Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. -gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA4H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including -, -, -, and -gingerol), five new and six known semi-synthesized -gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA4H aminopeptidase and epoxide hydrolase inhibitory studies. Methyl shogoal (D8) showed to be the most potent compound against HCT-116 cells (IC50; 1.54 μM). Remarkably, D8 proved to be non-cytotoxic to normal cells; (TIG-1) and (HF-19) with high selective index (SI; 52.3). Furthermore -gingerol derivatives showed potent LTA4H inhibitory activities in comparison to the universal positive controls (bestatin and 4BSA). Among the natural gingerols, -gingerol (N3) exhibited the highest LTA4H aminopeptidase and epoxide hydrolase inhibitory activities with IC50; 21.59 and 15.24 μM, respectively. Meanwhile, methyl shogoal (D8) and 4′-O-prenyl--gingerol (D10) retained the highest inhibition with IC50; 4.92 and 3.01 μM, for aminopeptidase, and 11.27 and 7.25 μM for epoxide hydrolase activities, respectively.
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