Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics.
Twelve peroxovanadium (pV) compounds, each containing an oxo ligand, one or two peroxo anions, and an ancillary ligand in the inner coordination sphere of V, were synthesized, crystallized, and characterized by 51V NMR as > 95% pure. These compounds activated the insulin receptor kinase (IRK) of cultured hepatoma cells, stimulated lipogenesis in adipocytes, and inhibited the in situ dephosphorylation of autophosphorylated IRs and epidermal growth factor receptors of rat liver endosomes. The phosphotyrosine phosphatase inhibitory and IRK activating potencies of these compounds were linearly correlated (r = 0.74; p < 0.003), decayed in parallel in solution, and varied considerably with the ancillary ligands within these compounds. In vivo administration activated rat liver IRK in parallel with its tyrosine phosphorylation. Co-administration of insulin plus pV was markedly synergistic in both respects. pV administration significantly decreased circulating insulin and plasma glucose concentrations; the latter to levels seen after a dose of insulin yielding > or = 50% occupancy of IRs in vivo. Two compounds (mpV(pic) and mpV(2,6-pdc)) displayed relative specificity as phosphotyrosine phosphatase inhibitors by inhibiting IR dephosphorylation to a significantly greater degree than epidermal growth factor receptor dephosphorylation. Thus, pV compounds are the most potent phosphotyrosine phosphatase inhibitors described to date. Their capacity to activate IRK appears to derive from their phosphotyrosine phosphatase inhibitory activity. Their hypoglycemic action is due to a direct tissue effect.
Posner
B I
BI
Department of Medicine, McGill University, Montreal, Canada.
Faure
R
R
Burgess
J W
JW
Bevan
A P
AP
Lachance
D
D
Zhang-Sun
G
G
Fantus
I G
IG
Ng
J B
JB
Hall
D A
DA
Lum
B S
BS
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D066298:In Vitro Techniques; D007328:Insulin / Q000737:chemistry; D008055:Lipids / Q000096:biosynthesis; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D010545:Peroxides / Q000737:chemistry* / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology*; D014639:Vanadium / Q000737:chemistry* / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D010545:Peroxides; C069276:peroxovanadate; D014639:Vanadium; D014638:Vanadates; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases