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Cipargamin: Biocatalysis in the Discovery and Development of an Antimalarial Drug
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Thomas Ruch, Elina Siirola, Radka Snajdrova
In order to understand the structure-activity-relationship (SAR) of the different diastereoisomers, a chiral synthesis was pursued. In this route, the same starting material—fluoro, chloroindole 1 was converted into the corresponding N-acetyl protected tryptophan derivative 8 (Scheme 15.3). Unfortunately, the stereochemistry of the serine is not conserved during the electrophilic aromatic substitution of 1 resulting in racemic 8 (Blaser et al., 2008). Racemic 8 was submitted for enzymatic screening in an attempt to access the desired enantiomer via kinetic resolution. From the screening experiment, L-aminoacylase from a commercial source offered the best results, in terms of enantioselectivity and efficiency of the resolution, yielding (R) N-acetyl protected tryptophan 8 in >99% ee while the (S) enantiomer was hydrolyzed (Hua et al., 2009). The efficiency of enzymatic resolution provided a high yield (48%) and high enantioselectivity. Despite achieving a successful preparation of the chiral intermediate, the route suffered from a low overall yield (1.7%). This was mainly due to the additional steps required to convert (R)-9 into (S)-tryptamine S-4 and the necessity to introduce additional chromatography purification steps (Scheme 15.3). Chiral synthesis of Cipargamin (KAE609) during its drug discovery phase. Chiral material was obtained via kinetic resolution with l-aminoacylase. Fluoro, chloroindole 1 was converted into the corresponding N-acetyl protected tryptophan derivative 8. Kinetic resolution with L-aminoacylase yielded the enantiomerically pure (R)-N-acetyl protected tryptophan 9 while the (S)-enantiomer was hydrolyzed. In a three step sequence the acetyl group was cleaved off with 6M hydrochloric acid, the methyl ester was formed with thionylchloride/methanol and the amine was Boc protected by reaction with Boc2O, leading to a 31% yield of 10. In subsequent steps, the ester was reduced to the alcohol with LiAlH4, activated as a mesylate with MesCl and reduced to a methyl group with LiAlH4. Final Boc deprotection with 6M HCl in methanol led to the enantiomerically pure (S)-amine S-4. Acid catalyzed Pictet-Spengler reaction with 5-chloroisatin led to Cipargamin (KAE609) with an ee of 95.6%.
Serum concentrations of aminoacylase 1 in schizophrenia as a potential biomarker: a case-sibling-control study
Published in Nordic Journal of Psychiatry, 2022
Diğdem Göverti, Rabia Nazik Yüksel, Hasan Kaya, Nihan Büyüklüoğlu, Çiğdem Yücel, Erol Göka
Aminoacylase 1 (ACY1; EC 3.5.1.14) is a homodimeric, cytosolic, zinc-metalloprotein, and endogenous mammalian enzyme that has a role in the catabolism of N-terminally acetylated proteins and amino acids by proteolytic degradation [5]. It hydrolyses N-acetylated derivates of methionine, glutamine, serine, alanine, glycine, leucine, and valine apart from N-acetyl-L-aspartate catalyzed by Aminoacylase 2 (EC 3.5.1.15) [6,7]. ACY1, also identified as a risk locus at schizophrenia and bipolar disorder, is encoded by chromosome 3p.21 and expressed by various tissue, particularly the brain and kidney [8,9]. Moreover, it regulates the function of the sphingosine kinase 1 enzyme defined with mitogenic and cytoprotective effects on cells [10].