Design, synthesis and antitumor activity of potent and safe para-quinone methides derivatives in vitro and in vivo.

Compounds containing Michael acceptor units display a wide variety of biological effects, and have attracted much attention in medicinal chemistry. In this paper, we designed and synthesized a panel of para -quinone methides (p -QMs) derivatives, classified as electron-deficient alkenes, and evaluated their cytotoxicity against cancer cells. These results revealed that drawing substituents into the ortho -position of the phenyl ring could obviously strengthen the cytotoxicity of p -QMs derivatives compared with that of meta - and para -substituents. Further biological studies demonstrated that the cytotoxicity of p -QMs derivatives originated from their ROS-generation abilities, which could further disrupt the redox balance, lipid peroxidation, the loss of MMP, cell cycle arrest at G0/G1 phase and apoptosis. 1h also exhibited potent antitumor activity through inhibiting TrxR and activating Bax and caspase 3 expression in vitro and in vivo , and 1h had certain safety in vivo. Moreover, the electrophilicity of the Michael acceptor, which could covalently modify with the TrxR, play a potent role in the ROS generation. From the perspective of chemistry, we affirmed that p -QMs derivatives could rapidly covalent binding with cysteamine, and the addition product was characterized by 1H NMR. Together, these new p -QMs derivatives may possess potential as leads for development of effective antitumor agents. [Display omitted] • p -QMs derivatives exhibited moderate to good cytotoxicity on cancer cells. • p -QMs derivatives showed strong electrophilicity and rapidly reacted with cysteamine. • p -QMs derivative 1h displayed potent antitumor activity by inhibiting TrxR in vitro and in vivo. • 1h had certain safety in vivo. [ABSTRACT FROM AUTHOR]