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ice0718铜虫 (正式写手)
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求翻译，化学生物学方面的
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In general, an effective G-quadruplex binder possesses a large electron deficient p-aromatic surface, positively charged substituents that can interact with the grooves of the quadruplex, as well as a positively charged center which can reside near the center of the guanine quartet.[16–18] Many elegant studies on organic G-quadruplex binders have appeared,[ 19–21] but examples involving inorganic complexes are rare. Thus far, inorganic G-quadruplex binders have included copper,[22] manganese,[23] and nickel porphyrins,[24, 25] nickel salens,[18] and ruthenium bis-intercalating complexes[ 26] in their design. Transition-metal complexes are extremely appealing as they introduce a myriad of geometries that are unattainable for carbon, thus expanding the existing organic G-quadruplex binder toolbox. Furthermore, these metal-based binders present an opportunity for modular and facile synthesis of compound libraries, in contrast to their organic counterparts, which often require time-consuming multistep syntheses. Through simple modifications of their coordination environment and the potential to alter their geometries, the incorporation of transition-metals into Gquadruplex binders offers unique possibilities to enhance binding affinity and selectivity for this DNA motif. Platinum-intercalating complexes have been extensively investigated in binding studies with duplex DNA.[27, 28] Previously, binding constants on the order of 106m1 were reported for a relatively small p-surface complex, [Pt(4,4’-diphenyl- 2,2’-bipyridyl)(ethylenediamine)] 2+ with duplex DNA.[29] However, for more p-extended complexes, such as [Pt(dipyridophenazine)( ethylenediamine)] 2+, surprisingly lower binding constants, on the order of 104m1 were reported.[27] These binding constants are markedly lower than those observed for octahedral ruthenium complexes possessing the same intercalating ligand (106–107m1),[30] which is not as “p-extended” as the squareplanar PtII complexes. This lowered affinity points to a likely size mismatch between the large p-surface of square-planar PtII complexes with extended aromatic ligands and the smaller p-surface of duplex DNA (in addition to other possible factors such as self-aggregation and electronic character).[31] On the other hand, G-quadruplex DNA structures present a planar p-extended system that is greater in size than the duplex DNA base-pairs. We were therefore interested in exploring whether PtII complexes containing extended p-surfaces would be better suited for binding to these structures. We here report the synthesis of the first PtII G-quadruplex selective binding complexes 2 and 3, with readily tunable phenanthroimidazole ligands. UV/Vis, circular dichroism, thermal denaturation, continuous variation analysis, and competitive dialysis experiments show that increasing the size of the p-surface in these complexes indeed leads to an increase in binding affinity and selectivity for G-quadruplexes over duplex DNA structures. This result is supported by molecular modeling studies, which in addition show endstacking of the complexes in an “off-center” location above the G-tetrad, and stabilization by hydrogen bonding of the ethylenediamine ligand to the phosphate backbone. Overall, this study shows that combining the square-planar geometry of PtII with extended aromatic ligands can result in a simple method to access effective G-quadruplex selective binders in a few synthetic steps. The modular and facile synthesis of the phenanthroimidazole PtII scaffold is readily amenable to library creation, and further binding optimization for use in telomerase-based antitumor therapy. |
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xxsst888
铜虫 (小有名气)
- 翻译EPI: 7
- 应助: 0 (幼儿园)
- 金币: 2042.2
- 帖子: 295
- 在线: 19.2小时
- 虫号: 999183
- 注册: 2010-04-17
- 性别: GG
- 专业: 情报学
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wypward(金币+2):谢谢参与，辛苦了！ 2010-05-30 18:21:39
ice0718(金币+30, 翻译EPI+1):谢谢，我已经翻译完了，但还是要谢谢你 2010-06-02 19:04:17
wypward(金币+2):谢谢参与，辛苦了！ 2010-05-30 18:21:39
ice0718(金币+30, 翻译EPI+1):谢谢，我已经翻译完了，但还是要谢谢你 2010-06-02 19:04:17
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通常，一个有效的G-四重结合基具有一个大的缺电子的p-芳香环表面，正电荷取代基除能在四重体的开口处发生取代反应外，也存在于鸟嘌呤四重体的中心附近做为正电荷中心【16-18】。，对有机物的G-四重结合基的许多精细研究见【19-21】，但涉及到无机物的例子则少见。到目前为止，应用的无机物的G-四重结合基包括铜【22】，锰【23】，卟啉类化合物【24.25】，镍salens【18】和钌二度-设置化合物【26】。过渡金属化合物由于有碳原子所不具有的多几何体而受到密切关注，也扩大了有机物的G-四重结合基的应用范围。还有，这些以金属为基础的结合基在化合物的合成方面展现出多模型性和灵活性，而与此相对应的有机化合物常常需要反应时间而且经历多个反应步骤。过渡金属通过简单的调整它们的反应环境和潜能去改变它们的几何构型，可结合到G-四重结合基的过程提供了独特的机会加强DNA链的选择性和亲和性。以前对铂-设置化合物与双链DNA【27.28】的结合性进行了广泛的研究，对相对小的p-表面络合物[Pt(4,4’-diphenyl-2,2’-bipyridyl)(ethylenediamine)] 2+ with duplex DNA.[29，在106 1级上的结合常数进行了记录。然而，对更多的p-扩充式化合物如[Pt(dipyridophenazine)( ethylenediamine)] 2+，在级数104m 1上的结合常数是令人惊奇的低。【27】这些结合常数明显低于那些拥有相同插位基的八面体钌络合物( 106–107m 1),[30]的结合常数，它们不像平面四面体的PtII络合物有“p-扩充”。这个低的亲和力指出在带有扩充芳香环配合基的平面四方PtII络合物的大p-表面和双绞链DNA的小的p-表面之间似乎存在面积搭配错误【31】（除了其它可能性因素如自我聚集和电子的特性等）。另一方面，G-四重DNA结构展现一个在面积上大于双绞链DNA-碱的平面p-扩充系统。因此，这一现象引起我们研究是否含有扩充的p-表面的 PtII络合物会更加适合连接到这些结构中的兴趣。这里，我们记录了PtII G-四重的选择性连接络合物2和3的合成，通过可调的phenanthroimidazole结合基，. UV/Vis,，循环分色性，热变性，连续变体分析和准确的分离实验等表明在这些络合物中增加p-表面面积确实能使G-四重对双链DNA结构增加亲和力和选择性。这个结果受到分子模型研究的支持。该项研究表明络合物在G-四重之上的非中心位置堆积，由乙二胺结合基的氢结合到磷酸盐主链上而显稳定性。总之，该项研究表明PtII的平面四方体几何结构与扩充的芳香环结合基的结合能产生一个简单的方法以至在一些合成反应步骤中去使用G-四重的有效选择结合基。，the phenanthroimidazole PtII结构的合成标准性和灵活性还需完善。在端粒酶-碱抗肿瘤治疗中还要进一步对结合基进行优化。 哪有交移民（加拿大，英国）的朋友网站 |
2楼2010-05-29 16:40:38
