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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors
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Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors

机译：寻求发现像表没食子儿茶素没食子酸酯类似物作为Hsp90抑制剂

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(-)-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.
机译：（-）-表没食子儿茶素没食子酸酯（EGCG）是绿茶中的主要类黄酮，已被广泛研究用于包括抗感染，抗炎，抗癌和神经保护在内的一系列生物活性。 EGCG的现有结构活性数据在很大程度上限于探索简单的醚和羟基缺失。由于多个酚羟基部分和代谢不稳定的酯，EGCG具有较差的类药物性质。这项工作报告了通过探索一系列具有酯取代基和含有更多类似药物的取代基的各种取代的芳族和脂环族基团的半合成和合成衍生物，大大扩展了对结构活性的理解。获得了这些分子的结构-活性关系以抑制Hsp90。结果表明酰胺和磺酰胺接头是合适的酯替代物。 EGCG中的羟基化芳环和顺式立体化学对于Hsp90抑制不是必需的。在针对Hsp90活性的萤光素酶重折叠测定中，该系列中的选定类似物比EGCG更有力。

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