Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes
Cyclopropanes are commonly employed structural moieties in drug design since their incorporation is often associated with increased target affinity, improved metabolic stability, and increased rigidity to access bioactive conformations. Robust chemical cyclopropanation procedures have been developed...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305206/ https://www.ncbi.nlm.nih.gov/pubmed/34997781 http://dx.doi.org/10.1002/jlcr.3962 |
_version_ | 1784752269930004480 |
---|---|
author | Sardana, Malvika Mühlfenzl, Kim S. Wenker, Sylvia T. M. Åkesson, Christian Hayes, Martin A. Elmore, Charles S. Pithani, Subhash |
author_facet | Sardana, Malvika Mühlfenzl, Kim S. Wenker, Sylvia T. M. Åkesson, Christian Hayes, Martin A. Elmore, Charles S. Pithani, Subhash |
author_sort | Sardana, Malvika |
collection | PubMed |
description | Cyclopropanes are commonly employed structural moieties in drug design since their incorporation is often associated with increased target affinity, improved metabolic stability, and increased rigidity to access bioactive conformations. Robust chemical cyclopropanation procedures have been developed which proceed with high yield and broad substrate scope, and have been applied to labeled substrates. Recently, engineered enzymes have been shown to perform cyclopropanations with remarkable diastereoselectivity and enantioselectivity, but this biocatalytic approach has not been applied to labeled substrates to date. In this study, the use of enzyme catalysis for the synthesis of labeled cyclopropanes was investigated. Two readily available enzymes, a modified CYP450 enzyme and a modified Aeropyrum pernix protoglobin, were investigated for the cyclopropanation of a variety of substituted styrenes. For this biocatalytic transformation, the enzymes required the use of ethyl diazoacetate. Due to the highly energetic nature of this molecule, alternatives were investigated. The final optimized cyclopropanation was successfully demonstrated using n‐hexyl diazoacetate, resulting in moderate to high enantiomeric excess. The optimized procedure was used to generate labeled cyclopropanes from (13)C‐glycine, forming all four labeled stereoisomers of phosphodiesterase type‐IV inhibitor, MK0952. These reactions provide a convenient and effective biocatalytic route to stereoselective (13)C‐labeled cyclopropanes and serve as a proof‐of‐concept for generating stereoselective labeled cyclopropanes. |
format | Online Article Text |
id | pubmed-9305206 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93052062022-07-28 Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes Sardana, Malvika Mühlfenzl, Kim S. Wenker, Sylvia T. M. Åkesson, Christian Hayes, Martin A. Elmore, Charles S. Pithani, Subhash J Labelled Comp Radiopharm Research Articles Cyclopropanes are commonly employed structural moieties in drug design since their incorporation is often associated with increased target affinity, improved metabolic stability, and increased rigidity to access bioactive conformations. Robust chemical cyclopropanation procedures have been developed which proceed with high yield and broad substrate scope, and have been applied to labeled substrates. Recently, engineered enzymes have been shown to perform cyclopropanations with remarkable diastereoselectivity and enantioselectivity, but this biocatalytic approach has not been applied to labeled substrates to date. In this study, the use of enzyme catalysis for the synthesis of labeled cyclopropanes was investigated. Two readily available enzymes, a modified CYP450 enzyme and a modified Aeropyrum pernix protoglobin, were investigated for the cyclopropanation of a variety of substituted styrenes. For this biocatalytic transformation, the enzymes required the use of ethyl diazoacetate. Due to the highly energetic nature of this molecule, alternatives were investigated. The final optimized cyclopropanation was successfully demonstrated using n‐hexyl diazoacetate, resulting in moderate to high enantiomeric excess. The optimized procedure was used to generate labeled cyclopropanes from (13)C‐glycine, forming all four labeled stereoisomers of phosphodiesterase type‐IV inhibitor, MK0952. These reactions provide a convenient and effective biocatalytic route to stereoselective (13)C‐labeled cyclopropanes and serve as a proof‐of‐concept for generating stereoselective labeled cyclopropanes. John Wiley and Sons Inc. 2022-02-02 2022-04 /pmc/articles/PMC9305206/ /pubmed/34997781 http://dx.doi.org/10.1002/jlcr.3962 Text en © 2022 AstraZeneca. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Sardana, Malvika Mühlfenzl, Kim S. Wenker, Sylvia T. M. Åkesson, Christian Hayes, Martin A. Elmore, Charles S. Pithani, Subhash Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
title | Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
title_full | Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
title_fullStr | Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
title_full_unstemmed | Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
title_short | Exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
title_sort | exploring the enzyme‐catalyzed synthesis of isotope labeled cyclopropanes |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305206/ https://www.ncbi.nlm.nih.gov/pubmed/34997781 http://dx.doi.org/10.1002/jlcr.3962 |
work_keys_str_mv | AT sardanamalvika exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes AT muhlfenzlkims exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes AT wenkersylviatm exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes AT akessonchristian exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes AT hayesmartina exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes AT elmorecharless exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes AT pithanisubhash exploringtheenzymecatalyzedsynthesisofisotopelabeledcyclopropanes |