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Ethynyl and Propynylpyrene Inhibitors of Cytochrome P450

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Abstract

The single-crystal X-ray structures and in vivo activities of three aryl acetylenic inhibitors of cytochromes P450 1A1, 1A2, 2A6, and 2B1 have been determined and are reported herein. These are 1-ethynylpyrene, 1-propynylpyrene, and 4-propynylpyrene. To investigate electronic influences on the mechanism of enzyme inhibition, the experimental electron density distribution of 1-ethynylpyrene has been determined using low-temperature X-ray diffraction measurements, and the resulting net atomic charges compared with various theoretical calculations. A total of 82,390 reflections were measured with Mo Kα radiation to a (sinθ/λ)max = 0.985 Å−1. Averaging symmetry equivalent reflections yielded 8,889 unique reflections. A least squares refinement procedure was used in which multipole parameters were added to describe the distortions of the atomic electron distributions from spherical symmetry. A map of the model electron density distribution of 1-ethynylpyrene was obtained. Net atomic charges calculated from refined monopole population parameters yielded charges that showed that the terminal acetylenic carbon atom (C18) is more negative than the internal carbon (C17). Net atomic charges calculated by ab initio, density functional theory, and semi-empirical methods are consistent with this trend suggesting that the terminal acetylenic carbon atom is more likely to be the site of oxidation. This is consistent with the inhibition mechanism pathway that results in the formation of a reactive ketene intermediate. This is also consistent with assay results that determined that 1-ethynylpyrene acts as a mechanism-based inhibitor of P450s 1A1 and 1A2 and as a reversible inhibitor of P450 2B1. Crystallographic data: 1-ethynylpyrene, C18H10, P21/c, a = 14.571(2) Å, b = 3.9094(5) Å, c = 20.242(3) Å, β = 105.042(2)°, V = 1,113.5(2) Å3; 1-propynylpyrene, C19H12, P21/n, a = 8.970(2) Å, b = 10.136(1) Å, c = 14.080(3) Å, β = 99.77(2)°, V = 1,261.5(4) Å3; 4-propynylpyrene, C19H12, Pbca, a = 9.904(1) Å, b = 13.174(2) Å, c = 19.401(1) Å, V = 2,531.4(5) Å3.

Graphical Abstract

The experimental electron density distribution of 1-ethynylpyrene as well as the single-crystal X-ray structures and in vivo inhibition activities of 1-ethynylpyrene, 1-propynylpyrene, and 4-propynylpyrene have been determined and are reported herein.

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Notes

  1. Conventional reliability indices: \( R = \sum \left\| {F_{ 0} } \right.| - |\left. {F_{\text{c}} } \right\|/\sum |F_{\text{o}} |\,{\text{and}}\,R_{w} = \left( {\sum \left( {F_{\text{o}} | - |F_{\text{c}} |} \right)^{2} /\sum w|F_{ 0} |^{2} } \right)^{1/2} \), where F o and F c are observed and calculated structure factors, w = 1/σ(F)2, and where σ(F) is the estimated standard deviation in F o.

  2. The supplementary crystallographic data for (a) 1-ethynylpyrene (1-EP) (CCDC 731480), (b) 1-propynylpyrene (1-PP) (CCDC 731481), and (c) 4-propynylpyrene (4-PP) (CCDC 731482), have been deposited. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

  3. SMART Software, Bruker-AXS, 6300 Enterprise Dr., Madison, WI 53719-1173, (1994); SAINT Software, Bruker-AXS, 6300 Enterprise Dr., Madison, WI 53719-1173, (1995).

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Acknowledgments

We would like to acknowledge the National Institutes of Health MBRS SCORE (Grant No. 1S06GM08008 and 1SC1GM084722) and RISE (Grant No. 2R25GM060926) Programs for support of this work.

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Authors and Affiliations

  1. Department of Chemistry, Xavier University of Louisiana, One Drexel Drive, New Orleans, LA, 70125, USA

    Naijue Zhu, Danielle Lightsey, Jiawang Liu, Maryam Foroozesh, Kathleen M. Morgan & Cheryl L. Klein Stevens

  2. Department of Chemistry, University of New Orleans, New Orleans, LA, 70148, USA

    Edwin D. Stevens

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  1. Naijue Zhu
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  2. Danielle Lightsey
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Correspondence to Cheryl L. Klein Stevens.

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Zhu, N., Lightsey, D., Liu, J. et al. Ethynyl and Propynylpyrene Inhibitors of Cytochrome P450. J Chem Crystallogr 40, 343–352 (2010). https://doi.org/10.1007/s10870-009-9659-0

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