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Synthesis and Biological Activity of Piperine Derivatives as Potential PPARγ Agonists.
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-05-26 , DOI: 10.2147/dddt.s238245 Yanli Wang 1, 2, 3 , Yuan Yao 4, 5 , Jing Liu 2, 6 , Lili Wu 7 , Tonghua Liu 7 , Jian Cui 1 , David Yue-Wei Lee 2
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-05-26 , DOI: 10.2147/dddt.s238245 Yanli Wang 1, 2, 3 , Yuan Yao 4, 5 , Jing Liu 2, 6 , Lili Wu 7 , Tonghua Liu 7 , Jian Cui 1 , David Yue-Wei Lee 2
Affiliation
Introduction: Peroxisome proliferator-activated receptor γ (PPARγ) 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.
Materials and Methods: In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ ligand screening assay to evaluate the agonistic activity of PPARγ. Then, we cultured human normal hepatocytes, which were treated with 100μM compounds 2a, 2t or 3d. Then, the levels of PPARγ gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ.
Results: A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ agonist with IC50 at 2.43 μM, which is 2 times more potent than the positive control rosiglitazone with IC50 at 5.61μM. The human hepatocytes cells were cultured and treated with compounds 2a, 2t or 3d as described in the “Materials and Methods” section. We found that compounds 2a, 2t and 3d could activate PPARγ by 11.8, 1.9 and 7.0 times compared with the “blank”, with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ complex active site, which is consistent with the results of the in vitro PPARγ ligand screening assay.
Keywords: PPARγ, piperine derivatives, ligand screening assay, molecular docking
中文翻译：
胡椒碱衍生物作为潜在 PPARγ 激动剂的合成和生物活性。
简介：过氧化物酶体增殖物激活受体γ（PPARγ）在葡萄糖中起关键作用，葡萄糖是一种配体介导的转录因子。脂质稳态通常作为新药发现和开发的药理学靶点。
材料与方法：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PPARγ配体筛选试验来评估PPARγ的激动活性。然后，我们培养人正常肝细胞，用100μM化合物2a、2t或3d处理。然后，PPARγ的水平确定基因以显示化合物是否可以激活或抑制PPARγ的表达。
结果：共合成并评价了30种胡椒碱衍生物。化合物2a被鉴定为潜在的PPARγ激动剂，其 IC 50为 2.43 μM，其效力是阳性对照罗格列酮的 2 倍，IC 50为 5.61 μM。如“材料和方法”部分所述，培养人肝细胞并用化合物2a、2t或3d处理。我们发现化合物2a、2t和3d可以激活PPARγ是“空白”的11.8、1.9和7.0倍，其中化合物2a的激活最为显着。分子对接研究表明，胡椒碱衍生物2a与PPARγ复合物活性位点的氨基酸残基稳定相互作用，这与体外PPARγ配体筛选试验结果一致。
关键词： PPARγ，胡椒碱衍生物，配体筛选试验，分子对接
更新日期：2020-05-26
Materials and Methods: In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ ligand screening assay to evaluate the agonistic activity of PPARγ. Then, we cultured human normal hepatocytes, which were treated with 100μM compounds 2a, 2t or 3d. Then, the levels of PPARγ gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ.
Results: A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ agonist with IC50 at 2.43 μM, which is 2 times more potent than the positive control rosiglitazone with IC50 at 5.61μM. The human hepatocytes cells were cultured and treated with compounds 2a, 2t or 3d as described in the “Materials and Methods” section. We found that compounds 2a, 2t and 3d could activate PPARγ by 11.8, 1.9 and 7.0 times compared with the “blank”, with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ complex active site, which is consistent with the results of the in vitro PPARγ ligand screening assay.
Keywords: PPARγ, piperine derivatives, ligand screening assay, molecular docking
中文翻译：
胡椒碱衍生物作为潜在 PPARγ 激动剂的合成和生物活性。
简介：过氧化物酶体增殖物激活受体γ（PPARγ）在葡萄糖中起关键作用，葡萄糖是一种配体介导的转录因子。脂质稳态通常作为新药发现和开发的药理学靶点。
材料与方法：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PPARγ配体筛选试验来评估PPARγ的激动活性。然后，我们培养人正常肝细胞，用100μM化合物2a、2t或3d处理。然后，PPARγ的水平确定基因以显示化合物是否可以激活或抑制PPARγ的表达。
结果：共合成并评价了30种胡椒碱衍生物。化合物2a被鉴定为潜在的PPARγ激动剂，其 IC 50为 2.43 μM，其效力是阳性对照罗格列酮的 2 倍，IC 50为 5.61 μM。如“材料和方法”部分所述，培养人肝细胞并用化合物2a、2t或3d处理。我们发现化合物2a、2t和3d可以激活PPARγ是“空白”的11.8、1.9和7.0倍，其中化合物2a的激活最为显着。分子对接研究表明，胡椒碱衍生物2a与PPARγ复合物活性位点的氨基酸残基稳定相互作用，这与体外PPARγ配体筛选试验结果一致。
关键词： PPARγ，胡椒碱衍生物，配体筛选试验，分子对接
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