Bipolaricins A–I, Ophiobolin-Type Tetracyclic Sesterterpenes from a Phytopathogenic Bipolaris sp. Fungus

A preliminary phytochemical investigation on the EtOAc extracts of the fungus Bipolaris sp. TJ403-B1 resulted in the identification of 12 ophiobolin-type phytotoxins (1–12), including nine new ones, termed bipolaricins A–I (1–9). The structures of 1–9 were elucidated via spectroscopic data (including HRESIMS and 1D and 2D NMR) and single-crystal X-ray diffraction (Cu Kα) analyses. All of the isolated compounds were tested in terms of HMG-CoA reductase inhibitory, anti-inflammatory, and cytotoxic activities. Compound 10 showed HMG-CoA reductase inhibitory activity (IC50 = 8.4 ± 0.4 μM), and 2, 3, and 10–12 showed significant inhibitory potency against lipopolysaccharide (LPS)-induced nitric oxide production, with IC50 values in the range of 5.1 ± 0.3 to 20 ± 1 μM. Further experiments showed that 10 could significantly inhibit the production of IL-1β, RANTES, MIP-1β, and TNF-α as well as enhance the release of IL-13 in macrophages through the inhibition of HO-1 induction as well as the NF-κB pathway. These findings provide a scientific rationale for an anti-inflammatory therapeutic and a template for a new HMG-CoA reductase inhibitor to produce a potential anti-hyperlipidemia agent.

本研究对平脐蠕孢属（Bipolaris sp.）真菌TJ403-B1的乙酸乙酯（ethyl acetate, EtOAc）提取物开展初步植物化学研究，从中分离鉴定出12个蛇孢菌素类植物毒素（ophiobolin-type phytotoxins，1~12），其中包含9个新化合物，命名为bipolaricins A–I（1~9）。通过高分辨电喷雾电离质谱（High Resolution Electrospray Ionization Mass Spectrometry, HRESIMS）、一维和二维核磁共振波谱（1D and 2D NMR）以及铜靶X射线单晶衍射（single-crystal X-ray diffraction, Cu Kα）分析，明确了化合物1~9的结构。对所有分离得到的化合物进行了羟甲基戊二酰辅酶A还原酶（3-hydroxy-3-methylglutaryl-CoA reductase, HMG-CoA reductase）抑制活性、抗炎活性及细胞毒活性评价。结果显示，化合物10表现出HMG-CoA还原酶抑制活性（半数抑制浓度IC50 = 8.4 ± 0.4 μM）；化合物2、3及10~12对脂多糖（lipopolysaccharide, LPS）诱导的一氧化氮生成具有显著抑制活性，其IC50值范围为5.1 ± 0.3 ~ 20 ± 1 μM。进一步实验表明，化合物10可通过抑制血红素加氧酶1（Heme Oxygenase 1, HO-1）的诱导以及核因子κB（Nuclear Factor-κB, NF-κB）通路，显著抑制巨噬细胞中白细胞介素1β（Interleukin 1β, IL-1β）、正常T细胞表达和分泌激活调节因子（Regulated upon Activation, Normal T Cell Expressed and Secreted, RANTES）、巨噬细胞炎症蛋白1β（Macrophage Inflammatory Protein 1β, MIP-1β）以及肿瘤坏死因子α（Tumor Necrosis Factor-α, TNF-α）的产生，同时促进白细胞介素13（Interleukin 13, IL-13）的释放。本研究结果为抗炎治疗药物的开发提供了科学依据，同时为新型HMG-CoA还原酶抑制剂的设计提供了模板，有望用于制备潜在的抗高脂血症药物。