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Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
As mentioned in a previous section, the amidase activity of microorganisms is responsible of the hydrolysis of amides into carboxylic acids, which is a very useful transformation. Alternatively, some microorganisms displayed nitrilases or nitrile hydratase-amidase activities for converting cyano groups in carboxylic acids, representing in some cases an alternative synthetic solution for the production of carboxylic acids. One example is the use of the Rhodococcus rhodochrous SP 361 microorganism from Novozymes, which was able to catalyse the formation of O-protected and unprotected (R)-3-hydroxy-4-cyanobutanoic acids (Scheme 9.18). The results for the desymmetrisation of the dinitriles were highly dependent on the C-2-functionality in terms of activity and selectivity (Kinfe et al., 2009). These compounds are valuable precursors in the synthesis of the blockbuster Atorvastatin, marketed by Pfizer as a calcium salt under the trade name of Lipitor®, drug used as HMG-CoA reductase inhibitor for lowering blood cholesterol preventing cardiovascular diseases. Cyano-converting microorganism for the synthesis of (R)-3-hydroxy-4-cyanobutanoic acid and derivatives through selective nitrile hydrolysis.
Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Michele De Luca, Maria Antonietta Occhiuzzi, Bruno Rizzuti, Giuseppina Ioele, Gaetano Ragno, Antonio Garofalo, Fedora Grande
In this work, we describe in detail the degradation profile of LTZ under different experimental conditions. It is well known that nitrile catabolism can follow two distinct pathways: (1) conversion to carboxylic acid catalysed by nitrilase, and (2) amide formation mediated by nitrile hydratase/amidase. These reactions can be easily reproduced using different hydrolytic chemical conditions14. A further factor leading to LTZ degradation is represented by non-hydrolytic oxidative conditions, when an easy formation of the corresponding 1-(bis(4-cyanophenyl)methyl)-1H-1,2,4-triazole-2-oxide (LNO) is observed. The formation of other minor degradation products has been reported6, but their presence has not been considered here. This study aimed to define the kinetics of the degradation products of LTZ, monitoring them by UV/Vis spectrophotometry and processing the spectral data by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) methodology. This chemometric procedure was used because it is particularly effective in following the chemical transformation processes, allowing to resolve the spectra and concentration profiles of the components involved. An independent HPLC-DAD method was defined to validate the results obtained by the multivariate resolution of the UV kinetic studies. The UV spectra from the HPLC-DAD detector were compared with the spectra predicted by the multivariate procedure, demonstrating a significant overlap of the spectral curves related to the degradation products. Furthermore, docking experiments were performed to verify whether the degradation compounds were able to accommodate in the aromatase active site with binding mode conformation and affinity comparable to the parent drug. To this aim, LTZ and its three main degradation compounds were docked in the crystal structure of aromatase and the results were compared with those obtained for androstenedione (ASD), the endogenous ligand of the enzyme.