Insulinomimetic Activity Research Articles

Hypoglycemic Effect of Nelumbo Nucifera Seed Extract on GLUT-4 mRNA and GLUT-4 Protein in Streptozotocin-Induced Diabetic Rats.

To investigate the effect of N. nucifera hydroalcoholic seed extract on fasting blood glucose (FBG) levels, glucose transporter (GLUT)-4 mRNA, and GLUT-4 protein in the adipose tissue of streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley (SD) rats were first fed with a high-fat diet (HFD) for three weeks, and then, diabetes was induced by intraperitoneal injection of STZ at a dose of 35 mg/kg bw. Rats were divided into four groups: group 1: normal rats (NC), group 2: STZ-induced diabetic rats (DC), group 3: diabetic rats with N. nucifera hydroalcoholic seed extract at a dose of 400 mg/kg bw (NN), and group 4: diabetic rats with metformin at a dose of 100 mg/kg bw (MET) for 28 days. FBG level was significantly lower in the NN group than in the DC group (P < 0.05). Also, the NN group increased GLUT-4 mRNA expression and GLUT-4 protein in the adipose tissue when compared to the diabetic group. We conclude that the observed hypoglycemic effect of N. nucifera seed extraction in STZ-induced diabetic rats could be due to insulinomimetic activity.

Инсулиномиметически активные макромолекулярные металлокомплексы ванадия на основе поли-N-винилпирролидона. Часть 2. Оценка гипогликемической активности макромолекулярного металлокомплекса ванадия

In a previous work, a method for the synthesis of a new metal-polymer complex of oxovanadium (IV) based on poly-N-vinylpyrrolidone was described, its structure was studied by spectral methods, and its composition was determined. Based on the data of electronic and vibrational spectroscopy, it was shown that the complex is formed due to the interaction of the metal with nitrogen and oxygen atoms of the polymer lactam ring, it should be noted that this type of interaction can occur both by intramolecular or intermolecular coordination. Using the Prozorovsky’s express method for estimation of acute oral toxicity the median value of LD50 of the synthesized complex was determined and it amounted to 1350 ± 160 mg/kg. The obtained LD50 value allow to attribute this metal-polymer complex to the class of low-toxic substances, which opens up some prospects for its further research on insulinomimetic activity. The aim of this work is to investigate the hypoglycemic activity of new polymer derivatives of vanadyl (VO2+) based on poly-N-vinylpyrrolidone (PVP) and to explore the possibility of using these compounds or compositions based on them for the prevention and treatment of type 2 diabetes. The work describes a method for creating an experimental model of type 2 diabetes mellitus in animals, combining the use of a high-fat diet and streptozotocin as a diabetogenic agent. The results of evaluating the effect of the studied metal-polymer complexes on such indicators of carbohydrate metabolism of laboratory animals as changes in blood glucose and urine, change daily diuresis of animals during treatment. The results of evaluating the effect of the metal-polymer complexes on such indicators of carbohydrate metabolism in laboratory animals as a change in blood and urine glucose, a change in the daily diuresis of animals during and after treatment are presented. The investigation of the effect of the obtained vanadium compounds on carbohydrate indices was carried out using metformin as a comparison drug. It was found that the new metal-polymer complexes of vanadium have hypoglycemic activity, normalizing the blood glucose level of laboratory animals with high-fat diet/ streptozotocin induced diabetes.

Potentiation of adipogenesis and insulinomimetic effects of novel vanadium complex (N'-[(E)-(5-bromo-2-oxophenyl)methylidene]-4-methoxybenzohydrazide)oxido(1,10-phenanthroline)vanadium(IV) in 3T3-L1 cells

The latest results in action of vanadium compounds show important influence on adipogenesis processes and adipocytes function. Based on previously screening tests in cellular models the novel vanadium complex (N'-[(E)-(5-bromo-2-oxophenyl)methylidene]-4-methoxybenzohydrazide)oxido(1,10-phenanthroline)vanadium(IV) was selected for this study. This complex shown potent inhibition ability of tyrosine phosphatases and differences in the degree of inhibition particular phosphatases was observed. Significantly increasing of intracellular lipid accumulation and proliferative effect on 3T3-L1 preadipocytes confirmed the ability of this complex to enhancement of adipogenesis. The insulinomimetic activity of the tested complex was also demonstrated in fully differentiated 3T3-L1 adipocytes, in which glucose utilization was potentiated. Presented results support the thesis that vanadium complexes show promising possibilities for opportunities of new therapeutic strategies for the treatment of type 2 diabetes involved adipocytes.

