Development of Flavone Propargyl Ethers as Potent and Selective Inhibitors of Cytochrome P450 Enzymes 1A1 and 1A2
Cheryl L. Stevens,
Naturally occurring flavonoids are known to be metabolized by several cytochrome P450 enzymes including
P450s 1A1, 1A2, 1B1, 2C9, 3A4, and 3A5. In general flavonoids can act as substrates, inducers, and/or inhibitors of P450
enzymes. The position of the substituents on the flavone backbone has been shown to impact the biological activity
against P450 enzymes. To explore the effect of a propargyl ether substitution on flavones and flavanones, 2´-flavone
propargyl ether (2´-PF), 3´-flavone propargyl ether (3´-PF), 4´-flavone propargyl ether (4´-PF), 5-flavone propargyl ether
(5-PF), 6-flavone propargyl ether (6-PF), 7-flavone propargyl ether (7-PF), 6-flavanone propargyl ether (6-PFN), and 7-
flavanone propargyl ether (7-PFN) were synthesized. All of the newly synthesized compounds and the parent hydroxy
flavones were tested for both direct inhibition and mechanism-based inhibition of cytochrome P450 enzymes 1A1, 1A2,
2A6, and 2B1. The flavone propargyl ether derivatives were found to be more potent inhibitors of P450s 1A1 and 1A2.
None of the flavones and flavanones in our study showed any inhibition of P450 2A6. Only 2´-PF and 6-PFN inhibited
P450 2B1. 3´-PF showed direct inhibition of P450 1A1 with the highest observed potency of 0.02 µM, in addition to its
ability to cause mechanism-based inhibition with KI and kinactivation values of 0.24 µM and 0.09 min-1 for this enzyme. 7-
Hydroxy flavone also exhibited mechanism-based inhibition of P450 1A1 with KI and kinactivation values of 2.43 µM and
0.115 min-1. Docking studies and QSAR studies on P450 enzymes 1A1 and 1A2 were performed which revealed
important insights into the nature of binding of these molecules and provided us with good QSAR models that can be used
to design new flavone derivatives.
Keywords: Cytochrome P450 enzyme, flavone propargyl ethers, mechanism based inhibition, QSAR models.
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