CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos s/n, 4450-208, Matosinhos, Portugal.
CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos s/n, 4450-208, Matosinhos, Portugal.
Eur J Med Chem. 2018 May 10;151:272-284. doi: 10.1016/j.ejmech.2018.03.036. Epub 2018 Mar 23.
Obesity is an increasing epidemic worldwide and novel treatments are urgently needed. Polyphenols are natural compounds derived from plants, which are known in particular for their antioxidant properties. However, some polyphenols were described to possess anti-obesity activities in vitro and in vivo. In this study, we aimed to screen a library of 85 polyphenol derivatives for their lipid reducing activity and toxicity. Compounds were analyzed at 5 μM with the zebrafish Nile red fluorescence fat metabolism assay and for general toxicity in vivo. To improve the safety profile, compounds were screened at 50 μM in murine preadipocytes in vitro for cytotoxicity. Obtained activity data were used to create a 2D-QSAR (quantitative structure activity relationship) model. 38 polyphenols showed strong lipid reducing activity. Toxicity analysis revealed that 18 of them did not show any toxicity in vitro or in vivo. QSAR analysis revealed the importance of the number of rings, fractional partial positively charged surface area, relative positive charge, relative number of oxygen atoms, and partial negative surface area for lipid-reducing activity. The five most potent compounds with EC values in the nanomolar range for lipid reducing activity and without any toxic effects are strong candidates for future research and development into anti-obesity drugs. Molecular profiling for fasn, sirt1, mtp and ppary revealed one compound that reduced significantly fasn mRNA expression.
肥胖是全球日益严重的流行疾病，迫切需要新的治疗方法。多酚是从植物中提取的天然化合物，以其抗氧化特性而闻名。然而，一些多酚已被描述具有体外和体内的抗肥胖活性。在这项研究中，我们旨在筛选 85 种多酚衍生物文库，以研究其降低血脂的活性和毒性。在 5μM 下用斑马鱼尼罗红荧光脂肪代谢测定法和体内一般毒性分析化合物。为了提高安全性，在 50μM 下在体外筛选小鼠前脂肪细胞中的细胞毒性。获得的活性数据用于创建二维 QSAR（定量构效关系）模型。38 种多酚表现出很强的降脂活性。毒性分析表明，其中 18 种在体外或体内均无任何毒性。QSAR 分析表明，对脂类还原活性重要的是环数、部分正电荷表面积分数、相对正电荷、相对氧原子数和部分负表面积。五种最有效的化合物具有 EC 值在纳摩尔范围内的脂类还原活性，且无任何毒性作用，是未来抗肥胖药物研发的有力候选物。Fasn、Sirt1、Mtp 和 Ppary 的分子特征分析显示，一种化合物显著降低了 fasn mRNA 的表达。
