Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding
Date
2004ICR Author
Author
Harrison, RJ
Reszka, AP
Haider, SM
Romagnoli, B
Morrell, J
Read, MA
Gowan, SM
Incles, CM
Kelland, LR
Neidle, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Research team
Cancer Pharmacology & Stress Response (CPSR)
Language
eng
License start date
2004
Citation
Bioorganic & Medicinal Chemistry Letters, 2004, 14 pp. 5845 - 5849