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Title

Characterization of the binding of mithramycin and chromomycin analogues to DNA

AuthorsBarceló, Francisca; Insua, J.L.; Ortiz-Lombardía, Miguel; Méndez, Carmen; Salas, José A.; Portugal, José
Issue Date3-Jul-2012
PublisherSociedad de Biofísica de España
CitationInternational Congress of the Spanish Biophysical Society (2012)
AbstractMithramycin A and chromomycin A3 are two antitumor antibiotics that bind reversibly to the minor groove of G/C-rich regions in DNA in the presence of dications such as Mg2+. Their antiproliferative activity has been associated with their ability to block the binding of certain transcription factors to gene promoters. In our pursuit of new structurallyrelated molecules showing both lower toxicity and higher biological activity than the antitumor drugs presently in clinical use, we have examined the binding to DNA of six analogues of mithramycin A and chromomycin A3 that we have obtained by combinatorial biosynthetic procedures in the producing organisms [1]. All these molecules bear a variety of changes in the side chain attached to the C-3 of the chromophore. The spectroscopic characterization of their binding to DNA followed by the evaluation of binding parameters and associated thermodynamics revealed differences in their binding affinity [2]. For the Mg2+-coordinated dimers of the different compounds the free energy of binding (¿G) was negative (favorable), as a consequence of various positive entropic contributions to binding in the minor groove, which include ions and water release, as well as `hydrophobic¿ interactions. In any case, the positive entropic term was enough to counterbalance the unfavorable entropic cost of forming DNA¿compound complexes. We have found a large entropic term and positive (small) enthalpies of binding, which imply an entropically-driven binding process that is considered a hallmark of minor-groove binding without intercalation [3]. Previously, NMR and crystallographic studies of mithramycin A and chromomycin A3 have shown hydrophobic contacts in the minor groove, which we observed to be fairly conserved among the different analogues.
DescriptionComunicación presentada en International Congress of the Spanish Biophysical Society : SBE Barcelona 2012, celebrado del 3 al 6 de julio de 2012 en Barcelona (España)
URIhttp://hdl.handle.net/10261/122076
Appears in Collections:(IBMB) Comunicaciones congresos
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