7,8-Dehydrorutaecarpine was a potent inhibitor of both CYP1A1 and CYP1A2. The introduction of methoxyl group reduced CYP1A1 inhibition and enhanced the relative inhibition selectivity to either CYP1A2 or CYP1B1. Among the synthesized derivatives, 2-methoxy-7,8-dehydrorutaecarpine had the best selectivity of CYP1A2 inhibition. In contrast, the introduction of 4-methoxyl group decreased the IC50 values for CYP1B1 and had the best selectivity of CYP1B1 inhibition. Results of molecular modeling showed that a hydrogen bond was formed between the 2-methoxyl group of 2-methoxy-7,8-dehydrorutaecarpine and Thr113 residue of CYP1A2. 2-Methoxy-7,8-dehydrorutaecarpine was a mixed type inhibitor of CYP1A2 with the inhibition constants of 9.5 ± 2.6 and 6.7 ± 2.6 nM for CYP1A2 and CYP1A2-substrate complex, respectively. For the 2-methoxyl derivatives of 7,8-dehydrorutaecarpine and rutaecarpine, the change of 2-methoxyl to an 2-ethoxyl group decreased and increased the IC50 values for CYP1A1 and CYP1A2, respectively. Our results demonstrated that introduction of alkoxyl modification to a heterocyclic compound, 7,8-dehydrorutaecarpine could change inhibitory selectivity among CYP1 enzymes. These results may provide important information for the interaction between CYP1 members and their inhibitors with a core structure of 7,8-dehydrorutaecarpine.
Tseng, J.-C.; Don, M.-J.; Lewis, D.F.V.; Wang, S.-Y.; and Ueng, Y.-F.
"Inhibition of CYP1 by 7,8-dehydrorutaecarpine and its methoxylated derivatives,"
Journal of Food and Drug Analysis: Vol. 15
, Article 15.
Available at: https://doi.org/10.38212/2224-6614.2400