Human Telomeric G-Quadruplex Selective Fluoro-Isoquinolines Induce Apoptosis in Cancer Cells,Bioconjugate Chemistry

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Human Telomeric G-Quadruplex Selective Fluoro-Isoquinolines Induce Apoptosis in Cancer Cells
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-02-13 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00781
Subhadip Maiti ₁ , Puja Saha ₁ , Tania Das ₁ , Irene Bessi ₂ , Harald Schwalbe ₂ , Jyotirmayee Dash ₁

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Small molecules that stabilize G-quadruplex structures in telomeres can prevent telomerase enzyme mediated telomere lengthening and subsequently lead to cell death. We herein report two fluoro-isoquinoline derivatives IQ1 and IQ2 as selective ligands for human telomeric G-quadruplex DNA. IQ1 and IQ2 containing different triazolyl side chains have been synthesized by Cu (I) catalyzed azide–alkyne cycloaddition. Fluorescence Resonance Energy Transfer (FRET) melting assay and fluorescence binding titrations indicate that both these ligands exhibit binding preference for telomeric G-quadruplex DNA (h-TELO) over other promoter DNA quadruplexes and duplex DNA. However, ligand IQ1, containing pyrrolidine side chains, is capable of discriminating among quadruplexes by showing higher affinity toward h-TELO quadruplex DNA. On the contrary, IQ2, containing benzamide side chains, interacts with all the investigated quadruplexes. NMR analysis suggests that IQ1 interacts strongly with the external G-quartets of h-TELO. Biological studies reveal that IQ1 is more potent than IQ2 in inhibiting telomerase activity by selectively interacting with telomeric DNA G-quadruplex. Moreover, a dual luciferase reporter assay indicates that IQ1 is unable to reduce the cellular expression of c-MYC and BCL2 at transcriptional level. Significantly, IQ1 mostly stains the nucleus, induces cell cycle arrest in G0/G1 phase, triggers apoptotic response in cancer cells, and activates caspases 3/7.

中文翻译：

人类端粒G四联体选择性氟异喹啉诱导癌细胞凋亡。

稳定端粒中G-四链体结构的小分子可以阻止端粒酶介导的端粒延长，从而导致细胞死亡。我们在本文中报道了两种氟-异喹啉衍生物IQ1和IQ2作为人类端粒G-四链体DNA的选择性配体。含有不同三唑基侧链的IQ1和IQ2是通过Cu（I）催化的叠氮化物-炔烃环加成反应合成的。荧光共振能量转移（FRET）熔解测定法和荧光结合滴定法表明，这两个配体相对于其他启动子DNA四链体和双链体DNA均表现出端粒G-四链体DNA（h-TELO）的结合偏好。但是，配体IQ1通过显示对h-TELO四链体DNA更高的亲和力，含有吡咯烷侧链的α能够区分四链体。相反，含有苯甲酰胺侧链的IQ2与所有研究的四链体相互作用。NMR分析表明，IQ1与h-TELO的外部G四重峰强烈相互作用。生物学研究表明，IQ1通过与端粒DNA G-四链体选择性相互作用，在抑制端粒酶活性方面比IQ2更有效。此外，双重荧光素酶报告基因检测表明IQ1无法降低c-MYC和BCL2的细胞表达在转录水平上。重要的是，IQ1主要染色细胞核，诱导细胞周期停滞在G0 / G1期，触发癌细胞的凋亡反应，并激活胱天蛋白酶3/7。

更新日期：2018-02-13

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