Interaction between double helix DNA fragments and the new antitumor agent sabarubicin, Men10755
Articolo
Data di Pubblicazione:
2010
Citazione:
Interaction between double helix DNA fragments and the new antitumor agent
sabarubicin, Men10755 / S. Mazzini, L. Scaglioni, F. Animati, R. Mondelli. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 18:4(2010), pp. 1497-1506.
Abstract:
Amongthe disaccharide derivatives of the antitumor anthracycline doxorubicin, sabarubicin (Men10755) is
more active and less cytotoxic than doxorubicin. It showed a strong in vivo antitumor activity in all preclinical
models examined, in conjunction with a better tolerability, and is now in phase II clinical trials.
The interaction of sabarubicin andMen10749(a similar disaccharidewith a different configuration at C-40 of
the proximal sugar) with the hexanucleotides d(CGTACG)2 and d(CGATCG)2 was studied by a combined use
of 2D-1Hand 31PNMRtechniques. Both 1Hand 31P chemical shifts of imino protons and phosphates allowed
to established the intercalation sites between the CG base pairs, as it occurs for other anthracyclines of the
series. The dissociation rate constants (koff) of the slow step of the intercalation process were measured for
Men10755 and Men10749, by NMR NOE-exchange experiments. The increase of koff , with respect of doxorubicin,
showed that the intercalation process is significantly faster for both drugs, leading to an average residence
time for sabarubicin into d(CGTACG)2 sixfold shorter than for doxorubicin. This could give account of
both higher cytoplasmic/nuclear ratio and lower cellular uptake of sabarubicin in comparison with doxorubicin
and accordingly of the lower cytotoxicity of these disaccharide analogues.
A relevant number of NOE interactions allowed the structure of the complexes in solution to be derived
through restrained MD calculations. NMR-DOSY experiments were performed with several drug/oligonucleotide
mixtures in order to determine the structure and the dimension of the aggregates.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Drug–DNA interactions ; NMR spectroscopy ;
Sabarubicin ;
Topoisomerase II inhibitors
Elenco autori:
S. Mazzini, L. Scaglioni, F. Animati, R. Mondelli
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