Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex
Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex
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DOI：
10.1016/j.biochi.2011.06.015
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发表时间：
2011-08-01
期刊：
影响因子：
3.9
通讯作者：
Freccero, Mauro
中科院分区：
文献类型：
--
作者：
Nadai, Matteo;Doria, Filippo;Freccero, Mauro
G-四链体寡核苷酸的选择性识别和烷基化已经通过取代的萘二酰亚胺（NDI）与工程化的苯酚部分通过具有可调长度和构象迁移率的烷基-酰胺间隔基缀合来实现。FRET-熔化测定，圆二色性滴定和凝胶电泳分析已进行评估可逆稳定和烷基化的G-四链体。通过最短的烷基-酰胺基间隔基与醌甲基化物前体（NDI-QMP）和苯酚部分缀合的NDI表现出平面且相当刚性的几何形状（通过DFT计算建模）。它们分别是最好的不可逆和可逆G-四链体结合剂。上述NDI-QMP能够在纳摩尔范围内烷基化端粒G-四链体DNA，并且对G-四链体的选择性比单链和双链寡核苷酸高100-1000倍。该化合物对肺癌细胞系的细胞毒性也最强。(C)2011年Elsevier Masson SAS。All rights reserved.
Selective recognition and alkylation of G-quadruplex oligonucleotides has been achieved by substituted naphathalene diimides (NDIs) conjugated to engineered phenol moieties by alkyl-amido spacers with tunable length and conformational mobility. FRET-melting assays, circular dichroism titrations and gel electrophoresis analysis have been carried out to evaluate both reversible stabilization and alkylation of the G-quadruplex. The NDIs conjugated to a quinone methide precursor (NDI-QMP) and a phenol moiety by the shortest alkyl-amido spacer exhibited a planar and fairly rigid geometry (modelled by DFT computation). They were the best irreversible and reversible G-quadruplex binders, respectively. The above NDI-QMP was able to alkylate the telomeric G-quadruplex DNA in the nanomolar range and resulted 100-1000 times more selective on G-quadruplex versus single- and double-stranded oligonucleotides. This compound was also the most cytotoxic against a lung carcinoma cell line. (C) 2011 Elsevier Masson SAS. All rights reserved.