Bhat Rohit, Adam Amna T, Lee Jungeun Jasmine, Gasiewicz Thomas A, Henry Ellen C, Rotella David P
Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, United States.
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States.
Bioorg Med Chem Lett. 2014 May 15;24(10):2263-6. doi: 10.1016/j.bmcl.2014.03.088. Epub 2014 Apr 4.
(-)-Epigallocatechin gallate (EGCG) is the major flavonoid of green tea and has been widely explored for a range of biological activities including anti-infective, anti-inflammatory, anti-cancer, and neuroprotection. Existing structure-activity data for EGCG has been largely limited to exploration of simple ethers and hydroxyl deletion. EGCG has poor drug-like properties because of multiple phenolic hydroxyl moieties and a metabolically labile ester. This work reports a substantial expansion of structure-activity understanding by exploring a range of semi-synthetic and synthetic derivatives with ester replacements and variously substituted aromatic and alicyclic groups containing more drug-like substituents. Structure-activity relationships for these molecules were obtained for Hsp90 inhibition. The results indicate that amide and sulfonamide linkers are suitable ester replacements. Hydroxylated aromatic rings and the cis-stereochemistry in EGCG are not essential for Hsp90 inhibition. Selected analogs in this series are more potent than EGCG in a luciferase refolding assay for Hsp90 activity.
（-）-表没食子儿茶素没食子酸酯（EGCG）是绿茶中的主要黄酮类化合物，已被广泛研究其一系列生物活性，包括抗感染、抗炎、抗癌和神经保护作用。现有的EGCG结构-活性数据在很大程度上局限于对简单醚类和羟基缺失的探索。由于多个酚羟基部分和代谢不稳定的酯，EGCG具有较差的类药性质。这项工作通过探索一系列具有酯替代物以及含有更多类药取代基的各种取代芳香族和脂环族基团的半合成和合成衍生物，报告了对结构-活性理解的大幅扩展。获得了这些分子对热休克蛋白90（Hsp90）抑制的构效关系。结果表明，酰胺和磺酰胺连接体是合适的酯替代物。EGCG中的羟基化芳香环和顺式立体化学对于Hsp90抑制并非必不可少。在用于Hsp90活性的荧光素酶重折叠试验中，该系列中选定的类似物比EGCG更有效。
