Vanadyl−Thiazolidinedione Combination Agents for Diabetes Therapy

A series of vanadium compounds, chelated by ligands containing a thiazolidinedione moiety as an additional insulin-enhancing component, were produced in this study to create potentially synergistic compounds. A set of four bifunctional ligand precursors were synthesized: (±)-5-{4-[(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)amino]benzyl}thiazolidine-2,4-dione (HL1), (±)-5-{4-[(5-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)amino]benzyl}thiazolidine-2,4-dione (HL2), 5-[4-(5-hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzylidene]thiazolidine-2,4-dione (HL3), and (±)-5-[4-(5-hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (HL4), each containing a metal chelating portion as well as a thiazolidinedione moiety. From this set of ligand precursors, air-stable VO(L1)2, VO(L3)2, and VO(L4)2 were prepared. The four ligand precursors and three complexes were tested for insulin-enhancing potential in STZ-diabetic rats and compared to rosiglitazone and BMOV, respectively. Both the ligand precursors HL1 and HL3 showed enhanced activity compared with that of rosiglitazone. The complex VO(L3)2 showed the most efficacious hypoglycemic effects in this study; however, neither additive nor synergistic effects were observed using this acute animal model.