Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
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
_version_ 1785119905494859776
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
work_keys_str_mv AT casamajoarnaurue biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT yuyuqi biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT schnepelchristian biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT morrillcharlotte biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT barkerrhys biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT levycolinw biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT finniganjames biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT spellingvictor biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT westerlundkristina biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT petcheymark biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT sheppardrobertj biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT lewisrichardj biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT falcionifrancesco biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT hayesmartina biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters
AT turnernicholasj biocatalysisindrugdesignengineeredreductiveaminasesredamsareusedtoaccesschiralbuildingblockswithmultiplestereocenters