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Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative
The current model of binding of the antitumor antibiotic olivomycin A (1) to GC-rich DNA regions presumes that coordination of the magnesium divalent cation with drug dimers is necessary for binding of 1 into the minor groove of the DNA duplex. Previously we have synthesized the derivatives of 1 ter...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805246/ https://www.ncbi.nlm.nih.gov/pubmed/29420558 http://dx.doi.org/10.1371/journal.pone.0191923 |
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author | Beniaminov, Artemy D. Dezhenkova, Lyubov G. Mamaeva, Olga K. Shchyolkina, Anna K. Tevyashova, Anna N. Kaluzhny, Dmitry N. Shtil, Alexander A. |
author_facet | Beniaminov, Artemy D. Dezhenkova, Lyubov G. Mamaeva, Olga K. Shchyolkina, Anna K. Tevyashova, Anna N. Kaluzhny, Dmitry N. Shtil, Alexander A. |
author_sort | Beniaminov, Artemy D. |
collection | PubMed |
description | The current model of binding of the antitumor antibiotic olivomycin A (1) to GC-rich DNA regions presumes that coordination of the magnesium divalent cation with drug dimers is necessary for binding of 1 into the minor groove of the DNA duplex. Previously we have synthesized the derivatives of 1 termed ‘short acid’ (2) and its N,N-dimethylaminoethylamide (3). The latter compound demonstrated an improved tolerance in vivo compared to 1 and good therapeutic potency in animal models. We herein report that compound 3 is able to form stable complexes with DNA in the absence of Mg(2+), in striking contrast to 1 whose binding to the DNA absolutely requires Mg(2+). The mode of binding of 3 to DNA is similar in the presence or absence of Mg(2+) as determined by circular dichroism. The affinity to DNA of 3 in Mg(2+)-free solution was similar to that of 1 or 3 in the presence of Mg(2+) at low ionic strength. Non-electrostatic contributions to total free energy of binding of 1 and 3 to DNA were comparable for Mg(2+)-free complexes. Our data strongly suggest that electrostatic interaction of the positively charged 3 can compensate for the absence of divalent ions in complexes with DNA. This new property of the olivomycin A derivative expands the mechanistic knowledge of the modes of interaction with DNA of small molecular weight drug candidates. |
format | Online Article Text |
id | pubmed-5805246 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-58052462018-02-23 Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative Beniaminov, Artemy D. Dezhenkova, Lyubov G. Mamaeva, Olga K. Shchyolkina, Anna K. Tevyashova, Anna N. Kaluzhny, Dmitry N. Shtil, Alexander A. PLoS One Research Article The current model of binding of the antitumor antibiotic olivomycin A (1) to GC-rich DNA regions presumes that coordination of the magnesium divalent cation with drug dimers is necessary for binding of 1 into the minor groove of the DNA duplex. Previously we have synthesized the derivatives of 1 termed ‘short acid’ (2) and its N,N-dimethylaminoethylamide (3). The latter compound demonstrated an improved tolerance in vivo compared to 1 and good therapeutic potency in animal models. We herein report that compound 3 is able to form stable complexes with DNA in the absence of Mg(2+), in striking contrast to 1 whose binding to the DNA absolutely requires Mg(2+). The mode of binding of 3 to DNA is similar in the presence or absence of Mg(2+) as determined by circular dichroism. The affinity to DNA of 3 in Mg(2+)-free solution was similar to that of 1 or 3 in the presence of Mg(2+) at low ionic strength. Non-electrostatic contributions to total free energy of binding of 1 and 3 to DNA were comparable for Mg(2+)-free complexes. Our data strongly suggest that electrostatic interaction of the positively charged 3 can compensate for the absence of divalent ions in complexes with DNA. This new property of the olivomycin A derivative expands the mechanistic knowledge of the modes of interaction with DNA of small molecular weight drug candidates. Public Library of Science 2018-02-08 /pmc/articles/PMC5805246/ /pubmed/29420558 http://dx.doi.org/10.1371/journal.pone.0191923 Text en © 2018 Beniaminov et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Beniaminov, Artemy D. Dezhenkova, Lyubov G. Mamaeva, Olga K. Shchyolkina, Anna K. Tevyashova, Anna N. Kaluzhny, Dmitry N. Shtil, Alexander A. Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative |
title | Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative |
title_full | Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative |
title_fullStr | Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative |
title_full_unstemmed | Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative |
title_short | Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative |
title_sort | divalent cations are dispensable for binding to dna of a novel positively charged olivomycin a derivative |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805246/ https://www.ncbi.nlm.nih.gov/pubmed/29420558 http://dx.doi.org/10.1371/journal.pone.0191923 |
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