Novel chalcone-derived pyrazoles as potential therapeutic agents for the treatment of non-small cell lung cancer

Natalia Maciejewska,Maciej Baginski,Katarzyna Cekala,Jakub Jurasz,Maria Dzierzynska,Marcin Serocki,Mateusz Olszewski,Ewa Wieczerzak

doi:10.1038/s41598-022-07691-6

Natalia Maciejewska, Maciej Baginski + Show 6 more

Open Access

https://doi.org/10.1038/s41598-022-07691-6

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Abstract

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related deaths worldwide and is therefore one of the most lethal malignancies. Pyrazole scaffold possesses a wide range of biological and pharmacological activities, which play important roles in medicinal chemistry. The present study reports the synthesis and in vitro biological characterization of nine pyrazoles derived from chalcones as potential anticancer agents for non-small cell lung cancer A-549, H226, and H460 cell lines. Most of the compounds efficiently inhibited the growth of all the tested cancer cell lines at micromolar concentrations. One of the most active compounds (PCH-1) was further evaluated for its effect on cell cycle distribution, apoptosis, migration, epithelial–mesenchymal transition, and oxidative stress. Furthermore, studies on the mechanism of action revealed that PCH-1 disrupts microtubule assembly, leading to cancer cell death. Molecular modeling studies confirmed the potent interaction of PCH-1 with the vinblastine binding site on tubulin. Overall, this study provides novel opportunities to identify anticancer agents in the pyrazole series.

Highlights

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related deaths worldwide and is one of the most lethal malignancies
Fluorine atoms have been incorporated into the methoxy group in PCH-6 derivative
The incidence of lung cancer is increasing dramatically each year, and this increase is associated with aging of the human population which has been exposed to several factors that promote mutations leading to cancer, such as smoking tobacco, unhealthy diet, or air p ollution[60]

Summary

Introduction

Lung cancer is considered to account for approximately one-fifth of all malignant tumor-related deaths worldwide and is one of the most lethal malignancies. The present study reports the synthesis and in vitro biological characterization of nine pyrazoles derived from chalcones as potential anticancer agents for non-small cell lung cancer A-549, H226, and H460 cell lines. Studies on the mechanism of action revealed that PCH-1 disrupts microtubule assembly, leading to cancer cell death. Similar to naturally occurring chalcones, methoxy and hydroxy groups in positions on the phenyl rings are important for anticancer activities of chalcone derivatives[13]. Wang et al found that chalcones bearing the 3-hydroxyl-4-methoxy phenyl moiety demonstrated high cytotoxic activity against the MCF-7 breast cancer cell line and displayed potent tubulin polymerization inhibitory a ctivity[15]. Similar to combretastatin and colchicine, methoxylated chalcones bind to tubulin and prevent its polymerization, leading to cell cycle arrest by interruption of mitotic spindle assembly and resulting in cell death[18]. Structural manipulations that vary in the basic structural framework or substitutions pattern have been reported for Scientific Reports | (2022) 12:3703

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