Department of Organic Chemistry , Indian Association for the Cultivation of Science , Jadavpur , Kolkata 700032 , India.
Bioconjug Chem. 2018 Aug 15;29(8):2636-2645. doi: 10.1021/acs.bioconjchem.8b00338. Epub 2018 Jul 16.
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.
G-四链体已被认为是开发抗癌药物的有吸引力的治疗靶标。本文通过使用模块化一锅法 Cu(I) 催化环加成反应，报道了一系列咔唑衍生物的合成。这些咔唑衍生物易于合成，在水相介质中具有良好的溶解性，并且能够与四链体强烈相互作用。基于荧光共振能量转移（FRET）的熔解实验和荧光滴定实验表明，咔唑衍生物 Cz-1 优先与 c-MYC 四链体 DNA 结合，而不是与其他研究的四链体和双链 DNA 结合。生物学研究表明，Cz-1 通过诱导细胞凋亡抑制癌细胞增殖。此外，Cz-1 在转录和翻译水平上抑制 c-MYC 的表达。外显子特异性分析证实，MYC 表达的下调主要是由 Cz-1 与启动子 G-四链体结构的结合所驱动的。使用四链体结合抗体 BG4 的免疫细胞化学进一步表明，Cz-1 在细胞系统中诱导并稳定 G-四链体。
