Novel Caffeic Acid - Zinc Acetate Complex: Studies on Promising Antidiabetic and Antioxidative Synergism Through Complexation.

BACKGROUND: The role of Zn(II) in storage, insulin secretion and function has been documented, while plant phenolics have antioxidant and other pharmacological credence. OBJECTIVE: The study aimed at synthesizing a novel medicinal Zn(II) complex. The medicinal properties of zinc(II) and caffeic acid were considered in synthesizing a novel complex with promising and improved antioxidant and anti-hyperglycaemic attributes. METHODS: Complex synthesis was done using a 1:2 molar ratio of zinc acetate and caffeic acid and structurally characterized using NMR, FT-IR, high resolution-mass spectroscopy and HPLC. Its cellular toxicity was assessed in Chang liver cells and L-myotubes. In vitro, cellular, and isolated tissue models were used to evaluate the antioxidant and anti-hyperglycaemic properties of the complex relative to its precursors. Molecular docking was used to investigate the interaction with insulin signalling target proteins: GLUT-4 and protein kinase B (Akt/PKB). RESULTS: Zinc(II) and caffeic acid interacted via Zn:O4 coordination, with the complex having one moiety of Zn(II) and 2 moieties of caffeic acid. The complex showed in vitro radical scavenging, α- glucosidase and α-amylase inhibitory activity up to 2.6 folds stronger than caffeic acid. The ability to inhibit lipid peroxidation (IC50 = 26.4 µM) and GSH depletion (IC50 = 16.8 µM) in hepatocytes was comparable to that of ascorbic acid (IC50 = 24.5 and 29.2 µM) and about 2 folds stronger than caffeic acid. Complexation improved glucose uptake activity of caffeic acid in L-6 myotubes (EC50 = 23.4 versus 169 µM) and isolated rat muscle tissues (EC50 = 339 versus 603 µM). Molecular docking showed better interaction with insulin signalling target proteins (GLUT-4 and Akt/PKB) than caffeic acid. The complex was not hepatotoxic or myotoxic. CONCLUSION: Data suggest a synergistic antioxidant and anti-hyperglycaemic potential between zinc and caffeic acid, which could be attributed to the Zn:O4 coordination. Thus, it may be of medicinal relevance.

Bioactive synergism between zinc mineral and p-coumaric acid: A multi-mode glycemic control and antioxidative study.

Natural supplements are important in diabetes and oxidative stress management. A complexation-mediated antihyperglycemic and antioxidant synergism between zinc(II) and p-coumaric acid was investigated. p-Coumaric acid was complexed with ZnSO4 and characterized by FT-IR, 1 H NMR, and mass spectroscopy. The antioxidant and antihyperglycemic potential of the complex and precursors were evaluated with different experimental models. Molecular docking with target proteins linked to diabetes was performed. A Zn(II)-bicoumarate.2H2 O complex was formed. The in vitro radical scavenging, α-glucosidase inhibitory, antiglycation, and anti-lipid peroxidative activities of the complex were several folds stronger than p-coumaric acid. In Chang liver cells and rat liver tissues, the complex inhibited lipid peroxidation (IC50  = 56.2 and 398 µM) and GSH depletion (IC50  = 33.9 and 38.7 µM), which was significantly stronger (2.3-5.4-folds) than p-coumaric acid and comparable to ascorbic acid. Zn(II) and p-coumaric synergistically modulated (1.7- and 2.8-folds than p-coumaric acid) glucose uptake in L-6 myotubes (EC50  = 10.7 µM) and rat muscle tissue (EC50  = 428 µM), which may be linked to the observed complexation-mediated increase in tissue zinc uptake. Glucose uptake activity was accompanied by increased hexokinase activity, suggesting increased glucose utilization. Docking scores α-glucosidase, GLUT-4, and PKB/Akt showed stronger interaction with the complex (-6.31 to -6.41 kcal/mol) compared to p-coumaric acid (-7.18 to -7.74 kcal/mol), which was influenced by the Zn(II) and bicoumarate moieties of the complex. In vitro, the complex was not hepatotoxic or myotoxic. Zn(II) complexation may be a therapeutic approach for improving the antioxidative and glycemic control potentials of p-coumaric acid. PRACTICAL APPLICATIONS: In functional medicine, natural supplements, plant-derived phenolics, and nutraceuticals are becoming popular in the management of diseases, including diabetes and oxidative stress. This has been largely attributed to their perceived holistic medicinal profile and the absence of notable toxicity concerns. In the past two decades, considerable attention has been drawn toward zinc mineral as a possible therapeutic supplement for diabetes due to its role in insulin secretion and reported insulin mimetic potentials. p-Coumaric acid is a known natural antioxidant with reported diabetes-related pharmacological effects. In this study, we took advantage of these properties and complexed both natural supplements, which resulted in a more potent nutraceutical with improved glycemic control and antioxidant potential. The complexation-mediated synergistic interaction between zinc and p-coumaric acid could be an important therapeutic approach in improving the use of these natural supplements or nutraceuticals in managing diabetes and associated oxidative complications.

