Affiliation:
1. College of Pharmacy, Shaanxi Key Lab Basic & New Herbal Medicament Res, Shaanxi University of Chinese Medicine,
Xian Yang, Shaanxi 712046, China
2. Instrumental Analysis Center, Xi'an Jiao Tong University, Xi'an, 710049,
P.R. China
3. Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering
Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong
Province, 519000, China
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.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine