부산대학교 도서관

Background and Purpose 1,4-Benzoquinones are well-known inhibitors of 5-lipoxygenase (5- LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5- LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4-benzoquinone derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione ( RF- Id) in vitro and its effectiveness in vivo. Experimental Approach Mechanistic investigations in cell-free assays using 5- LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell-based studies in human leukocytes and whole blood. Molecular docking of RF- Id into the 5- LOX structure was performed to illustrate molecular interference with 5- LOX. The effectiveness of RF- Id in vivo was also evaluated in two murine models of inflammation. Key Results RF- Id consistently suppressed 5- LOX product synthesis in human leukocytes and human whole blood. RF- Id also blocked COX-2 activity but did not significantly inhibit COX-1, microsomal PGE2 synthase-1, cytosolic PLA2 or 12- and 15- LOX. Although RF- Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5- LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF- Id ( RED- RF- Id) was a more potent inhibitor of 5- LOX as it had more bidirectional hydrogen bonds within the 5- LOX substrate binding site. Finally, RF- Id had marked anti-inflammatory effects in mice in vivo. Conclusions and Implications RF- Id represents a novel anti-inflammatory 1,4-benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5- LOX with effectiveness in vivo. Mechanistically, RF- Id inhibits 5- LOX in a non-redox manner by forming discrete molecular interactions within the active site of 5- LOX. [ABSTRACT FROM AUTHOR]