Insulinomimetic Effect of Citrullus Colocynthis Roots in STZ Challenged Rat Model

Abstract Diabetes mellitus is a metabolic disease characterized by hyperglycemia resulting from either defect in insulin secretion, insulin action, or both. Postprandial hyperglycemia is a prime characteristic of diabetes mellitus and has been a focus in the therapy for diabetes. One of the therapeutic approaches which involve decreasing hyperglycemia aims at lowering blood glucose by decreasing insulin resistance, raising insulin sensitivity at the tissues and inhibiting the carbohydrate absorbance in the intestine. Plants contain different chemical constituents with potential for insulin mimetic action, decrease in insulin resistance and of α-amylase inhibitory activity may be used as therapeutic agents in the treatment of diabetes mellitus. The present study investigates the hypoglycemic activity and insulinomimetic action of aqueous and ethanolic extracts of Citrullus colocynthis by invitro α-amylase enzyme inhibition and by histopathological studies in streptozotocin (STZ) induced diabetic rats. Male Wistar rats weighing about 180- 250g were taken and divided into fifteen groups. Diabetes was induced by giving streptozotocin (STZ) (30-50mg/kg) intraperitoneally. Rats that showed blood glucose levels > 250mg/dl were selected for the study. Metformin (45mg/kg) was given as standard oral hypoglycemic agent. The aqueous and ethanolic extracts of Citrullus colocynthis (AECC and EECC) at 100mg/kg, 200mg/kg and 300mg/kg were administered to the normal and diabetic rats. The invitro α – amylase inhibitory activity was done by spectrophotometric method. Blood glucose levels were measured by glucose oxidase method. Estimation of glycogen in the lever was carried out with anthrone method. Liver and pancreas were isolated and subjected to histopathological studies. Serum insulin was monitored through chemiluminescence assay. Oral administration of both extracts showed significant inhibition of α-amylase enzyme in-vitro and decrease in blood glucose also. Glycogen and Insulin levels too were found to increase in extract treated groups which attributed for its insulinomimetic activity. The findings revealed that Citrullus colocynthis possess a very strong anti-hyperglycemic potential justifying the use of the drug for the treatment of diabetes mellitus.

Investigation of Biodistribution and Speciation Changes of Orally Administered Dual Radiolabeled Complex, Bis(5-chloro-7-[131I]iodo-8-quinolinolato)[65Zn]zinc.

Many zinc (Zn) complexes have been developed as promising oral antidiabetic agents. In vitro assays using adipocytes have demonstrated that the coordination structures of Zn complexes affect the uptake of Zn into cells and have insulinomimetic activities, for which moderate stability of Zn complexes is vital. The complexation of Zn plays a major role improving its bioavailability. However, investigation of the speciation changes of Zn complexes after oral administration is lacking. A dual radiolabeling approach was applied in order to investigate the speciation of bis(5-chloro-7-iodo-8-quinolinolato)zinc complex [Zn(Cq)2], which exhibits the antidiabetic activity in diabetic mice. In the present study, 65Zn- and 131I-labeled [Zn(Cq)2] were synthesized, and their biodistribution were analyzed after an oral administration using both invasive conventional assays and noninvasive gamma-ray emission imaging (GREI), a novel nuclear medicine imaging modality that enables analysis of multiple radionuclides simultaneously. The GREI experiments visualized the behavior of 65Zn and [131I]Cq from the stomach to large intestine and through the small intestine; most of the administered Zn was transported together with clioquinol (5-chloro-7-iodo-8-quinolinol) (Cq). Higher accumulation of 65Zn for [Zn(Cq)2] than ZnCl2 suggests that the Zn associated with Cq was highly absorbed by the intestinal tract. In particular, the molar ratio of administered iodine to Zn decreased during the distribution processes, indicating the dissociation of most [Zn(Cq)2] complexes. In conclusion, the present study successfully evaluated the speciation changes of orally administered [Zn(Cq)2] using the dual radiolabeling method.

