METAL-BASED ANTICANCER AGENTS: CHEMISTRY, BIOLOGY AND MEDICINE

金属抗癌剂：化学、生物学和医学

• 批准号: 8359810
• 负责人: FLOYD A BECKFORD
• 金额: $ 10.72万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359810
• 关键词: Antineoplastic Agents; Area; Arkansas; Binding; Biological; Biology; Biomedical Research; Cell Proliferation; Cells; Chemicals; Chemistry; Complex; DNA; Dose-Limiting; Drug Delivery Systems; Enzymes; Fostering; Funding; Goals; Grant; In Vitro; Ligands; Medicine; Metals; National Center for Research Resources; Nucleic Acids; Pharmaceutical Chemistry; Pharmaceutical Preparations; Platinum; Principal Investigator; Probability; Property; Proteins; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Ruthenium; Ruthenium Compounds; Source; System; Thiosemicarbazones; Toxic effect; United States National Institutes of Health; base; cancer cell; career; cellular targeting; cost; cytotoxic; cytotoxicity; design; drug candidate; interest; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The ultimate aim of this research is to synthesize and characterize new ruthenium complexes with the goal of optimizing their ability to interact with DNA and other cellular receptors and establishing their ability to disrupt cell proliferation. The most well-known metal-containing drugs are platinum-based, but, due to their dose-limiting toxicity, it is important to synthesize new classes of anticancer agents. Current research is aimed at the design of new drugs that have enhanced potency, are less toxic, and have a wider spectrum of indication. Such research is increasingly focused on ruthenium complexes and a new class of organometallic ruthenium complexes, [(arene)Ru(LL)Cl]+ (LL = bidentate or monodentate ligands), have been reported to show significant cytotoxic and/or anti-metastatic activity. The mechanism of cytotoxicity for ruthenium compounds has not been equivocally established. The nucleic acids, particularly DNA, are commonly accepted as high- probability targets (similar to the platinum drugs); however proteins and various enzyme systems may also serve as drug targets. The identification of cellular targets is important for further refining strategy when designing drug candidates. This research will investigate the chemical and biological properties of organometallic ruthenium complexes. We have already established that we can prepare complexes of the type [(arene)Ru(LL)Cll]+, where LL is a biologically strategic thiosemicarbazone. These complexes are cytotoxic to cancer cells and can bind to DNA. We will continue to probe the mode as well as strength of binding to DNA. We will also investigate the possibility that our complexes are interacting with biomolecules other than DNA. We will show that the complexes are cytotoxic to cancer cells and are able to suppress proliferation in vitro. In addition, we will examine the cytotoxic effects of the complexes on non-tumorigenic cells. This project is very much in line with the INBRE core principles. The project will enable the undergraduate researchers to participate in a cutting-edge area of medicinal chemistry. This will hopefully foster an interest in graduate studies and the wide diversity of careers in biomedical research.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这项研究的最终目的是合成和表征新的钌络合物，目的是优化它们与DNA和其他细胞受体相互作用的能力，并建立它们破坏细胞增殖的能力。最知名的含金属药物是铂类药物，但由于其剂量限制性毒性，合成新类型的抗癌药物非常重要。目前的研究旨在设计具有增强效力，毒性较小，适应症范围更广的新药。此类研究越来越多地集中在钌配合物上，并且据报道一类新型有机金属钌配合物[（芳烃）Ru（LL）Cl]+（LL =双齿或单齿配体）显示出显着的细胞毒性和/或抗细胞毒性。转移活性。钌化合物的细胞毒性机制尚未明确确定。核酸，特别是DNA，通常被认为是高概率的靶点（类似于铂类药物）;然而，蛋白质和各种酶系统也可以作为药物靶点。在设计候选药物时，细胞靶点的鉴定对于进一步改进策略是重要的。本研究将探讨有机金属钌配合物的化学及生物性质。我们已经确定，我们可以制备[（芳烃）Ru（LL）Cll]+类型的配合物，其中LL是生物学上具有战略意义的缩氨基硫脲。这些复合物对癌细胞具有细胞毒性，并且可以与DNA结合。我们将继续探索与DNA结合的方式和强度。我们还将研究我们的复合物与DNA以外的生物分子相互作用的可能性。我们将证明该复合物对癌细胞具有细胞毒性，并且能够抑制体外增殖。此外，我们将研究的复合物对非致瘤细胞的细胞毒性作用。该项目非常符合INBRE的核心原则。该项目将使本科研究人员能够参与药物化学的前沿领域。这将有望培养研究生学习的兴趣和生物医学研究职业的广泛多样性。