DEVELOPMENT AND SCREENING OF TRANSITION METAL COMPLEXES AS CXCR4 ANTAGONISTS

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。 项目摘要 CXCR4趋化因子受体位于免疫细胞表面，与特定的天然配体--基质细胞衍生因子-1(SDF-1)一起，已被发现在多种疾病状态中发挥作用。例如，CXCR4SDF-1系统参与了癌症的进展和转移，以及类风湿性关节炎的发展。此外，在过去的十年中，CXCR4和CCR5共同受体被发现是HIV进入细胞的途径，这引起了人们对通过进入抑制剂药物而不是目前偏爱逆转录酶和蛋白酶抑制剂进行治疗的新治疗方法的兴趣。我们的目标是开发CXCR4共受体的新拮抗剂。它们是构象固定的大环化合物及其过渡金属络合物。不受限制的大环类等价物是一种已知的CXCR4拮抗剂，已在临床上测试了其抗HIV有效性及其在促进干细胞移植方面的效用。我们提出的构象固定应该导致CXCR4结合的改善，以及阐明了过渡金属络合物与这个重要的趋化因子受体结合的结构要求。我们已经通过成功地为我们提出的两种构象固定产生了初始目标分子，从而证明了我们的合成方案的实用性。我们还使用流式细胞术方法对这些先导化合物进行了CXCR4结合筛选，以定量我们的拮抗剂对免疫细胞中过表达CXCR4受体的已知CXCR4结合抗体的抑制作用。我们现在请求支持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一药物类别的基本设计特征。 相关性 趋化因子及其受体与多种疾病有关，包括艾滋病和癌症。我们打算生产专门针对CXCR4受体的分子，然后研究这些新分子如何有效地结合这个靶点。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. 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. 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.