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。 CXCR4趋化因子受体存在于免疫细胞表面，与其特定的天然配体一起在多种疾病状态中发挥作用。CXCR4参与了肿瘤的进展和转移，以及类风湿性关节炎的发展。在过去的十年里，CXCR4被发现是一些HIV毒株进入细胞的途径，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的新的治疗方法的兴趣。我们的目标是开发CXCR4共受体的新抑制剂。它们是刚性大环化合物及其过渡金属络合物，基于一种已知的CXCR4抑制剂，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。我们已经实现的硬化应该导致CXCR4结合的改善，以及阐明了过渡金属络合物与这一重要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类型的刚化反应生产了初始目标分子，证明了我们的合成方案的实用性。这些先导化合物还被用流式细胞术方法筛选CXCR4结合，以定量免疫细胞过度表达CXCR4受体对已知CXCR4结合抗体的抑制作用。我们期待着完成一系列相关化合物的合成和测试，以通过光谱和生物学研究进一步深入了解这一药物类别的基本设计特征。

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. CXCR4 chemokine receptors are found on the surface of immune cells, and together with their specific natural ligand, play a role in a number of disease states. CXCR4 has involvement in cancer progression and metastasis, and the development of rheumatoid arthritis. Within the last ten years the CXCR4 has been revealed as the entry route for some HIV strains 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 inhibitors for the CXCR4 co-receptor. They are rigid macrocyclic compounds and their transition metal complexes based on a known CXCR4 inhibitor that has been clinically tested for anti-HIV efficacy as well as its utility in facilitating stem cell transplantation. The rigidification we have implemented should lead to improved CXCR4 binding, as well as illuminating the structural requirements for binding transition metal complexes to this important 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 rigidification. These lead compounds have also been screened for CXCR4 binding using flow cytometry methods to quantify the inhibition of known CXCR4-binding antibodies by in immune cells which overexpress the CXCR4 receptor. We look forward to completing the synthesis and testing of a series of related compounds to gain further insights into the essential design features for this drug class through spectroscopic and biological studies.