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.

中文翻译：

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通过生物转化获得的新的pimarane型二萜通过抑制LTA 4 H活性来抑制人HCT-116大肠癌

由几种标记物介导的慢性炎症可促进癌症进展。白三烯A ₄水解酶（LTA ₄ H）是一种炎症标记，在结直肠癌中高表达。因此，抑制LTA ₄ H可以减少这种癌症类型的发生和发展。几项研究支持天然存在的二萜对多种疾病的宝贵作用。在这项研究中，一个新的海松烷类双萜，即，8,15 - [R -环氧，16-羟基pimaran -19-酸1是从8生物转化得到的β -hydroxypimar-15烯-19-酸2使用丝状真菌冬虫夏草。两种化合物均在体外测试了其对人结肠直肠癌（HCT-116）细胞的细胞毒性作用。此外，使用正常人成纤维细胞HF-19和TIG-1检查了它们的选择性。新的代谢产物1对HCT-116（IC ₅₀ 7.53μM）表现出有效的细胞毒性，而对TIG-1和HF-19无细胞毒性。因此，与Bestatin和4-（4-苄基苯基）-噻唑-2-胺（4BSA，ARM1）相比，分别评估了包括氨基肽酶（AP）和环氧水解酶（EH）功能的LTA ₄ H抑制活性为阳性控件。有趣的是，新代谢物1表现出更高的AP和EH抑制活性（IC ₅₀分别为11.21和6.64μM），证实了实现的结构修饰对相关抗癌活性的影响。为了进一步了解新代谢物1在LTA ₄ H的活性结合位点内的结合方式，进行了对接实验。结果表明，在设计有前途的LTA ₄ H抑制剂中，吡喃烷型二萜作为一种新的候选物具有重要意义。