Complexation of syringic and ρ-coumaric acids with zinc(ii) to improve their antidiabetic efficacy

Abstract

Background: The concept of Zn(II) complexation has long been explored as a possible scientific approach to developing potential therapeutic agents for managing impaired glucose tolerance in diabetes. This has been partly due to the safety profile of zinc mineral and its functional role in insulin preservation, secretion and function. Many types of ligands have been explored as suitable ligands to develop potent antidiabetic Zn(II) complexes. However, due to the critical role of oxidative stress in the development and progression of diabetes and vascular complications, the use of polyphenols as alternative ligands for antidiabetic Zn(II) complexes has been explored by scientists. It is perceived that the antioxidant attributes of natural polyphenols may afford a Zn(II) complex an antioxidant perspective in combating diabetic oxidative stress and reducing the risk of diabetic complications. Data from some studies that have complexed zinc with dietary flavonoids support this perception to an appreciable extent. However, natural phenolic acids, which are known dietary antioxidant have been scarcely explored as antioxidant ligands for developing antidiabetic Zn(II) complexes. Therefore, in the present study, p-coumaric acid and syringic acid were used as alternative ligands to develop Zn(II) complexes, due to their promising antioxidant attributes and some other diabetes-related pharmacological attributes.

Methodology: p-Coumaric acid and syringic acid were separately complexed with ZnSO4 in a 1:2 mole ratio, respectively. The complexes were characterized by spectroscopically using FT-IR, proton NMR and high-resolution mass spectroscopy. The cytotoxic effect of the complexes was evaluated in Chang liver cells and L-6 myotubes. The antioxidant and antihyperglycaemic potential of the complex and precursors were evaluated with different experimental models. Molecular docking with target proteins linked to diabetes was performed. The antioxidant and antihyperglycaemic potential of the complexes, relative to their respective precursors were determined using in vitro, cellular and ex vivo experimental models. The complexes and their respective phenolic acids were comparatively docked against protein targets linked to diabetes. The Zn(II) complex of syringic acid was subjected to in vivo antidiabetic and antioxidant study in diabetic rats. Diabetes was induced in SD rats using 10% fructose and 40 mg/kg bw streptozotocin and thereafter subjected to a 4-week treatment with the complex and its precursors (Syringic acid and zinc sulphate) for 4 weeks at predetermined doses. Then, the effect of the treatments on diabetes and oxidative stress related parameters was measured.

Results: Spectroscopic analysis showed the complexes were formed as a double hydrate Zn(II)- biphenolate product [Zn(II)-bicoumarate.2H2O and Zn(II)-bisyringate.2H2O complexes], which each had a moiety of Zn(II) and 2 moieties of their respective phenolic acids. The in vitro radical scavenging, α-glucosidase inhibitory, antiglycation and anti-lipid peroxidative activities of the complexes were several folds stronger than their respective phenolic acids. In Chang liver cells and rat liver tissues, the complexes inhibited lipid peroxidation and GSH depletion, which was notably stronger than their respective phenolic acids and comparable to ascorbic acid. Zn(II) and the phenolic acids synergistically modulated glucose uptake in L-6 myotubes and rat muscle tissue, which may be majorly influenced by to the observed complexation-mediated increase in muscle zinc uptake. Tissue glucose uptake activity of the complexes was accompanied by increased muscle hexokinase activity, suggesting increased glucose utilization. Moreover, treatment increased muscle phospho-Akt/pan-Akt ratio, while the complexes had stronger molecular docking interaction with insulin signalling protein targets (GLUT-4, Akt/PKB, insulin receptor tyrosine kinase and IRS-1) than their respective phenolic acid precursors. The Zn(II)- bisyringate.2H2O complex was more potent than the Zn(II)-bicoumarate.2H2O, thus was subjected to in vivo antidiabetic and antioxidant study in diabetic rats. The complex improved diabetic polyphagia, polydipsia and weight loss. Complexing Zn(II) with syringic acid improved their antihyperglycaemic action by ∼28 – 36% and ∼37 - 40%, respectively, suggesting a complexationmediated synergism. This may be attributed to the observed modulatory action of the complex on insulin secretion and sensitivity, tissue glycogen production, muscle hexokinase activity and Akt phosphorylation, thus improving glucose tolerance in diabetic rats, relative to its precursors. Concomitantly, the complex reduced systemic and tissue lipid peroxidation and increased antioxidant enzymes activity in the diabetic rats, while outperforming its precursors. In some cases, the antidiabetic action of the complex was comparable to metformin. The molecular properties of the complexes (i.e., the Zn(II) and biphenolate moieties) appears to be influential in the improved bioactivities of the complexes relative to their respective precursors, suggesting a complexation mediated synergistic potential.

Conclusion: Complexing Zn(II) with these phenolic acids (p-coumaric and syringic acid) may be an underexplored therapeutic approach to improving the effectiveness of therapies for diabetes and oxidative stress management.