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

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.