DEVELOPMENT AND SCREENING OF TRANSITION METAL COMPLEXES AS CXCR4 ANTAGONISTS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 CXCR 4趋化因子受体存在于免疫细胞表面，与其特异性天然配体一起在许多疾病状态中发挥作用。 CXCR 4参与癌症进展和转移以及类风湿性关节炎的发展。 在过去的十年中，CXCR 4已被揭示为一些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辅助受体的新抑制剂。 它们是刚性大环化合物及其过渡金属络合物，其基于已知的CXCR 4抑制剂，该CXCR 4抑制剂已被临床测试抗HIV功效以及其在促进干细胞移植中的效用。 我们已经实现的硬化应该会导致改善CXCR 4结合，以及阐明将过渡金属络合物结合到这个重要受体的结构要求。 我们已经证明了我们的合成方案的实用性，成功地产生了我们提出的两种类型的硬化的初始目标分子。 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，以定量过表达CXCR 4受体的免疫细胞中已知CXCR 4结合抗体的抑制。 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了解这类药物的基本设计特征。

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.