Positional Isomeric Effects on the Optical Properties, Multivalent Glycosidase Inhibition Effect, and Hypoglycemic Effect of Perylene Bisimide–deoxynojirimycin Conjugates

Abstract

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

Amphiphilic α-Peptoid-deoxynojirimycin Conjugate-based Multivalent Glycosidase Inhibitor for Hypoglycemic Effect and Fluorescence Imaging

“…44,45 This was due to the increasing flexibility of the chain, favoring the binding interaction with the active site of the α-glucosidase. This phenomenon has also been found in our previous work 34 and in the multivalent glycosidase inhibitors with α-mannosidase. 44,45 The relative potencies of LP-4DNJ-6C over LP-4DNJ-3C on the glycosidase inhibition constants (K i ) against multisource α-glucosidases from A. niger, rice, and mice were approximately 220-fold, 16-fold, and 5.7-fold, respectively.…”

“…31 Since 2019, multivalent glycosidase inhibitors based on self-assembling 1-deoxynojirimycin derivatives 32,33 targeting α-glucosidases were developed; these inhibitors demonstrate good α-glucosidase inhibition activities in vitro and potent hypoglycemic effects in vivo. The hypoglycemic activities in mice were related to the total hydrogen bond energy 34 and the binding strength between the inhibitors and the α-glucosidases. 35 These findings offer valuable insights for the future design of multivalent drugs targeting hypoglycemia.…”

Design and Synthesis of Sulfonium Derivatives: A Novel Class of α-Glucosidase Inhibitors with Potent In Vivo Antihyperglycemic Activities

“…Three currently approved α-glucosidase inhibitors acarbose, voglibose, and miglitol (Figure ) for hyperglycemia all belong to azasugar or iminosugar derivatives. , These agents can provide moderate therapeutic effects to T2DM while sometimes being associated with gastrointestinal disturbances such as bloating, diarrhea, nausea, liver dysfunction, and skin allergies . Thus, identification of potent α-glucosidase inhibitors with high safety profiles has always been a hot topic for medicinal chemists. − …”

Phosphorus Dendrimers for Metal‐Free Ligation: Design of Multivalent Pharmacological Chaperones against Gaucher Disease

“…Génisson dendrimers, calixarenes, cyclodextrins, cyclopeptides inter alia to generate multivalent glycosidases inhibitors. [7,[19][20][21][22][23][24][25][26] These studies have highlighted the importance of both platform topology and valency on the resulting biological activity. To graft the inhitope onto the surface of the multivalent scaffold, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) remains the preferred reaction.…”