Discovery of chalcone-modified estradiol analogs as antitumour agents that Inhibit tumour angiogenesis and epithelial to mesenchymal transition

Cong Wang; Leilei Li; Dongyang Fu; Tiantian Qin; Yange Ran; Feng Xu; Xinrui Du; Haiying Gao; Shuaijun Sun; Tengjiao Yang; Xueyan Zhang; Junfeng Huo; Wen Zhao; Zhenzhong Zhang; Xiufang Shi

doi:10.1016/j.ejmech.2019.04.071

Discovery of chalcone-modified estradiol analogs as antitumour agents that Inhibit tumour angiogenesis and epithelial to mesenchymal transition

Eur J Med Chem. 2019 Aug 15:176:135-148. doi: 10.1016/j.ejmech.2019.04.071. Epub 2019 Apr 30.

Authors

Cong Wang¹, Leilei Li¹, Dongyang Fu¹, Tiantian Qin¹, Yange Ran¹, Feng Xu¹, Xinrui Du², Haiying Gao³, Shuaijun Sun⁴, Tengjiao Yang⁵, Xueyan Zhang¹, Junfeng Huo¹, Wen Zhao¹, Zhenzhong Zhang¹, Xiufang Shi⁶

Affiliations

¹ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
² Department of Clinical Medicine, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan, 450052, China.
³ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China; Department of Pharmacy, People's Hospital of Daqing, 241 Jianshe Road, Development District, Daqing, 163316, Heilongjiang, China.
⁴ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China; Department of Pharmacy, Zhengzhou Central Hospital Affiliated to Zhengzhou University, 195 Tongbai Road, Zhengzhou, 450053, Henan, China.
⁵ HeNan No.3 Provincial People's Hospital, Funiu Road, Zhongyuan District, Zhengzhoum, 450000, Henan, China.
⁶ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address: xfshi@zzu.edu.cn.

PMID: 31102934
DOI: 10.1016/j.ejmech.2019.04.071

Abstract

Angiogenesis plays an essential role in tumourigenesis and tumour progression, and anti-angiogenesis therapies have shown promising antitumour effects in solid tumours. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been regarded as a potential antitumour agent mainly targeting angiogenesis. Here we synthesized a novel series of chalcones based on 2-methoxyestradiol and evaluated their potential activities against tumours. Compound 11e was demonstrated to have potent antiangiogenic activity. Further studies showed that 11e suppressed tumour growth in human breast cancer (MCF-7) xenograft models without obvious side effects. Evaluation of the mechanism revealed that 11e targeted the epithelial to mesenchymal transition (EMT) process in MCF-7 cells and inhibited HUVEC migration and then contributed to hindrance of angiogenesis. Thus, 11e may be a promising antitumour agent with excellent efficacy and low toxicity.

Keywords: 2-Methoxyestradiol; Angiogenesis; Antitumour; EMT; Migration.

MeSH terms

2-Methoxyestradiol / analogs & derivatives*
2-Methoxyestradiol / chemical synthesis
2-Methoxyestradiol / therapeutic use*
2-Methoxyestradiol / toxicity
Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / therapeutic use*
Angiogenesis Inhibitors / toxicity
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / therapeutic use*
Antineoplastic Agents / toxicity
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Chalcones / chemical synthesis
Chalcones / chemistry
Chalcones / therapeutic use*
Chalcones / toxicity
Chickens
Chorioallantoic Membrane / drug effects
Epithelial-Mesenchymal Transition / drug effects*
Female
Human Umbilical Vein Endothelial Cells
Humans
Male
Mice, Nude
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
Stereoisomerism
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Chalcones
2-Methoxyestradiol
Receptors, Vascular Endothelial Growth Factor