El-Naggar Mai H, Mira Amira, Abdel Bar Fatma M, Shimizu Kuniyoshi, Amer Mohamed M, Badria Farid A
Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacognosy Department, Faculty of Pharmacy, Sohag University, Sohag, Egypt.
Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Bioorg Med Chem. 2017 Feb 1;25(3):1277-1285. doi: 10.1016/j.bmc.2016.12.048. Epub 2016 Dec 29.
Leukotriene A4 hydrolase (LTAH) 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 LTAH, 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 LTAH aminopeptidase and epoxide hydrolase inhibitory studies. Methyl shogoal (D8) showed to be the most potent compound against HCT-116 cells (IC; 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 LTAH inhibitory activities in comparison to the universal positive controls (bestatin and 4BSA). Among the natural gingerols, [10]-gingerol (N3) exhibited the highest LTAH aminopeptidase and epoxide hydrolase inhibitory activities with IC; 21.59 and 15.24μM, respectively. Meanwhile, methyl shogoal (D8) and 4'-O-prenyl-[6]-gingerol (D10) retained the highest inhibition with IC; 4.92 and 3.01μM, for aminopeptidase, and 11.27 and 7.25μM for epoxide hydrolase activities, respectively.
白三烯A4水解酶（LTAH）是一种促炎酶，可生成炎症介质白三烯，其可能在与癌症发生相关的慢性炎症中起重要作用。[6]-姜酚是生姜的主要生物活性化合物，是LTAH的潜在抑制剂，LTAH是一种在结肠直肠癌中高表达的酶。使用对接、对人结肠癌细胞（HCT-116）的体外细胞毒性以及LTAH氨肽酶和环氧水解酶抑制研究，检测了18种化合物；7种天然来源的化合物（包括[4]-、[6]-、[8]-和[10]-姜酚）、5种新的和6种已知的半合成[6]-姜酚衍生物。甲基姜烯酚（D8）显示是对HCT-116细胞最有效的化合物（IC；1.54μM）。值得注意的是，D8被证明对正常细胞无细胞毒性；（TIG-1）和（HF-19）具有高选择性指数（SI；52.3）。此外，与通用阳性对照（贝司他汀和4BSA）相比，[6]-姜酚衍生物显示出强大的LTAH抑制活性。在天然姜酚中，[10]-姜酚（N3）表现出最高的LTAH氨肽酶和环氧水解酶抑制活性，IC分别为21.59和15.24μM。同时，甲基姜烯酚（D8）和4'-O-异戊烯基-[6]-姜酚（D10）对氨肽酶的抑制率最高，IC分别为4.92和3.01μM，对环氧水解酶活性的抑制率分别为11.27和7.25μM。
