Chemistry and Insulin-Mimetic Properties of Bis(acetylacetonate)oxovanadium(IV) and Derivatives¹

Abstract

The syntheses and the solid state structural and spectroscopic solution characterizations of VO(Me-acac)2 and VO(Et-acac)2 (where Me-acac is 3-methyl-2,4-pentanedionato and Et-acac is 3-ethyl-2,4-pentanedionato) have been conducted since both VO(acac)2 and VO(Et-acac)2 have long-term in vivo insulin-mimetic effects in streptozotocin-induced diabetic Wistar rats. X-ray structural characterizations of VO(Me-acac)2 and VO(Et-acac)2 show that both contain five-coordinate vanadium similar to the parent VO(acac)2. The unit cells for VO(Et-acac)2 and VO(Me-acac)2 are both triclinic, P1, with a = 9.29970(10) A, b = 13.6117(2) A, c = 13.6642(2) A, alpha = 94.1770(10) degrees, beta = 106.4770(10) degrees, gamma = 106.6350(10) degrees for VO(Et-acac)2 and a = 7.72969(4) A, b = 8.1856(5) A, c = 11.9029(6) A, alpha = 79.927(2) degrees, beta = 73.988(2)degrees, gamma = 65.1790(10)degrees for VO(Me-acac)2. The total concentration of EPR-observable vanadium(IV) species for VO(acac)2 and derivatives in water solution at 20 degreesC was determined by double integration of the EPR spectra and apportioned between individual species on the basis of computer simulations of the spectra. Three species were observed, and the concentrations were found to be time, pH, temperature, and salt dependent. The three complexes are assigned as the trans-VO(acac)2.H2O adduct, cis-VO(acac)2.H2O adduct, and a hydrolysis product containing one vanadium atom and one R-acac- group. The reaction rate for conversion of species was slower for VO(acac)2 than for VO(malto)2, VO(Et-acac)2, and VO(Me-acac)2; however, in aqueous solution the rates for all of these species are slow compared to those of other vanadium species. The concentration of vanadium(V) species was determined by 51V NMR. The visible spectra were time dependent, consistent with the changes in species concentrations that were observed in the EPR and NMR spectra. EPR and visible spectroscopic studies of solutions prepared as for administration to diabetic rats documented both a salt effect on speciation and formation of a new halogen-containing complex. Compound efficacy with respect to long-term lowering of plasma glucose levels in diabetic rats traces the concentration of the hydrolysis product in the administration solution.

Chemistry of molecular and supramolecular structures of vanadium(IV) and dioxygen-bridged V(V) complexes incorporating tridentate hydrazone ligands

“…However, at pharmacological concentrations, some species are potential therapeutic agents [3,4]. Thus, the insulin-enhancing, insulin mimetic properties of oxovanadium(V) complexes, their use as model complexes for the active site of vanadoenzymes, and their use as catalysts in biological and industrial processes have been reported [5][6][7][8][9]. Furthermore, these compounds exhibit potential as anti-tumour agents by inhibiting growth of malignant cell lines by induction of cell-cycle arrest and/or cytotoxic effects [10].…”

Alkaline phosphatase inhibition by vanadyl-β-diketone complexes: electron density effects

“…Results indicate that BSA does not interfere with the inhibition measurements. VO(acac) 2 , VO(Clacac) 2 , and VO(Benzac) 2 were reported to maintain their integrity in solution whereas VO(Meacac) 2 is immediately oxidized to a vanadium(V) species [18]. UV-visible spectral data for the VO(b-diketone) 2 complexes used in the present study were obtained on a Hewlett-Packard model 8453 spectrophotometer.…”

“…VO(acac) 2 , bis(acetylacetonato)oxovanadium(IV), and VO(Meacac) 2 , bis(3-methylacetylacetonato)oxovanadium(IV), Figure 1, as well as bis (3-ethylacetylacetonato)oxovanadium(IV) function as insulin-enhancing agents, lowering blood glucose levels of streptozocin-induced rats and increasing glucose uptake by 3T3-L1 adipocytes [16,17,18]. Katoh and co-workers demonstrated a correlation between the insulin-mimetic activity of vanadyl-hydroxythiazolethione complexes and the Hammett parameter for a substituent group on the ligand, however, very few such structure-activity relationships have been reported [19].…”

DNA cleavage activity of VIVO(acac)2 and derivatives

“…X-ray crystallography of 1 shows only the trans isomer in the solid state. Experimental evidence by ENDOR [28] and EPR [30] points to the formation of only the trans isomer of V IV O(acac) 2 in solution, but some authors argue the cis form may also exist [9,7,32].…”

“…The complex V IV O(Etmaltolato) 2 has successfully completed phase II of human clinical trials [5,6] and became a benchmark drug candidate in this field. The V IV -complex vanadyl(acetylacetonate), V IV O(acac) 2 , has been reported to have therapeutic properties, and this has attracted much interest in its biological behaviour [7,8]. It has been proposed as a particularly efficient insulin-enhancing compound [9], and a recent study [10] focused on its anticancer potential and mechanism of action in a human hepatoma cell line, V IV O(acac) 2 being found to block the cell cycle permanently at the G1 phase on HepG2 cells.…”