Synthetic approaches towards the synthesis of beta-blockers (betaxolol, metoprolol, sotalol, and timolol)

Saddique, Furqan Ahmad; Zahoor, Ameer Fawad; Yousaf, Muhammmad; Irfan, Muhammmad; Ahmad, Matloob; Mansha, Asim; Khan, Zulfiqar Ali; Naqvi, Syed Ali Raza

doi:10.3906/kim-1504-65

Cited by 12 publications

(4 citation statements)

References 22 publications

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“…Enzymes often catalyze transformations that have no analog in the traditional synthetic repertoire and enable new retrosynthetic approaches to complex molecules [35] . For example, 1,2‐amino alcohols have often been formed through ring‐opening of epoxides with an isopropyl amine nucleophile, relying on a pre‐assembled carbon skeleton [36–38] . To show how protecting group free biocatalysis can enable new disconnections, we completed the synthesis of some well‐known β‐blockers.…”

Section: Resultsmentioning

confidence: 99%

“…[35] For example, 1,2-amino alcohols have often been formed through ring-opening of epoxides with an isopropyl amine nucleophile, relying on a pre-assembled carbon skeleton. [36][37][38] To show how protecting group free biocatalysis can enable new disconnections, we completed the synthesis of some well-known β-blockers. Such molecules have been clinically used as racemic mixtures and the biologically active isomers have been identified as the Risomers.…”

Section: Forschungsartikelmentioning

confidence: 99%

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Engineering Enzyme Substrate Scope Complementarity for Promiscuous Cascade Synthesis of 1,2‐Amino Alcohols

et al. 2022

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Biocatalytic cascades are uniquely powerful for the efficient, asymmetric synthesis of bioactive compounds. However, high substrate specificity can hinder the scope of biocatalytic cascades because the constituent enzymes may have non-complementary activity. In this study, we implemented a substrate multiplexed screening (SUMS) based directed evolution approach to improve the substrate scope overlap between a transaldolase (ObiH) and a decarboxylase for the production of chiral 1,2-amino alcohols. To generate a promiscuous cascade, we engineered a tryptophan decarboxylase to act efficiently on β-OH amino acids while avoiding activity on L-threonine, which is needed for ObiH activity. We leveraged this exquisite selectivity with matched substrate scope to produce a variety of enantiopure 1,2-amino alcohols in a one-pot cascade from aldehydes or styrene oxides. This demonstration shows how SUMS can be used to guide the development of promiscuous, CÀ C bond forming cascades.

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Section: Resultsmentioning

confidence: 99%

Section: Forschungsartikelmentioning

confidence: 99%

Engineering Enzyme Substrate Scope Complementarity for Promiscuous Cascade Synthesis of 1,2‐Amino Alcohols

et al. 2022

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“…34 For example, 1,2amino alcohols have often been formed through ring-opening of epoxides with an isopropyl amine nucleophile, relying on a pre-assembled carbon skeleton. [35][36][37] To show how protecting group free biocatalysis can enable new disconnections, we completed the synthesis of some well-known β-blockers. Such molecules have been clinically used as racemic mixtures and the biologically active isomers have been identified as the R-isomers.…”

Section: Rgntdcmentioning

confidence: 99%

Engineering enzyme substrate scope complementarity for promiscuous cascade synthesis

McDonald

Bruffy

Kasat

et al. 2022

Preprint

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Biocatalytic cascades are uniquely powerful for the efficient, asymmetric synthesis of bioactive compounds. The high specificity of enzymes can enable one-pot reactions where the substrates, intermediates, and products react only with the intended enzyme. However, this same specificity can hinder the substrate scope of biocatalytic cascades because each constituent enzyme requires complementary activity. Here, we implement a substrate multiplexed screening (SUMS) approach to improve the substrate scope overlap of a two-enzyme cascade via directed evolution. This cascade leverages an L-threonine transaldolase, ObiH, to produce a range of β-OH amino acids that are subsequently decarboxylated to produce chiral 1,2-amino alcohols. Crucially, for the success of this cascade, we engineered a tryptophan decarboxylase to act efficiently on β-OH amino acids while avoiding activity on L-threonine, which is needed for ObiH activity. We leverage this exquisite selectivity with matched substrate scopes to produce a variety of chiral 1,2-amino alcohols in a one-pot cascade from aldehydes or styrene oxides. This route constitutes a new disconnection for the synthesis of β-adrenergic receptor agonists and shows how SUMS can be used to guide the development of promiscuous, C-C bond forming cascades.

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“…Although pronethalol exerted marked pharmacodynamic effects, its clinical use was abandoned due to its carcinogenicity detected in mice [31]. In more recent literature, pure enantiomers of these substances have been prepared by stereoselective synthesis or preparative enantioseparation and studied separately [32,33]. From the arylaminoethanol group of β-blockers, sotalol and labetalol are still in clinical use (Figure 2.).…”

Section: Pronethalolmentioning

confidence: 99%

Survey of Pharmacological Activity and Pharmacokinetics of Selected β-Adrenergic Blockers in Regard to Their Stereochemistry

et al. 2019

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The present survey concentrates on pharmacodynamics and pharmacokinetics of selected β-adrenergic blockers from the point of view of their stereochemistry. It could be shown that the activity in the arylaminoethanol and aryloxyaminopropanol group of β-blockers is higher in their (–)-enantiomers as compared with the (+)-enantiomers. The stereoisomers differ also in other types of bioactivity as well as in toxicity. The particular pharmacokinetic stages such as resorption, distribution, and metabolism are discussed in regard to their stereochemistry.

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Synthetic approaches towards the synthesis of beta-blockers (betaxolol, metoprolol, sotalol, and timolol)

Cited by 12 publications

References 22 publications

Engineering Enzyme Substrate Scope Complementarity for Promiscuous Cascade Synthesis of 1,2‐Amino Alcohols

Engineering Enzyme Substrate Scope Complementarity for Promiscuous Cascade Synthesis of 1,2‐Amino Alcohols

Engineering enzyme substrate scope complementarity for promiscuous cascade synthesis

Survey of Pharmacological Activity and Pharmacokinetics of Selected β-Adrenergic Blockers in Regard to Their Stereochemistry

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