Vanadium Complexes as Insulin Mimetic Agents:  Coordination Chemistry and in Vivo Studies of Oxovanadium(IV) and Dioxovanadate(V) Complexes Formed from Naturally Occurring Chelating Oxazolinate, Thiazolinate, or Picolinate Units

The synthesis and characterization of four complexes containing naturally occurring binding groups are reported: VO(pic) 2 ·H 2 O (Hpic = picolinic or pyridine-2-carboxylic acid), NH 4 [VO 2 (pic) 2 ]·2H 2 O, VO(oz) 2 (Hoz = 2-(2‘-hydroxyphenyl)-2-oxazoline), and VO(thoz) 2 (Hthoz = 2-(2‘-hydroxyphenyl)-2-thiazoline). The X-ray structures of NH 4 [VO 2 (pic) 2 ]·2H 2 O, VO(oz) 2, and VO(thoz) 2 have been determined. Crystals of NH 4 [VO 2 (pic) 2 ]·2H 2 O (C 12 H 12 N 3 O 6 V·2H 2 O) are monoclinic, space group Cc, a = 10.347(2) Å, b = 26.318(2) Å, c = 7.247(1) Å, β = 128.37(1)°, V = 1547.3(5) Å 3, Z = 4; those of VO(oz) 2 (C 18 H 16 N 2 O 5 V) are triclinic, P 1̄, a = 10.408(1) Å, b = 11.282(1) Å, c = 7.666(1) Å, α = 103.78(1)°, β = 109.64(1)°, γ = 84.75(1)°, V = 823.3(2) Å 3, Z = 2; and those of VO(thoz) 2 (C 18 H 16 N 2 O 3 S 2 V) are orthorhombic, Pbca, a = 12.331(2) Å, b = 26.090(2) Å, c = 11.125(2) Å, V = 3579.3(9) Å 3, Z = 4. The structures of NH 4 [VO 2 (pic) 2 ]·2H 2 O and VO(oz) 2 were solved by direct methods and that of VO(thoz) 2 by the Patterson method. The structures were refined by full-matrix least-squares procedures to R = 0.034, 0.035, and 0.034 ( R w = 0.031, 0.030, and 0.035) for 2428, 1672, and 4595 reflections with I ≥ 3σ( I ), respectively. In the case of NH 4 [VO 2 (pic) 2 ]·2H 2 O, the [VO 2 (pic) 2 ] - anion consists of a cis -VO 2 + center with the two picolinate ligands bound with an interplanar angle of 97.25°. Both VO(oz) 2 and VO(thoz) 2 demonstrate the common distorted square pyramidal geometry, with bidentate oxazolinate or thiazolinate ligands bound to the vanadium center through trans phenolate oxygens and trans oxazoline or thiazoline ring nitrogens giving anti arrangements for the two ligands in each compound. The vanadium atoms in these complexes are elevated by approximately 0.6 Å from the basal square planes defined by the two pairs of ligand O and N donors. Of the four complexes, VO(pic) 2 ·H 2 O, on the basis of solubility and stability, was selected as the most appropriate for in vivo testing. VO(pic) 2 ·H 2 O was administered in drinking water for 6 weeks to control−treated (CT) and streptozotocin-induced diabetic−treated (DT) male Wistar rats. Treatment in drinking water resulted in 38% of diabetic−treated animals responding with significant lowering of plasma glucose levels at an initial concentration of 1.52 mM; a subsequent increase to 2.28 mM resulted in 50% response. Lowering of plasma glucose in treated animals was not accompanied by any increase in plasma insulin levels. Intraperitoneal treatment with VO(pic) 2 ·H 2 O at an acute dose of 0.06 mmol kg - 1 produced significant lowering of plasma glucose within 2 h of administration with a peak lowering effect at 8 h. Chronic intraperitoneal administration of VO(pic) 2 ·H 2 O at a dose of 0.03 mmol kg - 1 d - 1 for 3 weeks resulted in significant lowering of fasted plasma glucose without any increase in insulin output.