Department of Chemistry, College of Arts and Sciences, East Tennessee State University, Johnson City, Tennessee 37614, USA.
J Org Chem. 2010 Jan 15;75(2):324-33. doi: 10.1021/jo901862x.
During DNA repair, uracil DNA glycosylase (UDG) pulls unwanted uracil into its active site through hydrogen bonding and pi-pi stacking interactions. The reason why UDG binds only uracil tightly--and not its derivatives, such as thymine--remains unclear. In this study, we synthesized the stable, water-soluble receptor 1a as a structural mimic of the active site in UDG. Compound 1a contains a 2,6-bis(glycylamino)pyridine group, which mimics the amino acid residues of UDG that interact with uracil through a hydrogen-bonding network; it also possesses a pyrene moiety as a pi-pi stacking interaction element and fluorescent probe that mimics the aromatic groups (phenyl and fluorescent indolyl units) found in the active site of UDG. Receptor 1a binds selectively to uracil and derivatives (including thymine, 5-formyluracil, 5-fluorouracil, and 5-nitrouracil) and some DNA and RNA nucleosides (including thymidine and uridine) through hydrogen bonding and pi-pi stacking interactions. Interestingly, a plot of log K(b) with respect to the values of pK(a) of the N(3)H units of uracil and its derivatives was linear, with a negative slope (beta) of -0.24 +/- 0.03. Thus, compounds featuring lower values of pK(a) for their N(3)H units provided greater apparent binding constants for their complexes with receptor 1a, suggesting acidity-dependent binding of uracil and its derivatives to this receptor; notably, uracil bound more tightly than did thymine. Our study provides some insight into how uracil and its derivatives in DNA are bound by DNA repair enzymes through hydrogen bonding and pi-pi stacking interactions.
在 DNA 修复过程中，尿嘧啶 DNA 糖基化酶 (UDG) 通过氢键和π-π堆积相互作用将不需要的尿嘧啶拉入其活性部位。UDG 为什么只紧密结合尿嘧啶——而不是其衍生物，如胸腺嘧啶——仍然不清楚。在这项研究中，我们合成了稳定的水溶性受体 1a，作为 UDG 活性部位的结构模拟物。化合物 1a 包含一个 2,6-双（甘氨酰氨基）吡啶基团，该基团模拟了与尿嘧啶通过氢键网络相互作用的 UDG 氨基酸残基；它还具有一个芘部分作为π-π堆积相互作用元素和荧光探针，模拟 UDG 活性部位中的芳香基团（苯和荧光吲哚基单元）。受体 1a 通过氢键和π-π堆积相互作用选择性地结合尿嘧啶及其衍生物（包括胸腺嘧啶、5-甲酰基尿嘧啶、5-氟尿嘧啶和 5-硝基尿嘧啶）以及一些 DNA 和 RNA 核苷（包括胸苷和尿苷）。有趣的是，log K(b)与尿嘧啶及其衍生物的 N(3)H 单位的 pK(a)值的关系呈线性，斜率为-0.24±0.03。因此，具有较低 N(3)H 单位 pK(a)值的化合物为其与受体 1a 的复合物提供了更大的表观结合常数，表明尿嘧啶及其衍生物与该受体的结合依赖于酸度；值得注意的是，尿嘧啶的结合比胸腺嘧啶更紧密。我们的研究为尿嘧啶及其衍生物在 DNA 中如何通过氢键和π-π堆积相互作用被 DNA 修复酶结合提供了一些见解。
