Perrone Maria Grazia, Vitale Paola, Ferorelli Savina, Boccarelli Angelina, Coluccia Mauro, Pannunzio Alessandra, Campanella Federica, Di Mauro Giuseppe, Bonaccorso Carmela, Fortuna Cosimo G, Scilimati Antonio
Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124 Bari, Italy.
Eur J Med Chem. 2017 Dec 1;141:404-416. doi: 10.1016/j.ejmech.2017.09.066. Epub 2017 Sep 30.
Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15-20 years before the appearance of specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof, Galmof and Galmof, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof (3) was found to be a selective COX-1 inhibitor (COX-1 IC = 0.27 μM and COX-2 IC = 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof (3) powerfully inhibits PGE release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site.
神经炎症是多种神经和神经退行性疾病的最早阶段。在神经退行性疾病中，它发生在特定神经退行性临床症状出现前约15 - 20年。组成型小胶质细胞COX - 1是神经炎症的促炎因子之一。通过酯键直接或通过C5或C11单元连接子将高选择性COX - 1抑制剂莫非佐辛（COXs选择性指数>6000）与半乳糖连接，设计了新型化合物3、14和15（分别为Galmof、Galmof和Galmof），并开发了它们的合成方法，以获得能够穿过血脑屏障（BBB）并控制中枢神经系统炎症反应的物质。3、14和15（Galmofs）的制备产率良好至中等。发现Galmof（3）是一种选择性COX - 1抑制剂（COX - 1 IC = 0.27μM，COX - 2 IC = 3.1μM，选择性指数 = 11.5），化学和代谢稳定，能够穿过类似于BBB的Caco - 2细胞单层，表明其转运是由GLUT - 1介导的。此外，在脂多糖刺激的小鼠BV2小胶质细胞系（一种全球公认的神经炎症模型）中，Galmof（3）比莫非佐辛（1）更有效地抑制前列腺素E的释放。此外，使用配体和蛋白质指纹图谱（FLAP）来解释Galmofs与COX - 1活性位点的不同结合相互作用。
