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Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters
[Image: see text] Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure–activity–property–toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important comp...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571080/ https://www.ncbi.nlm.nih.gov/pubmed/37782882 http://dx.doi.org/10.1021/jacs.3c07010 |
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author | Casamajo, Arnau Rué Yu, Yuqi Schnepel, Christian Morrill, Charlotte Barker, Rhys Levy, Colin W. Finnigan, James Spelling, Victor Westerlund, Kristina Petchey, Mark Sheppard, Robert J. Lewis, Richard J. Falcioni, Francesco Hayes, Martin A. Turner, Nicholas J. |
author_facet | Casamajo, Arnau Rué Yu, Yuqi Schnepel, Christian Morrill, Charlotte Barker, Rhys Levy, Colin W. Finnigan, James Spelling, Victor Westerlund, Kristina Petchey, Mark Sheppard, Robert J. Lewis, Richard J. Falcioni, Francesco Hayes, Martin A. Turner, Nicholas J. |
author_sort | Casamajo, Arnau Rué |
collection | PubMed |
description | [Image: see text] Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure–activity–property–toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important component in compound library expansion but can be difficult to access by traditional organic synthesis. Herein, we report a biocatalytic process to access a specific diastereomer of a chiral amine building block used in drug discovery. A reductive aminase (RedAm) was engineered following a structure-guided mutagenesis strategy to produce the desired isomer. The engineered RedAm (IR-09 W204R) was able to generate the (S,S,S)-isomer 3 in 45% conversion and 95% ee from the racemic ketone 2. Subsequent palladium-catalyzed deallylation of 3 yielded the target primary amine 4 in a 73% yield. This engineered biocatalyst was used at preparative scale and represents a potential starting point for further engineering and process development. |
format | Online Article Text |
id | pubmed-10571080 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-105710802023-10-14 Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters Casamajo, Arnau Rué Yu, Yuqi Schnepel, Christian Morrill, Charlotte Barker, Rhys Levy, Colin W. Finnigan, James Spelling, Victor Westerlund, Kristina Petchey, Mark Sheppard, Robert J. Lewis, Richard J. Falcioni, Francesco Hayes, Martin A. Turner, Nicholas J. J Am Chem Soc [Image: see text] Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure–activity–property–toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important component in compound library expansion but can be difficult to access by traditional organic synthesis. Herein, we report a biocatalytic process to access a specific diastereomer of a chiral amine building block used in drug discovery. A reductive aminase (RedAm) was engineered following a structure-guided mutagenesis strategy to produce the desired isomer. The engineered RedAm (IR-09 W204R) was able to generate the (S,S,S)-isomer 3 in 45% conversion and 95% ee from the racemic ketone 2. Subsequent palladium-catalyzed deallylation of 3 yielded the target primary amine 4 in a 73% yield. This engineered biocatalyst was used at preparative scale and represents a potential starting point for further engineering and process development. American Chemical Society 2023-10-02 /pmc/articles/PMC10571080/ /pubmed/37782882 http://dx.doi.org/10.1021/jacs.3c07010 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Casamajo, Arnau Rué Yu, Yuqi Schnepel, Christian Morrill, Charlotte Barker, Rhys Levy, Colin W. Finnigan, James Spelling, Victor Westerlund, Kristina Petchey, Mark Sheppard, Robert J. Lewis, Richard J. Falcioni, Francesco Hayes, Martin A. Turner, Nicholas J. Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters |
title | Biocatalysis in Drug Design:
Engineered Reductive
Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple
Stereocenters |
title_full | Biocatalysis in Drug Design:
Engineered Reductive
Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple
Stereocenters |
title_fullStr | Biocatalysis in Drug Design:
Engineered Reductive
Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple
Stereocenters |
title_full_unstemmed | Biocatalysis in Drug Design:
Engineered Reductive
Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple
Stereocenters |
title_short | Biocatalysis in Drug Design:
Engineered Reductive
Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple
Stereocenters |
title_sort | biocatalysis in drug design:
engineered reductive
aminases (redams) are used to access chiral building blocks with multiple
stereocenters |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571080/ https://www.ncbi.nlm.nih.gov/pubmed/37782882 http://dx.doi.org/10.1021/jacs.3c07010 |
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