Hiromu Sakurai’s research while affiliated with Suzuka University of Medical Science and other places

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.

We prepared [meso-tetrakis(4-carboxylatophenyl)porphyrinato]oxovanadium(IV) tetrasodium, ([VO(tcpp)]Na4), and investigated its in vitro insulin-mimetic activity and in vivo metallokinetic feature in healthy rats. The results were compared with those of previously proposed insulin-mimetic oxovanadium(IV)porphyrin complexes and oxovanadium(IV) sulphate. The in vitro insulin-mimetic activity and bioavailability of [VO(tcpp)]Na4 were considerably better than those of [meso-tetrakis (1-methylpyridinium-4-yl)porphyrinato]oxovanadium(IV)(4+) tetraperchlorate ([VO(tmpyp)](ClO4)4) and oxovanadium(IV) sulphate. On the other hand, [VO(tcpp)]Na4 and [meso-tetrakis(4-sulfonatophenyl) porphyrinato]oxidovanadate(IV)(4-)([VO(tpps)]) showed very similar in vitro insulin-mimetic activity and in vivo metallokinetic feature in healthy rats. In particular, the order of in vitro insulin-mimetic activity of the complexes was determined to be: [VO(tcpp)]Na4 ≈ [VO(tpps)] > ([VO(tmpyp)](ClO4)4 > oxovanadium(IV) sulphate.

In recent years, people all over the world have suffered from various diseases such as cancer, myocardial infarction, osteoporosis, hypertension, and diabetes mellitus (DM). Especially, DM, well-known as one of lifestyle-related diseases, has been regarded as a serious problem, because it is difficult to fully recover. The number of patients suffering from DM in 2007 was reported to be approximately 200 million people worldwide. However, insulin preparations and synthetic therapeutics, which are clinically used treatment of DM, have been associated with problems such as physical and mental pain due to daily injections and certain severe side effects, respectively. Zn, which is an essential trace element in animals and humans and plays an important role in maintenance of their lives, has been indicated to exhibit insulin-like activity. Since the finding of insulin-like effects of Zn, several Zn complexes have been proposed as a new type of anti-diabetic therapeutics which is differ from existing medicines. In this symposium, we introduce the anti-diabetic effect, complication relieving effect, and action mechanism of bis(2-mercaptopyridine-N-oxidato)Zn complex with Zn(S(2)O(2)) coordination mode.

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.

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.

Simultaneous and fractional determination of iron(II) and iron(III) was accomplished with o-hydroxyhydroquinonephthalein (QP) in the presence of poly (N-vinyl pyrrolidone). In the determination of total iron (iron(II)+iron(III)), Beer's law was obeyed in the range of 0.02-0.67 μg·ml(-1), with an effective molar absorptivity (at 570 nm) and a relative standard deviation of 1.30×10(5)·l·mol(-1)·cm(-1) and 0.77% (n = 8), respectively. This method was about 10-15 times and more than the methods using 1,10-phenanthroline and 2,2'-bipyridine. In addition, the iron-QP complex was characterized using spectrophotometry and the electron spin resonance. This method was successfully applied to assays of total iron and iron(III) in pharmaceutical preparations.

The number of worldwide patients suffering from diabetes mellitus (DM) is forecasted to increase over time. The development of compounds without severe side effects for type 2 DM is required not only to treat DM but also to improve the quality of life (QOL) of patients. In this paper, we have described the synthesis of novel first transition metal complexes with S2O2 coordination mode and discussed their anti-diabetic activities. Di(1-oxy-2-pyridinethiolato)Zn complex (Zn(opt)2) with Zn(S2O2) coordination mode displayed higher insulin mimetic with anti-diabetic activity, compared to the ZnCl2 or clinically used medicine (pioglitazone). In addition, Zn(opt)2 improved the insulin and adiponectine levels in the plasma. The gastrointestinal absorption of the Zn complex was found to be higher than that of ZnCl(2). Based on these results, we propose that the Zn(opt)2 complex with Zn(S2O2) coordination mode is a novel candidate for the treatment of type 2 DM; through oral administration.

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.

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In developing new insulin-mimetic vanadyl complexes with various ligands including biodegradable polymers, we prepared and characterized three VO(γ γ γ γ-pga) complexes in solution and evaluated their in vitro insulin-mimetic activities and in vivo anti-diabetic effects in streptozotocin (STZ)-induced type 1 like diabetic mice (STZ-mice). All three VO(γ γ γ γ-pga) complexes normalized the hyperglycemia in STZ-mice within 14 d when administered orally at doses of 10 mg V kg –1 body mass for 28 d. In addition, the impaired glucose tolerance, elevated HbA 1c levels and metabolic syndromes were significantly improved in VO(γ γ γ γ-pga) complexes-treated STZ-mice relative to those administrated with saline and VS. Vanadium was distributed in the tissues examined in the following decreasing order: bones, liver, muscles, spleen, heart, kidneys, brain, lungs and pancreas. VO(γ γ γ γ-pga) complexes in which γ γ γ γ-pga having average molecular weight 480 – 4700 kDa are promising oral therapeutic agents for the treatment of type 1 diabetic animals.