Small Molecule Driven Stabilization of Promoter G-Quadruplexes and Transcriptional Regulation of c-MYC,Bioconjugate Chemistry

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Small Molecule Driven Stabilization of Promoter G-Quadruplexes and Transcriptional Regulation of c-MYC
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-29 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00338
Tania Das ₁ , Deepanjan Panda ₁ , Puja Saha ₁ , Jyotirmayee Dash ₁

Affiliation

G-quadruplexes have been considered attractive therapeutic targets for the development of anticancer agents. We herein report synthesis of a series of carbazole derivatives by employing modular one-pot Cu(I) catalyzed cycloaddition. These carbazole derivatives are easily synthesizable, soluble in aqueous media, and able to strongly interact with quadruplexes. FRET based melting assay and fluorescence titration experiments suggest that a carbazole derivative, Cz-1, preferentially binds c-MYC quadruplex DNA over other investigated quadruplex and duplex DNAs. The biological studies revealed that Cz-1 inhibits cancer cell proliferation by inducing apoptosis. Moreover, Cz-1 inhibits the expression of c-MYC at transcriptional as well as translational levels. Exon-specific-assay confirms that the downregulation of MYC expression is mainly driven by the binding of Cz-1 with the promoter G-quadruplex structures. Immunocytochemistry, using quadruplex binding antibody BG4, further suggests that Cz-1 induces and stabilizes G-quadruplexes in a cellular system.

中文翻译：

启动子G四链体的小分子驱动稳定和c-MYC的转录调控。

G-四链体被认为是开发抗癌药的有吸引力的治疗靶标。我们在本文中报道了通过使用模块式单锅Cu（I）催化的环加成反应合成一系列咔唑衍生物。这些咔唑衍生物易于合成，可溶于水介质，并能与四链体强烈相互作用。基于FRET的熔解测定和荧光滴定实验表明，咔唑衍生物Cz-1与其他已研究的四链体和双链体DNA优先结合c-MYC四链体DNA。生物学研究表明，Cz-1通过诱导细胞凋亡来抑制癌细胞的增殖。此外，Cz-1抑制c-MYC的表达在转录和翻译水平上。外显子特异性测定证实MYC表达的下调主要是由Cz-1与启动子G-四链体结构的结合驱动的。使用四链体结合抗体BG4的免疫细胞化学进一步表明Cz-1诱导并稳定了细胞系统中的G-四链体。

更新日期：2018-06-29

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