Antidiabetic vanadium compound and membrane interfaces: interface-facilitated metal complex hydrolysis

Abstract

The interactions of metabolites of the antidiabetic vanadium-containing drug bis(maltolato)oxovanadium(IV) (BMOV) with lipid interface model systems were investigated and the results were used to describe a potentially novel mechanism by which these compounds initiate membrane-receptor-mediated signal transduction. Specifically, spectroscopic studies probed the BMOV oxidation and hydrolysis product interaction with interfaces created from cetyltrimethylammonium bromide (CTAB) which mimics the positively charged head group on phosphatidylcholine. (1)H and (51)V NMR spectroscopies were used to determine the location of the dioxobis(maltolato)oxovanadate(V) and the maltol ligand in micelles and reverse micelles by measuring changes in the chemical shift, signal linewidth, and species distribution. Both micelles and reverse micelles interacted similarly with the complex and the ligand, suggesting that interaction is strong as anticipated by Coulombic attraction between the positively charged lipid head group and the negatively charged complex and deprotonated ligand. The nature of the model system was confirmed using dynamic light scattering studies and conductivity measurements. Interactions of the complex/ligand above and below the critical micelle concentration of micelle formation were different, with much stronger interactions when CTAB was in the form of a micelle. Both the complex and the ligand penetrated the lipid interface and were located near the charged head group. These studies demonstrate that a lipid-like interface affects the stability of the complex and raise the possibility that ligand exchange at the interface may be important for the mode of action for these systems. Combined, these studies support recently reported in vivo observations of BMOV penetration into 3T3-L1 adipocyte membranes and increased translocation of a glucose transporter to the plasma membrane.

Counterion Affects Interaction with Interfaces: The Antidiabetic Drugs Metformin and Decavanadate

“…Many studies have been carried out in vivo and ex vivo to understand how these compounds act to develop new and superior compounds. [7][8][9]13,22,25,26,[54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] The modes of action of vanadium compounds are poorly understood, in part because the compounds exert insulin-like effects, which are very involved. In addition, these coordination compounds undergo hydrolytic and redox reactions as well as protonation and oligomerization reactions.…”

“…[7][8][9][10] V 10 forms from vanadium in oxidation state +5 and is particularly stable at acidic pH. Recently, studies of how vanadium compounds interact with interface model systems and traverse membranes [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] have shown that several anionic complexes readily penetrate the interfaces, [16,17,20,21,26] but large oxometalates such as V 10 reside away from a negatively charged interface and close to a positively charged interface, as expected. [19][20][21]23,24,27,28] Because counterions can affect the properties, a suitable counterion choice could poten-By using 51 V NMR spectroscopy, we found only small differences between the metformium and Na + decavanadate materials.…”

Biomembrane models

“…In particular, positively charged surfactants are considered to be a good model for the PC head group and are used as lipid substitutes. 40 Micelles that are formed by mixtures of lipids and detergents are called mixed micelles. It should be pointed out that the CMC as well as the average number of detergent molecules per micelle can be signifi cantly changed when lipids or proteins are added to the micelles.…”

“…Using NMR spectroscopy, Crans and coworkers investigated the interactions of the antidiabetic vanadium-containing drug bis(maltolato)oxovanadium (IV) (BMOV) with a lipid interface in a CTAB micelle system and concluded that the drug penetrated the lipid interface, becoming located near the charged head groups. 40 The nature and strength of the interactions between a cationic fl uorophore, rhodamine 123 (R123), and surfactants of different head charge were investigated by Freire and coworkers. 46 Their results showed the complex physicochemical and photophysical behaviour of a charged dye in micellar systems, which resembles the situation expected in biological membranes.…”

Synthesis, crystal structure, and insulin-like activity of dimeric vanadium complex derived from 4-bromo-N'-(2-hydroxy-5-methoxybenzylidene)benzohydrazide

“…[6] The element is present in vanadium-containing enzymes such as nitrogenase and haloperoxidases. [7] Due to structural similarity between vanadates and phosphate and being able to be transported into cells through the anion channel of the plasma membranes, [8,9] many vanadium compounds have been shown to increase glucose transport into cells and its oxidation via glycolysis. [10,11] Oxovanadium (IV) sulphate has demonstrated to possess oral insulin-like activity similar to that of the vanadates, with lowered toxicity.…”