Complexation potentiated promising anti-diabetic and anti-oxidative synergism between ZN(ii) and ferulic acid: A multimode study.

AIM: This study was done to investigate the anti-diabetic and anti-oxidative synergism between zinc(II) and ferulic acid through complexation. METHODS: Zinc sulphate was complexed with ferulic acid in a 1:2 molar ratio. The complex was characterized using Fourier-transform infrared spectroscopy, proton NMR and high-resolution mass spectroscopy techniques and evaluated for cellular toxicity. In silico, in vitro, cell-based and tissue experimental models were used to test the anti-diabetic and anti-oxidant activities of the complex relative to its precursors. RESULTS: A zinc(II)-biferulate.2H2 O complex was formed. The in vitro radical scavenging, anti-lipid peroxidative and α-glucosidase and α-amylase inhibitory activity of the complex was 1.7-2.1 folds more potent than ferulic acid. Zn(II) complexation increased the anti-glycation activity of ferulic acid by 1.5 folds. The complex suppressed lipid peroxidation (IC50  = 48.6 and 331 µM) and GHS depletion (IC50  = 33.9 and 33.5 µM) in both Chang liver cells and isolated rat liver tissue. Its activity was 2.3-3.3 folds more potent than ferulic acid and statistically comparable to ascorbic acid. Zn(II) complexation afforded ferulic acid improved glucose uptake activity in L-6 myotube (EC50  = 11.7 vs. 45.7 µM) and isolated rat muscle tissue (EC50  = 501 and 1510 µM). Complexation increased muscle tissue zinc(II) uptake and hexokinase activity. Docking scores of the complex (-7.24 to -8.25 kcal/mol) and ferulic acid (-5.75 to 6.43 kcal/mol) suggest the complex had stronger interaction with protein targets related to diabetes, which may be attributed to the 2 ferulic acid moieties and Zn(II) in the complex. Moreover, muscle tissue showed increased phospho-Akt/pan-Akt ratio upon treatment with complex. The complex was not hepatotoxic and myotoxic at in vitro cellular level. CONCLUSION: Zn(II) complexation may be promising therapeutic approach for improving the glycaemic control and anti-oxidative potential of natural phenolic acids.

Vanillic acid-Zn(II) complex: a novel complex with antihyperglycaemic and anti-oxidative activity.

OBJECTIVES: Our aim was to synthesize, characterize and evaluate the antihyperglycaemic and anti-oxidative properties of a new Zn(II) complex of vanillic acid. METHODS: The complex was synthesized using ZnSO4.7H2O and vanillic acid as precursors. NMR and FTIR techniques were used to characterize the synthesized complex. The cytotoxicity of the complex was measured. The antihyperglycemic and anti-oxidative properties of the complex were evaluated using in vitro, cell-based and ex vivo models and compared with those of its precursors. KEY FINDINGS: Zn(II) coordinated with vanillic acid via a Zn(O6) coordination, with the complex having three moieties of vanillic acid. The radical scavenging, Fe3+ reducing and hepatic antilipid peroxidative activity of the complex were, respectively, 2.3-, 1.8- and 9.7-folds more potent than vanillic acid. Complexation increased the α-glucosidase and glycation inhibitory activity of vanillic acid by 3- and 2.6-folds, respectively. Zn(II) conferred potent L-6 myotube (EC50 = 20.4 µm) and muscle tissue (EC50 = 612 µm) glucose uptake effects on vanillic acid. Cytotoxicity evaluation showed that the complex did not reduce the viability of L-6 myotubes and Chang liver cells. CONCLUSIONS: The data suggest that Zn(II)-vanillic acid complex had improved bioactivity relative to vanillic acid. Thus, Zn(II) may be further studied as an antihyperglycaemic and anti-oxidative adjuvant for bioactive phenolic acids.

Zinc(II) mineral increased the in vitro, cellular and ex vivo antihyperglycemic and antioxidative pharmacological profile of p-hydroxybenzoic acid upon complexation.

