Hammadi Reham, Kúsz Norbert, Dávid Csilla Zsuzsanna, Behány Zoltán, Papp László, Kemény Lajos, Hohmann Judit, Lakatos Lóránt, Vasas Andrea
Department of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary.
Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, 6720 Szeged, Hungary.
Plants (Basel). 2021 Jun 14;10(6):1206. doi: 10.3390/plants10061206.
Ingenol mebutate, isolated from , is an ingenane-type diterpenoid, primarily used for the topical treatment of actinic keratosis, a premalignant skin condition. The aim of our work was to investigate other species to find structurally similar diterpenes that can be used as alternatives to ingenol mebutate. Pharmacological investigation of , , , and revealed the potent keratinocyte (HPV-Ker cell line) inhibitory activity of these spurge species. From the methanolic extract of the aerial parts of Miller, the most active species, five ingol (-) and four ingenane-type diterpenoids (-) were isolated by various chromatographic separation techniques, including open column chromatography, vacuum liquid chromatography, thin-layer chromatography, and high-performance liquid chromatography. The structures of the compounds were determined by NMR spectroscopic analysis and by comparison of the assignations with the literature data. The cytotoxic activity of the compounds against keratinocytes was tested in vitro by using ingenol mebutate as a positive control. Among the isolated compounds, two ingenane derivatives ( and ) exhibited remarkably stronger cytotoxic activity (IC values 0.39 μM and 0.32 μM, respectively) on keratinocytes than ingenol mebutate (IC value 0.84 μM). These compounds could serve as starting materials for further investigations to find alternatives to Picato (with active substance ingenol mebutate), which was withdrawn from marketing authorization in the European Union.
ingenol mebutate是从 中分离得到的一种大戟烷型二萜类化合物，主要用于光化性角化病（一种皮肤癌前病变）的局部治疗。我们工作的目的是研究其他 物种，以寻找结构相似的二萜类化合物，用作ingenol mebutate的替代品。对 、 、 和 的药理研究表明，这些大戟属植物具有强大的角质形成细胞（HPV-Ker细胞系）抑制活性。从活性最强的物种Miller的地上部分甲醇提取物中，通过各种色谱分离技术，包括开放柱色谱、真空液相色谱、薄层色谱和高效液相色谱，分离出了五种间苯三酚（-）和四种大戟烷型二萜类化合物（-）。通过核磁共振光谱分析以及将归属与文献数据进行比较，确定了这些化合物的结构。以ingenol mebutate作为阳性对照，在体外测试了这些化合物对角质形成细胞的细胞毒性活性。在分离出的化合物中，两种大戟烷衍生物（ 和 ）对角质形成细胞的细胞毒性活性（IC值分别为0.39 μM和0.32 μM）比ingenol mebutate（IC值为0.84 μM）显著更强。这些化合物可作为进一步研究的起始材料，以寻找Picato（活性物质为ingenol mebutate）的替代品，Picato已在欧盟撤回上市许可。
