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Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures

Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve...

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Autores principales: Škopić, Mateja Klika, Salamon, Hazem, Bugain, Olivia, Jung, Kathrin, Gohla, Anne, Doetsch, Lara J., dos Santos, Denise, Bhat, Avinash, Wagner, Bernd, Brunschweiger, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416911/
https://www.ncbi.nlm.nih.gov/pubmed/28507705
http://dx.doi.org/10.1039/c7sc00455a
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author Škopić, Mateja Klika
Salamon, Hazem
Bugain, Olivia
Jung, Kathrin
Gohla, Anne
Doetsch, Lara J.
dos Santos, Denise
Bhat, Avinash
Wagner, Bernd
Brunschweiger, Andreas
author_facet Škopić, Mateja Klika
Salamon, Hazem
Bugain, Olivia
Jung, Kathrin
Gohla, Anne
Doetsch, Lara J.
dos Santos, Denise
Bhat, Avinash
Wagner, Bernd
Brunschweiger, Andreas
author_sort Škopić, Mateja Klika
collection PubMed
description Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination. A hexathymidine oligonucleotide, called “hexT” allows the chemist utilizing these classes of catalysts to access a potentially broad variety of structures in the initial step of library synthesis. We exploited its catalyst tolerance to efficiently synthesize diverse substituted β-carbolines, pyrazolines, and pyrazoles from readily available starting materials as hexT conjugates by acid- and Au(i)-catalysis, respectively. The hexT conjugates were ligated to coding DNA sequences yielding encoded screening libraries inspired by drug structures.
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spelling pubmed-54169112017-05-15 Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures Škopić, Mateja Klika Salamon, Hazem Bugain, Olivia Jung, Kathrin Gohla, Anne Doetsch, Lara J. dos Santos, Denise Bhat, Avinash Wagner, Bernd Brunschweiger, Andreas Chem Sci Chemistry Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination. A hexathymidine oligonucleotide, called “hexT” allows the chemist utilizing these classes of catalysts to access a potentially broad variety of structures in the initial step of library synthesis. We exploited its catalyst tolerance to efficiently synthesize diverse substituted β-carbolines, pyrazolines, and pyrazoles from readily available starting materials as hexT conjugates by acid- and Au(i)-catalysis, respectively. The hexT conjugates were ligated to coding DNA sequences yielding encoded screening libraries inspired by drug structures. Royal Society of Chemistry 2017-05-01 2017-02-28 /pmc/articles/PMC5416911/ /pubmed/28507705 http://dx.doi.org/10.1039/c7sc00455a Text en This journal is © The Royal Society of Chemistry 2017 http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Škopić, Mateja Klika
Salamon, Hazem
Bugain, Olivia
Jung, Kathrin
Gohla, Anne
Doetsch, Lara J.
dos Santos, Denise
Bhat, Avinash
Wagner, Bernd
Brunschweiger, Andreas
Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
title Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
title_full Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
title_fullStr Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
title_full_unstemmed Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
title_short Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
title_sort acid- and au(i)-mediated synthesis of hexathymidine-dna-heterocycle chimeras, an efficient entry to dna-encoded libraries inspired by drug structures
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5416911/
https://www.ncbi.nlm.nih.gov/pubmed/28507705
http://dx.doi.org/10.1039/c7sc00455a
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