Vanadyl–biguanide complexes as potential synergistic insulin mimics

Abstract

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo. The design of new oxovanadium(IV) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biguanides, most importantly metformin, are oral hypoglycemic agents used today to treat type 2 diabetes mellitus. In this study, biguanide, metformin, and phenformin, all biguanides, were coordinated to oxovanadium(IV) to form potential insulin-enhancing compounds. Highly colored, air-stable, bis(biguanidato)oxovanadium(IV), [VO(big) 2], bis( N′,N′-dimethylbiguanidato)oxovanadium(IV), [VO(metf) 2], and bis(β-phenethylbiguanidato)oxovanadium(IV), [VO(phenf) 2], were prepared. Solvation with dimethylsulfoxide occurred with VO(metf) 2 to form a six-coordinate complex. Precursor ligands and oxovanadium(IV) coordination complexes were characterized by infrared spectroscopy, mass spectrometry, elemental analyses, magnetic susceptibility, and, where appropriate, 1H NMR spectroscopy. Biological testing with VO(metf) 2, a representative compound, for insulin-enhancing potential included acute (72 h) administration, both by intraperitoneal (i.p.) injection and by oral gavage (p.o.) in streptozotocin (STZ)-diabetic rats. VO(metf) 2 administration resulted in significant blood-glucose lowering at doses of 0.12 mmol kg −1 i.p. and 0.60 mmol kg −1 p.o. (previously established as ED 50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.