Vanadium and zinc complexes of 5-cyanopicolinate and pyrazine derivatives: synthesis, structural elucidation and in vitro insulino-mimetic activity study

Inhibition of free fatty acid release from rat adipocytes was observed for vanadium(iv), vanadium(v) and zinc(ii) complexes.

GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products.

The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes and, recently, of obesity. The insulinotropic activity of the native incretin hormone GLP-1(7-36)amide, which is mainly exerted through a unique G protein-coupled receptor (GLP-1R), is terminated via enzymatic cleavage by dipeptidyl peptidase-IV that generates a C-terminal GLP-1 metabolite GLP-1(9-36)amide, the major circulating form in plasma. GLP-1(28-36)amide and GLP-1(32-36)amide are further cleavage products derived from GLP-1(7-36)amide and GLP-1(9-36)amide by the action of a neutral endopeptidase known as neprilysin. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive. However, emerging evidence indicates that GLP-1 byproducts have insulinomimetic activities that may contribute to the pleiotropic effects of GLP-1 independently of the canonical GLP-1R. The recent studies reporting the beneficial effects of the administration of these metabolites in vivo and in vitro are the focus of this review. Collectively, these results suggest that GLP-1 metabolites inhibit hepatic glucose production, exert antioxidant cardio- and neuroprotective actions, reduce oxidative stress in vasculature and have both anti-apoptotic and proliferative effects in pancreatic β-cells, putatively by the modulation of mitochondrial functions. These findings have implication in energy homeostasis, obesity and its associated metabolic and cardiovascular complications as well as incretin-based therapies for the treatment of diabetes and obesity.

Molecular evidence of insulinomimetic property exhibited by steviol and stevioside in diabetes induced L6 and 3T3L1 cells

BackgroundThe defective responsiveness of body tissues to insulin involves the insulin receptors of cell membranes. The binding of insulin to its receptor induce an increase of high affinity glucose transporter molecules in target cell surface that enhance the uptake of glucose in to these cells. The WHO expert committee recommended the importance to investigate the hypoglycemic agents from plant origin, which are used in traditional medicine for the treatment of diabetes. Stevioside, a natural sweetener and a diterpene glycoside extracted from Stevia rebaudiana (Bertoni) has been used as an anti-hyperglycemic agent for the treatment of diabetes for decades. HypothesisTo reveal the molecular mechanism underlying the insulinomimetic activity of stevioside and its aglycone metabolite, steviol using cell line models. Study designEfficacy of stevioside and steviol in inducing glucose absorption was studied at transcript level, protein level and by measuring glucose absorption in the cell using in-vitro cell line studies. MethodQuantification of glucose transporter (GLUT4) transcript was done in 3T3-L1 adipocytes and L6 myotubes by qPCR using RPL23 as the internal control. GLUT4 protein was quantified using anti GLUT4 antibody by ELISA and radioactive glucose uptake studies were done to measure the rate of glucose absorption. ResultsThe absolute and relative quantitation of GLUT4 gene by qPCR showed the activation of GLUT4 transcript at lower concentration of steviol (1 µM) and higher concentration of stevioside (100 µM) in both L6 myotubes and 3T3-L1 adipocytes. The increased level of glut4 protein and the glucose uptake in both the cell lines using the same concentration of steviol and stevioside further supports the qPCR data. The copy number and the expression level of GLUT4 gene, the amount of GLUT4 protein and the glucose uptake efficacy support the insulinomimetic effect of steviol and stevioside. ConclusionThe results of the study clearly demonstrate the functional similarity of steviol and stevioside with that of insulin in controlling the level of glucose in both the cell lines. In other words, the insulinomimetic property of stevioside and steviol was evident from the data.

