Jiangsu Key Laboratory of Drug Design and Optimization, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
Eur J Med Chem. 2017 Nov 10;140:421-434. doi: 10.1016/j.ejmech.2017.09.046. Epub 2017 Sep 22.
Phenotypic screening of high quality compound library is one of the most effective strategy to obtain novel bioactive compounds. Recently, our group have constructed a Wogonin-scaffold library with substituents diversity and successfully obtained a series of potent compounds. Herein, we reported the synthesis of these compounds and evaluated the in vitro antitumor activity against a panel of human tumor cell lines. Most of them showed good activity with a broad spectrum and preliminary structure-activity relationship for the substitutions were obtained. Further biological assays showed that the most potent compounds 18n and 20b could significantly enhance the intracellular ROS level and induce the cell apoptosis at low micromole level. Through similarity searching, CDK9 was identified as the potential target for 20b, which could be a start point for next structure-based drug design.
高通量化合物库的表型筛选是获得新型生物活性化合物的最有效策略之一。最近，我们小组构建了一个具有取代基多样性的黄苓素支架库，并成功获得了一系列具有高活性的化合物。在此，我们报道了这些化合物的合成，并评估了它们对一系列人肿瘤细胞系的体外抗肿瘤活性。它们大多数都具有广谱活性，并且初步获得了取代基的构效关系。进一步的生物学实验表明，活性最强的化合物 18n 和 20b 能够在低微摩尔浓度下显著增加细胞内 ROS 水平并诱导细胞凋亡。通过相似性搜索，鉴定出 CDK9 是 20b 的潜在靶标，这可能成为基于结构的药物设计的起点。
