Synthesis and evaluation of 2,5 and 2,6 pyridine-based CXCR4 inhibitors

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• 作者：Theresa Gaines^a ; Davita Camp^a ; Renren Bai^b ; Zhongxing Liang^b ; ^c ; Younghyoun Yoon^c ; Hyunsuk Shim^a ; ^b ; Suazette Reid Mooring^a ;
• 关键词：Pyridine ; CXCR4 inhibitor ; Matrigel invasion ; Binding affinity ; Cancer metastasis ; Anti-inflammatory
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5052-5060
• 全文大小：1654 K

文摘

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 (1000 nM) and six of the nine compounds had an effective concentration (EC) less than or equal to WZ811 (10 nM). 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.