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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
It is well known that inhibitors of intestinal α-glucosidase enzymes promote a delay in the absorption of sugars because of the retard in the final steps of carbohydrate digestion, so that they are useful for reducing postprandial hyperglycemia in diabetes (Derosa and Maffioli, 2012; Campo et al., 2013). These α-glucosidase inhibitors act as glycomimetics, because they bear a certain grade of resemblance to the natural carbohydrates, but the differential part of their structure promotes a blockade of enzymatic action (Ernst and Magnani, 2009). The use of iminosugars (N atom replacing O) (Winchester, 2009; Horne et al., 2011), thiosugars (S instead of O) (Witczak and Culhane, 2005) or carbasugars (ethereal bridge substituted by a methylene) (Mayato et al., 2012) as glycomimetics is a well-developed strategy. More specifically, iminosugars mimics transition state (oxocarbenium) of glycosidases mechanism, due to the nitrogen protonation at physiological pH values (Caines et al., 2007; Winchester, 2009), and we will show some examples of biocatalyzed synthesis of this type of α-glucosidase inhibitors.
Probing the role of an invariant active site His in family GH1 β-glycosidases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Andrea Strazzulli, Giuseppe Perugino, Marialuisa Mazzone, Mosè Rossi, Stephen G. Withers, Marco Moracci
As is the case for the other GH1 β-glycosidases, Ssβ-gly follows the classical retaining reaction mechanism proposed by Koshland. The hydrolysis of the glycosidic bond proceeds through a double displacement via two oxocarbenium-ion-like transition states involving a covalent glycosyl-enzyme intermediate (Figure 1). Catalysis is promoted by a couple of carboxylic acids in the active site working as acid/base nucleophile of the reaction, E206 and E387, respectively. In the first step of the reaction, or glycosylation step, glutamic acid 206 works as an acid donating a proton to the glycosidic oxygen while the nucleophile attacks the anomeric carbon leading to the departure of the aglycone group of the donor and to the formation of a covalent bond between the glycosyl group and E387 of the enzyme. In the second step, the same E206 residue works as a base activating the incoming water molecule that hydrolyses the glycosyl-enzyme intermediate leading to a product with the same anomeric configuration as the substrate.
O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer’s disease and related tauopathies: analysis of the patent literature
Published in Expert Opinion on Therapeutic Patents, 2021
Jose M. Bartolomé-Nebreda, Andrés A. Trabanco, Adriana Ingrid Velter, Peter Buijnsters
The first OGA inhibitor used for in vitro studies was the natural product streptozotocin (STZ, 1, Figure 2) [36,37]. STZ is a modest micromolar inhibitor in vitro with limited applicability due to structure-related toxicities unrelated to its ability to inhibit OGA [38]. PUGNAc [39] (2, Figure 2) is a significantly more potent in vitro inhibitor than STZ. However, its limited selectivity versus lysosomal hexosaminidases [35] has also hampered its wider use. Off-target inhibition of the lysosomal hexosaminidases is undesirable due to the association of these enzymes with the lysosomal storage disorders Tay-Sachs and Sandhoff diseases. Figure 2 depicts a series of fused thiazoline-containing OGA inhibitors designed and inspired by oxazoline intermediate 3. NAG-Thiazoline [40] (4, Figure 2), the first member of the series, is a potent OGA inhibitor but lacks adequate selectivity versus lysosomal hexosaminidases [35]. The introduction of larger substituents on the thiazoline core resulted in a significantly improved selectivity in NButGT [41] (5, Figure 2), especially in Thiamet G [42] (6, Figure 2). Thiamet G is a highly potent and selective inhibitor that additionally possesses the ability to penetrate the blood-brain barrier and is currently the most widely used OGA tool compound. Figure 2 depicts a structurally unrelated OGA inhibitor, GlcNAcstatin C [43] (7), a highly potent and selective tetrahydro-imidazopyridine-containing, picomolar inhibitor. The imidazopyridine core of GlcNAcstatin C is proposed to act as a transition state mimic of the planar oxocarbenium ion-like OGA transition state, which could explain this compound’s high potency[43]. Noteworthy is the publication of iminocyclitol derivative 8, a potent, orally available and brain-penetrant OGA-inhibitor. [44]