Design, Synthesis, and Characterization of Novel CXCR4 Antagonists Featuring Cyclic Amines. (29th May 2020)

• Record Type: Journal Article
• Authors: Lin, Yu; Li, Zhanhui; Ma, Haikuo; Wang, Yujie; Wang, Xu; Song, Shiwei; Zhao, Li; Wu, Shuwei; Tian, Sheng; Fu, Chunyan; Luo, Lusong; Zhu, Fang; He, Sudan; Zheng, Jiyue; Zhang, Xiaohu
• Is Part Of: ChemMedChem. Volume 15:Number 13(2020)
• Page Start: 1150
• Page End: 1162
• Publication Date: 2020-05-29
• Subjects: Chemokines -- CXCL12 -- CXCR4 -- G protein-coupled receptors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000268
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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, IC50 =24 nM; functional inhibition of CXCL12‐induced cytosolic calcium increase, IC50 =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. Abstract : Running rings round CXCR4 : Compound 24 has been identified as a potent CXCR4 antagonist (competitive inhibition of 12G5 binding, IC50 =24 nM; functional inhibition of CXCL12 induced cytosolic calcium increase, IC50 =0.1 nM) and was also found to inhibit cell migration in CXCR4/CXLC12‐mediated chemotaxis in a matrigel invasion assay. The absolute configuration of compound 24 was elucidated by X‐ray crystallography.