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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2017
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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. |
format | Online Article Text |
id | pubmed-5416911 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
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
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title_full | Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
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title_fullStr | Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
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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
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title_short | Acid- and Au(i)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures
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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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