Effects of customary drugs and modified herbal therapy on blood glucose and total antioxidant capacity in Streptozotocin induced diabetes in albino rats: A comparative analysis

346 million people worldwide have diabetes. In 2004, an estimated 3.4 million people died from consequences of high blood sugar. Diabetes and its complications have a significant economic impact on individuals, families, health systems and countries. Diabetes increases the risk of heart disease and stroke. Some evidences suggest that oxidative stress may play an important role in the etiology of diabetes and diabetic complications. The free radicals can be encountered by the treatment of diabetes mellitus with insulin and/or oral synthetic hypoglycemics. These are giving encouraging results, yet they are expensive, painful giving undesirable psychological effects. Alternatively, some plants and trace elements may be proven the candidates to bring about the promising and desirable results including Coriander and Vanadyl sulphate. To produce hypoglycemic effects a huge amount of Coriander (200 mg/kg/day/15days) and Vanadyl sulphate (0.75mg/100gm/day/17days) is required. This quantity is expensive and toxic. Even small dose (0.3 and 0.5 mmol/kg) of vanadyl sulphate may cause toxicity but during our study, the dose used of vanadyl sulphate and Coriandrum sativum, to evaluate the insulinomimetic activity, did not exhibit any lethal effect. In the present study, an innovate method has been developed in which the vanadyl sulphate was up taken by coriander that being in its natural environment probably through auto-oxidation rendered it non toxic. Pharmacological studies of vanadyl sulphate uptaken herb demonstrated no deleterious effects.

Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc

Disturbances of zinc homeostasis have been observed in several diseases, including diabetes mellitus. To further characterize the association between zinc and diabetes, we recruited 75 patients with type 1 or type 2 diabetes and 75 nondiabetic sex-/age-matched control subjects in order to analyze differences concerning human zinc transporter 8 (hZnT-8) expression, single nucleotide polymorphisms (SNPs) in the genes of hZnT-8 as well as metallothionein 1A and serum/intracellular zinc. Furthermore, we investigated the relation between insulin and zinc homeostasis in type 2 diabetic subjects and consolidated our results by in vitro analysis of the effect of insulin on cellular zinc status and by analysis of the modulation of insulin signal transduction by intracellular zinc homeostasis. Concerning the expression of hZnT-8 and the SNPs analyzed, we did not observe any differences between diabetic and control subjects. Serum zinc was significantly lower in diabetic patients compared to controls, and intracellular zinc showed the same tendency. Interestingly, type 2 diabetes patients treated with insulin displayed lower serum zinc compared to those not injecting insulin. In vitro analyses showed that insulin leads to an increase in intracellular zinc and that insulin signaling was enhanced by elevated intracellular zinc concentrations. In conclusion, we show that type 1 and type 2 diabetic patients suffer from zinc deficiency, and our results indicate that zinc supplementation may qualify as a potential treatment adjunct in type 2 diabetes by promoting insulin signaling, especially in zinc-deficient subjects.

Copper Compounds Ameliorate Cardiovasclur Dysfunction and Diabetes in Animals

Copper (Cu) is essential for our daily life and it is found at approximately 110 mg in human adults with the body weight of 70 kg, in which this metal occurs at 46 mg in the bone and 26 mg in the muscle. Although Cu exists in the brain (approximately 5 mg/kg), liver (6 mg/kg), kidney (13 mg/kg), erythrocytes (90 mg/L), bile (6 mg/L) and serum (120 mg/L), its organ-specific distribution is not yet known. In metalloenzymes such as oxidoreductases, Cu is abundantly found and greatly contributes in life functions. In addition, intracellular Cu transport system has been revealed in connection with iron (Fe) and zinc (Zn) intracellular transport systems. In spite of such great contribution of Cu in life, no Cu-containing pharmaceutics have yet been known. Under such background, the author and his research group have tried to examine a possibility of Cu compounds as potential pharmaceutics. In the review, the following topics are concerned; (1) improvement of cardiovascular dysfunction in animals by di-nuclear Cu-asprinate complex on the basis of the results on its reactive oxygen scavenging (ROS) effect, (2) blood glucose-lowering effect of mono-nuclear Cu-picolinate complex in streptozotocin (STZ)-induced type 1-like diabetic animals, based on the results on in vitro insulinomimetic activity, and (3) anti-diabetic effect of copper sulfate in animals with regard to the inhibition of α-glucosidase activity. These results suggest that copper ion and its complexes are possible seeds for developing Cu-containing pharmaceutics in the future.