In this study, zinc was complexed with p-hydroxybenzoic acid to synthesize a complex with improved pharmacological profile. Proton NMR and FTIR analysis were used to characterize the complex. Several in vitro, cellular and ex vivo antihyperglycemic and antioxidative assays were used to evaluate the potency of the complex, relative to its precursors, while molecular docking was used to investigate interactions with insulin signaling targets (GLUT-4 and PKB). Also, the cytotoxicity of the complex was evaluated in Chang liver cells and L-6 myotubes using MTT assay. Complexation was through a Zn(O4 ) coordination. This afforded the complex two moieties of p-hydroxybenzoic acid, which influenced its activities. While the complex retained the α-glucosidase and α-amylase inhibitory activity of its phenolic acid precursor, complexation increased in vitro and ex vivo antioxidant activity of the phenolic acid by 1.4 to 10.5-folds. Complexation, further, conferred a potent antiglycation activity and L-6 myotube and psoas muscle glucose uptake properties (2.1 to 3.5-folds more than p-hydroxybenzoic acid) on the phenolic acid, without notably inhibiting or reducing the viability of Chang liver cells (IC50  = 5,120 µM) and L-6 myotubes (IC50  = 2,172 µM). Docking studies showed the complex had better interactions with insulin signaling targets (GLUT-4 and PKB) than p-hydrobenzoic acid, which may influence its glucose uptake effects. Data suggest that Zn(II) complexation improved and/or broadened the pharmacological profile of p-hydroxybenzoic acid, thus, may be further studied as a promising adjuvant for phenolic acids. PRACTICAL APPLICATIONS: Most antidiabetic drugs are used as two or more combinations to achieve better efficacy, which may cause drug interaction and increase the risk of side effects associated with these drugs. This study takes advantage of the glycemic control property of zinc and the antioxidant and/or diabetes-related pharmacological properties of p-hydroxybenzoic acid to form a complex with improved and broader antioxidant and antihyperglycemic profile and minimal toxicity concerns. With appropriate further studies, Zn(II)-phenolic acid complexes may be safe nutraceuticals for diabetes and related oxidative complications.

Analysis of Commercial Proanthocyanidins. Part 6: Sulfitation of Flavan-3-Ols Catechin and Epicatechin, and Procyanidin B-3.

Proanthocyanidins (PACs) are natural plant-derived polymers consisting of flavan-3-ol monomers. Quebracho (Schinopsis lorentzii and balansae) heartwood and mimosa (Acacia mearnsii) bark extracts are the major industrial sources of PACs. These commercial extracts are often sulfited to reduce their viscosity and increase their solubility in water. The chemical process of sulfitation is still poorly understood regarding stereochemical influences during the reaction and during the cleavage of the interflavanyl bond of oligomers. To gain a better understanding of sulfitation, two diastereomeric flavan-3-ol monomers were sulfited under industrial conditions, and procyanidin B-3 (catechin-4α→8-catechin) were sulfited to investigate interflavanyl bond cleavage with sulfitation at C-4. Treatment of diastereomeric flavan-3-ols 2R,3S-catechin and 2R,3R-epicatechin with NaHSO3 at 100 °C in aqueous medium afforded the enantiomeric (1R,2S)- and (1S,2R)-1-(3,4-dihydroxyphenyl)-2-hydroxy-3-(2,4,6-trihydroxyphenyl)propane-1-sulfonic acid, respectively. Utilizing computational NMR PD4 calculations it was determined that the direction of stereoselective nucleophilic attack is controlled by the C-3 configuration of the flavan-3-ols catechin and epicatechin. Sulfitation of the catechin-4α→8-catechin dimer 7 (procyanidin B-3) under the same conditions led to the cleavage of the interflavanyl bond yielding the C-4 sulfonic acid substituted catechin momomer. From the heterocyclic ring coupling constants it was determined that nucleophilic attack occurs from the ß-face of the dimer leading to the 2,3-trans-3,4-cis isomer as product.

Synthesis, characterization, antidiabetic and antioxidative evaluation of a novel Zn(II)-gallic acid complex with multi-facet activity.

OBJECTIVES: This study was done to synthesize a novel Zn(II)-gallic acid complex with improved antidiabetic and antioxidative properties. METHODS: The complex was synthesized and characterized using Fourier Transform Infrared (FT-IR) and 1 H NMR. Cytotoxicity was evaluated using Chang liver cells and L6 myotubes. Radical scavenging and Fe3+ -reducing, as well as α-glucosidase, α-amylase and glycation inhibitory properties were measured. Glucose uptake was measured in L6 myotubes, while the complex was docked against glucose transporter type 4 (GLUT-4) and protein kinase B (PKB). KEY FINDINGS: Analysis showed that complexation occurred through a Zn(O4 ) coordination; thus, the complex acquired two moieties of gallic acid, which suggests why complexation increased the DPPH (IC50  = 48.2 µm) and ABTS (IC50  = 12.7 µm) scavenging and α-glucosidase inhibitory (IC50  = 58.5 µm) properties of gallic acid by several folds (5.5, 3.6 and 2.7 folds; IC50  = 8.79, 3.51 and 21.5 µm, respectively). Zn(II) conferred a potent dose-dependent glucose uptake activity (EC50  = 9.17 µm) on gallic acid, without reducing the viability of L6 myotubes and hepatocytes. Docking analysis showed the complex had stronger interaction with insulin signalling proteins (GLUT-4 and PKB) than its precursor. CONCLUSIONS: Data suggest that complexation of Zn(II) with gallic acid resulted in a complex with improved and multi-facet antioxidative and glycaemic control properties.

