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

  • Bioorg Med Chem. 2017 Feb 1;25(3):1277-1285. doi: 10.1016/j.bmc.2016.12.048.
Mai H El-Naggar  1 ,  Amira Mira  2 ,  Fatma M Abdel Bar  3 ,  Kuniyoshi Shimizu  4 ,  Mohamed M Amer  5 ,  Farid A Badria  6
Affiliations
  • 1. Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacognosy Department, Faculty of Pharmacy, Sohag University, Sohag, Egypt. Electronic address: [email protected].
  • 2. Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 3. Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 4. Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Japan. Electronic address: [email protected].
  • 5. Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 6. Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
PMID: 28065501 DOI: 10.1016/j.bmc.2016.12.048
Abstract

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; 1.54μM). 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 15.24μM, respectively. Meanwhile, methyl shogoal (D8) and 4'-O-prenyl-[6]-gingerol (D10) retained the highest inhibition with IC50; 4.92 and 3.01μM, for Aminopeptidase, and 11.27 and 7.25μM for Epoxide Hydrolase activities, respectively.

Keywords
Aminopeptidase; Epoxide hydrolase; Gingerols; HCT-116; LTA(4)H; Semi synthesis; Zingiber officinale.
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