DEVELOPMENT AND SCREENING OF TRANSITION METAL COMPLEXES AS CXCR4 ANTAGONISTS

作为 CXCR4 拮抗剂的过渡金属配合物的开发和筛选

• 批准号: 7610291
• 负责人: TIMOTHY HUBIN
• 金额: $ 7.85万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610291
• 关键词: Antibodies; Binding; Biological; CXCR4 Receptors; CXCR4 gene; Cells; Class; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Flow Cytometry; Funding; Grant; HIV; Immune; Institution; Lead; Ligands; Macrocyclic Compounds; Methods; Neoplasm Metastasis; Numbers; Pharmaceutical Preparations; Play; Protease Inhibitor; Protein Overexpression; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Rheumatoid Arthritis; Role; Route; Scheme; Screening procedure; Series; Source; Stem cell transplant; Surface; Testing; Transition Elements; United States National Institutes of Health; base; chemokine receptor; design; improved; inhibitor/antagonist; insight; interest; metal complex; novel therapeutics; preference; receptor; tumor progression

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 CXCR4趋化因子受体在免疫细胞的表面发现，并与其特定的天然配体一起在许多疾病状态中起作用。 CXCR4参与癌症的进展和转移，以及类风湿关节炎的发展。 在过去的十年中，CXCR4被揭示为某些HIV菌株进入细胞的进入途径，从而对通过进入抑制剂药物进行新的治疗方法引起了人们的兴趣，而不是当前对逆转录酶和蛋白酶抑制剂的偏爱。 我们的目的是为CXCR4共受体开发新的抑制剂。 它们是基于已知的CXCR4抑制剂的刚性大环化合物及其过渡金属络合物，该抑制剂已在临床测试中的抗HIV疗效以及其在促进干细胞移植方面的效用。 我们实施的刚化应导致改善的CXCR4结合，并阐明结合过渡金属复合物与该重要受体的结构要求。 我们已经通过成功地为我们提出的两种刚化类型的刚化类型的初始目标分子来证明了合成方案的实用性。 这些铅化合物还使用流式细胞仪方法筛选了CXCR4结合，以量化过表达CXCR4受体的免疫细胞中已知的CXCR4结合抗体的抑制。 我们期待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该药物类别的基本设计特征。