Hiromu Sakurai

Structural and redox requirements for the action of anti-diabetic vanadium compounds

This study presents the first systematic investigation of the anti-diabetic properties of non-oxido V(IV) complexes. In particular, the insulin-mimetic activity of [V(IV)(taci)2](4+), [V(IV)(inoH-3)2](2-), [V(IV)(dhab)2], [V(IV)(hyph(Ph))2], [V(IV)(cat)3](2-) and [V(IV)(pdbh)2]--where taci is 1,3,5-triamino-1,3,5-trideoxy-cis-inositol, ino is cis-inositol, H2dhab is 2,2-dihydroxyazobenzene, H2hyph(Ph) is 3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole, H2cat is catechol and H2pdbh is pentan-2,4-dione benzoylhydrazone--was evaluated in terms of free fatty acid (FFA) release. Among the six compounds examined, only [V(IV)(pdbh)2], [V(IV)(cat)3](2-) and [V(IV)(hyph(Ph))2], which at the physiological pH convert to the corresponding V(IV)O complexes, were found to exhibit a significant insulin-mimetic activity compared to VOSO4. In contrast, [V(taci)2](4+), [V(inoH-3)2](2-) and [V(dhab)2], which at pH 7.4 keep their bare non-oxido structure, did not cause any inhibition of FFA. The results, therefore, suggest that a V(IV)O functionality is necessary for vanadium complexes to exhibit anti-diabetic effects. This agrees with the notion that the biotransformations of V compounds in the organism are more important than the nature of the species.

Metallo-allixinate complexes with anti-diabetic and anti-metabolic syndrome activities.

Metabolic syndrome and the accompanied diabetes mellitus are both important diseases worldwide due to changes of lifestyle and eating habits. The number of patients with diabetes worldwide is estimated to increase to 300 million by 2025 from 150-220 million in 2010. There are two main types of diabetes. In type 1 diabetes, caused by destruction of pancreatic β-cells resulting in absolute deficiency of intrinsic insulin secretion, the patients require exogenous insulin injections several times a day. In type 2 diabetes, characterized by insulin resistance and abnormal insulin secretion, the patients need exercise, diet control and/or several types of hypoglycemics. The idea of using metal ions for the treatment of diabetes originates from the report in 1899. The research on the role of metal ions that may contribute to the improvement of diabetes began. The orally active metal complexes containing vanadyl (oxidovanadium(iv)) ion and cysteine or other ligands were first proposed in 1990, and a wide class of vanadium, copper and zinc complexes was found to be effective for treating diabetes in experimental animals. We noticed a characteristic compound, allixin, which is a non-sulfur component in dry garlic. Its vanadyl and zinc complexes improved both types of diabetes following oral administration in diabetic animals. We then developed a new zinc complex with thioxoallixin-N-methyl (tanm), which is both a sulfur and N-methyl derivative of allixin, and found that this complex improves not only diabetes but also metabolic syndrome. Furthermore, new zinc complexes inspired from the zinc-tanm were prepared; one of them exceeded the activity of zinc-tanm. The mechanism of such complexes was studied in adipocytes. We describe here the usefulness of the development of metal-based complexes in the context of potential therapeutic application for diabetes and metabolic syndrome.

Aminoacid-derivatised picolinato-oxidovanadium(IV) complexes: characterisation, speciation and ex vivo insulin-mimetic potential.

