Metal-organic compounds as scaffolds and libraries, for the exploration of biologically relevant chemical space.

金属有机化合物作为支架和库，用于探索生物相关的化学空间。

• 批准号: 326972-2013
• 负责人: Luyt, Leonard
• 金额: $ 2.48万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571883
• 关键词: Metal; organic; compounds; scaffolds; libraries

The ability to create ligands with affinity for a protein target depends upon the presentation of functionality in specific locations of three dimensional space. Metal-based ligands have typically not been utilized for receptor targeting, and yet metal complexes have unique abilities in terms of addressing chemical space due to their higher coordination number and increased structural diversity. In addition, metal-organic ligands can be designed with features that are particularly valuable for combinatorial library screening and may be created to have fluorescent properties. This research proposal seeks to explore metal-organic compounds as novel entities capable of targeting cell surface receptors. These compounds are uniquely created such that they exist as integrated metal-organic constructs, where the metal complex itself is critical for receptor binding and/or for unique functional properties. The following proposal focuses on metal complexes based on the very stable rhenium and technetium tricarbonyl core as the scaffold; a core that is well established as a biologically inert system. For diagnostic purposes, the short lived gamma emitter Tc-99m (t1/2 = 6 hr) is the most widely used isotope for SPECT imaging and continues to play an important role in molecular imaging, while Re isotopes are proposed for cancer therapy. The proposal also investigates the use of gallium, with novel complexes that are capable of dual modality imaging, using Ga-68 (t1/2 = 68 min) for PET imaging and natural Ga-69/71 for fluorescence microscopy. The proposed research program will develop the following sub-projects within the theme of metal-organic scaffolds and libraries: beta-sheet organometallics, metal-cyclic peptides, OBOC organometallic libraries, Ga chelates for multi-modality imaging, and plant viruses as a nanoplatform for imaging.

产生对蛋白质靶标具有亲和力的配体的能力取决于在三维空间的特定位置中的功能性的呈现。基于金属的配体通常不用于受体靶向，但金属络合物由于其较高的配位数和增加的结构多样性而在寻址化学空间方面具有独特的能力。此外，金属-有机配体可以被设计为具有对组合文库筛选特别有价值的特征，并且可以被创建为具有荧光性质。 这项研究计划旨在探索金属有机化合物作为能够靶向细胞表面受体的新型实体。这些化合物被独特地产生，使得它们作为整合的金属-有机构建体存在，其中金属络合物本身对于受体结合和/或独特的功能性质是关键的。下面的建议集中在金属络合物的基础上非常稳定的铯和三羰基锝核心作为支架;一个核心，这是一个良好的生物惰性系统。为了诊断的目的，短寿命的γ发射体Tc-99 m（t1/2 = 6 hr）是SPECT成像中最广泛使用的同位素，并且继续在分子成像中发挥重要作用，而Re同位素被提议用于癌症治疗。该提案还研究了镓的使用，具有能够进行双模态成像的新型复合物，使用Ga-68（t1/2 = 68 min）进行PET成像，使用天然Ga-69/71进行荧光显微术。拟议的研究计划将在金属有机支架和图书馆的主题内开发以下子项目：β-折叠有机金属，金属环肽，OBOC有机金属图书馆，用于多模态成像的Ga螯合物，以及植物病毒作为成像的纳米平台。