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Biocatalysis in Dru...
Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters
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- Casamajo, Arnau Rué (författare)
- Department of Chemistry, UniDepartment of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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- Yu, Yuqi (författare)
- Department of Chemistry, UnDepartment of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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- Schnepel, Christian (författare)
- KTH,Industriell bioteknologi
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- Morrill, Charlotte (författare)
- Department of Chemistry, University of Manchester, Manchester Institute of BiotechnologDepartment of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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- Barker, Rhys (författare)
- Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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- Levy, Colin W. (författare)
- Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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- Finnigan, James (författare)
- Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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- Spelling, Victor (författare)
- Early Chemical Development, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, Gothenburg, 431 50, Sweden
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- Westerlund, Kristina (författare)
- Medicinal Chemistry, Research and Early Development; Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50 Gothenburg Sweden
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- Petchey, Mark (författare)
- Compound Synthesis and Management, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, Gothenburg, 431 50, Sweden
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- Sheppard, Robert J. (författare)
- Medicinal Chemistry, Research and Early Development; Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50 Gothenburg Sweden
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- Lewis, Richard J. (författare)
- Department of Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Sweden
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- Falcioni, Francesco (författare)
- Early Chemical Development, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, CB21 6GP, United Kingdom
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- Hayes, Martin A. (författare)
- Compound Synthesis and Management, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, Gothenburg, 431 50, Sweden
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- Turner, Nicholas J. (författare)
- Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, United Kingdom
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(creator_code:org_t)
- NA, 2023
- 2023
- Engelska.
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Ingår i: Journal of the American Chemical Society. - : NA. - 0002-7863 .- 1520-5126. ; 145:40, s. 22041-22046
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
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Casamajo, Arnau ...
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Yu, Yuqi
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Schnepel, Christ ...
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Morrill, Charlot ...
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Barker, Rhys
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Levy, Colin W.
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Finnigan, James
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Spelling, Victor
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Westerlund, Kris ...
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Petchey, Mark
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Sheppard, Robert ...
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Lewis, Richard J ...
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Falcioni, France ...
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Hayes, Martin A.
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Turner, Nicholas ...
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