Synthesis and Cellular Evaluation of Specific Porphyrin and Salen Based G-Quadruplex Ligands – QUARPDIEMS

In this project, we plan to use different approach to achieve selectivity. Starting from the recognition of G-quadruplex motifs by aromatic molecules stacked on a terminal G-quartet plateau, we propose to establish differential interactions with distinct features of G-quartet connecting loops and grooves. The porphyrin and salen motifs provide an excellent anchor point for stacking and subsituents should allow specific interactions and thus high specificity.

Several derivatives have already been synthesized and are currently tested

We expect to find new rules for selective recognition.

In vitro, single-stranded G-rich nucleic acid sequences can adopt a particular conformation called a G-quadruplex (or G4) based on the stacking of two or more guanine quartets. Although the structures of G-quadruplexes have been well studied in vitro, if, when, and where they form in vivo and how they might affect cell biology remain key questions. The search for specific G-quadruplex ligands was initially directed to telomere repeats and telomerase. Although cellular studies have shown that G-quadruplex specific ligands provoke marked effects on telomere replication and capping, several reports indicated that these ligands may act in extra-telomeric regions. Bioinformatic analysis of the human genome indicates that it contains as many as 370,000 sequences possessing the potential to form stable G-quadruplex structures. Biophysical studies have shown that intramolecular G-quadruplexes can have distinct features as a consequence of the length, sequence, and folded topology of their loops. For G-quadruplex ligands to be used as therapeutics or as biological G-quadruplex-directed probes, a level of specificity for particular G-quadruplex conformations that might be simultaneously present in the cell is necessary. Recognition of G-quadruplex motifs by small molecules generally involves an aromatic system that stacks on a terminal G-quartet plateau, but selective binding of particular G-quadruplex structures by G-quadruplex ligands must be achieved using small molecules that are able to establish differential interactions with distinct features of G-quartet connecting loops or grooves. The main objectives of this project are the design, the synthesis and the biophysical and cellular characterization of porphyrin and salen-based G-quadruplex ligands selective for particular G-quadruplex structures.