A comprehensive review on zinc(II) complexes as anti-diabetic agents: The advances, scientific gaps and prospects.

Zinc has gained notable attention in the development of potent anti-diabetic agents, due to its role in insulin storage and secretion, as well as its reported insulin mimetic properties. Consequently, zinc(II) has been complexed with numerous organic ligands as an adjuvant to develop anti-diabetic agents with improved and/or broader scope of pharmacological properties. This review focuses on the research advances thus far to identify the major scientific gaps and prospects. Peer-reviewed published data on the anti-diabetic effects of zinc(II) complexes were sourced from different scientific search engines, including, but not limited to "PubMed", "Google Scholar", "Scopus" and ScienceDirect to identify potent anti-diabetic zinc(II) complexes. The complexes were subcategorized according to their precursor ligands. A critical analysis of the outcomes from published studies shows promising leads, with Zn(II) complexes having a "tri-facet" mode of exerting pharmacological effects. However, the promising leads have been flawed by some major scientific gaps. While zinc(II) complexes of synthetic ligands with little or no anti-diabetic pharmacological history remain the most studied (about 72 %), their toxicity profile was not reported, which raises safety concerns for clinical relevance. The zinc(II) complexes of plant polyphenols; natural ligands, such as maltol and hinokitiol; and supplements, such as ascorbic acid (a natural antioxidant), l-threonine and l-carnitine, showed promising insulin mimetic and glycemic control properties but remain understudied and lack clinical validation, in spite of their minimal safety concerns and health benefits. A paradigm shift toward probing (including clinical studies) supplements, plant polyphenol and natural ligands as anti-diabetic zinc(II) complex is, therefore, recommended. Also, promising anti-diabetic Zn(II) complexes of synthetic ligands should undergo critical toxicity evaluation to address possible safety concerns.

Analysis of commercial proanthocyanidins. Part 5: A high resolution mass spectrometry investigation of the chemical composition of sulfited wattle (Acacia mearnsii De Wild.) bark extract.

Wattle (Acacia mearnsii De Wild., Leguminosae) bark extract is used commercially to tan leather and manufacture adhesives. The extract is treated with sodium hydrogen sulfite (sulfited) to improve its tanning properties. These include reduced viscosity, improved solubility, and better raw skin penetration. High resolution ESIMS allows unambiguous assignment of sulphur-containing monomeric and oligomeric products from sulfitation. It reveals that during sulfitation the constituent flavan-3-ol building blocks are sulfited at both C-2 and C-4 by a sulfite ion. A sulfonic acid moiety is introduced at C-2 to open the pyran ring, and C-4 to cleave the interflavanyl bond and reduce the degree of polymerization, respectively, explaining the improved tanning properties. MS2 fragmentation spectra and comparison with unsulfited extract support the interpretation of peaks and composition of sufited wattle bark extract. It also supports our published work that mimosa bark extract consists of a catechin or gallocatechin starter unit and fisetinidol or robinetinidol extender units.

Synthesis and Bioactivity of Reduced Chalcones Containing Sulfonamide Side Chains.

The effect on the bioactivity of antibacterial sulfonamide drugs against malaria and tuberculosis via an increase of the lipid solubility groups by condensation with a reduced chalcone was investigated. Sulfonamide derivatives (8a-8d) were obtained via a 1,3-diarylpropane scaffold, prepared by reduction of the relevant chalcones, followed by the addition of a sulfonamide moiety via the Mannich and the Mannich exchange reactions. The ClogP values indicated that the lipophilicities of 8a-8d and intermediate reduced chalcones and N-alkylated reduced chalcones (5a-7a) were much higher than those of the sulfonamides (1a-1c). The N-alkylated reduced chalcone derivatives 6 and 7 exhibited the highest antimalarial (Plasmodium falciparum (NF54 strain)) activity. Addition of the sulfonamide group weakened the activity, even though some ClogP values were higher, while 1a-1c showed no activity. The reduced chalcones 5a and 5 showed potent growth inhibition of Mycobacterium tuberculosis (H37Rv strain), but the sulfonamide derivatives 8a and 8d showed no or insignificant activity (0 and 14%, respectively) against M. tuberculosis, despite high ClogP values. Thus, the possible increase in bioactivity expected from an increase in ClogP values (lipophilicity) might be counteracted by the higher molecular weight of the studied analogues.

Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues.

A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1-55) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC50 values similar to or better than chloroquine (CQ). The most active compound (26) had an IC50 value of 0.01 µM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices.