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首页> 外文期刊>Chemistry: A European journal >Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors
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Design, Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors

机译：槲皮素类似物作为JNK1抑制剂的设计，合成和生物学评估

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摘要

The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy-(2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4 mu M and 12.2 mu M, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50=4.6 mu M). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.
机译：天然槲皮素（1）抑制c-Jun NH2-末端激酶JNK1的最新发现是开发新型抗癌药的有希望的先导。使用X射线结构和对接分析，我们预测5'-羟基-（2）和5'-羟甲基-槲皮素（3）比母体化合物1更能抑制JNK1。值得注意的是，我们的药物设计基于活性酶-配体复合物，而不是酶的相对开放的载脂蛋白结构。在本文中，我们通过对接模型实验测试了我们的理论预测，并报告了槲皮素类似物2和3的首次合成和生物学评估。经计算，这两种化合物均能强烈抑制JNK1活性。测定的IC 50值分别为3.4μM和12.2μM，这表明2超过母体化合物1的效力（IC 50 ＝4.6μM）。还显示了化合物2在紫外线照射后以高特异性抑制基质金属蛋白酶-1的表达。

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