title: Synthesis and evaluation of 2,5 and 2,6 pyridine-based CXCR4 inhibitors.
abstract: Targeting the interaction between G-Protein Coupled Receptor, CXCR4, and its natural ligand CXCL12 is a leading strategy to mitigate cancer metastasis and reduce inflammation. Several pyridine-based compounds modeled after known small molecule CXCR4 antagonists, AMD3100 and WZ811, were synthesized. Nine hit compounds were identified. These compounds showed lower binding concentrations than AMD3100 (1000nM) and six of the nine compounds had an effective concentration (EC) less than or equal to WZ811 (10nM). Two of the hit compounds (2g and 2w) inhibited invasion of metastatic cells at a higher rate than AMD3100 (62%). Compounds 2g and 2w also inhibit inflammation in the same range as WZ811 in the paw edema test at 40% reduction in inflammation. These preliminary results are the promising foundation of a new class of pyridine-based CXCR4 antagonists.
authors: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors: Theresa
authors: T
authors: Gaines
authors: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors: Davita
authors: D
authors: Camp
authors: Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Renren
authors: R
authors: Bai
authors: 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: Zhongxing
authors: Z
authors: Liang
authors: Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors: Younghyoun
authors: Y
authors: Yoon
authors: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA; Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Hyunsuk
authors: H
authors: Shim
authors: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors: Suazette Reid
authors: SR
authors: Mooring
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D011725:Pyridines; D019718:Receptors, CXCR4; D002351:Carrageenan
keywords: Anti-inflammatory; Binding affinity; CXCR4 inhibitor; Cancer metastasis; Matrigel invasion; Pyridine