Abstract：OBJECTIVE To design and construct a small class of ethyl α-arylthio-α-aminoacetate derivatives, and carry out biological activity evaluation and molecular simulation study.METHODS The target compounds were constructed through a multi-component one-pot cascade reaction from amine, ethyl glyoxylate and thiophenol. All the compounds were screened for their LSD1 inhibition effect, and the most potent compound was further tested for its IC50 value and binding mode. Dilution assay was applied to investigate the reversibility of the potent inhibitor, and both transwell and Western blot methods were used to investigate its effect on anti-migration and EMT process. RESULTS A total of 11 compounds were prepared and tested for their inhibitory activity against LSD1. Among them, compound 4j displayed the most potent LSD1 inhibitory activity with the IC50 value of 0.28 μmol·L-1, and it was further proved to be a reversible and cellular active LSD1 inhibitor. In addition, compound 4j displayed both anti-migration and anti-EMT effects on lung cancer cell line H1299.CONCLUSION This class of arylthio amino ester derivatives represent a novel chemical skeleton of LSD1 inhibitors, and deserve further structural optimization and SAR study to design new LSD1 inhibitors.
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2023, Vol. 58 
