Anti-α-Glucosidase and Antiglycation Activities of α-Mangostin and New Xanthenone Derivatives: Enzymatic Kinetics and Mechanistic Insights through In Vitro Studies

Abstract

Diabetes mellitus is characterized by chronic hyperglycemia that promotes ROS formation, causing severe oxidative stress. Furthermore, prolonged hyperglycemia leads to glycation reactions with formation of AGEs that contribute to a chronic inflammatory state. This research aims to evaluate the inhibitory activity of α-mangostin and four synthetic xanthenone derivatives against glycation and oxidative processes and on α-glucosidase, an intestinal hydrolase that catalyzes the cleavage of oligosaccharides into glucose molecules, promoting the postprandial glycemic peak. Antiglycation activity was evaluated using the BSA assay, while antioxidant capacity was detected with the ORAC assay. The inhibition of α-glucosidase activity was studied with multispectroscopic methods along with inhibitory kinetic analysis. α-Mangostin and synthetic compounds at 25 µM reduced the production of AGEs, whereas the α-glucosidase activity was inhibited only by the natural compound. α-Mangostin decreased enzymatic activity in a concentration-dependent manner in the micromolar range by a reversible mixed-type antagonism. Circular dichroism revealed a rearrangement of the secondary structure of α-glucosidase with an increase in the contents of α-helix and random coils and a decrease in β-sheet and β-turn components. The data highlighted the anti-α-glucosidase activity of α-mangostin together with its protective effects on protein glycation and oxidation damage.

Comparative Evaluation of the Antiglycation and Anti-α-Glucosidase Activities of Baicalein, Baicalin (Baicalein 7-O-Glucuronide) and the Antidiabetic Drug Metformin

“…To study the type of interaction between α–glucosidase and baicalein, the plot of enzyme activity ( v ) versus α–glucosidase enzyme concentration was obtained ( Figure 7 C), suggesting a concentration–dependent reversible interaction since all straight lines obtained at different concentrations of baicalein pass through the origin of the axes, and their slope decreased with increasing concentrations of the inhibitor. Previous research showed similar behavior for other natural compounds, for example, luteolin, morin, magnolol, and α–mangostin [ 48 , 50 , 51 , 52 ]. Furthermore, the type of baicalein inhibition was also estimated with Michaelis–Menten and Lineweaver–Burk plots ( Figure 8 A,B) obtained using different substrate concentrations (0.5, 1.0, 1.5 and 2.0 mM p NPG), while maintaining constant enzyme concentration (0.05 µM).…”

“…The inhibitory activity of baicalein and baicalin was studied using the α–glucosidase assay, with p NPG as substrate and acarbose as positive control [ 47 , 48 ]. The absorbance curves were detected during the 60 min reaction between enzyme (0.05 µM) and p NPG (2 mM) alone and in the presence of different concentrations of baicalein (1–100 µM), revealing a concentration-dependent inhibition of enzyme activity ( Figure 7 A).…”

The metabolic and molecular mechanisms of α‑mangostin in cardiometabolic disorders (Review)

“…AGEs are involved in the pathogenesis of diabetes-related complications, including cardiomyopathy, retinopathy and nephropathy (64). At a 25 µM concentration, α-mangostin was found to reduce the production of AGEs (65). In another study, the treatment of mice with STZ-induced diabetes with α-mangostin resulted in decreased glycated hemoglobin levels and reduced key gluconeogenic enzymes fructose-1-6-bisphosphatase and glucose-6-phosphatase lowering glucose production (66).…”

“…The mechanisms through which α-mangostin affects these enzymes remain unknown. However, a recent study investigating α-mangostin and α-glucosidase suggested, that in the presence of α-mangostin, α-glucosidase has a more α-helical secondary structure, making it more compact and decreasing its catalytic activity (65). Acting via these mechanisms, antioxidant enzymes including SOd, GPx, cAT, GSH are increased and oxidative stress markers including MdA and ROS are reduced.…”

Synthesis, characterization, and α‐glucosidase, cholinesterases, and tyrosinase inhibitory effects of axial substituted silicon and peripheral tetra‐substituted copper (II), manganese (III) phthalocyanines

“…The products formed are detected at 405 nm. The change in absorbance is related to the [39] In this work, the results were expressed as inhibition (%) versus concentration and were presented in Table 1. Acarbose was used as a positive control.…”