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

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。 本研究的最终目的是合成和表征新的钌和铜络合物，目的是优化它们与DNA相互作用的能力，并建立它们破坏细胞增殖的能力。过渡金属离子在生物系统中发挥的关键作用已得到充分证实，过渡金属配合物在临床医学（包括肿瘤学）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，重要的是要合成新类别的抗癌剂和新的潜在药物的设计越来越多地集中在钌配合物。[（芳烃）Ru（XY）Cl]+（XY =乙二胺）是一类新型的有机金属钌配合物。铜也长期用于医学应用，自20世纪60年代以来，一些铜络合物的抗肿瘤特性已经被人们所知。钌化合物的细胞毒性机制尚未确定。核酸，特别是DNA，被认为是高概率的目标。本研究旨在研究有机金属和无机钌和铜配合物的化学和生物学性质。我们的目标是建立，我们可以制备类型的配合物[Ru（芳烃）（XY）Cl]+，可以结合到DNA在一个主要的嵌入方式。在这些配合物中，XY是一类配体，其包括生物学上具有战略意义的缩氨基硫脲（TSC）。缩氨基硫脲具有广泛的生物效应，如抗病毒、抗肿瘤和抗癌特性，我们期望通过与有机金属钌部分偶联或与铜中心连接来改善生物活性。我们将进行许多实验以探测与核酸结合的模式以及强度。我们还希望证明该复合物对癌细胞具有细胞毒性，并且能够在体外防止增殖。使用的方法包括吸收光谱法、热变性研究、电化学和粘度测量。将进行确定动力学和热力学数据的机制研究。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。这对于这些和其他癌症化疗的进一步发展至关重要。

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.