Design, synthesis and evaluation of 4,5-di-substituted acridone ligands with high G-quadruplex affinity and selectivity, together with low toxicity to normal cells.
A series of 4,5-di-substituted acridones have been designed and synthesized. Several compounds show high affinity for telomeric G-quadruplex DNA in classical and competition FRET assays, together with low duplex DNA affinity, although they do not show activity in a telomerase assay or evidence of telomere shortening. They have low toxicity against a panel of cancer cell lines and a normal human fibroblast line, and produce potent senescence-based long-term growth arrest in the MCF7 and A549 cancer cell lines.
Cuenca
Francisco
F
CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London, UK.
Moore
Michael J B
MJ
Johnson
Karin
K
Guyen
Bérangère
B
De Cian
Anne
A
Neidle
Stephen
S
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D054831:Acridones; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D044366:Transition Temperature
D000166:Acridines; D054831:Acridones; D000970:Antineoplastic Agents; D008024:Ligands; C041300:acridone; D019098:Telomerase