Interactions of flavones and related compounds with nucleic acids.

Ragazzon, Patricia Alejandra (2006). Interactions of flavones and related compounds with nucleic acids. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fe4b

Abstract

This project focused on a group of active ingredients isolated from herbal medicines, most of them flavonoids, as a foundation for the development of new anticancer drugs. Interactions between these compounds and genomic DNA, synthetic polynucleotides, or higher order DNA isoforms (triple and quadruple helical forms) have been studied using a range of physicochemical and biological techniques. The studies demonstrated that flavonoids and isoflavonoids bind to the various nucleic acid forms with weak or moderate affinities and no significant specificity, apart from quercetin that demonstrated a differential binding for G-quadruplex structures.

Rational drug design has been subsequently employed to elucidate the mode of binding and novel compounds have been synthesized in order to provide precise structure-activity related studies and result in a second generation of chemotherapeutic anticancer agents with improved properties. Interaction with DNA is thought to involve the planar ring structures. The double bond of the O in C4 in a flavone scaffold gives planarity to the molecule, and this allows the molecule to intercalate between the bases in the different nucleic acid structures. The comparison between flavone, flavanone and isoflavonoid indicates that the position of the B ring and the double bond in the C ring are important for the interactions with DNA. Introduction of nitrogen in the ring did not improve the binding but tertiary amines improved binding 100 fold. Introduction of sulfur produced two binding constants. Position 7 in the A ring of the flavones is extremely relevant for the binding to the nucleic acids, but substitutions in the B ring did not improve the binding. Methoxylation or acetoxylation in positions 5 and 7 decreased the affinity for DNA. Novel compounds were tested for their specificity against different DNA isoforms and their anticancer activity in various tumour cell lines.

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