A new type of DNA minor-groove complex: carbazole dication-DNA interactions.
A new type of DNA minor-groove complex: carbazole dication-DNA interactions.
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DOI：
10.1021/bi971599r
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发表时间：
1997-12
期刊：
影响因子：
2.9
通讯作者：
F. Tanious;D. Ding;D. A. Patrick;R. Tidwell;W. David Wilson
中科院分区：
文献类型：
--
作者：
F. Tanious;D. Ding;D. A. Patrick;R. Tidwell;W. David Wilson
机会性感染（OI）对免疫功能低下人群的影响已经知道了几十年，但最近艾滋病的流行再次引发了人们对开发新的抗OI药物的兴趣。一系列阳离子非融合芳香抗成骨不全症药物的作用机制被认为与药物与DNA小凹槽中的AT序列结合有关。一些新的抗成骨不全症候选药物已经用融合芳香环系统（如咔唑）合成，这些系统不像DNA at序列上的小凹槽相互作用的经典范例。为了表征这些化合物的DNA相互作用，我们使用了紫外-可见吸光度、荧光、动力学测量和圆二色性，并结合核磁共振光谱来评估咔唑和DNA之间形成的配合物的结构。将这些方法应用于被阳离子咪唑啉基团取代的3,6或2,7位咔唑，得到了确凿但非常令人惊讶的证据，表明这两种化合物在at DNA序列的小凹槽中结合强烈。利用核磁共振和分子模型分析了3,6-和2,7-咔唑与自互补低聚物d（GCGAATTCGC）之间形成的配合物，建立了小凹槽配合物的结构细节。这些结果被用作分子模型计算的约束，以构建小凹槽-咔唑配合物的模型，并得出关于取代基位置对咔唑- dna亲和性影响的分子基础的结论。令人惊讶的结果是，2,7咔唑在AT序列中与一个咪唑啉基团和咔唑NH的氢键结合。3,6-咔唑化合物以更“经典”的模式结合，使用两个咪唑啉基团作为h键，而咔唑的NH指向小槽。因此，咔唑形成了一种新型的DNA小凹槽复合物，其优异的生物活性表明，应研究各种融合环小凹槽结合剂。
The effect of opportunistic infections (OI) on immune-compromised populations has been known for decades, but the recent AIDS epidemic has sparked renewed interest in the development of new anti-OI agents. The mechanism of action of a series of cationic unfused-aromatic anti-OI drugs is believed to involve binding of the drug to AT sequences in the minor groove of DNA. Some new anti-OI drug candidates have been synthesized with fused aromatic ring systems (e.g. carbazoles) that do not resemble the classical paradigm for minor-groove interactions at AT sequences in DNA. To characterize the DNA interactions of these compounds, we have used UV-vis absorbance, fluorescence, kinetic measurements, and circular dichroism in conjunction with NMR spectroscopy to evaluate the structure of the complexes formed between the carbazoles and DNA. Application of these methods to carbazoles substituted at either the 3,6 or 2,7 positions with cationic imidazoline groups gave conclusive, but very surprising, evidence that both compounds bind strongly in the minor groove at AT DNA sequences. NMR and molecular modeling of the complexes formed between the 3,6- and 2,7-carbazoles and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor-groove complex. These results have been used as constraints for molecular modeling calculations to construct models of the minor-groove-carbazole complexes and to draw conclusions regarding the molecular basis for the effects of substituent position on carbazole-DNA affinities. The surprising result is that the 2,7 carbazole binds in AT sequences with hydrogen bonds involving one imidazoline group and the carbazole NH. The 3,6-carbazole compound binds in a more "classical" model that uses both imidazoline groups for H-bonding while the carbazole NH points out of the minor groove. The carbazoles thus form a new type of DNA minor groove complex and their excellent biological activities indicate that a variety of fused-ring minor-groove binding agents should be investigated.