Human Telomeric G-Quadruplex Selective Fluoro-Isoquinolines Induce Apoptosis in Cancer Cells.
Bioconjug Chem
; 29(4): 1141-1154, 2018 04 18.
Article
in En
| MEDLINE
| ID: mdl-29433312
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Telomere
/
Apoptosis
/
G-Quadruplexes
/
Fluorine
/
Isoquinolines
Limits:
Humans
Language:
En
Journal:
Bioconjug Chem
Journal subject:
BIOQUIMICA
Year:
2018
Document type:
Article
Affiliation country: