Methoxyflavone Inhibitors of Cytochrome P450

Abstract

Cytochrome P450 enzymes are a superfamily of enzymes involved in the metabolism of endogenous compounds as well as xenobiotics. Due to the large number of reactions catalyzed by these enzymes and their importance in drug metabolism and carcinogenesis, they have been the focus of many studies over the years. Based on the knowledge that flavones are natural substrates of certain P450 enzymes (such as P450 1A2) involved in carcinogenesis, we have synthesized and studied a number of flavonoids as potential inhibitors of these enzymes. These compounds are structurally very similar to the natural flavone substrates of these enzymes but have methoxy substituents at various positions. Here we are reporting the synthesis, structural analysis, X-ray crystal structures, and preliminary inhibition studies of four methoxyflavones from this series. Crystallographic data: 2′-methoxyflavone, P-1, a = 7.2994(8) Å, b = 8.3322(7) Å, c = 10.8240(10) Å, α = 97.905(8)°, β = 92.779(10)°, γ = 111.105(8)°, V = 604.9(1) Å³; 3′-methoxyflavone, P2₁/n, a = 15.1313(16) Å, b = 3.9699(4) Å, c = 19.9454(16) Å, β = 91.673(8)°, V = 1197.6(2) Å³; 4′-methoxyflavone, P2₁/n, a = 16.451(12) Å, b = 3.881(1) Å, c = 19.529(16) Å, β = 106.65(1)°, V = 1195.1(4) Å³; 3′,4′-dimethoxyflavone, C2/c, a = 30.819(5) Å, b = 4.0857(7) Å, c = 26.100(3) Å, β = 124.21(1)°, V = 2717.6(7) Å³.

Index Abstract

Methoxyflavone Inhibitors of Cytochrome P450

Michael McKendall, Tasha Smith, Kien Anh, Jamie Ellis, Terri McGee, Maryam Foroozesh, Naijue Zhu and Cheryl L. Klein Stevens*

This paper is a report of the synthesis, structural analysis, X-ray crystal structures, and preliminary inhibition studies of 2′-methoxyflavone, 3′-methoxyflavone, 4′-methoxyflavone, and 3′,4′-dimethoxyflavone.