The telomeric DNA sequences found at the end of chromosomes are of particular interest. An example of such sequence repeats is (TTAGGG)n found in the human telomeres. These have been developed to protect the chromosome ends from a large range of cellular damage. Maintenance of telomeres is undertaken by specialized DNA polymerase complexes, more commonly called telomerases. However, in normal cells telomeres progressively decrease in length with each successive round of cell division, until the cells enter an irreversible phase of growth arrest, then directed to the physiological cell death. In contrast, telomeres of cancer cells show a very different behavior: they do not shorten on replication thus participating to cancer cells immortality. In order to interact with telomerase, the telomere must be in linear conformation, wheras if it assumes or is induced to assume the conformation of G-quadruplex can no longer be a substrate for telomerase. This non-canonical conformation of DNA has recently been highlighted in human cells (1). These observations have generated great interest in the potential of the telomeres and telomerase as anticancer target, especially when the enzymatic activity of telomerase was found (2) to be inhibited by the formation of stabilized G-quadruplex structures. For all these reasons, G-quadruplex DNA structures are a potential target for drug design. Recently a small library of naphtoquinones was synthesized and some of these were selected for our work, because they could have an interaction with G-quadruplex DNA, caused by the presence of aromatic naphtoquinone moiety, heteroatoms and positive charges. First of all, we tested these compounds by G4-FID experiments in order to evaluate the affinity for DNA fragments and their selectivity for G-quadruplex compared to duplex structures. Some of these compounds were tested with model oligonucleotides by NMR experiments. In the case of d(TAGGGTTA)4, the ligands could be found both in A2pG3 and G5pT6 step, while the complex with d(TTGGGTT)4 could involve T2pG3 or G5pT6 step. These findings were confirmed by docking experiments, which provided initial models of the complexes. For these promising results we decided to test some derivatives with the larger oligonucleotide sequences c-myc and Bcl2mid, which represent relevant biological targets implicated in a wide variety of pathologies.

Molecular recognition in naphtoquinone derivatives - G quadruplex complexes by NMR / R. Ferreira, L. Musso, B. Riva, R. Artali, L. Scaglioni, A. Altieri, S. Mazzini. ((Intervento presentato al 25. convegno Convegno Nazionale della Divisione di Chimica Organica tenutosi a Sassari nel 2013.

Molecular recognition in naphtoquinone derivatives - G quadruplex complexes by NMR

L. Musso;L. Scaglioni;S. Mazzini
2013

Abstract

The telomeric DNA sequences found at the end of chromosomes are of particular interest. An example of such sequence repeats is (TTAGGG)n found in the human telomeres. These have been developed to protect the chromosome ends from a large range of cellular damage. Maintenance of telomeres is undertaken by specialized DNA polymerase complexes, more commonly called telomerases. However, in normal cells telomeres progressively decrease in length with each successive round of cell division, until the cells enter an irreversible phase of growth arrest, then directed to the physiological cell death. In contrast, telomeres of cancer cells show a very different behavior: they do not shorten on replication thus participating to cancer cells immortality. In order to interact with telomerase, the telomere must be in linear conformation, wheras if it assumes or is induced to assume the conformation of G-quadruplex can no longer be a substrate for telomerase. This non-canonical conformation of DNA has recently been highlighted in human cells (1). These observations have generated great interest in the potential of the telomeres and telomerase as anticancer target, especially when the enzymatic activity of telomerase was found (2) to be inhibited by the formation of stabilized G-quadruplex structures. For all these reasons, G-quadruplex DNA structures are a potential target for drug design. Recently a small library of naphtoquinones was synthesized and some of these were selected for our work, because they could have an interaction with G-quadruplex DNA, caused by the presence of aromatic naphtoquinone moiety, heteroatoms and positive charges. First of all, we tested these compounds by G4-FID experiments in order to evaluate the affinity for DNA fragments and their selectivity for G-quadruplex compared to duplex structures. Some of these compounds were tested with model oligonucleotides by NMR experiments. In the case of d(TAGGGTTA)4, the ligands could be found both in A2pG3 and G5pT6 step, while the complex with d(TTGGGTT)4 could involve T2pG3 or G5pT6 step. These findings were confirmed by docking experiments, which provided initial models of the complexes. For these promising results we decided to test some derivatives with the larger oligonucleotide sequences c-myc and Bcl2mid, which represent relevant biological targets implicated in a wide variety of pathologies.
9-set-2013
Settore CHIM/06 - Chimica Organica
Molecular recognition in naphtoquinone derivatives - G quadruplex complexes by NMR / R. Ferreira, L. Musso, B. Riva, R. Artali, L. Scaglioni, A. Altieri, S. Mazzini. ((Intervento presentato al 25. convegno Convegno Nazionale della Divisione di Chimica Organica tenutosi a Sassari nel 2013.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/231390
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