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)benzylidenelthiazolidine-2,4-dione (HL1), 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(L-1)(2), VO(L-3)(2), and VO(L-4)(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(L-3)(2) showed the most efficacious hypoglycemic effects in this study; however, neither additive nor synergistic effects were observed using this acute animal model.