Defining the mode, energetics and specificity with which a macrocyclic hexaoxazole binds to human telomeric G-quadruplex DNA.
Defining the mode, energetics and specificity with which a macrocyclic hexaoxazole binds to human telomeric G-quadruplex DNA.
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DOI：
10.1093/nar/gkm188
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发表时间：
2007
影响因子：
14.9
通讯作者：
Pilch DS
中科院分区：
文献类型：
--
作者：
Barbieri CM;Srinivasan AR;Rzuczek SG;Rice JE;LaVoie EJ;Pilch DS
含恶唑的大环化合物代表了一类有前途的靶向G-四链体DNA的抗癌剂。我们报告的光谱研究的结果，旨在定义的模式，能量学和特异性与含六恶唑的大环（HXDV）结合到由人端粒DNA模型寡核苷酸d（T2 AG 3）4在钾离子的存在下形成的分子内四链体。HXDV仅与四链体核酸形式结合，但不与双链体或三链体形式结合。HXDV以每四链体两个药物分子的化学计量结合d（T2 AG 3）4，这些结合反应与来自末端G-四链体的腺嘌呤残基的去堆积偶联。HXDV与d（T2 AG 3）4的结合不改变四链体的长度。这些集体观察结果表明，一个HXDV分子结合到四链体的每个末端的非插入性“末端加帽”相互作用模式。HXDV与d（T2 AG 3）4的结合是熵驱动的，该熵驱动力反映了来自宿主四链体的构型熵以及净水合中的有利药物诱导的改变的贡献。通过我们的研究揭示的“末端加帽”结合模式可能被证明是含恶唑的大环配体（包括端粒抑素）与分子内DNA四链体之间相互作用的一般特征。
Oxazole-containing macrocycles represent a promising class of anticancer agents that target G-quadruplex DNA. We report the results of spectroscopic studies aimed at defining the mode, energetics and specificity with which a hexaoxazole-containing macrocycle (HXDV) binds to the intramolecular quadruplex formed by the human telomeric DNA model oligonucleotide d(T2AG3)4 in the presence of potassium ions. HXDV binds solely to the quadruplex nucleic acid form, but not to the duplex or triplex form. HXDV binds d(T2AG3)4 with a stoichiometry of two drug molecules per quadruplex, with these binding reactions being coupled to the destacking of adenine residues from the terminal G-tetrads. HXDV binding to d(T2AG3)4 does not alter the length of the quadruplex. These collective observations are indicative of a nonintercalative ‘terminal capping’ mode of interaction in which one HXDV molecule binds to each end of the quadruplex. The binding of HXDV to d(T2AG3)4 is entropy driven, with this entropic driving force reflecting contributions from favorable drug-induced alterations in the configurational entropy of the host quadruplex as well as in net hydration. The ‘terminal capping’ mode of binding revealed by our studies may prove to be a general feature of the interactions between oxazole-containing macrocyclic ligands (including telomestatin) and intramolecular DNA quadruplexes.
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