异甘草素衍生物的合成及其抑制单胺氧化酶B的活性研究

Synthesis and monoamine oxidase B inhibitory activities of isoquiritigenin derivatives

异甘草素是中药甘草的活性成分之一,被发现对单胺氧化酶B(MAO-B)具有一定的抑制活性(IC50为47. 2μmol·L-1)。然而,其确切构效关系迄今尚未明确,此外,异甘草素对MAO-B的抑制专一性也不算理想。为探讨异甘草素抑制MAO-B的构效关系及寻找活性更优,专一性更好的MAO-B抑制剂,该文基于异甘草素母体结构,合成了13个衍生物,其纯度和结构均经UPLC,1H-NMR,13C-NMR及HRMS确证。以异甘草素为阳性对照,评价了所合成化合物对人MAO-B的抑制活性。活性结果初步阐明了异甘草素抑制MAO-B的构效关系,并发现了高活性化合物C8,其IC50为1. 4μmol·L-1,比异甘草素提高了约16倍,选择性提高了30倍以上。酶抑制动力学研究显示,C8属于竞争型抑制剂。另外,C8在体外对神经胶质细胞并未表现出明显的细胞毒性,值得进一步深入研究。

Isoquiritigenin,one of the active constituents in the Chinese herb liquorice,is found to have moderate inhibitory activity against rat monoamine oxidase B(MAO-B,IC5047.2μmol·L-1).However,the structure-activity relationship(SAR)remains unclear until now.In an attempt to reveal the SAR of inhibition by isoquiritigenin,and to identify more potent and selective inhibitors of MAOB,a series of 13 derivatives based on the scaffold of isoquiritigenin were prepared,and their purities and structures were confirmed by UPLC,1 H-NMR,13 C-NMR and HRMS.These compounds were then evaluated for their ability to inhibit the enzymatic activity of human MAO-B.The SAR of inhibition was summarized and a potent compound C8 with high inhibitory activity(IC501.4μmol·L-1)and selectivity(>57 folds over MAO-A)was identified.Enzyme kinetics studies suggested that C8 acted as a competitive inhibitor.In addition,C8 showed little cytotoxicity to glial cells in vitro,which could be a promising lead compound for further study.