Synthesis of Chalcone Derivatives: Inducing Apoptosis of HepG2 Cells via Regulating Reactive Oxygen Species and Mitochondrial Pathway.

Hongtian Zhu,Lei Tang,Pingrong Yang,Baochu Wei,Chenghong Zhang,Yang Zhang,Dian He,Lifang Zheng

doi:10.3389/fphar.2019.01341

Hongtian Zhu, Lei Tang + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2019.01341

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Abstract

Chalcone derivatives, as a hot research field, exhibit a variety of physiological bioactivities and target multiple biological receptors. Based on the skeleton of (E)-1,3-diphenyl-2-propene-1-one, 14 chalcone derivatives were designed and synthesized, and evaluated as the antitumor candidates agents against four human cancer cell lines (A549, Hela, HepG2, and HL-60) as well as one normal cell line (WI-38). Among the title compounds, compound a14 showed better inhibitory activity against HepG2 cells (IC50 = 38.33 µM) and had relatively weak cytotoxicity towards normal cells WI-38 (IC50 = 121.29 µM). In this study, apoptosis, cycle arrest, assessment of reactive oxygen species (ROS) level, and measurement of mitochondrial membrane potential were adopted to explore the inhibitory mechanism of a14 towards HepG2. Compound a14 could effectively block the division of HepG2 cell lines in the G2/M phase and robustly induced generation of ROS, demonstrating that the generation of ROS induced by a14 was the main reason for resulting in the apoptosis of HepG2 cells. Moreover, the mitochondrial membrane potential (MMP) of HepG2 cells treated with a14 was significantly decreased, which was closely related to the enhanced ROS level. Furthermore, based on Western blot experiment, cell apoptosis induced by a14 also involved the expression of B-cell lymphoma-2 (Bcl-2) family and Caspase 3 protein. In summary, compound a14 could contribute to the apoptosis of HepG2 cells through regulating ROS-mitochondrial pathway, which provides valuable hints for the discovery of novel anti-tumor drug candidates.

Highlights

IntroductionMore and more researchers have realized that nature is a potential resource of new therapeutic candidate compounds with diverse molecular skeletons, and an increasing number of studies have shown that natural products or their derivatives play a vital role in the treatment of various diseases (da Rocha et al, 2001; Cao et al, 2018; Jin et al, 2018), making the application of raw materials to synthesize the natural product analogs become much more indispensable (Koehn and Carter, 2005; Cai et al, 2012; Sahu et al, 2012; Singh et al, 2014; Yang et al, 2014; Zhang et al, 2015; Zhang et al, 2019)
Many studies have explored the molecular mechanism of anti-tumor effects of chalcone derivatives, and it is necessary to note that chalcone derivatives can inhibit angiogenesis, induce caspase-dependent apoptotic cell death, and regulate the expression of pro-apoptotic proteins and antiapoptotic cells related to the Bcl family (Zi and Simoneau, 2005; George et al, 2007; Wani et al, 2016)
Chalcone derivatives generally consist of two aryl groups connected by an α, β-unsaturated ketone moiety, which forms the more thermodynamically stable trans-conformation (Zhang et al, 2017)

Summary

Introduction

More and more researchers have realized that nature is a potential resource of new therapeutic candidate compounds with diverse molecular skeletons, and an increasing number of studies have shown that natural products or their derivatives play a vital role in the treatment of various diseases (da Rocha et al, 2001; Cao et al, 2018; Jin et al, 2018), making the application of raw materials to synthesize the natural product analogs become much more indispensable (Koehn and Carter, 2005; Cai et al, 2012; Sahu et al, 2012; Singh et al, 2014; Yang et al, 2014; Zhang et al, 2015; Zhang et al, 2019). It is very necessary to design and synthesize a series of chalcone derivatives and study their mechanisms of promoting apoptosis of tumor cell

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