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; Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
Eur J Med Chem. 2019 Nov 1;181:111562. doi: 10.1016/j.ejmech.2019.111562. Epub 2019 Jul 29.
The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.
G 蛋白偶联受体 CXCR4 与其天然配体 CXCL12 的相互作用与患有肠易激综合征（IBD）的患者的炎症有关。阻断这种相互作用可能会降低 IBD 患者的炎症症状。在这项工作中，根据 AMD3100 和 WZ811（两种已知的中断 CXCR4-CXCL12 相互作用的拮抗剂）模拟了几种噻吩基和呋喃基化合物，并对其进行了合成和分析。确定了 15 种有效化合物；这些化合物的有效浓度（EC）低于 1000 nM（AMD3100），并抑制转移性细胞的侵袭至少 45%。选择的化合物（2d、2j、8a）比 WZ811（62%）以更高的速率抑制转移性侵袭，被提交用于角叉菜胶炎症测试，其中 8a 和 2j 减轻炎症的效果与 WZ811（40%）相同，但不超过 40%。还对选定的化合物进行了计算机模拟，以显示关键残基相互作用。这些基于呋喃和噻吩的类似物的初步结果为新型 CXCR4 拮抗剂提供了依据。
