Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding

[Display omitted] The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies sug...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-12, Vol.14 (23), p.5845-5849
Main Authors: Harrison, R. John, Reszka, Anthony P., Haider, Shozeb M., Romagnoli, Barbara, Morrell, James, Read, Martin A., Gowan, Sharon M., Incles, Christopher M., Kelland, Lloyd R., Neidle, Stephen
Format: Article
Language:English
Subjects:
Acridines - chemistry
Acridines - metabolism
Acridines - pharmacology
Acridone
Acridones
Biological and medical sciences
Cell Line, Tumor
DNA - metabolism
Drug Evaluation, Preclinical - methods
Enzyme Inhibitors
G-Quadruplexes
Humans
Medical sciences
Miscellaneous
Models, Molecular
Pharmacology. Drug treatments
Protein Binding - physiology
Quadruplex DNA
Telomerase
Telomerase - antagonists & inhibitors
Telomerase - metabolism
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Summary:[Display omitted] The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies suggest an equivalent binding mode to human intramolecular G-quadruplex DNA, but with significantly reduced affinity, as a result of the limited delocalisation of the acridone chromophore compared to the acridine system. Thermal melting studies on acridone and acridine quadruplex complexes using a FRET approach support these predictions. Long-term cell proliferation studies at sub-cytotoxic doses with two representative acridones using the SKOV3 cell line, show that neither compound produces growth arrest, in contrast with the effects produced by the tri-substituted acridine compound BRACO-19. It is concluded that telomerase inhibitory activity is a necessary though by itself insufficient property in order for cellular growth arrest to occur at sub-toxic concentrations, and that tight quadruplex binding is also required.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.09.037