trans-Stilbenoids: Potent and selective inhibitors for human cytochrome P450 1B1

On the basis of our previous insights into the structural requirements of stilbenoids for the inhibition of cytochrome P450 1B1 (CYP1B1), a series of 2,4-dimethoxy group-containing stilbenes was prepared and evaluated for their inhibitory effects on the activity of CYP1s with the ultimate goal of identifying a potent and selective CYP1B1 inhibitor. Among the thirteen derivatives prepared, five compounds exhibited similar or greater potency compared to the previous lead compound, 2,4,3′,5′- tetramethoxystilbene (2,4,3′,5′-TMS), in inhibiting CYP1B1. In particular, 2,2′,3′,4,6′-pentamethoxystilbene was found to be a more selective and more potent CYP1B1 inhibitor than 2,4,3′,5′- TMS. 2,4,2′,6′-TMS showed remarkably potent inhibitory activity against CYP1B1 (IC₅₀ = 1.77 ± 0.14 nM) and also had a very high selectivity toward CYP1 isoenzymes. Molecular modeling was performed to determine the key molecular interactions with the CYP1B1 and CYP1A2 structures. On the basis of these structural and biological studies, the design of more potent and more selective drug-like derivatives can be envisaged.