Sodium Tungstate Administration Ameliorated Diabetes-Induced Electrical and Contractile Remodeling of Rat Heart without Normalization of Hyperglycemia

Recently, sodium tungstate was suggested to improve cardiac performance of diabetic rats in perfused hearts based on its insulinomimetic activity. In this study, we aimed to investigate the cellular and molecular mechanisms underlying this beneficial effect of sodium tungstate. Tungstate was administered (100 mg/kg/day) to diabetic and control rats intragastrically for 6 weeks. Blood glucose levels increased, whereas body weight, heart weight and plasma insulin levels decreased significantly in diabetic animals. Interestingly, none of these parameters was changed by tungstate treatment. On the other hand, fractional shortening and accompanying intracellular Ca(2+) [Ca(2+)](i) transients of isolated ventricular myocytes were measured, and sodium tungstate was found to improve the peak shortening and the amplitude of [Ca(2+)](i) transients in diabetic cardiomyocytes. Potassium and L-type Ca(2+) currents were also recorded in isolated ventricular cells. Significant restoration of suppressed I (to) and I (ss) was achieved by tungstate administration. Nevertheless, L-type calcium currents did not change either in untreated or treated diabetic rats. Tissue biochemical parameters including TBARS, protein carbonyl content, xanthine oxidase (XO) and xanthine dehydogenase (XDH) were also determined, and diabetes revealed a marked increase in TBARS and carbonyl content which were decreased significantly by tungstate treatment. Conversely, although XO and XDH activities didn't change in untreated diabetic rats, a remarkable but insignificant decrease was detected in treated animals. In conclusion, tungstate treatment improved diabetes-induced contractile abnormalities via restoration of dysregulated [Ca(2+)](i) and altered ionic currents. This beneficial effect is due to antioxidant property of sodium tungstate rather than normalization of hyperglycemia.

Development Research of New Zn Complexes with Anti-diabetic Effect&lt;br/&gt;—Structure-activity-related Studies by Displacement of Coordination Atom—

The number of patients suffering from diabetes mellitus in 2007 was reported to be approximately 200 million people worldwide. Since the finding of insulinomimetic activity of Zn ion, several insulinomimetic Zn complexes have been reported. Zn complexes are expected to be useful in the treatment of diabetes mellitus. We reported that Zn complexes with coordinating sulfur atom exhibit higher insulin-mimetic activity. In this study, we investigated the pharmacological and pharmacokinetic differences between Zn(O₄) and Zn(S₂O₂) coordination environments of tropolonate-Zn complexes with antidiabetic effect. Among the tropolonate-Zn complexes with various coordination environments, di(2-mercaptotropolonato)Zn with the Zn(S₂O₂) coordination environments was found to exhibit the highest in vitro insulinomimetic activity with respect to glucose uptake in isolated rat adipocytes treated with adrenaline. In vivo experiments, di(2-mercaptotropolonato)Zn was found to exhibit potent hypoglycemic activity and improve insulin resistance in type 2 diabetic KKA(y) mice at a low orally administered daily dose. On the other hand, di(tropolonato)Zn, which has the Zn(O₄) coordination mode, had a lesser effect at the same dose. In a pharmacokinetic analysis based on the tracer method, di(2-mercaptotropolonato)Zn was found to be absorbed at a significantly slower rate with a longer half-life than di(tropolonato)Zn. These results suggest that the potent hypoglycemic activity of di(2-mercaptotropolonato)Zn with Zn(S₂O₂) coordination environments might be attributed to its long half-life.

