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. 2020 Jul 3;15(13):1150-1162.
doi: 10.1002/cmdc.202000268. Epub 2020 May 29.

Design, Synthesis, and Characterization of Novel CXCR4 Antagonists Featuring Cyclic Amines

Yu Lin  1 , Zhanhui Li  1 , Haikuo Ma  1   2 , Yujie Wang  1 , Xu Wang  1 , Shiwei Song  1 , Li Zhao  1 , Shuwei Wu  1 , Sheng Tian  1 , Chunyan Fu  3 , Lusong Luo  3 , Fang Zhu  2   4 , Sudan He  2   4 , Jiyue Zheng  1 , Xiaohu Zhang  1
Affiliations

Design, Synthesis, and Characterization of Novel CXCR4 Antagonists Featuring Cyclic Amines

Yu Lin et al. ChemMedChem. .

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.

Keywords: CXCL12; CXCR4; Chemokines; G protein-coupled receptors.

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