Natalia Kocot, Rafał Mastalerz, Jacek Dulęba, Tomasz Siódmiak, Michał Piotr Marszałł
Chiral drugs – a standard or a challenge for modern pharmacy? Considerations on selected derivatives of 2-arylpropionic acid
2022-03-25
The US Food and Drug Administration (FDA) issued a statement in 1992, which drew attention to the importance of chiral drugs. Enantiomers, which are optical isomers of a molecule with a stereogenic center, most often have different pharmacological and toxicological profiles. Optically active drugs can be obtained and commercially available as single enantiomers or as equimolar mixtures thereof, i.e. racemates.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that act as anti-inflammatory, analgesic, and antipyretic drugs. 2-arylpropionic acid derivatives belonging to this group, have a stereogenic center, and their therapeutic activity results mainly from the action of the S-enantiomer. It should be noted that the second enantiomer - (R) is often considered to be a compound that increases side effects, including those affecting gastrointestinal tract, liver and kidneys. It is worth noting that studies on the therapeutic activity of (R) -flurbiprofen have shown its antinociceptive and anticancer properties.
An important phenomenon characteristic of 2-arylpropionic acid derivatives is metabolic chiral inversion. The result for these metabolic transformations is the transformation of the R-enantiomer into the S-enantiomer. It has been documented that (R) -ibuprofen succumbs to it to the greatest extent.
Since the FDA issued a mentioned statement, manufacturing drugs as pure enantiomers has become an important aspect for the pharmaceutical industry. More attention was paid to studying their fate in the organism and developing methods of their synthesis. Due to the growing role of biocatalysis, which is a part of “green chemistry” trend, an enzymatic kinetic resolution has gained particular importance in obtaining enantiomers of medicinal substances. It takes advantage of enantioselectivity of enzymes that catalyze the reaction of one enantiomer faster than the other. As a result, a mixture is obtained, consisting mainly of the reaction product of one enantiomer and small amounts of the other, and unreacted substrates. In the kinetic resolution of (R,S)-flurbiprofen, one of the most frequently used enzymes is lipase B from Candida antarctica (CALB) – Novozym® 435.
Keywords: enantiomers, biocatalysis, kinetic resolution, chiral drugs, NSAIDs.
© Farm Pol, 2022, 78(1): 29–37