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Vanadate and Peroxovanadate Complexes of Biomedical Relevance: A speciation approach with focus on diabetes
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes mellitus is one of the most threatening epidemics of modern times with rapidly increasing incidence. Vanadium and peroxovanadium compounds have been shown to exert insulin–like actions and, in contrast to insulin, are orally applicable. However, problems with side–effects and toxicity remain. The exact mechanism(s) by which these compounds act are not yet fully known. Thus, a better understanding of the aqueous chemistry of vanadates and peroxovanadates in the presence of various (bio)ligands is needed.

The present thesis summarises six papers dealing mainly with aqueous speciation in different vanadate – and peroxovanadate – ligand systems of biological and medical relevance. Altogether, five ligands have been studied, including important blood constituents (lactate, citrate and phosphate), a potential drug candidate (picolinic acid), and a dipeptide (alanyl serine) to model the interaction of (peroxo)vanadate in the active site of enzymes. Since all five ligands have been studied both with vanadates and peroxovanadates, the number of systems described in the present work is eleven, including the vanadate – citrate – lactate mixed ligand system. The pH–independent formation constants have been determined for 33 ternary vanadate – ligand, 41 quaternary peroxovanadate – ligand and two vanadate – mixed ligand species in addition to the pKa values of all five ligands. These constants have been used to model physiological conditions, and the biomedical relevance of the different species is discussed.

The studies have been performed at 25 ºC in the physiological medium of 0.150 M Na(Cl), i.e. the ionic strength of human blood. No buffers have been used, and wide pH–ranges have usually been covered. The applied experimental techniques comprise mostly 51V NMR and potentiometry, but 31P, 13C, 1H and 14N NMR as well as EPR and ESI–MS have also been used to gain additional information. Multimethod data have been treated by the least–squares program LAKE and modelling has been carried out by the software package WinSGW.

Whenever possible, solution structures of the species have been proposed. In addition, simple biological tests have been carried out to determine the stability of the formed peroxovanadate complexes in the presence of human catalase. A brief comparison is given of the different vanadate – ligand and peroxovanadate – ligand systems with emphasis on observed trends and general features.

Place, publisher, year, edition, pages
Umeå: Kemi , 2005. , 74 p.
Keyword [en]
Inorganic chemistry, vanadium, hydrogen peroxide, lactate, citrate, phosphate, alanyl serine, picolinic acid, speciation, formation constants, equilibrium, solution structure, potentiometry, NMR (51V, 31P, 13C, 1H)
Keyword [sv]
Oorganisk kemi
National Category
Inorganic Chemistry
Research subject
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-489ISBN: 91-7305-854-8 (print)OAI: oai:DiVA.org:umu-489DiVA: diva2:143573
Public defence
2005-04-22, KB3A9, KBC-huset, Umeå Universitet, Umeå, 13:00
Opponent
Supervisors
Available from: 2005-03-31 Created: 2005-03-31 Last updated: 2012-06-26Bibliographically approved
List of papers
1. Speciation in the aqueous H+/H2VO4–/H2O2/picolinate system relevant to diabetes research
Open this publication in new window or tab >>Speciation in the aqueous H+/H2VO4–/H2O2/picolinate system relevant to diabetes research
2004 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, no 3, 421-428 p.Article in journal (Refereed) Published
Abstract [en]

A detailed study of the quaternary aqueous H+/H2VO4/H2O2/picolinate (Pi) system has been performed at 25 °C in 0.150 M Na(Cl) medium using quantitative 51V NMR (500 MHz) and potentiometric data (glass electrode). In the ternary H+/H2VO4/Pi system, six complexes have been found in the pH region 1–10. In the quaternary H+/H2VO4/H2O2/Pisystem, eight additional complexes have been found. Generally, equilibria are fast in both systems. The rate of peroxide decomposition depends on the species in solution. Chemical shifts, compositions and formation constants for the species are given. Equilibrium conditions and the fit of the model to the experimental data are illustrated in distribution diagrams. Possible formation of mixed ligand species with imidazole, lactic acid and citric acid have been investigated and ruled out under the same experimental conditions. Structural proposals are given, based on 13C NMR data and available crystal structures.

Place, publisher, year, edition, pages
Cambridge: Royal Society of Chemistry, Thomas Graham House, 2004
Identifiers
urn:nbn:se:umu:diva-4451 (URN)10.1039/B313424E (DOI)
Available from: 2005-03-31 Created: 2005-03-31 Last updated: 2017-12-14Bibliographically approved
2. A speciation study of the aqueous H+/H2VO4–/H2O2/L–α-alanyl–L–serine system
Open this publication in new window or tab >>A speciation study of the aqueous H+/H2VO4–/H2O2/L–α-alanyl–L–serine system
Show others...
2003 (English)In: Dalton Transactions, 1161- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4452 (URN)
Available from: 2005-03-31 Created: 2005-03-31 Last updated: 2013-02-14Bibliographically approved
3. Speciation in the aqueous H+/H2VO4–/H2O2/L–(+)–lactate system
Open this publication in new window or tab >>Speciation in the aqueous H+/H2VO4–/H2O2/L–(+)–lactate system
2003 (English)In: Dalton Transactions, 2503- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4453 (URN)
Available from: 2005-03-31 Created: 2005-03-31 Last updated: 2013-02-14Bibliographically approved
4. Speciation in the aqueous H+/H2VO4–/H2O2/citrate system of biomedical interest
Open this publication in new window or tab >>Speciation in the aqueous H+/H2VO4–/H2O2/citrate system of biomedical interest
2004 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, no 18, 2873-2882 p.Article in journal (Refereed) Published
Abstract [en]

