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The Unusual Monomer Recognition of Guanine-Containing Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine
[Image: see text] DB1255 is a symmetrical diamidinophenyl-dithiophene that exhibits cellular activity by binding to DNA and inhibiting binding of ERG, an ETS family transcription factor that is commonly overexpressed or translocated in leukemia and prostate cancer [Nhili, R., Peixoto, P., Depauw, S....
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985535/ https://www.ncbi.nlm.nih.gov/pubmed/24495039 http://dx.doi.org/10.1021/bi401582t |
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author | Munde, Manoj Kumar, Arvind Peixoto, Paul Depauw, Sabine Ismail, Mohamed A. Farahat, Abdelbasset A. Paul, Ananya Say, Martial V. David-Cordonnier, Marie-Hélène Boykin, David W. Wilson, W. David |
author_facet | Munde, Manoj Kumar, Arvind Peixoto, Paul Depauw, Sabine Ismail, Mohamed A. Farahat, Abdelbasset A. Paul, Ananya Say, Martial V. David-Cordonnier, Marie-Hélène Boykin, David W. Wilson, W. David |
author_sort | Munde, Manoj |
collection | PubMed |
description | [Image: see text] DB1255 is a symmetrical diamidinophenyl-dithiophene that exhibits cellular activity by binding to DNA and inhibiting binding of ERG, an ETS family transcription factor that is commonly overexpressed or translocated in leukemia and prostate cancer [Nhili, R., Peixoto, P., Depauw, S., Flajollet, S., Dezitter, X., Munde, M. M., Ismail, M. A., Kumar, A., Farahat, A. A., Stephens, C. E., Duterque-Coquillaud, M., Wilson, W. D., Boykin, D. W., and David-Cordonnier, M. H. (2013) Nucleic Acids Res. 41, 125–138]. Because transcription factor inhibition is complex but is an attractive area for anticancer and antiparasitic drug development, we have evaluated the DNA interactions of additional derivatives of DB1255 to gain an improved understanding of the biophysical chemistry of complex function and inhibition. DNase I footprinting, biosensor surface plasmon resonance, and circular dichroism experiments show that DB1255 has an unusual and strong monomer binding mode in minor groove sites that contain a single GC base pair flanked by AT base pairs, for example, 5′-ATGAT-3′. Closely related derivatives, such as compounds with the thiophene replaced with furan or selenophane, bind very weakly to GC-containing sequences and do not have biological activity. DB1255 is selective for the ATGAT site; however, a similar sequence, 5′-ATGAC-3′, binds DB1255 more weakly and does not produce a footprint. Molecular docking studies show that the two thiophene sulfur atoms form strong, bifurcated hydrogen bond-type interactions with the G-N-H sequence that extends into the minor groove while the amidines form hydrogen bonds to the flanking AT base pairs. The central dithiophene unit of DB1255 thus forms an excellent, but unexpected, single-GC base pair recognition module in a monomer minor groove complex. |
format | Online Article Text |
id | pubmed-3985535 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-39855352015-02-04 The Unusual Monomer Recognition of Guanine-Containing Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine Munde, Manoj Kumar, Arvind Peixoto, Paul Depauw, Sabine Ismail, Mohamed A. Farahat, Abdelbasset A. Paul, Ananya Say, Martial V. David-Cordonnier, Marie-Hélène Boykin, David W. Wilson, W. David Biochemistry [Image: see text] DB1255 is a symmetrical diamidinophenyl-dithiophene that exhibits cellular activity by binding to DNA and inhibiting binding of ERG, an ETS family transcription factor that is commonly overexpressed or translocated in leukemia and prostate cancer [Nhili, R., Peixoto, P., Depauw, S., Flajollet, S., Dezitter, X., Munde, M. M., Ismail, M. A., Kumar, A., Farahat, A. A., Stephens, C. E., Duterque-Coquillaud, M., Wilson, W. D., Boykin, D. W., and David-Cordonnier, M. H. (2013) Nucleic Acids Res. 41, 125–138]. Because transcription factor inhibition is complex but is an attractive area for anticancer and antiparasitic drug development, we have evaluated the DNA interactions of additional derivatives of DB1255 to gain an improved understanding of the biophysical chemistry of complex function and inhibition. DNase I footprinting, biosensor surface plasmon resonance, and circular dichroism experiments show that DB1255 has an unusual and strong monomer binding mode in minor groove sites that contain a single GC base pair flanked by AT base pairs, for example, 5′-ATGAT-3′. Closely related derivatives, such as compounds with the thiophene replaced with furan or selenophane, bind very weakly to GC-containing sequences and do not have biological activity. DB1255 is selective for the ATGAT site; however, a similar sequence, 5′-ATGAC-3′, binds DB1255 more weakly and does not produce a footprint. Molecular docking studies show that the two thiophene sulfur atoms form strong, bifurcated hydrogen bond-type interactions with the G-N-H sequence that extends into the minor groove while the amidines form hydrogen bonds to the flanking AT base pairs. The central dithiophene unit of DB1255 thus forms an excellent, but unexpected, single-GC base pair recognition module in a monomer minor groove complex. American Chemical Society 2014-02-04 2014-02-25 /pmc/articles/PMC3985535/ /pubmed/24495039 http://dx.doi.org/10.1021/bi401582t Text en Copyright © 2014 American Chemical Society |
spellingShingle | Munde, Manoj Kumar, Arvind Peixoto, Paul Depauw, Sabine Ismail, Mohamed A. Farahat, Abdelbasset A. Paul, Ananya Say, Martial V. David-Cordonnier, Marie-Hélène Boykin, David W. Wilson, W. David The Unusual Monomer Recognition of Guanine-Containing Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine |
title | The Unusual Monomer Recognition of Guanine-Containing
Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine |
title_full | The Unusual Monomer Recognition of Guanine-Containing
Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine |
title_fullStr | The Unusual Monomer Recognition of Guanine-Containing
Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine |
title_full_unstemmed | The Unusual Monomer Recognition of Guanine-Containing
Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine |
title_short | The Unusual Monomer Recognition of Guanine-Containing
Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine |
title_sort | unusual monomer recognition of guanine-containing
mixed sequence dna by a dithiophene heterocyclic diamidine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985535/ https://www.ncbi.nlm.nih.gov/pubmed/24495039 http://dx.doi.org/10.1021/bi401582t |
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