[Synthesis and monoamine oxidase B inhibitory activities of isoquiritigenin derivatives].

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. 2 µmol·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. 4 µmol·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.

Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide-Rich Peptides.

Disulfide-rich peptides containing three or more disulfide bonds are promising therapeutic and diagnostic agents, but their preparation is often limited by the tedious and low-yielding folding process. We found that a single cystine-to-diaminodiacid replacement could significantly increase the folding efficiency of disulfide-rich peptides and thus improve their production yields. The practicality of this strategy was demonstrated by the synthesis and folding of derivatives of the µ-conotoxin SIIIA, the preclinical hormone hepcidin, and the trypsin inhibitor EETI-II. NMR and X-ray crystallography studies confirmed that these derivatives of disulfide-rich peptide retained the correct three-dimensional conformations. Moreover, the cystine-to-diaminodiacid replacement enabled structural tuning, thereby leading to an EETI-II derivative with higher bioactivity than the native peptide.