ANTICAN THIOSEMICARBAZONE COMPXS OF RUTHENIUM&COPPER/SYNTHESIS BIOCHEM&CELLULAR

钌抗硫缩氨基脲络合物

• 批准号: 7959439
• 负责人: FLOYD A BECKFORD
• 金额: $ 9.62万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959439
• 关键词: Antineoplastic Agents; Antiviral Agents; Arkansas; Binding; Biological; Biomedical Research; Carboplatin; Cell Proliferation; Chemicals; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Medicine; Complex; Computer Retrieval of Information on Scientific Projects Database; Copper; Coupling; DNA; Data; Development; Ethylenediamines; Funding; Goals; Grant; In Vitro; Institution; Ions; Kinetics; Knowledge; Ligands; Measurement; Medical; Methods; Nucleic Acids; Pharmaceutical Preparations; Platinum; Play; Probability; Property; Reporting; Research; Research Personnel; Resources; Role; Ruthenium; Ruthenium Compounds; Source; Spectrum Analysis; Thermodynamics; Thiosemicarbazones; Transition Elements; United States National Institutes of Health; absorption; base; biological systems; cancer cell; cytotoxic; cytotoxicity; design; improved; metal complex; neoplastic; oncology; prevent; research study

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. The ultimate aim of this research is to synthesize and characterize new ruthenium and copper complexes with the goal of optimizing their ability to interact with DNA and to establish their ability to disrupt cell proliferation. The key roles that transition metal ions play in biological systems are well established and transition metal complexes are finding increasing usage in clinical medicine including oncology. The platinum-based anticancer drugs cisplatin and carboplatin are the most well known. However, it is important to synthesize new classes of anticancer agents and the design of new potential drugs is increasingly focused on ruthenium complexes. A new class of organometallic ruthenium complexes, [(arene)Ru(XY)Cl]+ (XY = ethylenediamine) have been reported to show significant cytotoxic activity. Copper too has long been used in medical applications and the antitumor properties of some copper complexes have been known since the 1960s. The mechanism of cytotoxicity for ruthenium compounds has not been established. Nucleic acids, particularly DNA, are considered a high probability target. This research is designed to investigate the chemical and biological properties of organometallic and inorganic ruthenium and copper complexes. We aim to establish that we can prepare complexes of the type [Ru(arene)(XY)Cl]+ that can bind to DNA in a predominantly intercalating fashion. In these complexes XY is a class of ligand that includes biologically strategic thiosemicarbazones (TSCs). Thiosemicarbazones have a versatile range of biological effects such as antiviral, anti-neoplastic and anticancer properties, and we expect to see improved biological activity by coupling with the organometallic ruthenium moiety or attachment to a copper center. We will carry out a number of experiments in order to probe the mode as well as strength of binding to the nucleic acid. We expect to also show that the complexes are cytotoxic to cancer cells and are able to prevent proliferation in vitro. The methods to be used include absorption spectroscopy, thermal denaturation studies, electrochemical and viscometric measurements. Mechanistic studies to determine kinetic and thermodynamic data will be done. Successful completion of these goals will add to the body of knowledge concerning inorganic anticancer agents and will deepen our understanding of the mechanisms occurring at the cellular level. This is crucial for further development of these and other cancer chemotherapies.

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。 这项研究的最终目的是合成和表征新的Ru和铜络合物，目的是优化它们与DNA相互作用的能力，并建立它们干扰细胞增殖的能力。过渡金属离子在生物系统中扮演的关键角色已经确立，过渡金属络合物在包括肿瘤学在内的临床医学中的应用越来越多。以铂为基础的抗癌药物顺铂和卡铂是最知名的。然而，合成新的抗癌药物是非常重要的，设计新的潜在药物越来越集中在Ru的络合物上。一类新型金属有机金属配合物[(芳烃)Ru(XY)Cl]+(XY=乙二胺)具有显著的细胞毒活性。铜也长期用于医疗应用，自20世纪60年代以来，一些铜配合物的抗肿瘤特性就已为人所知。Ru化合物的细胞毒性机制尚未确定。核酸，特别是DNA，被认为是一个高概率的目标。本研究旨在研究有机金属和无机Ru、Cu络合物的化学和生物学性质。我们的目标是确定我们可以制备[Ru(芳烃)(XY)Cl]+类型的配合物，它可以以插层方式主要与DNA结合。在这些配合物中，XY是一类具有生物战略意义的缩氨基硫脲(TSCs)配体。缩氨基硫脲具有广泛的生物学效应，如抗病毒、抗肿瘤和抗癌特性，我们希望通过偶联有机金属Ru部分或连接到铜中心来提高生物活性。我们将进行一系列实验，以探索与核酸结合的方式和强度。我们希望还能证明这些化合物对癌细胞具有细胞毒性，并能够防止体外增殖。所使用的方法包括吸收光谱、热变性研究、电化学和粘度学测量。将进行确定动力学和热力学数据的机理研究。这些目标的成功完成将增加关于无机抗癌剂的知识体系，并将加深我们对细胞水平上发生的机制的理解。这对这些和其他癌症化疗药物的进一步发展至关重要。