The speciation in the quaternary aqueous H+/H2VO4–/H2O2/citrate (Cit3–) and H+/H2VO4–/Cit3–/L-(+)-lactate (Lac–) systems has been determined at 25 °C in the physiological medium of 0.150 M Na(Cl). A combination of 51V NMR integral intensities and chemical shift (Bruker AMX500) as well as potentiometric data (glass electrode) have been collected and evaluated with the computer program LAKE, which is able to treat multimethod data simultaneously. The pKa-values for citric acid have been determined as 2.94, 4.34 and 5.61. Altogether six vanadate–citrate species have been found in the ternary H+/H2VO4–/Cit3– system in the pH region 2–10, only two of which are mononuclear. Reduction of vanadium(V) becomes more pronounced at pH < 2. Solutions, in which reduction occurred to any extent, were excluded from all calculations. In the quaternary H+/H2VO4–/H2O2/Cit3– system, eight complexes have been found in addition to all binary and ternary complexes over the pH region 2–10, including three mononuclear species. Equilibria in general are fast, but the significant and rapid decomposition of peroxide in acidic solutions limited the final model to pH > 4. In the quaternary H+/H2VO4–/Cit3–/Lac– system, two mixed-ligand species have been determined, with the compositions V2CitLac2– and V2CitLac3–(pKa= 5.0). To our knowledge, this is the first time such complexes have been reported for vanadium(V). 51V NMR chemical shifts, compositions and formation constants are given, and equilibrium conditions are illustrated in distribution diagrams as well as the fit of the model to the experimental data. When suitable, structural proposals are given, based on 13C NMR measurements and available literature data of related compounds.

Place, publisher, year, edition, pages
Cambridge: Royal Society of Chemistry, Thomas Graham House, 2004
Identifiers
urn:nbn:se:umu:diva-13674 (URN)10.1039/B409429H (DOI)
Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2017-12-14Bibliographically approved
5. Speciation in the aqueous H+/H2VO4–/H2O2/phosphate system
Open this publication in new window or tab >>Speciation in the aqueous H+/H2VO4–/H2O2/phosphate system
Show others...
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4455 (URN)
Available from: 2005-03-31 Created: 2005-03-31 Last updated: 2013-02-14Bibliographically approved
6. Speciation in peroxovanadate systems
Open this publication in new window or tab >>Speciation in peroxovanadate systems
2003 (English)In: Coordination Chemistry Reviews, Vol. 237, no 1-2, 77-87 p.Article in journal (Refereed) Published
Abstract [en]

Detailed and thorough potentiometric and 51V-NMR spectroscopic investigations of H+–H2VO4−–H2O2–Ligand systems have been performed at 25 °C in 0.15 M Na(Cl) ionic medium. Extensive ranges of vanadate, hydrogen peroxide and ligand concentration and of pH have been covered. The medium was chosen to represent the physiological conditions in human blood. The computer program , designed to treat different types of data simultaneously, has been used to establish the entire speciation in the systems. Before studying systems containing the ligand (L), the complete speciation in the subsystem H+–H2VO4−–H2O2 must be known under the same experimental conditions. The formation constants in this subsystem have earlier been determined and it was found that hydrogen peroxide interacts with vanadate in the whole pH range studied (0.5–10.5). In all, 10 peroxovanadate species were identified and diperoxovanadate species were found to be exceptionally stable at physiological pH. The ligands studied so far include imidazole (Im), -α-alanyl--histidine (Ah), -α-alanyl--serine (As), picolinic acid (Pi), and -(+)-lactic acid (La). In these five systems, as many as 3, 8, 6, 8, and 5 different peroxovanadate—L species (isomers included) were identified. A feature common to all these systems is that V(H2O2)2L species are formed at physiological pH. Notably, the 51V chemical shift values of diperoxovanadate moieties are always found in the range −670 to −770 ppm, and those of monoperoxovanadate from −540 to −670 ppm. The equilibrium conditions are illustrated in distribution diagrams and the effectiveness of the different ligands as complexation agents are compared. In the case of diperoxovanadate complexes, ligands with aromatic nitrogen (Im, Pi, Ah) are the most effective, the one with both aliphatic nitrogen and oxygen (As) is less effective, and the one with oxygen only (La) is the least preferred.

Keyword
Potentiometry, 51V-NMR, Speciation, Bioinorganic chemistry, Insulin-mimetic activity, Peroxovanadate complexes
Identifiers
urn:nbn:se:umu:diva-9294 (URN)10.1016/S0010-8545(02)00223-0 (DOI)
Available from: 2008-03-18 Created: 2008-03-18 Last updated: 2013-02-14Bibliographically approved

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