Analysis of Flavonoid-Based Pharmacophores that Inhibit Aggrecanases (ADAMTS-4 and ADAMTS-5) and Matrix Metalloproteinases Through the Use of Topologically Constrained Peptide Substrates
Analysis of Flavonoid-Based Pharmacophores that Inhibit Aggrecanases (ADAMTS-4 and ADAMTS-5) and Matrix Metalloproteinases Through the Use of Topologically Constrained Peptide Substrates
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DOI：
10.1111/j.1747-0285.2009.00885.x
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发表时间：
2009-11-01
影响因子：
3
通讯作者：
Lauer-Fields, Janelle
中科院分区：
文献类型：
--
作者：
Cudic, Mare;Burstein, Gayle D.;Lauer-Fields, Janelle
绿茶和红酒中的多酚类天然产物已被鉴定为金属蛋白酶抑制剂。从类黄酮类和二苯乙烯类化合物中发现具有金属蛋白酶抑制活性的成员包括(-)-表儿茶素没食子酸酯、(-)-表儿茶素没食子酸酯和倍他雄醇，但它们最低活性的药效团尚未被评估。本研究考察了(-)-表没食子儿茶素没食子酸酯、(-)-表没食子儿茶素没食子酸酯、(-)-表没食子儿茶素没食子酸酯、(-)-表没食子儿茶素没食子酸酯、(-)-表没食子儿茶素没食子酸酯、(-)-表没食子儿茶素没食子酸酯、(-)-表没食子儿茶素没食子酸酯、(-)-表儿茶素没食子酸酯和匹卡坦醇的结构组成或结构上与之相关的化合物，以抑制聚集酶和四种典型的基质金属蛋白酶。研究表明，表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯、表没食子儿茶素没食子酸酯和表儿茶素没食子酸酯的活性依赖于多个羟基。用两种结构不同的底物测定的焦性没食子酸的K-I值的差异表明，这种化合物可能以非竞争性的方式结合。进一步的分析表明，焦性没食子酸酯是一种外排抑制物，与(-)-表没食子儿茶素没食子酸酯的作用一致。相反，Piceat注l被证明是一种竞争性结合抑制剂，并且在不同底物测定的表观K-I值上没有差异，说明了使用两种结构不同的底物来辅助分析蛋白酶抑制剂的好处。这些化合物可以用来开发新的金属蛋白酶探针或作为更有活性的抑制剂的片段成分。
Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metalloproteinases. Piceatannol and pyrogallol were found to inhibit all aggrecanases and matrix metalloproteinases studied, indicating a crucial reliance on multiple hydroxyl groups for (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol activity. Differences in K-i values for pyrogallol as determined with two structurally distinct substrates indicated the likelihood that this compound binds in a non-competitive modality. Further analysis showed that pyrogallol acts as an exosite inhibitor, consistent with the action of (-)-epigallocatechin gallate. In contrast, piceatannol was shown to be a competitive binding inhibitor and showed no differences in apparent K-i values as determined by distinct substrates, illustrating the benefits of using two structurally distinct substrates to assist the analysis of protease inhibitors. The compounds identified here could be utilized to develop novel metalloproteinase probes or as fragment components of more active inhibitors.