The proligands PicMe-AaR (PicMe=methoxipicolyl-5-amide, where the amide substituent is an amino acid AaR=HisH, HisMe, IleH, IleMe, TrpH, TrpMe, HTyrEt, tBuTyrMe, HThrMe, tBuThrMe) and the complexes [VO(Pic-AaR)(2)] have been synthesised and characterised. A detailed EPR study of the VO(2+)/Pic-His systems in water revealed the predominance of the complex [VO(Pic-His)H(2)O] in the pH range 2-6, with tridentate coordination of Pic-His via the picolinate moiety and imidazole-Ndelta. Speciation analyses of the binary systems VO(2+)/Pic-Aa (Aa=His, Ile, Trp) and the ternary systems VO(2+)/Pic-Aa/B (Aa=His, Ile; B=citrate (cit), lactate (lac), phosphate) showed a predominance of the ternary complexes [VO(Pic-Aa)(cit/lac)] and [VO(Pic-Aa)(cit/lac)OH](-) in the physiological pH regime. If, in addition, human serum albumin (HAS) and apotransferrin (Tf) are present, with all of the low and high molecular mass constituents in their blood serum concentrations, about two thirds of VO(2+) is bound to the protein, while there is still a sizable amount of ternary complex [VO(Pic-Aa)(cit/lac)] present (about 1/4 for Pic-His and 1/3 for Pic-Ile) when the vanadium(IV) concentration is relatively high; at lower concentrations Tf is the predominant binder. Insulin-mimetic studies for VO(2+)/Pic-Aa (Aa=His, Ile, Tyr and Trp), based on a lipolysis assay with rat adipocytes, provided IC(50) values of 0.41(1) for VO(2+)/Pic-His and VO(2+)/Pic-Ile, which compares with 0.87(17) for VOSO(4).

Novel 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes to investigate structure/activity relationships.

A previous evaluation of the insulin-like activity of three 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes raised questions about structure/activity relationships, namely the influence of the hydrophilic/lipophilic balance of the complex and the capacity of the ligand to stabilize the +4 oxidation state of vanadium ion, on achieving an positive effect. To address these questions, we synthesized six new oxidovanadium(IV) complexes with variable hydrophilic/lipophilic balance, obtained by introducing different substituents on the nitrogen atom, and used two 3-hydroxy-4-pyrones as starting reagents to provide methyl and ethyl groups in the ortho position of the ring. For the new and previously reported complexes, we studied the oxidation-reduction properties and insulin-like activity in terms of inhibitory effect on Free fatty acid (FFA) release in isolated rat adipocytes. The results obtained show that only one of the complexes, Bis(3-hydroxy-1(H)-2-methyl-4-pyridonato)oxidovanadium(IV), VO(mpp)(2), exhibits a significantly greater capacity to inhibit FFA release than VOSO(4) and consequently is worthy to be considered for further studies. The establishment of structure activity relationships was not attainable but this study brings new information about the influence of some properties of the compounds on the achievement of an insulin-like effect. The results reveal that: (i) the oxidation-reduction cycles of the complexes are identical; (ii) the presence of more lipophilic substituents on the nitrogen atom does not enhance insulin-like properties; (iii) a high solubility in water proved to be not sufficient for a positive activity in inhibiting FFA release; (iv) a small molecular size may be an important property for reaching the right targets.

Investigation of the insulin-like properties of zinc(II) complexes of 3-hydroxy-4-pyridinones: Identification of a compound with glucose lowering effect in STZ-induced type I diabetic animals

Results from an investigation in an in vivo model of STZ-induced diabetic rats demonstrate that compound bis(1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate)zinc(II), Zn(dmpp)(2), significantly lowers the blood glucose levels of individuals, thus showing evidence of glucose lowering activity. The compound was selected from a set of eight zinc(II) complexes of 3-hydroxy-4-pyridinones with diverse lipophilicity that were prepared and characterized in our laboratory. Assessment of insulin-like activity of the complexes was firstly performed in vitro by measuring the inhibition of FFA release in isolated rat adipocytes. The results indicate that compounds bis(2-methyl-3-hydroxy-4-pyridinonate)zinc(II), Zn(mpp)(2) and Zn(dmpp)(2) display significantly higher activity than that of the respective positive control thus suggesting its selection for in vivo tests. Safety evaluation of the active zinc(II) compounds was performed in freshly isolated rat hepatocytes. The results support that cell viability is not significantly different from the control set after 1 and 2h of incubation with both zinc(II) complexes.

