Cyclic ferrocenylnaphthalene diimide derivative as a new class of G-quadruplex DNA binding ligand
Cyclic ferrocenylnaphthalene diimide derivative as a new class of G-quadruplex DNA binding ligand
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环状二茂铁基萘二酰亚胺衍生物作为一类新型 G-四链体 DNA 结合配体
DOI：
10.1016/j.bmcl.2016.11.037
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发表时间：
2017
影响因子：
2.7
通讯作者：
Shigeori Takenaka
中科院分区：
文献类型：
--
作者：
Md. Monirul Islam;Shinobu Sato;Shingo Shinozaki;Shigeori Takenaka
为了寻找一种能有效结合g -四重体而非双链DNA （dsDNA）的配体，我们利用新合成的环二茂铁萘二亚胺（cFNDI,1）或不同结构的g -四重体DNA和dsDNA的非环衍生物(2)进行了一系列生物物理和生化实验。在含有100 mM KCl的100 mM AcOH-AcOK缓冲液（pH 5.5）中，化合物1与g -四联体dna （106M−1阶）结合强烈，与dsDNA （104M−1阶）结合减弱。有趣的是，1对混合杂交型端粒g -四重体DNA （K= 3.4 × 106M−1和2:1的化学计量）的选择性比dsDNA （K= 7.5 × 104M−1）高约50倍。此外，1对g -四重体dna表现出比对dsDNA更高的热稳定性，与端粒和凝血酶结合适体相比，它对c- kitg和c- mycg -四重体dna表现出更强的偏好。此外，1表现出端粒酶抑制活性，半最大抑制浓度（IC50）为0.4 μM。化合物2表现出对g -四重体的偏好；然而，由于前者具有环状结构，因此在1中结合亲和度和偏好度得到了提高。
To identify an effective ligand that binds to a G-quadruplex structure but not a double-stranded DNA (dsDNA), a set of biophysical and biochemical experiments were carried out using newly synthesized cyclic ferrocenylnaphthalene diimide (cFNDI,1) or the non-cyclic derivative (2) with various structures of G-quadruplex DNAs and dsDNA. Compound1bound strongly to G-quadruplexes DNAs (106M−1order) with diminished binding to dsDNA (104M−1order) in 100 mM AcOH-AcOK buffer (pH 5.5) containing 100 mM KCl. Interestingly,1showed an approximately 50-fold higher selectivity to mixed hybrid-type telomeric G-quadruplex DNA (K= 3.4 × 106M−1and a 2:1 stoichiometry) than dsDNA (K= 7.5 × 104M−1) did. Furthermore,1showed higher thermal stability to G-quadruplex DNAs than it did to dsDNA with a preference forc-kitandc-mycG-quadruplex DNAs over telomeric and thrombin binding aptamers. Additionally,1exhibited telomerase inhibitory activity with a half-maximal inhibitory concentration (IC50) of 0.4 μM. Compound2showed a preference for G-quadruplex; however, the binding affinity magnitude and preference were improved in1because the former had a cyclic structure.