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...

Descripción completa

Detalles Bibliográficos
Autores principales: Sardana, Malvika, Mühlfenzl, Kim S., Wenker, Sylvia T. M., Åkesson, Christian, Hayes, Martin A., Elmore, Charles S., Pithani, Subhash
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