DEVELOPMENT AND SCREENING OF TRANSITION METAL COMPLEXES AS CXCR4 ANTAGONISTS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 项目摘要 CXCR 4趋化因子受体存在于免疫细胞表面，与特异性天然配体基质细胞衍生因子-1 <$（SDF-1 <$）一起，已被揭示在许多疾病状态中发挥作用。 例如，CXCR 4SDF-1系统参与癌症的进展和转移，以及类风湿性关节炎的发展。 此外，在过去的十年中，CXCR 4和CCR 5共受体已被揭示为HIV进入细胞的途径，从而产生了对通过进入抑制剂药物而不是目前对逆转录酶和蛋白酶抑制剂的偏好进行治疗的新治疗方法的兴趣。 我们的目标是开发CXCR 4辅助受体的新拮抗剂。 它们是构象固定的大环化合物及其过渡金属配合物。 不受限制的大环等效物是已知的CXCR 4拮抗剂，其已经临床测试了抗HIV功效以及其在促进干细胞移植中的效用。 我们提出的构象固定应该会导致CXCR 4结合的改善，以及阐明过渡金属复合物与这种重要的趋化因子受体结合的结构要求。 我们已经证明了我们的合成方案的效用，成功地产生了我们提出的两种类型的构象固定的初始目标分子。 还使用流式细胞术方法筛选了这些先导化合物的CXCR 4结合，以定量我们的拮抗剂在过表达CXCR 4受体的免疫细胞中对已知CXCR 4结合抗体的抑制。 我们现在请求支持，以完成一系列化合物的合成和测试，并通过光谱和生物学研究进一步了解这类药物的基本设计特征。 相关性 趋化因子及其受体参与多种疾病，包括艾滋病和癌症。 我们打算生产特异性靶向CXCR 4受体的分子，然后研究这些新分子如何有效地结合该靶标。 结果可能包括研究人员的新工具或新药本身。

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. Project Summary CXCR4 chemokine receptors are found on the surface of immune cells, and together with the specific natural ligand, stromal cell-derived factor-1¿ (SDF-1¿), have been revealed to play a role in a number of disease states. For example, the CXCR4SDF-1¿ system has involvement in cancer progression and metastasis, and the development of rheumatoid arthritis. Also, within the last ten years the CXCR4 and CCR5 co-receptors have been revealed as the entry route for HIV into cells, generating interest in a new therapeutic approach to treatment via entry inhibitor drugs rather than the current preference for reverse transcriptase and protease inhibitors. Our aim is to develop new antagonists for the CXCR4 co-receptor. They are conformationally fixed macrocyclic compounds and their transition metal complexes. The unrestrained macrocyclic equivalent is a known CXCR4 antagonist that has been clinically tested for anti-HIV efficacy as well as its utility in facilitating stem cell transplantation. The conformational fixing we propose should lead to improved CXCR4 binding, as well as illuminating the structural requirements for binding transition metal complexes to this important chemokine receptor. We have already demonstrated the utility of our synthetic schemes by successfully producing the initial target molecules for both of our proposed types of conformational fixing. These lead compounds have also been screened for CXCR4 binding using flow cytometry methods to quantify the inhibition of known CXCR4-binding antibodies by our antagonists in immune cells which overexpress the CXCR4 receptor. We now request support to complete the synthesis and testing of a series of compounds, and gain further insights into the essential design features for this drug class through spectroscopic and biological studies. Relevance Chemokines and their receptors are involved in multiple diseases, including AIDS and cancer. We intend to produce molecules that will specifically target the CXCR4 receptor, and then study how efficiently these new molecules bind this target. Results may include new tools for researchers or new medicines themselves.