Oral Administration of Bis(aspirinato)zinc(II) Complex Ameliorates Hyperglycemia and Metabolic Syndrome-Like Disorders in Spontaneously Diabetic KK-Ay Mice: Structure-Activity Relationship on Zinc-Salicylate Complexes

In recent years, the number of patients suffering from diseases, such as cancer, apoplexy, osteoporosis, hypertension, and type 2 diabetes mellitus is increasing worldwide. Type 2 diabetes, a lifestyle-related disease, is recognized as a serious disease. Various types of pharmaceutics for diabetes have been used. Since the relationship between diabetes and biometals such as vanadium, copper, and zinc ions has been recognized for many years, we have been developing the anti-diabetic metal complexes as new candidates. We found that several zinc(II) (Zn) complexes exhibit glucose-lowering activity for treating type 2 diabetes. High doses of salicylates have been known to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients. These findings strongly suggest that the combined use of Zn and salicylates achieves the synergism in treating type 2 diabetes. Because aspirin, acetyl salicylic acid, has a chelating ability, we used it as a ligand to Zn. Several Zn-salicylate complexes were prepared and their biological activities were examined in this study. The complexes with an electron-withdrawing group in the ligand exhibited higher in vitro insulinomimetic activity than those of Zn complexes with an electron-donating group in the ligand. When bis(aspirinato)Zn (Zn(asp)₂) complex was orally administered on KK-A(y) mice with hereditary type 2 diabetes, the diabetic state was improved. In addition, this complex exhibited normalizing effects on serum adiponectin level and high blood pressure in metabolic syndrome. In conclusion, Zn(asp)₂ complex is newly proposed as a potent anti-diabetic and anti-metabolic syndrome agent.

Effects of Zn(ii) complex with vitamins C and U, and carnitine on metabolic syndrome model rats

The insulinomimetic activity of a Zn(ii) complex is reported. The effects of the Zn(ii) complex with ascorbic acid (Vitamin C; VC), methylmethionine sulfonium chloride (Vitamin U; VU) and l-carnitine were assessed in diet-induced metabolic syndrome model rats. Zn(VU)(2)Cl(2) and Zn(VC)Cl(2) were suggested to be useful supplementary materials for preventing metabolic syndrome by reducing visceral adipose tissues or accelerating blood fluidity.

Formation and structure in aqueous solution of complexes between vanadium(V) and aminohydroxamic acids that potentiates vanadium’s insulinomimetic activity: l-glutamic γ-hydroxamic and l-aspartic-β-hydroxamic acids

The full speciation of the vanadium(V) complexation systems with two aminohydroxamic acids, aspartic-β- and glutamic-γ-hydroxamic acid, has been determined using potentiometric and spectroscopic techniques. Formation constants were calculated in a systematic study at different ligand to metal molar ratios and the coordination types are proposed. An almost constant value of the 51V NMR signal in neutral medium can be attributed to two (1:1 and 1:2 metal to ligand ratios) similar structures, both of which can be either protonated or deprotonated. The two ligands have a carboxylic group in the structure and show comparable biological activities. In this work analogous complexation behavior at physiological conditions was found despite the presence of two or three methylenic groups between the amino and hydroxamate groups. The carboxylic groups are quite distant from the hydroxamic groups and are not involved directly in the coordination process. Therefore the coordination structures are related to that found in the vanadium(V)-β-alaninehydroxamic acid in which there is not a carboxylic group.

Insulinomimetic activity of two new gallotannins from the fruits of Capparis moonii

Bioassay guided fractionation of the hydro-alcoholic extract of the fruits of Capparis moonii, led to the isolation of two new chebulinic acid derivatives. The compounds 1 and 2 displayed significant glucose uptake effect of 223% and 219% over the control at the 10ng/ml and 100ng/ml concentration, respectively. The increased glucose uptake effects of the compounds were associated with significant IR and IRS-1 phosphorylation, GLUT4 and PI3-kinase mRNA expression in the L6 cells.

New approaches to the treatment of diabetes

The underlying pathomechanism of the interdependent metabolic diseases diabetes, obesity and atherosclerosis is an imbalance of carbohydrate and lipid metabolism as well as energy homeostasis. The therapeutic goal for new medicines to treat metabolic diseases is thus the normalization and maintainance of macronutrient and energy homeostasis with drugs affecting transport, biosynthesis and signaling of carbohydrate and lipid pathways. The insulin analog HOE 901 is a new promising basal insulin for the treatment of Type I and Type 2 diabetic patents in late stage clinical development. Thc increased hepatic glucose production in type 2 diabetics can be normalized by novel inhibitors of the hepatic glucose-6-phosphate transporter of the glucose-6-phosphatase systems being the terminal step of hepatic glucose production from both, glcycogenolysis and gluconeogenesls. To overcome peripheral insulin resistance, phosphoinositolglycans were identified and synthesized showing insulinomimetic activity on adipose and muscle tissue also in the insulin-resistant state in contrast to insulin.

