School of Pharmacy, Minzu University of China, Beijing 100081, People's Republic of China.
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, Boston, MA 02478, USA.
Drug Des Devel Ther. 2020 May 26;14:2069-2078. doi: 10.2147/DDDT.S238245. eCollection 2020.
Peroxisome proliferator-activated receptor () plays a key role in glucose, which is a ligand-mediated transcription factor. The lipid homeostasis often serves as a pharmacological target for new drug discovery and development.
In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based ligand screening assay to evaluate the agonistic activity of . Then, we cultured human normal hepatocytes, which were treated with 100μM compounds or . Then, the levels of gene were determined so as to show whether the compounds could activate or inhibit the expression of .
A total of 30 piperine derivatives were synthesized and evaluated. Compound was identified as a potential agonist with IC at 2.43 μM, which is 2 times more potent than the positive control rosiglitazone with IC at 5.61μM. The human hepatocytes cells were cultured and treated with compounds , or as described in the "Materials and Methods" section. We found that compounds and could activate by 11.8, 1.9 and 7.0 times compared with the "blank", with compound activation being the most significant. Molecular docking studies indicated that the piperine derivative stably interacts with the amino acid residues of the complex active site, which is consistent with the results of the in vitro ligand screening assay.
过氧化物酶体增殖物激活受体 () 在葡萄糖代谢中发挥关键作用，是一种配体介导的转录因子。脂代谢平衡通常是新药发现和开发的药理学靶点。
在研究中，我们合成了一系列胡椒碱衍生物，然后使用基于荧光偏振的配体筛选测定法来评估 的激动活性。接着，我们培养人正常肝细胞，用 100μM 的化合物 或 处理这些细胞。然后，测定 基因的水平，以表明这些化合物是否能激活或抑制 的表达。
共合成和评价了 30 种胡椒碱衍生物。化合物 被鉴定为具有潜在活性的 激动剂，IC 为 2.43μM，比阳性对照罗格列酮（IC 为 5.61μM）的活性强 2 倍。按照“材料和方法”部分所述培养人肝细胞并用化合物 、 或 处理。我们发现，与“空白”相比，化合物 和 可分别将 激活 11.8、1.9 和 7.0 倍，其中化合物 的激活作用最为显著。分子对接研究表明，胡椒碱衍生物 可与 复合物活性位点的氨基酸残基稳定相互作用，这与体外配体筛选测定的结果一致。
