title: Ethynyl and Propynylpyrene Inhibitors of Cytochrome P450.
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-propy-nylpyrene, and 4-propynylpyrene. To investigate electronic influences on the mechanism of enzyme inhibition, the experimental electron density distribution of 1-ethynylpy-rene 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, C(18)H(10), P2(1)/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) Å(3); 1-propynylpyrene, C(19)H(12), P2(1)/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) Å(3); 4-propynylpyrene, C(19)H(12), Pbca, a = 9.904(1) Å, b = 13.174(2) Å, c = 19.401(1) Å, V = 2,531.4(5) Å(3).
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, One Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Naijue
authors.initials: N
authors.lastname: Zhu
authors.forename: Danielle
authors.initials: D
authors.lastname: Lightsey
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: Maryam
authors.initials: M
authors.lastname: Foroozesh
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Morgan
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Stevens
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Klein Stevens
references.citation: Structure. 1995 Jan 15;3(1):41-62
references.pmid: 7743131
references.citation: Chem Res Toxicol. 1997 Jan;10(1):91-102
references.pmid: 9074808
references.citation: Biochem Pharmacol. 1994 Aug 30;48(5):923-36
references.pmid: 8093105
references.citation: J Biol Chem. 1987 Jul 15;262(20):9793-802
references.pmid: 3597438
references.citation: Biochem Pharmacol. 1992 Aug 18;44(4):787-96
references.pmid: 1510726
references.citation: J Biol Chem. 1995 May 12;270(19):11595-602
references.pmid: 7744798
references.citation: Biochem Pharmacol. 1988 May 1;37(9):1731-9
references.pmid: 3259881
references.citation: FASEB J. 1996 Feb;10(2):205
references.pmid: 8641553
references.citation: FASEB J. 1996 Feb;10(2):202-4
references.pmid: 8641552
references.citation: J Pharmacol Exp Ther. 1999 Jul;290(1):445-51
references.pmid: 10381811
references.citation: J Biol Chem. 1988 Dec 15;263(35):18640-9
references.pmid: 3198593
references.citation: Biochem Pharmacol. 1993 Nov 2;46(9):1577-84
references.pmid: 8240414
references.citation: Chem Res Toxicol. 1998 Sep;11(9):1048-56
references.pmid: 9760279