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) Å, b=8.062(1) Å, c=13.110(1) Å, α=84.32(1)°, β=75.42(1)°, γ=86.56(1)°, V=790.8(2) Å3; β-naphthoflavone 2′-propargyl ether, \(P\bar 1\), a=7.605(2) Å, b=7.793(1) Å, c=14.167(2) Å, α=77.06(1)°, β=75.41(1)°, γ=89.54(1)°, V=790.9(2) Å3; α-naphthoflavone 4′-propargyl ether, P21/n, a=14.595(2) Å, b=4.708(1) Å, c=24.745(6) Å, β=106.31(2)°, V=1631.8(7) Å3; β-naphthoflavone 4′-propargyl ether, P1, a=4.8871(5) Å, b= 7.9597(7) Å, c=21.788(3) Å, α=81.771(9)°, β=89.918(10)°, γ=72.223(8)°, V= 797.9(2) Å3.
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Acknowledgments
We would like to acknowledge the National Institutes of Health MBRS SCORE Program (Grant No. GM08008) for support of this work and the MBRS RISE Program for support of the undergraduate research student, D. Lightsey (Grant No. GM060926).
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The supplementary crystallographic data for (a) α-naphthoflavone 2′-propargyl ether (1) (CCDC 26896), (b) β-naphthoflavone 2′-propargyl ether (2) (CCDC 268697), (c) α-naphthoflavone 4′-propargyl ether (3) (CCDC 268698), and (d) β-naphthoflavone 4′-propargyl ether (4) (CCDC 268699) have been deposited. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
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Zhu, N., Lightsey, D., Foroozesh, M. et al. Naphthoflavone propargyl ether inhibitors of cytochrome P450. J Chem Crystallogr 36, 289–296 (2006). https://doi.org/10.1007/s10870-005-9061-5
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DOI: https://doi.org/10.1007/s10870-005-9061-5