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 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.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Sebastian
S
Müller
Deborah A
DA
Sanders
Marco
M
Di Antonio
Stephanos
S
Matsis
Jean-François
JF
Riou
Raphaël
R
Rodriguez
Shankar
S
Balasubramanian
D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D055672:Static Electricity; D016615:Telomere / Q000187:drug effects*
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D010848:Picolinic Acids; C567962:pyridostatin