Glynn Stephen J, Gaffney Kevin J, Sainz Marcos A, Louie Stan G, Petasis Nicos A
Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California 90089, USA.
Org Biomol Chem. 2015 Apr 7;13(13):3887-99. doi: 10.1039/c4ob02512a.
The green tea polyphenol epigallocatechin-3-gallate (EGCG) was reported to effectively antagonize the ability of Bortezomib (BZM) to induce apoptosis in cancer cells. This interaction was attributed to the formation of a covalent adduct between a phenolic moiety of EGCG with the boronic acid group of Bortezomib. However, the structural details of this boron adduct and the molecular factors that contribute to its formation and its ability to inhibit Bortezomib's activity remain unclear. This paper describes the use of NMR spectroscopy and cell assays to characterize the structures and properties of the boron adducts of EGCG and related polyphenols. The observed boron adducts included both boronate and borate derivatives, and their structural characteristics were correlated with cell-based evaluation of the ability of EGCG and other phenols to antagonize the anticancer activity of Bortezomib. The enhanced stability of the BZM/EGCG adduct was attributed to electronic and steric reasons, and a newly identified intramolecular interaction of the boron atom of BZM with the adjacent amide bond. The reported approach provides a useful method for determining the potential ability of polyphenols to form undesired adducts with boron-based drugs and interfere with their actions.
据报道,绿茶多酚表没食子儿茶素-3-没食子酸酯(EGCG)能有效拮抗硼替佐米(BZM)诱导癌细胞凋亡的能力。这种相互作用归因于EGCG的酚类部分与硼替佐米的硼酸基团之间形成了共价加合物。然而,这种硼加合物的结构细节以及促成其形成及其抑制硼替佐米活性能力的分子因素仍不清楚。本文描述了使用核磁共振光谱和细胞试验来表征EGCG及相关多酚的硼加合物的结构和性质。观察到的硼加合物包括硼酸酯和硼酸盐衍生物,并且它们的结构特征与基于细胞对EGCG和其他酚类拮抗硼替佐米抗癌活性能力的评估相关。BZM/EGCG加合物稳定性增强归因于电子和空间原因,以及新发现的BZM硼原子与相邻酰胺键的分子内相互作用。所报道的方法为确定多酚与硼基药物形成不期望加合物并干扰其作用的潜在能力提供了一种有用的方法。