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Interaction of an acridine dimer with DNA quadruplex structures
P Alberti1, J Ren, M P Teulade-Fichou
1Laboratoire de Biophysique, Muséum National d'Histoire Naturelle, INSERM U 201,CNRS UMR 8646, Paris, France.
Abstract:
The reactivation of telomerase activity in most cancer cells supports the concept that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. The telomeric G-rich single-stranded DNA can adopt an intramolecular G-quadruplex structure in vitro, which has been shown to inhibit telomerase activity. The C-rich sequence can also adopt a quadruplex (intercalated) structure (i-DNA). Two acridine derivatives were shown to increase the melting temperature of the G- quadruplex and the C-quadruplex at 1 microM dye concentration. The increase in Tm value of the G-quadruplex was associated with telomerase inhibition in vitro. The most active compound, "BisA", showed an IC(50) value of 0.75 microM in a standard TRAP assay.
Insights
Telomerase is a cancer target. Acridine derivatives like BisA inhibit telomerase by stabilizing G-quadruplex DNA structures, showing potential as anticancer agents.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Telomerase activity is reactivated in most cancers, making it a key target for anticancer drug development.
- Telomeric G-rich DNA forms G-quadruplex structures that inhibit telomerase.
- C-rich DNA can also form quadruplex structures (i-DNA).
Purpose of the Study:
- To investigate acridine derivatives as potential telomerase inhibitors.
- To evaluate the effect of these compounds on G-quadruplex and C-quadruplex stability.
- To correlate structural stabilization with telomerase inhibition.
Main Methods:
- Synthesis and testing of two acridine derivatives.
- Measurement of melting temperature (Tm) for G-quadruplex and C-quadruplex structures.
- Telomerase inhibition assay (TRAP assay) to determine IC(50) values.
Main Results:
- Two acridine derivatives increased the melting temperature of both G-quadruplex and C-quadruplex structures at 1 microM.
- The stabilization of G-quadruplex structures correlated with telomerase inhibition in vitro.
- The compound BisA demonstrated significant telomerase inhibition with an IC(50) of 0.75 microM.
Conclusions:
- Acridine derivatives can stabilize G-quadruplex and C-quadruplex DNA structures.
- Stabilization of G-quadruplex DNA by acridine derivatives leads to telomerase inhibition.
- BisA is a potent telomerase inhibitor with potential as an anticancer therapeutic.