trans-Styrylquinazolinone CYP1B1 inhibitors as potential therapeutics in A549 cells.

Cytochrome CYP1B1 is a member of the monooxygenase subfamily. It can lead to tumorigenesis by catalyzing the activation of a variety of exogenous carcinogens and endogenous estrogens. In addition, overexpression of CYP1B1 in hormone-related tumors can inactivate certain anticancer drugs, leading to resistance. Accordingly, selective inhibition of CYP1B1 expression represents a potential therapeutic strategy to overcome tumor drug resistance. To this end, we designed and synthesized 46 trans-styrylquinazolinone CYP1B1 inhibitors, The most important feature of these compounds is that the introduction of double bonds makes the molecular structure in the same plane to form a conjugated system. 7-Ethoxyresorufin-O-deethylase (EROD) screening revealed that one of these compounds exhibited an IC50 value of 6.75 × 10-3 nM against CYP1B1. Based on this initial hit, a series of 2-styrylquinazolin-4-amines were synthesized as a means to optimize inhibitory ability and water solubility. Aromatization and the introduction of amino groups was found to greatly improve inhibitory ability, with one such derivative presenting IC50 = 6.05 × 10-6 nM. Molecular docking experiments were used to explore the binding of the most potent compounds to CYP1B1. A549 cell experiments showed that three of the compounds (including the initial trans-styrylquinazolinone hit) significantly reversed resistance to paclitaxel and greatly inhibited invasion and migration, demonstrating the application potential of trans-styrylquinazolinone CYP1B1 inhibitors in the prevention and treatment of hormone-related tumors.