REACTION CHEMISTRY OF BMOV, BIS(MALTOLATO)OXOVANADIUM(IV) - A POTENT INSULIN MIMETIC AGENT

The reaction chemistry of the potent insulin-mimetic agent bis(maltola to)oxovanadium(IV) (abbreviated BMOV or VO(ma)(2)) is reported. VO(ma) (2) (log K-1 = 8.80(2), log K-2 = 7.51(2), log beta(2) = 16.31(3)) has a rich coordination chemistry, forming a number of V(IV) and V(V) der ivatives. In aqueous solution it is slowly oxidized by molecular oxyge n to [VO2(ma)(2)](-) (log K-1 = 7.5(1), log K-2 = 6.2(1), log beta(2) = 13.7(1)); in alcohols a variety of V(V) analogs VO(OR)(ma)(2) (R = C H3, C2H5, i-C3H7) are formed by aerial oxidation. All these vanadate c omplexes can be interconverted by reaction with the appropriate alcoho l or water. In addition, the six-coordinate V(IV) pyridine adduct VO(m a)(2)py can be formed and this undergoes oxidation to V(V) complexes m uch more slowly, demonstrating that a vacant coordinate site is requir ed for the coordination of O-2 to VO(ma)(2) before inner-sphere oxidat ion can take place. V-51 NMR and electrochemistry have been studied as a function of pH; a complete study of the aqueous chemistry of VO(ma) (2) and [VO2(ma)(2)](-) has been undertaken because the oral activity of VO(ma)(2) as an insulin-mimetic may be related to the chemical prop erties of the two compounds in water. Oral gavage studies in STZ-diabe tic rats have been performed which showed that the intact complex is r equired for activity and that the presence of a biologically compatibl e reducing agent, ascorbic acid, neither interferes with nor augments the insulin-mimetic effect of VO(ma)(2). The X-ray structures of VO(ma )(2) and the cis-VO2 compound K[VO2(ma)(2)]. H2O have been determined; crystals of VO(ma)(2)[BMOV] are monoclinic, P2(1)/n, a = 7.366(1), b = 12.759(2), c = 13.190(1) Angstrom, beta = 97.31(1)degrees, Z = 4, an d those of K[VO2(ma)(2)]. H2O are monoclinic, P2(1)/n, a = 7.1841(9), b = 12.196(1), c 17.147(1) Angstrom, beta = 96.64(1)degrees, Z = 4. Th e structure of VO(ma)(2) was solved by direct methods and that of K[VO 2-(ma)(2)]. H2O by the Patterson method. The structures were refined b y full-matrix least-squares procedures to R = 0.076 and 0.033 (R(w) = 0.075 and 0.034) for 1078 and 3232 reflections with I greater than or equal to 3 sigma(I), respectively. VO(ma)(2) forms a square pyramid wi th the O-4 Set from the two maltolato ligands in the base and the vana dyl V = O apical. [VO2(ma)(2)](-) is roughly octahedral with a cis-[VO 2](+) unit being completed by two ma(-) ligands. The macroscopic struc ture is a chain with six-coordinate K+ ions linking adjacent [VO2(ma)( 2)](-) units through coordination to the chelating ligand O atoms and water molecules.