Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8150, Japan.
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Bioorg Med Chem. 2019 Mar 15;27(6):1130-1138. doi: 10.1016/j.bmc.2019.02.013. Epub 2019 Feb 6.
The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5-7.5 Å showed potent binding affinity selective for CXCR4 with IC values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with ECs of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.
趋化因子受体 CXCR4/基质细胞衍生因子-1（SDF-1：CXCL12）信号轴是一个重要的药物靶点，因为它与几种疾病有关，如 HIV-1 感染、癌症、白血病和类风湿性关节炎。本研究旨在提高一种有效 CXCR4 配体的结合亲和力和抗 HIV 活性，设计、合成并对 23 种含有二吡啶基胺（Dpa）和环脒阳离子部分的低分子量化合物进行了生物学评价，这些化合物具有不同的间隔基和空间定位。在纳米 BRET 测定系统中，所有在 1.0μM 下筛选的化合物对竞争性探针 TAMRA-Ac-TZ14011（10nM）与锌（II）离子存在下 CXCR4 的结合均表现出>70%的抑制作用。此外，具有二吡啶基胺和环脒之间的下一个碳原子之间的空间距离在 6.5-7.5Å 范围内的选定化合物 3、8、9、19 和 21 对 CXCR4 具有很强的结合亲和力，IC50 值分别为 1.6、7.9、5.7、3.5 和 4.5nM，相应的 EC50 值在锌（II）离子存在下分别为 28、13、21、28 和 61nM，具有很高的抗 HIV 活性。获得了一些与初始先导化合物相比具有显著更高的 CXCR4 结合亲和力的化合物。这些化合物与 CXCR4 的不同但重叠的氨基酸残基相互作用。本研究开发了具有高 CXCR4 结合和抗 HIV 活性的新型低分子量 CXCR4 配体，为开发更有效的 CXCR4 配体开辟了途径。
