A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Department of Chemistry, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States.
Bioorg Med Chem Lett. 2013 Nov 1;23(21):5860-4. doi: 10.1016/j.bmcl.2013.08.097. Epub 2013 Sep 6.
Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to identify the structural determinants of substrate-selective inhibition. The hydrogen-bonding potential of the substituents at the ortho positions of the aniline ring dictated the potency and substrate selectivity of the inhibitors. The presence of a 5'-methyl group on the phenylacetic acid ring increased the potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2) was the most potent and selective inhibitor of endocannabinoid oxygenation. The positioning of critical substituents in the binding site was identified from a 2.35Å crystal structure of lumiracoxib bound to COX-2.
鲁米昔布是环氧化酶-2（COX-2）对内源性大麻素氧化作用的底物选择性抑制剂。我们检测了一系列鲁米昔布衍生物，以确定底物选择性抑制的结构决定因素。苯胺环邻位取代基的氢键潜力决定了抑制剂的效力和底物选择性。苯乙酸环上 5'-位甲基的存在增加了单邻位取代基分子的效力。去氟鲁米昔布（2）是对氧化内源性大麻素最有效和选择性的抑制剂。通过鲁米昔布与 COX-2 结合的 2.35Å 晶体结构确定了结合位点中关键取代基的定位。
