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Synthesis and biological Evaluation of G4-inducing Telomerase Inhibitors


Telemetries are essential in maintaining the stability of chromosome ends and are synthesized by a specialized enzyme named telemetries. Telemetries are not expressed in most somatic cells but are over expressed in a large number of tumours and are involved with cell immortalisation and tumorigenesis processes. This differential expression was the initial rationale for the evaluation of telemetries inhibitors as potential anticancer drugs. The peculiar structure of telemetries, composed of Guanine repeats, allows forming an unusual DNA conformation based on a Guanine-quadruple (G-quadruple). In vitro, G-quadruple DNA inhibits telemetries activity, which has recently stimulated the search for legends that stabilize telemetric DNA under its G- quadruple conformation, as a new strategy to impair telemetries function in cancer cells. We have developed monomer MMQ and dimerism macro cyclic BOQ quinacridine (dibenzophenanthroline) derivatives that are strong G-quadruple interactive legends and potent telemetries inhibitors. The first objective of the research project is the improvement of the binding selectivity of the MMQ series. This will be achieved by the synthesis of polyamide- trisubstituted MMQ conjugates. This new generation of legend is hoped to achieve specific recognition of quadruple DNA in combining two binding modes, namely G-quartet stacking and anchorage in three grooves. The second objective of the research project is the evaluation of the potential of the BOQ macro cycles as selective G4 binders. This will be conducted through biophysical and biochemical studies of interactions of the BOQ series with various oligonucleotides forming quadruple. In addition, fluorescent derivatives of BOQ will be prepared in order to use them as quadruple-DNA probes both in vitro and in vivo.

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