DNA Binding Characteristics of Mithramycin and Chromomycin Analogues Obtained by Combinatorial Biosynthesis

The antitumor antibiotics mithramycin A and chromomycin A3 bind reversibly to the minor groove of G/C-rich regions in DNA in the presence of dications such as Mg2+, and their antiproliferative activity has been associated with their ability to block the binding of certain transcription factors to ge...

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Published inBiochemistry (Easton) Vol. 49; no. 49; pp. 10543 - 10552
Main Authors Barceló, Francisca, Ortiz-Lombardía, Miguel, Martorell, Miquel, Oliver, Miquel, Méndez, Carmen, Salas, José A, Portugal, José
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 14.12.2010
Subjects
Animals
Binding Sites - physiology
Chromomycins - biosynthesis
Chromomycins - chemistry
Chromomycins - metabolism
Combinatorial Chemistry Techniques - methods
DNA - chemistry
DNA - metabolism
Male
Models, Molecular
Nucleic Acid Conformation
Plicamycin - analogs & derivatives
Plicamycin - metabolism
Salmon
Testis - chemistry
Thermodynamics
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Summary:The antitumor antibiotics mithramycin A and chromomycin A3 bind reversibly to the minor groove of G/C-rich regions in DNA in the presence of dications such as Mg2+, and their antiproliferative activity has been associated with their ability to block the binding of certain transcription factors to gene promoters. Despite their biological activity, their use as anticancer agents is limited by severe side effects. Therefore, in our pursuit of new structurally related molecules showing both lower toxicity and higher biological activity, we have examined the binding to DNA of six analogues that we have obtained by combinatorial biosynthetic procedures in the producing organisms. All these molecules bear a variety of changes in the side chain attached to 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. DNA binding was entropically driven, dominated by the hydrophobic transfer of every compound from solution into the minor groove of DNA. Among the analogues, mithramycin SDK and chromomycin SDK possessed the higher DNA binding affinities.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi101398s