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

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• 作者：Mai H. El-Naggar^a ; ^b ; ^{mai.h.elnaggar@gmail.com} ; Amira Mira^a ; ^{dramiramera@gmail.com} ; Fatma M. Abdel Bar^a ; ^{fatma_maar@yahoo.com} ; Kuniyoshi Shimizu^c ; ^{shimizukuni@gmail.com} ; Mohamed M. Amer^a ; ^{pharmamer_47@yahoo.com} ; Farid A. Badria^a ; ^{faridbadria@gmail.com}
• 关键词：Zingiber officinale ; Gingerols ; Semi synthesis ; HCT-116 ; LTA4H ; Aminopeptidase ; Epoxide hydrolase
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1277-1285
• 全文大小：1339 K
• 卷排序：25

文摘

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.