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 AbstractThe 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.

中文翻译：

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细胞色素 P450 的乙炔基和丙炔基芘抑制剂

细胞色素 P450 1A1、1A2、2A6 和 2B1 的三种芳基炔类抑制剂的单晶 X 射线结构和体内活性已被确定并在本文中报告。它们是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，使用低温 X 射线衍射测量确定了 1-乙炔基芘的实验电子密度分布，并将由此产生的净原子电荷与各种理论计算进行了比较。使用 Mo Kα 辐射测量了总共 82,390 次反射，达到 (sinθ/λ)max = 0.985 Å-1。平均对称等效反射产生了 8,889 个独特的反射。使用了最小二乘法精修程序，其中添加了多极参数来描述原子电子分布的球对称性失真。获得了 1-乙炔基芘的模型电子密度分布图。根据精制的单极子种群参数计算的净原子电荷产生的电荷表明，末端炔碳原子 (C18) 比内部碳原子 (C17) 更负。从头算、密度泛函理论和半经验方法计算的净原子电荷与这一趋势一致，表明末端炔属碳原子更可能是氧化位点。这与导致形成反应性乙烯酮中间体的抑制机制途径一致。这也与确定 1-乙炔基芘作为 P450s 1A1 和 1A2 的基于机制的抑制剂以及 P450 2B1 的可逆抑制剂的测定结果一致。晶体学数据：1-乙炔基芘，C18H10，P21/c，a = 14.571(2) Å，b = 3.9094(5) Å，c = 20.242(3) Å，β = 105.042(2)°，V = 1,213. ) Å3; 1-丙炔基芘，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 1-乙炔基的实验电子密度分布以及 1-乙炔基芘、1-丙炔基芘和 4-丙炔基芘的单晶 X 射线结构和体内抑制活性已被确定并在本文中报道。