Evaluation of insulin-mimetic activities of vanadyl and zinc(II) complexes from the viewpoint of heterocyclic bidentate ligands

Vanadyl sulfate (VOSO(4)) has been clinically tested in diabetic patients since 1995. Oral administrations of VOSO(4) improved the type 2 diabetic state with respect to plasma glucose, HbA(1c), and fructosamine levels. The development of toxicity by increasing the administration of VOSO(4) should be avoided. One method was the utilization of vanadyl complexes with coordination compounds that are low-toxic and low-molecular-weight ligands to enhance the permeation of the metal ion to lipid bilayer membrane. Over a decade we have focused on a variety of heterocyclic compounds as bidentate ligands for metal ions. Vanadyl and zinc(II) complexes of 1-substituted 3-hydroxy-2-methyl-4(1H)-pyridinethiones, 4,5,6-substituted 1-hydroxy-2(1H)-pyrimidinones, 4-(p-substituted)phenyl-3-hydroxythiazole-2(3H)-thiones, 3-hydroxypyrone, 1-alkyl- or 1-phenylalkyl-3-hydroxy-2(1H)-pyridinethiones, optically active 1-substituted 3-hydroxy-4(1H)-pyridinethiones, and 5-dialkylsulfonamido- or 5,7-bis(dialkylsulfonamido)-8-hydroxyquinolines were prepared, and their insulin-mimetic activities were evaluated in terms of IC(50) values which stand for a 50% inhibitory concentration of the free fatty acid release from isolated rat adipocytes. In this article, the relationship between the insulin-mimetic activity and the partition coefficient, the chirality, the substituent effect, molecular weight, the pK(a) value, and the coordination mode was discussed. In vivo blood glucose-lowering effects of the vanadyl complex with 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone in streptozotocin (STZ)-induced diabetic rats and the zinc(II) complexes with 4-(p-chlorophenyl)thiazole- and 4-methylthiazole-2(3H)-thione in KK-A(y) mice were also discussed.

Action Mechanism of Insulin‐Mimetic Vanadyl–Allixin Complex

In the 21st century, there has been a dramatic worldwide increase in the prevalence of metabolic syndromes, including diabetes mellitus (DM). Several synthetic pharmaceutical agents have been developed and used for the treatment of type‐2 DM; however, these compounds have several problems such as side effects, hypoglycemia, and weight gain. Therefore, new drugs are required for DM therapy. We have proposed that some vanadyl complexes function as potent insulin‐mimetic and antidiabetic agents in type‐1 and type‐2 DM animal models. In this article, we review the possible action mechanism of insulin‐mimetic and antidiabetic vanadyl complexes, focusing on a recently proposed complex, bis(allixinato)oxovanadium(IV), with respect to the insulin‐signaling pathway in cultured adipocytes.

Alpha-glucosidase inhibitory effect of anti-diabetic metal ions and their complexes.

We found alpha-glucosidase inhibitory (alpha-GI) effect of metal ions and their complexes which showed the high blood glucose lowering effect in diabetic model animals. The Cu(II) ion and its complexes showed strong alpha-GI activity greater than clinically used acarbose in in vitro studies. Furthermore, in in vivo experiments, alpha-GI action was newly discovered in normal ddy mice. These results suggested that one of action mechanisms of the anti-diabetic metal ions and complexes is related to the alpha-GI effects.

Action mechanism of metallo-allixin complexes as antidiabetic agents*

The metabolic syndrome is a group of factors associated with an increased risk of atherosclerosis and diabetes. Diabetes mellitus (DM) is classified into 2 major types - type 1 DM and type 2 DM - characterized by chronic hyperglycemia resulting from defects in insulin secretion and insulin action, respectively. Several synthetic pharmaceuticals have been developed and clinically used for treating DM; however, these pharmaceuticals continue to cause side effects. Recently, we proposed that oxovanadium(IV) (vanadyl) and zinc(II) (zinc) complexes are potent antidiabetic agents for both type 1 and type 2 DM therapy. This article reviews the vanadyl- and zinc-allixin and their related complexes that are being currently developed as novel types of antidiabetic metal complexes, focusing on their action mechanism in terms of regulation of the insulin signaling pathway and inhibition of lipolysis signaling in adipocyte cells.