title: Symmetrical bis-tertiary amines as novel CXCR4 inhibitors.
abstract: CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency.
authors.affiliation: Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Renren
authors.initials: R
authors.lastname: Bai
authors.affiliation: Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Shuangping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Gaines
authors.affiliation: Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Yoonhyeun
authors.initials: Y
authors.lastname: Oum
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA. Electronic address: smooring@gsu.edu.
authors.forename: Suazette Reid
authors.initials: SR
authors.lastname: Mooring
authors.affiliation: Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA. Electronic address: hshim@emory.edu.
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004487:Edema / Q000188:drug therapy; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019718:Receptors, CXCR4
keywords: Anti-inflammatory activity; Binding affinity; CXCR4 inhibitors; Matrigel invasion; Tertiary amines