Preparation of Dearomatized p-Coumaric Acid Derivatives as DNA Damage Response Inhibitors with Potent In Vitro Antitumor Effect.
Laura FásiTímea GondaNoémi TóthMáté VassAndrás GyovaiViktória NagyImre OcsovszkiIstván ZupkóNorbert KúszMárta NovéGabriella SpenglerRóbert BerkeczHui-Chun WangFang-Rong ChangAttila HunyadiPublished in: ChemMedChem (2024)
Our research group previously identified graviquinone (1) as a promising antitumor metabolite that is formed in situ when the antioxidant methyl caffeate scavenges free radicals. Furthermore, it exerted a DNA damaging effect on cancer cells and a DNA protective effect on normal keratinocytes. To expand and explore chemical space around qraviquinone, in the current work we synthesized 9 new alkyl-substituted derivatives and tested their in vitro antitumor potential. All new compounds bypassed ABCB1-mediated multidrug resistance and showed highly different cell line specificity compared with 1. All compounds were more potent in MDA-MB-231 than on MCF-7 cells. The n-butyl-substituted derivatives 2 and 8 modulated the cell cycle and inhibited the ATR-mediated phosphorylation of checkpoint kinase-1 in MCF-7 cells. As a significant expansion of our previous findings, our results highlight the potential antitumor value of alkyl-substituted graviquinone derivatives.
Keyphrases
- cell cycle
- dna damage response
- induced apoptosis
- cell cycle arrest
- breast cancer cells
- molecular docking
- cell proliferation
- anti inflammatory
- ionic liquid
- oxidative stress
- dna damage
- endoplasmic reticulum stress
- protein kinase
- human health
- dna repair
- structure activity relationship
- pi k akt
- mass spectrometry
- molecular dynamics simulations