title: Synthesis, docking, cytotoxicity, and LTA4H inhibitory activity of new gingerol derivatives as potential colorectal cancer therapy.
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.
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacognosy Department, Faculty of Pharmacy, Sohag University, Sohag, Egypt. Electronic address: mai.h.elnaggar@gmail.com.
authors.forename: Mai H
authors.initials: MH
authors.lastname: El-Naggar
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: dramiramera@gmail.com.
authors.forename: Amira
authors.initials: A
authors.lastname: Mira
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: fatma_maar@yahoo.com.
authors.forename: Fatma M
authors.initials: FM
authors.lastname: Abdel Bar
authors.affiliation: Division of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Japan. Electronic address: shimizukuni@gmail.com.
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: pharmamer_47@yahoo.com.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Amer
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: faridbadria@gmail.com.
authors.forename: Farid A
authors.initials: FA
authors.lastname: Badria
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005233:Fatty Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D011994:Recombinant Proteins; C007845:gingerol; D004851:Epoxide Hydrolases; D000626:Aminopeptidases; C043134:leukotriene A4 hydrolase
keywords: Aminopeptidase; Epoxide hydrolase; Gingerols; HCT-116; LTA(4)H; Semi synthesis; Zingiber officinale