Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells

The synthesis, biophysical and biological evaluation of a series of G-quadruplex interacting small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold is described. The synthetic analogues were evaluated for their ability to stabilize telomeric G-quadruplex DNA, some of...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2012-08, Vol.10 (32), p.6537-6546
Main Authors: Müller, Sebastian, Sanders, Deborah A, Di Antonio, Marco, Matsis, Stephanos, Riou, Jean-François, Rodriguez, Raphaël, Balasubramanian, Shankar
Format: Article
Language:English
Subjects:
Aminoquinolines - chemistry
Aminoquinolines - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Base Sequence
Cancer
Cell Line, Tumor
Cell Survival - drug effects
Chemistry
Data processing
DNA damage
G-Quadruplexes - drug effects
Genomes
Humans
Models, Biological
Molecular Sequence Data
Molecular Structure
Picolinic Acids - chemistry
Picolinic Acids - pharmacology
scaffolds
Senescence
Static Electricity
Telomere - drug effects
Telomeres
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Summary:The synthesis, biophysical and biological evaluation of a series of G-quadruplex interacting small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold is described. The synthetic analogues were evaluated for their ability to stabilize telomeric G-quadruplex DNA, some of which showed very high stabilization potential associated with high selectivity over double-stranded DNA. The compounds exhibited growth arrest of cancer cells with detectable selectivity over normal cells. Long-time growth arrest was accompanied by senescence, where telomeric dysfunction is a predominant mechanism together with the accumulation of restricted DNA damage sites in the genome. Our data emphasize the potential of a senescence-mediated anticancer therapy through the use of G-quadruplex targeting small molecules based on the molecular framework of pyridostatin.
ISSN:1477-0520
1477-0539
DOI:10.1039/c2ob25830g