Vanadium - American Chemical Society

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 2, 2015 | http://pubs.acs.org Publication Date: August 30, 2007 | doi: 10.1021/bk-2007-0974.ch009

Chapter 9

Structure-Activity Relationship and Molecular Action Mechanism in the Family of Antidiabetic bis(Picolinato)oxovanadium(IV) Complexes Hiromu Sakurai Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan

Trials for the use of vanadium in treating diabetes mellitus (DM) was reported in 1899, which was 23 years before Banting and Best discovered insulin and used it to treat diabetic patients. However, pharmaceutical interest in vanadium as an insulin substitute started in 1980. Ten years after, in 1990, orally active insulin substitutes were found as chelated oxovanadium(IV) complexes such as bis— (methylcysteinato)oxovanadium(IV) and bis(malonato)oxovanadium(IV). Since these findings, a wide variety of antidiabetic oxovanadium(IV) complexes have been proposed. In 1995, bis(picolinato)oxovanadium(IV) complexes [VO(pa)2] was found to have excellent in vitro insulinomimetic and in vivo antidiabetic activities in type 1—like diabetic rats. This VO(pa) complex has an advantage to study structure-activity relationships in both in vitro and in vivo levels, and produce many interesting results. This article reviews the recent new progress in our research groups on the structure-activity relationship and the molecular action mechanism in the family of VO(pa) complex. 2

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© 2007 American Chemical Society

In Vanadium: The Versatile Metal; Kustin, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.


Ill The total number of patients with diabetes mellitus (DM) worldwide is estimated to rise from 171 million in 2000 to 366 million in 2030 (/). Insulin-dependent type 1 D M is a result of the autoimmune destruction of the pancreatic P cells (2), thus the patients require daily insulin injections for survival. On the other hand, non-insulin-dependent type 2 D M is associated with metabolic syndromes with obesity, impaired glucose metabolism, insulin resistance, and other complications, thus the patients require several types of synthetic pharmaceuticals (2). In place of insulin injections with physical and mental pain and synthetic pharmaceuticals with severe side effects, development of therapeutics with new approaches is anticipated. For many years, oxovanadium(IV) sulfate, V O S 0 , has been tested in the treatment of both type 1 and 2 D M since 1899 (3-6). In fact, treatment by V O S 0 improved D M as well as hepatic, peripheral, and muscle insulin sensitivity (7, 8). However, because the bioavailability of V O S 0 is low (9, 10), we proposed methods to enhance vanadium uptake by an encapsulation via enteric coating of V O S 0 (//) and by a drug delivery system consisting of VOSO4 and poly(y-glutamic acid) (12). Alternatively, in 1990, we proposed first several types of orally active oxovanadium(IV) complexes such as bis(methylcysteinato)oxovanadium(IV) [VO(cysm) ] and bis(malonato)oxovanadium(IV) [VO(mal) ] with different coordination environments involving V O ( S N ) and V O ( 0 ) , that enhanced the bioavailability and efficacy o f V O S 0 ( / 3 , 14). During these investigations (4-6), in 1995, an oxovanadium(IV)-picolinate complex with V O ( N 0 ) coordination environment was found to exhibit excellent in vitro insulinomimetic activity and in vivo antidiabetic effect on daily oral administrations (75). The finding indicated that the complex has an advantage to examine not only the structure-activity relationship with regard to insulinomimetic and antidiabetic activities but also their molecular mechanisms for insulinomimetic and antidiabetic activities. This article reviews our recent progress in the development of insulinomimetic antidiabetic oxovanadium(IV) complexes in terms of structureactivity relationship and action mechanism in molecular level focusing on the family of oxovanadium(IV)-picolinate complex. 4

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Establishment of In Vitro Evaluation System of Insulinomimetic Compounds Before subjecting metal ions and metal complexes in vivo hypoglycemic test, we had to establish a reliable in vitro appraisal system to evaluate them for their potential antidiabetic activity. The system was developed with respect to the interaction of metal ions and metal complexes with isolated rat adipocytes treated with adrenaline (epinephrine) (16, 17).


112 Because the molecular basis of the action mode of insulin and insulinomimetic compounds has gradually been revealed, there is strong evidence that insulin receptor is activated by inhibiting protein tyrosine phosphatase (PTP-1B), which in turn relates to the activation by phosphrylation of insulin receptor substrate 1 (IRS-1), activation of phosphatidylinosital 3 kinase ( P I B - K ) , and then Akt phosphorylation, leading to glucose transporter-4 (GLUT4) translocation, as well as the activation of phosphodiesterase (PDE) (4-6, 18). In fact, insulin and V O S 0 exhibited both incorporation of glucose (13, 19) and inhibition of free fatty acids (FFA) release in the rat adipocytes (13, 16, 19). Although insulin has sole action site, insulin receptor, V O S 0 has been found to have multiple action sites in the cells, as named as "Ensemble mechanism" (18). Consequently, both glucose incorporation and suppression of F F A release in the adipocytes were measured to evaluate in vivo insulinomimetic activity of compounds by using commercially available determination kits.


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Bis(picolinato)oxovanadium(IV) [VO(pa) ] Complex 2

By using the in vitro evaluation system, in 1995, we found that bis(picolinato)oxovanadium(IV) [VO(pa) ] complex (Figure 1) with V O ( N 0 ) coordination mode exhibits excellent insulinomimetic activity and in vivo hypoglycemic ability in streptozocin-induced type 1—like diabetic rats (STZ-rats) on daily intraperitoneal (ip) injections and oral administrations (15). It is noteworthy that when this complex was given daily to STZ-rat by oral administrations, at the dose of 196 nmolV/kg body/weight/day for 14 days, the normoglycemic effect was observed within 7 days, and the effect continued as long as the complex was given to the animals. After the end of treatment, normoglycemic effect was maintained for approximately 80 days. VO(pa) was also revealed to promote the incorporation of not only 2-deoxy-D-[l- H]glucose in Ehrlich ascites tumor cells (20) but also glucose in isolated rat adipocytes (16) dose-dependently. 2

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Structure-Activity Relationships of VO(pa)2 Related Complexes VO(pa) with a partition coefficient (log/*) of - 0.48 in n-octanol/buffer (pH 7.4) system has an advantage of preparing several analogs to examine the structure-activity relationship of insulinomimetic and antidiabetic activities, by introducing electron-donating or electron-withdrawing groups at different positions of the picolinate ligand. 2


In Vanadium: The Versatile Metal; Kustin, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007. \

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Vanadium - American Chemical Society

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