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

Francisco Cuenca; Michael J B Moore; Karin Johnson; Bérangère Guyen; Anne De Cian; Stephen Neidle

doi:10.1016/j.bmcl.2009.07.033

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

Bioorg Med Chem Lett. 2009 Sep 1;19(17):5109-13. doi: 10.1016/j.bmcl.2009.07.033. Epub 2009 Jul 10.

Authors

Francisco Cuenca¹, Michael J B Moore, Karin Johnson, Bérangère Guyen, Anne De Cian, Stephen Neidle

Affiliation

¹ CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London, UK.

PMID: 19640709
DOI: 10.1016/j.bmcl.2009.07.033

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acridines / chemical synthesis
Acridines / chemistry*
Acridines / toxicity
Acridones
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Cell Line, Tumor
Drug Design
Drug Screening Assays, Antitumor
G-Quadruplexes*
Humans
Ligands
Telomerase / metabolism
Telomere / metabolism
Transition Temperature

Substances

Acridines
Acridones
Antineoplastic Agents
Ligands
acridone
Telomerase