Vanadyl-biguanide complexes as potential synergistic insulin mimics.
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(beta-phenethyl-biguanidato)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 ED50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.
Woo
L C
LC
Department of Chemistry, University of British Columbia, Vancouver, Canada.
Yuen
V G
VG
Thompson
K H
KH
McNeill
J H
JH
Orvig
C
C
D000818:Animals; D001645:Biguanides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D004357:Drug Synergism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D010629:Phenformin / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D014638:Vanadates / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry
D001645:Biguanides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D014638:Vanadates; D008687:Metformin; D010629:Phenformin