Abstract 2464: Flavone derivatives as small-molecule probes of cytochrome P450 enzymes: Inhibitory activity and selectivity.

Abstract

Abstract Cytochrome P450 enzymes are the most important enzymes involved in the conversion of environmental procarcinogens such as polycyclic aromatic hydrocarbons (PAHs) from fuels, cigarette smoke, and charcoal-grilled foods into carcinogenic species. These carcinogenic species have the potential to bond to cellular macromolecules such as DNA and can lead to cancer formation. Therefore, selectively inhibiting certain P450 enzymes involved in carcinogenesis is a potential approach to cancer prevention. To investigate the 3D-structural features of the active site cavities of our target P450s, our approach in this project is to use the natural P450 substrate, flavone, as a lead compound. Here we report the synthesis of six novel flavonoids (5,6-pyranflavone, 6,5-pyranflavone, 7,8-pyranflavone, 2’,3’-pyranflavone, 3’,2’-pyranflaovne, and 4’,3’-pyranflavone) and the evaluation of their inhibitory activities, mechanisms of action, and selectivity towards P450 enzymes 1A1, 1A2, 2A6, and 2B1. All of these target compounds were found to be competitive inhibitors of these P450 enzymes. A high inhibitory activity represents a high affinity between the compound and the enzyme. Our data show that the α-naphthoflavone-like flavone derivative, 7,8-pyranflavone, has a high affinity for P450 1A2 (IC50: 0.05 μM), and a relatively low affinity for P450 1A1 (IC50: 0.25 μM). On the contrary, β-naphthoflavone-like flavone derivatives, 5,6-pyranflavone and 6,5-pyranflavone, show higher affinities for P450 1A1 compared to P450 1A2. However, none of these three compounds shows any inhibitory activity towards P450s 2A6 and 2B1. Interestingly, the C-ring modified derivatives (2’,3’-pyranflavone, 3’,2’-pyranflaovne, and 4’,3’-pyranflavone) have relatively low inhibitory activities toward the P450s 1A1 and 1A2, while showing a weak inhibition of P450 2B1 (IC50s: ca. 7.0 μM). These structural data suggest that the length of the P450 1A1 active site cavity is probably longer than that of P450 1A2, while the width of the P450 1A2 active site cavity may be larger than that of P450 1A1. Further studies of 7,8-pyranflavone, 5,6-pyranflavone, and 6,5-pyranflavone will provide us with more detailed structural information about the target P450 enzymes. Citation Format: Jiawang Liu, Shannon Taylor, Patrick Dupart, Corey Arnold, Maryam Foroozesh. Flavone derivatives as small-molecule probes of cytochrome P450 enzymes: Inhibitory activity and selectivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2464. doi:10.1158/1538-7445.AM2013-2464