Naphthoflavone propargyl ether inhibitors of cytochrome P450

Abstract

Cytochrome P450 enzymes protect the body from foreign substances through a mechanism that involves oxidation of those substances into more readily excretable polar compounds. It has been shown that some naphthoflavones function as substrates of certain P450 enzymes (CYP1A1 and CYP1B1) and with appropriate structural changes may become inhibitors. Moreover, propargyl ether derivatives of adamantane have been shown to function as selective inactivators of some P450 enzymes (CYP2B1 and CYP2B5). In an attempt to improve the potency and selectivity of inhibition, we have designed and synthesized a series of naphthoflavone propargyl ethers. We report here the synthesis, X-ray crystal structures, and inhibition data (IC50 of EROD inhibition in CYP1A1 and CYP1B1 enzymes) of α-naphthoflavone 2′-propargyl ether, β-naphthoflavone 2′-propargyl ether, α-naphthoflavone 4′-propargyl ether, and β-naphthoflavone 4′-propargyl ether. Crystallographic data: α-naphthoflavone 2′-propargyl ether, $$P\bar 1$$ , a=7.775(1) A, b=8.062(1) A, c=13.110(1) A, α=84.32(1)°, β=75.42(1)°, γ=86.56(1)°, V=790.8(2) A3; β-naphthoflavone 2′-propargyl ether, $$P\bar 1$$ , a=7.605(2) A, b=7.793(1) A, c=14.167(2) A, α=77.06(1)°, β=75.41(1)°, γ=89.54(1)°, V=790.9(2) A3; α-naphthoflavone 4′-propargyl ether, P21/n, a=14.595(2) A, b=4.708(1) A, c=24.745(6) A, β=106.31(2)°, V=1631.8(7) A3; β-naphthoflavone 4′-propargyl ether, P1, a=4.8871(5) A, b= 7.9597(7) A, c=21.788(3) A, α=81.771(9)°, β=89.918(10)°, γ=72.223(8)°, V= 797.9(2) A3.