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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....

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
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.
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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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