Enzymatic asymmetric synthesis of the silodosin amine intermediate

Simon, Robert C.; Sattler, Johann H.; Farnberger, Judith E.; Fuchs, Christine; Richter, Nina; Zepeck, Ferdinand; Kroutil, Wolfgang

doi:10.1016/j.tetasy.2013.12.012

Cited by 16 publications

(9 citation statements)

References 39 publications

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“…Previous use of DMF as a solvent has been applied to TAm‐catalyzed reactions in the production of pharmaceuticals. Its addition as a co‐solvent improved both the reaction process and substrate loading in the production of an intermediate for the pro‐drug silodosin, used in the treatment of benign prostatic hypertrophy . With Ad2‐TAm, an increase above 10% concentration of DMF led to a dramatic reduction in conversion.…”

Section: Resultsmentioning

confidence: 99%

Isolation and Characterisation of a Halotolerant ω‐Transaminase from a Triassic Period Salt Mine and Its Application to Biocatalysis

et al. 2017

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Chiral amines are valuable intermediates for the pharmaceutical industry, with up to 40% of current pharmaceuticals containing an amine functionality. However, their syntheses by conventional chemical methods often suffer from a number of key drawbacks. Transaminases (TAms) are pyridoxal phosphate (PLP) dependent enzymes capable of transferring an amine group to a prochiral ketone, offering a green and economically viable alternative to chiral amine production. Despite some high profile successes, TAms suffer from limited substrate scope and the ability to function under challenging conditions often required in reaction processes. Mining of untapped, extremophilic environments represents a viable approach in the search for novel enzymes. We report the cloning and expression of an (S)‐selective ω‐TAm from a Halomonas sp. (Ad2‐TAm), isolated from an extreme hypersaline environment formed during the Triassic period (circa 220 mya). Ad2‐TAm exhibits an ability to convert a range of structurally diverse aldehyde and ketone substrates, with no decrease in conversion up to 1.5 M (8.8%) NaCl. The enzyme is also tolerant to the presence of organic cosolvents up to 30% and accepts a range of amino donors. These characteristics make Ad2‐TAm a promising candidate for industrial applications, whilst also highlighting the value of extreme environments as a source of novel enzymes for the pharmaceutical industry as a whole.

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Section: Resultsmentioning

confidence: 99%

Isolation and Characterisation of a Halotolerant ω‐Transaminase from a Triassic Period Salt Mine and Its Application to Biocatalysis

et al. 2017

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“…An enzyme-catalyzed transamination was also considered for the preparation of the amine 49 , an intermediate on the pathway to the pro-drug silodosin ( 48 ), which is used for the treatment of dysuria and urinary disturbance (Scheme 18 , c). [ 81 ]…”

Section: Applicationsmentioning

confidence: 99%

The Industrial Age of Biocatalytic Transamination

2015

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During the last decade the use of ω-transaminases has been identified as a very powerful method for the preparation of optically pure amines from the corresponding ketones. Their immense potential for the preparation of chiral amines, together with their ease of use in combination with existing biocatalytic methods, have made these biocatalysts a competitor to any chemical methodology for (asymmetric) amination. An increasing number of examples, especially from industry, shows that this biocatalytic technology outmaneuvers existing chemical processes by its simple and flexible nature. In the last few years numerous publications and patents on synthetic routes, mainly to pharmaceuticals, involving ω-transaminases have been published. The review gives an overview of the application of ω-transaminases in organic synthesis with a focus on active pharmaceutical ingredients (APIs) and the developments during the last few years.

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“…4c). The additions of DMF and DMSO have previously been applied in API synthesis and other TAm-containing processes [42,43]. The greatest conversion was seen at 30 °C, which decreased with increasing temperature (Fig.…”

Section: Evaluation Of Enzyme Performance Under Varying Reaction Paramentioning

confidence: 99%

Characterization of a novel ω-transaminase from a Triassic salt mine metagenome

Kelly

Skvortsov

Magill

et al. 2018

Biochemical and Biophysical Research Communications

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Chiral amines are valuable building blocks for the pharmaceutical industry, and are increasingly synthesized by transaminase-mediated (TAm) synthesis. Currently available TAms, primarily isolated from the genomes of cultured mesophilic bacteria, often suffer from a number of drawbacks, including poor substrate range and an inability to tolerate the harsh conditions often demanded by industrial processes. These characteristics have, in part, driven the search for novel biocatalysts from both metagenomic sources and extreme environments. Herein, we report the isolation and characterization of an ω-TAm from a metagenome of a Triassic salt mine in Kilroot, N. Ireland, an extremely hypersaline environment formed circa 220-250 mya. The gene sequence was identified based on homology with existing bacterial TAms, synthesized within a pET28a(+) plasmid and expressed in E. coli BL21 DE3 cells. The resultant 49 kDa protein accepted (S)-methylbenzylamine (MBA) as amino donor and had a specific activity of 0.54 U/mg using α-ketoglutarate (ΑKG) as substrate. Molecular modeling and substrate docking indicated the presence of key residues, conserved in a number of other TAms. Despite the hypersaline environment from which it was isolated, the enzyme displayed low halotolerance, highlighting that not all biocatalysts will demonstrate the extreme characteristics associated with their source environment. This study does however reinforce the viability of mining metagenomic datasets as a means of discovering novel and functional biocatalysts, and adds to a currently scant list of such examples in the field of TAms.

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Enzymatic asymmetric synthesis of the silodosin amine intermediate

Cited by 16 publications

References 39 publications

Isolation and Characterisation of a Halotolerant ω‐Transaminase from a Triassic Period Salt Mine and Its Application to Biocatalysis

Isolation and Characterisation of a Halotolerant ω‐Transaminase from a Triassic Period Salt Mine and Its Application to Biocatalysis

The Industrial Age of Biocatalytic Transamination

Characterization of a novel ω-transaminase from a Triassic salt mine metagenome

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