Synthesis, characterization and crystal structure of novel mononuclear peroxotungsten(VI) complexes. Insulinomimetic activity of W(VI) and Nb(V) peroxo complexes

Two new mononuclear peroxo complexes of tungsten of the formula (gu)(2)[WO(2)(O(2))(2)] (1) and (gu)[WO(O(2))(2)(quin-2-c)] (2a) (where gu(+)=guanidinium ion, CN(3)H(6)(+) and quin-2-c=quinoline-2-carboxylate ion) have been synthesized and characterized by elemental analysis, infrared, Raman, UV-visible and (1)H NMR spectroscopies. The crystal structure of (gu)[WO(O(2))(2)(quin-2-c)].H(2)O (2b) determined by X-ray diffraction indicates that the side-on peroxo groups and the bidentate quinaldate ligand bind the W(VI) centre leading to an hepta coordination mode. The guanidinium ion occurring as a counterion and the hydrogen-bound interactions stabilize the complexes. The in vitro insulin-mimetic effect of the complexes has been evaluated by the inhibitory effect on free fatty acid release in isolated fat adipocytes treated with epinephrine. Moreover the niobate analogues, synthesized and characterized previously, (gu)(3)[Nb(O(2))(4)] and (gu)(2)[Nb(O(2))(3)(quin-2-c)].H(2)O have been tested for the insulin-like activity.

Axial Ligand Coordination in Sterically Strained Vanadyl Porphyrins: Synthesis, Structure, and Properties

A hitherto unknown family of six-coordinate vanadyl porphyrins of the sterically crowded, nonplanar 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetranitroporphyrin incorporating axial ligand L [where L is pyridine, tetrahydrofuran (THF), or methanol (MeOH)] has been isolated as VO(tn-OEP)(L) in the solid phase for the first time and also structurally characterized. The presence of four electron-withdrawing, bulky nitro groups at the meso positions of vanadyl octaethylporphyrins severely distorts the porphyrin macrocycles and significantly enhances the affinity for the axial ligands, where even weak sigma-donating ligands, such as MeOH, bind strongly enough to be isolable in the solid phase and that too under the offset effects of the macrocyclic distortions. Thus, the axial ligand affinity is influenced by both the electronic and conformational effect, which cannot be separated completely in this series. The solid-state magnetic measurements and their typical electron paramagnetic resonance (EPR) spectrum show the presence of a single, unpaired electron, consistent with V(IV) formulation. The VO stretching frequency for VO(tn-OEP) occurs as a sharp, strong peak at 1008 cm(-1), which is consistent with five-coordinate vanadyl porphyrins, while VO(tn-OEP)(L) displays a strong band at lower wavenumbers. The downshift in nu(VO) upon axial coordination increases with increasing donor strength of the axial ligands; for pyridine, the downshift is 30 cm(-1), while for THF and MeOH, the downshifts are nearly 18 cm(-1). X-ray structure determinations authenticate axial coordination in a purely saddle-distorted porphyrin macrocycle for all of the complexes reported here in which V-Np distances are significantly shorter, while the porphyrin cores have been expanded on axial ligand coordination. As a result, vanadium atoms are more inplane than in a five-coordinate species. The binding of L does not change the spin or metal oxidation states (V(IV), d(1)-system) of the complexes; therefore, the changes observed are truly the reflections of axial ligand coordination. Electrochemical data obtained from cyclic voltammetric studies reveal that the complexes are much easier to reduce (by approximately 1200 mV) but more difficult to oxidize (by approximately 500 mV) as compared to nearly planar VO(OEP). The complexes undergo two one-electron oxidations due to pi-cation radical and dication formation and three one-electron reductions. The first two reductions are because of pi-anion radical and dianion formation, while the third quasi-reversible reduction is assigned to a metal-centered process (V(IV) --> V(III)). These results can be useful for identifying the interaction of the vanadyl porphyrins with the biological targets in their reported involvement in potent insulinomimetic activity and in anti-HIV agents.