Preparation of Dearomatized p‐Coumaric Acid Derivatives as DNA Damage Response Inhibitors with Potent In Vitro Antitumor Effect

Abstract

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.