METAL-BASED ANTICANCER AGENTS: CHEMISTRY, BIOLOGY AND MEDICINE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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Ru配合物，目标是优化它们与DNA和其他细胞受体相互作用的能力，并建立它们干扰细胞增殖的能力。最广为人知的含金属药物是以铂为基础的，但是，由于它们的剂量限制毒性，合成新的抗癌药物是很重要的。目前的研究旨在设计出效力更强、毒性更低、适应症范围更广的新药。这方面的研究越来越多地集中在Ru配合物上，一类新型的有机金属Ru(LL)配合物[(芳烃)Ru(LL)Cl]+(LL=双齿或单齿配体)被报道显示出显著的细胞毒活性和/或抗转移活性。Ru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靶标(类似于铂类药物)；然而，蛋白质和各种酶系统也可能是药物靶标。在设计候选药物时，细胞靶标的识别对于进一步完善策略非常重要。本研究将研究有机金属Ru络合物的化学和生物学性质。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是一种具有生物战略意义的缩氨基硫脲。这些复合体对癌细胞具有细胞毒性，并能与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络合物与DNA以外的生物分子相互作用的可能性。我们将证明这些化合物对癌细胞具有细胞毒性，并能够在体外抑制细胞增殖。此外，我们还将研究这些化合物对非致瘤细胞的细胞毒作用。该项目非常符合INBRE的核心原则。该项目将使本科生研究人员能够参与药物化学的前沿领域。这将有望培养人们对研究生学习的兴趣，以及生物医学研究中广泛多样的职业。

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.