设计、合成及新型 CXCR4 拮抗剂的环状胺结构特征研究。
Design, Synthesis, and Characterization of Novel CXCR4 Antagonists Featuring Cyclic Amines.
机构信息
Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, P. R. China.
出版信息
ChemMedChem. 2020 Jul 3;15(13):1150-1162. doi: 10.1002/cmdc.202000268. Epub 2020 May 29.
Chemokine receptor CXCR4 and its natural ligand CXCL12 (also known as stromal cell-derived factor-1, or SDF-1) regulate a broad range of physiological functions. Dysregulation of the CXCL12/CXCR4 axis is involved in numerous pathological conditions such as HIV infection, inflammation and cancer. Herein, we report the design, synthesis, and characterization of novel CXCR4 antagonists based on cyclic amine scaffolds. Compound 24 was identified as a potent CXCR4 receptor antagonist (competitive inhibition of 12G5 binding, IC =24 nM; functional inhibition of CXCL12-induced cytosolic calcium increase, IC =0.1 nM). In addition, compound 24 potently inhibited cell migration in CXCR4/CXCL12-mediated chemotaxis in a matrigel invasion assay. The absolute configuration of compound 24 was elucidated by X-ray crystallography.
趋化因子受体 CXCR4 及其天然配体 CXCL12（也称为基质细胞衍生因子 1，或 SDF-1）调节广泛的生理功能。CXCL12/CXCR4 轴的失调与许多病理状况有关，如 HIV 感染、炎症和癌症。在此，我们报告了基于环状胺支架的新型 CXCR4 拮抗剂的设计、合成和表征。化合物 24 被鉴定为一种有效的 CXCR4 受体拮抗剂（12G5 结合的竞争性抑制，IC =24 nM；CXCL12 诱导的胞质钙离子增加的功能抑制，IC =0.1 nM）。此外，化合物 24 在基质胶侵袭测定中以 CXCR4/CXCL12 介导的趋化性强烈抑制细胞迁移。通过 X 射线晶体学阐明了化合物 24 的绝对构型。
Zotero 插件