Synthesis, docking, cytotoxicity, and LTA₄H inhibitory activity of new gingerol derivatives as potential colorectal cancer therapy

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. [6]-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 [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-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 [6]-gingerol derivatives showed potent LTA₄H inhibitory activities in comparison to the universal positive controls (bestatin and 4BSA). Among the natural gingerols, [10]-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-[6]-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.