The Design, Synthesis, and Evaluation of Evodiamine Derivatives with Hydroxy Groups

Abstract

Background: Most of the structural modifications to evodiamine (EVO) have focused on the 3- and 10-positions, while structural modifications to the EVO 2-position have not yet been reported. In this study, we investigated the scaffold diversity and bioactivity of EVO from position 2 to gain more insight into the influence of the chemical space around EVO on bioactivity. Objective: The study aims to synthesize two derivatives of EVO with hydroxy groups, 8a and 8b, and to investigate the antitumor activity of EVO derivatives with hydroxy groups compared to EVO. Methods: The synthesized compounds were structurally characterized by 1H NMR, 13C NMR, and mass spectrometry. The effects of compounds 8a, 8b, and EVO on the proliferation of H460, A549, and Eca109 cells in vitro were determined by MTT. The effect of EVO, 8a and 8b on apoptosis of H460 cells was investigated by the annexed V-FITC/propidium iodide (PI) combination assay. The expression of EVO, 8a and 8b on apoptosis-related proteins was examined by Western blot analysis. To simulate the binding ability between small molecules and proteins, molecular docking calculations of EGFRWT and EGFRT790M with 8a and 8b, respectively, were performed using Schrödinger software. Results: In the cytotoxicity assay, compound 8b showed lower IC50 values for the three tumor cell lines (6.69 μM for H460 cells, 20.02 μM for A549 cells, and 16.47 μM for Eca109 cells) compared to compound 8a and EVO, and 8b induced apoptosis by affecting apoptosis-related proteins CRAF, AKT, and ERK in a late apoptotic manner. The molecular docking results showed that 8b has a good binding ability to EGFR upstream of apoptosis-related proteins. Conclusion: These findings suggest that 8b has significantly higher antitumor biological activity than EVO and 8a. This antitumor effect has important implications for the study of EVO derivatives in antitumor models.