Zhu Naijue, Lightsey Danielle, Liu Jiawang, Foroozesh Maryam, Morgan Kathleen M, Stevens Edwin D, Klein Stevens Cheryl L
Department of Chemistry, Xavier University of Louisiana, One Drexel Drive, New Orleans, LA 70125, USA.
J Chem Crystallogr. 2010 Apr 1;40(4):343-352. doi: 10.1007/s10870-009-9659-0.
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).
已测定并在此报告了三种细胞色素P450 1A1、1A2、2A6和2B1的芳基乙炔抑制剂的单晶X射线结构及体内活性。它们分别是1-乙炔基芘、1-丙炔基芘和4-丙炔基芘。为了研究电子对酶抑制机制的影响，利用低温X射线衍射测量确定了1-乙炔基芘的实验电子密度分布，并将所得净原子电荷与各种理论计算结果进行比较。用钼Kα辐射共测量了82390个反射，(sinθ/λ)(max)=0.985 Å(-1)。对对称等效反射进行平均得到8889个独立反射。采用最小二乘法精修程序，其中加入多极参数以描述原子电子分布偏离球对称的畸变。得到了1-乙炔基芘的模型电子密度分布图。根据精修的单极布居参数计算得到的净原子电荷表明，末端炔碳（C18）比内部碳（C17）更负。通过从头算、密度泛函理论和半经验方法计算得到的净原子电荷与此趋势一致，表明末端炔碳更可能是氧化位点。这与导致形成活性乙烯酮中间体的抑制机制途径一致。这也与测定结果一致，即1-乙炔基芘是P450 1A1和1A2的基于机制的抑制剂以及P450 2B1的可逆抑制剂。晶体学数据：1-乙炔基芘，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 = 1113.5(2) Å(3)；1-丙炔基芘，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 = 1261.5(4) Å(3)；4-丙炔基芘，C(19)H(12)，Pbca，a = 9.904(1) Å，b = 13.174(2) Å，c = 19.401(1) Å，V = 2531.4(5) Å(3)。
