The use of biocatalysis in the synthesis of labelled compounds

Allen, John G.; Brasseur, Denis; Bruin, Béatrice de; Denoux, Mireille; Pérard, Serge; Philippe, Nicolas; Roy, Sébastien

doi:10.1002/jlcr.1388

Cited by 18 publications

(12 citation statements)

References 17 publications

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“…An example is the synthesis of 1 0 -hydroxy[ 13 C 4 ]midazolam (31) 39 Hydrolysis of the nitriles 36a and 36b 44 by an immobilized enzyme system (nitrilase/ amidase activity) prepared from Rhodococcus sp. An example is the synthesis of 1 0 -hydroxy[ 13 C 4 ]midazolam (31) 39 Hydrolysis of the nitriles 36a and 36b 44 by an immobilized enzyme system (nitrilase/ amidase activity) prepared from Rhodococcus sp.…”

Section: Transformations Of Functional Groupsmentioning

confidence: 99%

“…Remethylation under standard conditions demonstrated that 57 was a precursor suitable for carbon-11 (and therefore probably tritium or carbon-14) labeling 39 . As recently communicated, SSR126768 (56) was demethylated by incubation with Mortierella isabellina MMP108 to obtain the required SSR1136660 (57).…”

Section: Dealkylation-realkylation Approachmentioning

confidence: 99%

“…30 Tritium labeling of SD121463(61) An example39 of a multistep chemoenzymatic approach is the preparation of [ 3 H]SR121960 (61). Attempts to dealkylate 61 itself using a culture of the fungus Cunninghamella echinulata LCP73.2203 were unsuccessful, but the microbial deethylation of the synthetic intermediate 58 did work.…”

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confidence: 99%

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Biotransformations in the Preparation of Compounds Labeled with Carbon and Hydrogen Isotopes

Voges¹,

Heys

Moenius

2009

Preparation of Compounds Labeled With Tritium and Carbon‐14

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Biotransformations are selective chemical modifications of molecules by biological entities ranging from isolated enzymes (cell-free systems) to intact organisms 1 . In particular cases they are exploited by the chemical and pharmaceutical industries for production of chemicals; this approach can be especially advantageous for structurally complex compounds 2 . Preparative biotransformations have been used on a laboratory scale by radiochemists to prepare isotopically labeled compounds 3 necessary for drug development and other applications in the life sciences. Their synthetic use for isotope labeling includes:. selective modifications of individual functional groups; . synthesis of structurally complex molecules from less complex isotopically labeled precursors; . synthesis of key intermediates for reconstitution approaches to labeled compounds (see Chapter 10).Enzymes are proteins able to catalyze reactions with very high regio-and/or stereoselectivities under mild conditions. Those enzymes combining low substrate specificity (broad applicability) with high product selectivity are of optimal suitability for organic synthesis. Further increase of structural variety and stability by protein-and mediumengineering 4 has extended their synthetic applicability significantly and made them important tools in organic synthesis. The broad scope of their synthetic use is documented in numerous papers, reviews and textbooks 5 . Although successful in particular applications, biotransformations are less common in isotopic labeling.As the complexity of the biological system varies from highly purified enzymes to whole cell-containing systems, so do some of the practical dimensions of the experiments vary. Therefore this chapter is organized accordingly.In one-step biotransformations particularly, isolated enzymes have distinctive advantages, since they can be used simply, almost like any chemical reagent, and -importantly for isotopic labeling -they do not result in any isotope dilution. Since a large number of enzymes are commercially available, many types of reactions can be carried out.Examples of the use of isolated enzymes in isotopic labeling include N-or O-acylations, hydrolyses, redox reactions and group transfer reactions. Most of them aim for applications such as racemate resolution, catalysis of reactions and synthesis of enantiomerically pure molecules. Optical Resolutions via DerivativesDespite the availability of several chemical strategies for diastereo-and enantioselective syntheses in isotopic labeling (see Chapter 11), kinetic racemate resolution remains a major application of enzymes in the chemistry of isotopically labeled compounds. Depending on the molecular entity, different possibilities have been described for achieving enantioselective differentiation through either derivatization (e.g. N-acyl formation and cleavage, O-acyl formation and cleavage) or selective degradation (e.g. redox reactions). N-Acyl Formation: Enzymatically catalyzed N-acylation of racemates is used for preparative synthesis of ...

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Section: Transformations Of Functional Groupsmentioning

confidence: 99%

Section: Dealkylation-realkylation Approachmentioning

confidence: 99%

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Biotransformations in the Preparation of Compounds Labeled with Carbon and Hydrogen Isotopes

Voges¹,

Heys

Moenius

2009

Preparation of Compounds Labeled With Tritium and Carbon‐14

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“…[13][14][15] The direct singlestep/one-pot transformation of parent drugs would be a challenging but highly efficient alternative approach for the preparation of difficult accessible metabolite structures. On preparative scale, besides conventional chemical oxidation, [16][17][18][19] biomimetic catalysis, [20][21][22][23][24] electrochemical oxidation 25 and also microbial transformations 26,27 have been applied for the oxyfunctionalization of drug molecules. However, existing chemical methods for direct oxygen incorporation into organic molecules are often accompanied by low yields and specificities whereas whole-cell biotransformation processes typically require specific fermentation know-how and equipment.…”

Section: Introductionmentioning

confidence: 99%

One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases

Kiebist

Holla

Heidrich

et al. 2015

Bioorganic & Medicinal Chemistry

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“…The syntheses of unlabelled, stable‐labelled, and tritium‐labelled midazolam have been detailed in the literature 7–9. The use of carbon‐14‐labelled midazolam in metabolism studies has also been reported 10–12.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of carbon‐14 labelled midazolam

Easter

Burrell

Bonacorsi

et al. 2009

Labelled Comp Radiopharmac

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Cytochrome P450 (CYP) enzymes are responsible for much of the phase I oxidative metabolism observed in vivo. Many important pharmaceutical compounds are metabolized by CYP. Co-administration of a drug with another agent can alter the efficacy or the toxicity, especially in cases where drug clearance depends primarily on the CYP metabolism. Compounds that induce or inhibit the CYP activity are often used in drug-drug interaction studies. Midazolam is one such compound that is routinely used in drug-drug interaction studies because it is a known substrate for CYP3A enzymes. The synthesis of this important tool molecule has been documented, but unfortunately a detailed preparation of carbon-14-labelled midazolam has not been reported in the literature. This paper describes a two-step synthesis leading to [ The radiochemical purity as determined by HPLC was 99.8% and the overall radiochemical yield was 9%.

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The use of biocatalysis in the synthesis of labelled compounds

Cited by 18 publications

References 17 publications

Biotransformations in the Preparation of Compounds Labeled with Carbon and Hydrogen Isotopes

Biotransformations in the Preparation of Compounds Labeled with Carbon and Hydrogen Isotopes

One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases

Synthesis of carbon‐14 labelled midazolam

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