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首页> 外文期刊>Medicinal chemistry >Polyamide curvature and DNA sequence selective recognition: use of 4-aminobenzamide to adjust curvature.
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Polyamide curvature and DNA sequence selective recognition: use of 4-aminobenzamide to adjust curvature.

机译：聚酰胺曲率和DNA序列选择性识别：使用4-氨基苯甲酰胺调节曲率。

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摘要

Imidazole and pyrrole-containing polyamides belong to an important class of compounds that can be designed to target specific DNA sequences, and they are potentially useful in applications of controlling gene expression. The extent of polyamide curvature is an important consideration when studying the ability of such compounds to bind in the minor groove of DNA. The current study investigates the importance of curvature using polyamides of the form f-Im-Phenyl-Im, in which the imidazole heterocycles are placed in ortho-, meta-, and para-configurations of the phenyl moiety. The synthesis and biophysical evaluation of each compound binding to its cognate DNA sequence (5'-ACGCGT-3') and a negative control sequence (5'-AAATTT-3') is reported, along with their comparison to the parent binder, f-Im-Py-Im (3). ACGCGT is a medicinally significant sequence present in the MluI cell-cycle box (MCB) transcriptional element found in the promoter of a gene associated with cell division. The results demonstrated that the para-derivative has the greatest affinity for its cognate sequence, as indicated via thermal denaturation, CD, ITC, SPR analyses, and DNase I footprinting. ITC studies showed that binding of the para-isomer (2c) to ACGCGT was significantly more exothermic than binding to AAATTT. In contrast, no heat change was observed for binding of the meta- (2b) and ortho- (2a) isomers to both DNAs, due to low binding affinities. This is consistent with results from SPR studies, which indicate that the para-derivative binds in a 2:1 fashion to ACGCGT and binds weakly to ACCGGT (K = 1.8 x 10(6) and 4.0 x 10(4) M(-1), respectively). Interestingly, it binds in a 1:1 fashion to AAATTT (K = 5.4 x 10(5) M(-1)). The meta-compound does not bind to any sequence. The para-derivative also was the only compound to show an induced peak via CD at 330 nm, indicative of minor groove binding, and produced a DeltaT(m) value of 5.8 degrees C. Molecular modeling experiments have been performed to determine the shape differences between the three compounds, and the results indicate that the para-derivative 2c has a closest curvature to previously synthesized polyamides. DNase I footprinting studies confirmed earlier observations that only the para-derivative 2c produced a footprint with ACGCGT (1 microM) and no significant footprint was observed at any sites examined for meta-2b and ortho-2a analogs up to 40 microM. The results of these studies suggest that the shape of the ortho- and meta- derivatives is too curved to match the curvature of the DNA minor groove to facilitate binding. The para-derivative gives the highest binding affinity in the series and the results illustrate that 4-aminobenzamide is a reasonable substitute for 4-aminopyrrole-2-carboxylate.
机译：含咪唑和含吡咯的聚酰胺属于一类重要的化合物，可以设计为靶向特定的DNA序列，它们潜在地可用于控制基因表达的应用中。在研究这类化合物在DNA的小沟中结合的能力时，聚酰胺曲率的程度是重要的考虑因素。当前的研究调查了使用f-Im-Phenyl-Im形式的聚酰胺曲率的重要性，其中的咪唑杂环以苯基部分的邻，间和对位构型存在。报告了每种化合物与其同源DNA序列（5'-ACGCGT-3'）和阴性对照序列（5'-AAATTT-3'）结合的合成和生物物理评估，以及与母体结合物f的比较。 -Im-Py-Im（3）。 ACGCGT是存在于与细胞分裂有关的基因启动子中的MluI细胞周期盒（MCB）转录元件中的具有医学意义的序列。结果表明，如热变性，CD，ITC，SPR分析和DNase I足迹所示，对位衍生物对其关联序列具有最大亲和力。 ITC研究表明，对位异构体（2c）与ACGCGT的结合比与AAATTT的结合明显放热。相反，由于低的结合亲和力，未观察到间-（2b）和邻-（2a）异构体与两种DNA结合的热变化。这与SPR研究的结果一致，该研究表明对位衍生物以2：1方式与ACGCGT结合，而与ACCGGT的结合较弱（K = 1.8 x 10（6）和4.0 x 10（4）M（-1 ）， 分别）。有趣的是，它以1：1的方式绑定到AAATTT（K = 5.4 x 10（5）M（-1））。元化合物不结合任何序列。对位衍生物也是唯一在330 nm处通过CD表现出诱导峰的化合物，表明存在微小的沟槽结合，并产生5.8 T的DeltaT（m）值。已进行了分子建模实验以确定形状差异结果表明，对位衍生物2c的曲率与先前合成的聚酰胺最接近。 DNase I足迹研究证实了较早的观察结果，即只有对位衍生物2c产生了ACGCGT（1 microM）的足迹，在任何检查到的高达40 microM的meta-2b和ortho-2a类似物的位点均未观察到明显的足迹。这些研究的结果表明，邻位和间位衍生物的形状过于弯曲，无法与DNA小沟的曲率相匹配，以利于结合。对衍生物在该系列中具有最高的结合亲和力，结果表明4-氨基苯甲酰胺是4-氨基吡咯-2-羧酸酯的合理替代品。

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