A new pimarane-type diterpene obtained by biotransformation inhibits human HCT-116 colorectal carcinoma through inhibition of LTA4H activity

Amira Mira, Mohamed A. Sabry, Kuniyoshi Shimizu, Fatma M. Abdel Bar

研究成果: ジャーナルへの寄稿記事


Chronic inflammation mediated by several markers promotes cancer progression. Leukotriene A4 hydrolase (LTA4H), an inflammatory marker, is highly expressed in colorectal cancer. Therefore, inhibition of LTA4H could reduce the incidence and progression of this cancer type. Several studies supported the valuable effects of naturally occurring diterpenes against several diseases. In this study, a new pimarane-type diterpene, namely, 8,15R-epoxy,16-hydroxy-pimaran-19-oic acid 1 was obtained from the biotransformation of 8β-hydroxypimar-15-en-19-oic acid 2 using a filamentous fungus, Cordyceps sinensis. Both compounds were in vitro tested for their cytotoxic effects against human colorectal carcinoma (HCT-116) cells. In addition, their selectivity was examined using the normal human fibroblast cells, HF-19 and TIG-1. The new metabolite 1 exhibited potent cytotoxic activity against HCT-116 (IC50 7.53 μM) with no cytotoxicity against TIG-1 and HF-19. Thus, LTA4H inhibitory activity including both aminopeptidase (AP) and epoxide hydrolase (EH) functionalities were assessed in comparison with bestatin and 4-(4-Benzylphenyl)-thiazol-2-amine (4BSA, ARM1), respectively, as positive controls. Interstingly, the new metabolite 1 showed higher AP, and EH inhibitory activities (IC50 11.21 and 6.64 μM, respectively), confirming the impact of the achieved structure modification on the related anticancer activity. To gain further understanding of the mode of binding of the new metabolite 1 within the active binding site of LTA4H, docking experiments were conducted. The results indicated the significance of pimarane-type diterpenes as a new candidate for the design of promising LTA4H inhibitors.

ジャーナルMedicinal Chemistry Research
出版物ステータス出版済み - 4 1 2020


All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry