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Biocatalytic Approaches to Optically Active β-Blockers

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Abstract:

Beta-blockers are a very important group of drugs widely used for the treatment of cardiovascular diseases. All aryloxyaminopropanols are chiral and show different stereoselectivity in their pharmacodynamic and pharmacokinetic properties for each enantiomer. The more potent beta-adrenoceptor blocking activity is generally associated with (S)-enantiomers. Most beta-blocking agents are sold as racemates although (R)- enantiomers not only show in some cases lack of activity but might be responsible for undesirable effects.

Among reports on the direct enzymatic resolution of the most representative beta-blocker propranolol, the most interesting is N-acetylation method with commercially available lipases to yield (S)-Nacetylpropranolol. Another type of the one-step (S)-isomer biocatalytic preparation from racemic mixture of propranolol is the biodegradation with the fungus.

Biocatalytic methods of obtaining homochiral beta-blockers that are focused on production of versatile precursors are widely described in literature. The strategies based on the use of glycidol and derivatives as C-3 synthones have been shown to be extremely useful for the introduction of the 2-propanol chain on the aromatic system.

Halohydrins are the established intermediates in the preparation of optically active beta-blockers. Its resolution by esterhydrolases has been used as a standard alternative in preparation of the homochiral propranolol. Additionally, the enzymatic resolution of the following intermediates was reported: 1-azido-3- aryloxy-2-propanols, 4-(1-aryloxy)-3-hydroxybutyric acid esters, glycerol and cyanohydrin derivatives. However, even the highly enantioselective lipase-catalyzed process can only provide 50% of the starting racemate in an optically active form. An alternative method such as a reduction of a prochiral ketone by various strains of yeast might quantitatively provide an enantiomeric product with a yield greater than 50%. The reported substrates for microbial reductions were: 1-halo-aryloxypropan-2-ones and 1-acetoxyaryloxypropan- 2-ones.

Keywords: Enantiopure beta-blockers; biotransformations; chiral building blocks; enantioselectivity; hydrolases; kinetic resolution of beta-blockers; lipases; stereoselective reductions

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986707779313480

Affiliations: Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University;Medyczna 9; 30-688 Krakow; Poland.

Publication date: January 1, 2007

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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