Enantioselective Conversion of Racemic Sotalol to R(-)-Sotalol by Lipase AP6

Abstract

Most pharmaceutical compounds have asymmetric nature and are optically active. Compounds with one asymmetric centre (chiral centre) would exhibit two enantiomeric forms and among them one is pharmacologically active (eutomer) while the other one contributed side effects or toxic effects or totally inert (distomer) [1] . Hence, current interest is towards development and administration of eutomer instead of its racemic mixture to improve therapeutic efficacy and reduce the unwanted effects due to the distomer [2] . Biocatalysts have excellent selectivity under mild reaction conditions [2] and hence in this study various whole-cell microorganisms like Bacillus subtilis [3] , Escherichia coli [4] , Pseudomonas putida [5] , Sphingomonas paucimobilis [6] , Rhodococcus erythropolis [7] , Streptomyces halstedii [8] , Aspergillus niger [9] , Candida parapsilosis [10] , Geotrichum candida [11] , Rhizopus oryzae [12] , Cunninghamella elegans [13] and Cunninghamella blakesleeana [14] were employed as biocatalysts for the stereo inversion of racemic sotalol to its active enantiomer. However, a limitation for using whole-cell microorganisms as biocatalysts is reduced stereo selectivity due to competition between multiple enzymes of the microorganism for the same substrate [15] . The use of isolated pure enzymes with suitable cofactors as biocatalysts would help overcome this limitation of using whole-cell microorganisms [16] and the reactions catalysed by pure enzymes also serves some other advantages like they are highly selective under mild conditions, more catalytic in nature and environmentally benign [2] . Lipases have great versatility in catalysing different reactions like aminolysis, esterification, transesterification and interesterification. The means followed by lipases to catalyse these reactions can be described as a ping-pong bi-bi mechanism. Accordingly, first step involves nucleophilic attack on the carbonyl group of a drug, which results in acyl-

Effect of Reaction Parameters on the Lipase-Catalyzed Kinetic Resolution of (RS )-Metoprolol

“…were the highest results recorded during the observation.The E (62) value in this study was found to be moderate (i.e., 20-100)(Swetha et al, 2018) when the reaction was catalyzed by free Candida antarctica lipase B and the value was slightly higher than the E value obtained byBarbosa et al (2010), which recorded a value of 57 in Candida antarctica B lipase-catalyzed esterification of (RS)propanolol. The researchers have thus concluded the enol esters (i.e., commonly vinyl acetate) have higher efficiency in organic solvents in esterification due to their high reactivity in serine residues from the catalytic site of lipases (Banoth et al 2015; Barbosa et al 2010; Dwivedee et al 2015; Agustian et al 2016).…”

Enantioselective Resolution of (R,S)-Carvedilol to (S)-(−)-Carvedilol by Biocatalysts

“…There are several advantages for single enantiomer products when compared to their racemates like more selective and comparatively simple pharmacodynamic as well as pharmacokinetic profile, potential for an improved therapeutic index and very less probability for complex drug interactions [1]. Though there are quite a few ways to obtain chiral molecules in commercially pure form like resolution of racemates, chiral pool synthesis, laboratory-invented chiral building blocks, asymmetric synthesis and bio-transformations, no single method is ideal.…”

“…Though there are quite a few ways to obtain chiral molecules in commercially pure form like resolution of racemates, chiral pool synthesis, laboratory-invented chiral building blocks, asymmetric synthesis and bio-transformations, no single method is ideal. Hence combination of biotransformation with chromatographic resolution [1] was employed in the present study. Development of a single enantiomer from a previously marketed racemate is known as chiral switch [2] and there are different new resolution procedures for obtaining pure enantiomer from a racemic mixture with 100% yield, theoretically, like dynamic kinetic resolution, stereoinversion by deracemization, cyclic racemization and enantioconvergent processes, etc.…”