12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: A new class of highly selective ligands for c-myc G-quadruplex DNA
12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: A new class of highly selective ligands for c-myc G-quadruplex DNA
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12-N-甲基化 5,6-二氢苯并[c]吖啶衍生物：c-myc G-四链体 DNA 的一类新型高选择性配体
DOI：
10.1016/j.ejmech.2012.03.034
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发表时间：
2012-07-01
影响因子：
6.7
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Liao, Sheng-Rong;Zhou, Chen-Xi;Huang, Zhi-Shu
设计并合成了 12-N-甲基化和非甲基化 5,6-二氢苯并[c]吖啶衍生物作为新系列的 c-myc G-四联体结合配体。使用荧光共振能量转移 (FRET) 熔解测定、圆二色性 (CD) 光谱、表面等离子共振 (SPR)、聚合酶链式反应 (PCR) 终止测定和分子建模评估它们与 c-myc G-四链体的相互作用。与非甲基化衍生物相比，12-N-甲基化衍生物对c-myc G-四联体结构具有更强的结合亲和力和稳定能力，能够更有效地堆叠在G-四联体表面。所有这些衍生物对 c-myc G-四链体 DNA 的选择性高于双链体 DNA。逆转录(RT) PCR检测表明，化合物21c可以下调含有NHE III1元件的Ramos细胞系中c-myc基因的转录，但在去除NHE III1元件的CA46细胞系中没有作用。 (C) 2012 Elsevier Masson SAS。版权所有。
12-N-Methylated and non-methylated 5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized as new series of c-myc G-quadruplex binding ligands. Their interactions with c-myc G-quadruplex were evaluated using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), polymerase chain reaction (PCR) stop assay, and molecular modeling. Compared with the non-methylated derivatives, 12-N-methylated derivatives had stronger binding affinity and stabilizing ability to c-myc G-quadruplex structure, and could more effectively stack on the G-quartet surface. All these derivatives had high selectivity for c-myc G-quadruplex DNA over duplex DNA. The reverse transcription (RT) PCR assay showed that compound 21c could down-regulate transcription of c-myc gene in Ramos cell line containing NHE III1 element, but had no effect in CA46 cell line with NHE III1 element removed. (C) 2012 Elsevier Masson SAS. All rights reserved.