Maiti, Subhadip ; Saha, Puja ; Das, Tania ; Bessi, Irene ; Schwalbe, Harald ; Dash, Jyotirmayee (2018) Human Telomeric G-Quadruplex Selective Fluoro-Isoquinolines Induce Apoptosis in Cancer Cells Bioconjugate Chemistry, 29 (4). pp. 1141-1154. ISSN 1043-1802
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Official URL: http://doi.org/10.1021/acs.bioconjchem.7b00781
Related URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00781
Abstract
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.
Item Type: | Article |
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Source: | Copyright of this article belongs to American Chemical Society. |
ID Code: | 126643 |
Deposited On: | 17 Oct 2022 05:44 |
Last Modified: | 17 Oct 2022 05:44 |
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