Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors

Moran Sun; Minghua Yuan; Yingying Kang; Jinling Qin; Yixin Zhang; Yongtao Duan; Longfei Wang; Yongfang Yao

doi:10.1080/14756366.2021.2014831

Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors

J Enzyme Inhib Med Chem. 2022 Dec;37(1):339-354. doi: 10.1080/14756366.2021.2014831.

Authors

Moran Sun^{1

2}, Minghua Yuan², Yingying Kang², Jinling Qin², Yixin Zhang², Yongtao Duan¹, Longfei Wang¹, Yongfang Yao^{1

2

3}

Affiliations

¹ Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China.
² Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou, China.
³ State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.

Abstract

α-Fluorinated chalcones were prepared and evaluated for their cell growth inhibitory properties against six human cancer cell lines. The most potent chalcone 4c demonstrated excellent selective toxicity against cancer cells versus normal human cells, with IC₅₀ values at nanomolar concentration ranges against 5 cancer cell lines. A further study revealed that 4c could bind to the colchicine site of tubulin, disrupt the cell microtubule networks, and effectively inhibit tubulin polymerisation. Cellular-based mechanism studies elucidated that 4c arrested MGC-803 cell cycle at G2/M phase. In addition, 4c dose-dependently caused Caspase-induced apoptosis of MGC-803 cells through mitochondrial dysfunction. Notably, compound 4c was found to inhibit the HUVECs tube formation, migration, and invasion in vitro. Furthermore, our data suggested that treatment with 4c significantly reduced MGC-803 cells metastasis and proliferation in vitro. Overall, this work showed that chalcone hybrid 4c is a potent inhibitor of tubulin assembly with prominent anti-angiogenesis and anti-cancer properties.

Keywords: Microtubules; angiogenesis; chalcone; fluorinated; zebrafish.

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Binding Sites / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chalcones / chemical synthesis
Chalcones / chemistry
Chalcones / pharmacology*
Colchicine / antagonists & inhibitors*
Colchicine / metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Halogenation
Humans
Molecular Structure
Neovascularization, Pathologic / drug therapy*
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Polymerization / drug effects
Structure-Activity Relationship
Tubulin / metabolism
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Chalcones
Tubulin
Tubulin Modulators
Colchicine

Grants and funding

This work was supported by National Natural Science Foundation of China (Project No. 81903623 and 22007086), Henan science and technology key project [No. 202102310148] and Henan Medical Science and Technology Program [No. 2018020601].