Synthesis and Anticancer Evaluation of 4-Anilinoquinolinylchalcone Derivatives

Abstract

A series of 4-anilinoquinolinylchalcone derivatives were synthesized and evaluated for antiproliferative activities against the growth of human cancer cell lines (Huh-7 and MDA-MB-231) and normal lung cells (MRC-5). The results exhibited low cytotoxicity against human lung cells (MRC-5). Among them, (E)-3-{4-{[4-(benzyloxy)phenyl]amino}quinolin-2-yl}-1-(4-methoxyphenyl) prop-2-en-1-one (4a) was found to have the highest cytotoxicity in breast cancer cells and low cytotoxicity in normal cells. Compound 4a causes ATP depletion and apoptosis of breast cancer MDA-MB-231 cells and triggers reactive oxygen species (ROS)-dependent caspase 3/7 activation. In conclusion, it is worth studying 4-anilinoquinolinylchalcone derivatives further as new potential anticancer agents for the treatment of human cancers.

Keywords: 4-anilinoquinolinylchalcone; apoptosis; cytotoxicity; lapatinib; reactive oxygen species.

Figure 1

The target 4-(benzyloxy)aniline-quinolinylchalcone hybrids.

Scheme 1

Synthesis of 4-(benzyloxy)aniline-quinolinylchalcone derivatives 4a–5i.

Figure 2

Inhibition of cellular ATP contents of breast cancer cells by compound 4a. MDA-MB-231 cells were treated with 4a for 24 h. Data, means ± SDs (n = 3). Data containing non-overlapping notes exhibited significant differences (p < 0.05). The letters (a, b, c) were provided by the statistical JMP software for determine significance. “a” is the biggest value and others follow the order.

Figure 3

Upregulation of annexin V-based apoptosis of breast cancer cells by compound 4a. MDA-MB-231 cells were treated with 4a for 24 h, and their apoptosis status was determined by flow cytometry. Populations of annexin V (+)/7AAD were assigned as apoptosis (+) (%). Data, means ± SDs (n = 3). Data containing non-overlapping notes exhibited significant differences (p < 0.05). The letters (a, b, c) were provided by the statistical JMP software for determine significance. “a” is the biggest value and others follow the order.

Figure 4

ROS levels of breast cancer cells were induced by compound 4a. MDA-MB-231 cells were treated with 4a for 24 h. ROS levels were determined by flow cytometry. Populations of high ROS intensities were assigned as ROS (+) (%). Data, means ± SDs (n = 3). Data containing non-overlapping notes exhibited significant differences (p < 0.05). The letters (a, b, c, d) were provided by the statistical JMP software for determine significance. “a” is the biggest value and others follow the order.

Figure 5

Upregulation of caspase 3/7 activity of breast cancer cells by compound 4a. MDA-MB-231 cells were pretreated with 1 h N-acetylcysteine (NAC) and post-treated with 4a for 24 h. Caspase 3/7 activity was determined by luminescence detection. Data, means ± SDs (n = 3). Data containing non-overlapping notes exhibited significant differences (p < 0.05). The letters (a, b, c, d) were provided by the statistical JMP software for determine significance. “a” is the biggest value and others follow the order.