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Medicinal chemistry approaches for novel DNA ligands
Publication . Duarte, Ana Rita Português 1986-; Ressurreição, Ana Sofia Marques da; Moreira, Rui, 1960-
As nucleic acid lesions are involved in most of the diseases, deoxyribonucleic acid (DNA) and ribonucleic acid are attractive targets for drug design. Due to the high homogeneity of B-DNA, the main drawback of DNA binding drugs is their random distribution thereby affecting genome functions in an uncontrolled manner. To overcome this situation, secondary structures such as G-quadruplexes (G4), which can be found in genome regions involved in cell proliferation and genome stability, can be target. This thesis opened new perspectives and reinforced previously existing perceptions over the structural feactures that G4 ligand should have. With regards to non-fused aromatic ligands, this work confirmed that the presence of more than one aromatic core (such as benzene or naphtalene) seems to be essential to: (a) have an aromatic surface big enough to selectively interact with the G-quartet; (b) give some rigidity to the structure. Respecting the polyaromatic fused compounds, a new scaffold (benzo[h][1,6]naphthyridin-2(1H)-one) was tested as G4 ligand aromatic core and the FRET melting data give information that can be used in the design of new derivatives. Besides that, it is also essential to highlight the very good antiproliferative results obtained with some of the compounds synthesised. Alternativelly, peptide nucleic acids (PNAs) also have nucleic acids as drug target. Attempts to understand the structureactivity relationship and improve solubility, cell permeability, bioavailability, and binding orientation with nucleic acids of PNA have resulted in several structural modifications, such as α-PNA. α-PNA has a backbone consisting of α-amino acids, some of them carrying a nucleobase in their side chain. This thesis also described their synthesis of new α-PNA monomers containing sulfur. From a chemical point of view, this work is also interesting for the variety of reactions that were employed where the click thiol-ene reactions stood out.
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Fundação para a Ciência e a Tecnologia
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SFRH
Número da atribuição
SFRH/BD/70491/2010