Biologically Active Metal Complexes: New Designs Inspired by Mechanistic Studies

生物活性金属配合物：受机理研究启发的新设计

• 批准号: RGPIN-2017-04979
• 负责人: Walsby, Charles
• 金额: $ 2.55万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748146
• 关键词: Biologically; Active; Metal; Complexes; New

We are developing new metal complexes as probes of biological processes and for therapeutic applications. To do this, we design and synthesize molecules and study their reactions in biological environments using spectroscopic methods. These studies will produce compounds that address a primary challenge in cancer research: how to preferentially target cancer cells while leaving normal cells unaffected. This work involves three interrelated themes:1) In vitro spectroscopy of metal complexesTo explain why some ruthenium and copper complexes have anticancer activity, we will develop spectroscopic techniques to investigate their reactions in cancer cells. One approach will probe interactions of Cu complexes with biomolecules such as proteins and DNA, and processes that lead to the generation of active species. These studies will apply the techniques electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) to analyze reactions of complexes in whole cells. Another approach will use magnetic resonance imaging (MRI) of Ru complexes containing fluorine to study the effects of low-oxygen environments in tumors. These methods will be used to study the mechanisms of action of new compounds synthesized in our laboratory.2) Complexes targeting transport into cellsWe are developing new metal complexes towards the goal of anticancer agents that have higher activity and lower side effects. To achieve this we are tethering metal complexes to biological compounds that enhance their transport into cells. Many cancer cells have elevated levels of proteins that recognize and internalize specific biomolecules. For example, the iron-transport protein transferrin (TF) is taken up preferentially by many cancer cells. By linking metal complexes to amino acids of TF we will generate new anticancer species and study the protein-mediated transport process. Rapidly growing cancer cells can also have higher levels of vitamin transport proteins. We will harness this property using vitamin molecules linked to metal complexes. A third approach will use short amino acid chains to promote the transport and targeting of metal compounds into cancer cells. 3) Selectively activated metal complexesDifferences in biological processes in normal and cancer cells mean that metal complexes can undergo distinct reactions in each environment. We are developing Cu and Ru complexes that generate toxic species in the low-oxygen environments found in many tumors, while remaining inactivated in blood or normal tissues. We are also targeting elevated levels of sulfur-containing molecules that are found in many cancer cells. This involves the development of complexes that release nitric oxide, which can be toxic to cells at high concentrations. These compounds will lead to new therapeutics that preferentially kill cancer cells and also can act as probes of biological processes related to tumor growth.

我们正在开发新的金属配合物作为生物过程的探针和治疗应用。为此，我们设计和合成分子，并使用光谱方法研究它们在生物环境中的反应。这些研究将产生解决癌症研究中主要挑战的化合物：如何优先靶向癌细胞，同时不影响正常细胞。本论文的工作涉及三个相互关联的主题：1）金属配合物的体外光谱研究为了解释某些钌和铜配合物具有抗癌活性的原因，我们将发展光谱技术来研究它们在癌细胞中的反应。一种方法将探测Cu络合物与生物分子（如蛋白质和DNA）的相互作用，以及导致活性物质产生的过程。这些研究将应用电子顺磁共振（EPR）和电子核双共振（ENDOR）技术来分析整个细胞中复合物的反应。另一种方法将使用含氟钌络合物的磁共振成像（MRI）来研究低氧环境对肿瘤的影响。这些方法将用于研究我们实验室合成的新化合物的作用机制。2）靶向转运到细胞内的配合物我们正在开发新的金属配合物，以实现具有更高活性和更低副作用的抗癌药物的目标。为了实现这一目标，我们正在将金属络合物与生物化合物结合，以增强它们进入细胞的运输。许多癌细胞具有升高水平的识别和内化特定生物分子的蛋白质。例如，铁转运蛋白转铁蛋白（TF）优先被许多癌细胞吸收。通过将金属配合物连接到TF的氨基酸上，我们将产生新的抗癌物种并研究蛋白质介导的转运过程。快速生长的癌细胞也可能具有更高水平的维生素转运蛋白。我们将利用维生素分子连接到金属络合物来利用这种特性。第三种方法将使用短氨基酸链来促进金属化合物进入癌细胞的运输和靶向。3)选择性激活金属络合物正常细胞和癌细胞中生物过程的差异意味着金属络合物在每种环境中都可以发生不同的反应。我们正在开发Cu和Ru络合物，这些络合物在许多肿瘤中发现的低氧环境中产生有毒物质，同时在血液或正常组织中保持灭活。我们还针对在许多癌细胞中发现的含硫分子水平升高。这涉及到释放一氧化氮的复合物的发展，一氧化氮在高浓度时对细胞有毒。这些化合物将导致新的治疗方法，优先杀死癌细胞，也可以作为与肿瘤生长相关的生物过程的探针。