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

• 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
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c2ob25830g

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.