $ 0.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170118
• 关键词: Antineoplastic Agents; Biochemical; Biological; Characteristics; Complex; Computer Retrieval of Information on Scientific Projects Database; Drug Delivery Systems; Environment; Funding; Grant; Institution; Ligands; Nature; Pharmaceutical Preparations; Pharmacologic Substance; Property; Research; Research Personnel; Resources; Role; Ruthenium; Selenium; Series; Source; United States National Institutes of Health; analog; base; drug candidate; metal complex; oxidation

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.

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 定义和理解药物的作用机制是一个持续的研究挑战，需要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，挑战通常更复杂，因为它们具有更广泛的反应性，并且在运输到生物靶标期间发生相互作用的可能性相应更大。我们正在研究一系列已证实具有抗肿瘤活性的基于顺铂的药物靶点的基本生物化学性质。[Ru（ar）（en）L]X形式的Ru芳烃配合物已经显示出作为抗癌剂的优异活性，但是L的性质对生物活性具有重要但有些不可预测的影响。我们特别注意到，硫羟配合物（L=RS-）在酸性和氧化条件下具有极强的生物活性。目前正在探索这些络合物的不同氧化形式（例如L=RSO-、RSOH、RSO 2-、RSO 2 H）及其相关硒类似物的性质，并显示出被认为与其生物活性非常相关的不寻常的键合特征。因此，我们建议利用S K-边和Se K-边XAS（以及其他配体K-边，在适当的情况下），以评估这些和相关物种的Ru-X键合的性质。