Anti-cancer activity of benzoxazinone derivatives via targeting c-Myc G-quadruplex structure.

Aims: This study aimed to analyze the impact of four synthesized benzoxazinone derivatives as screening drugs on c-Myc-overexpressed cancer cells (H7402, HeLa, SK-RC-42, SGC7901, and A549) and to explore their interaction mechanisms in detail.
Materials and Methods: Using morphological analysis, real-time cytotoxicity analysis, wound healing assay, reverse transcription PCR, electrophoretic mobility shift assay, and circular dichroism spectroscopy techniques.
Key Findings: Results revealed that these four compounds could inhibit proliferation of SK-RC-42, SGC7901, and A549 cells in five cancer cell lines to varying degrees and significantly hinder migration. More importantly, the RT-PCR assay showed that the compounds could surprisingly downregulate the expression of c-Myc mRNA in a dose-dependent manner in the five cancer cells, which may be one of the causes of cancer cell proliferation in vitro inhibition. Further EMSA assays demonstrated that at the molecular level of DNA, four compounds can induce the formation of G-quadruplexes (G4-DNAs) in the c-Myc gene promoter. In addition, the CD result of compound 1 clearly indicates that it specifically induces a c-Myc GC-rich 36mer double-stranded DNA in the c-Myc promoter to form a G-quadruplex hybrid configuration. In conclusion, the compounds studied could dose-dependently inhibit the growth and migration of the cancer cells being investigated. This is positively associated with the reduction of overexpression of the c-Myc gene, which may be significantly regulated by the association of compounds with the G-quadruplexes produced in the c-Myc gene promoter region.
Significance: We conclude that three compounds merit further study, particularly against non-small-cell lung cancer, as leading compounds of anticancer drugs.
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