Objective
Nitric oxide (NO., nitrogen monoxide) synthesised in vivo controls an astonishing range of physiological processes. Its toxic effects can be attributed to peroxynitrite and higher oxides of nitrogen. However, their basic chemistry remains controversial, and there is presently no consensus on many mechanistic issues related to their action.
The goal of this project is to obtain a basic knowledge of the reactivity and reaction mechanisms of peroxynitrite and related species. This will allow us to develop a range of measures to detoxify these toxic compounds.
New chemical models of active site analogues of metalloproteins (iron-sulphur proteins, heme proteins, copper oxygenases and oxidases) will be synthesised, because these species are the main targets for interaction with nitric oxides, and studies of their reactions with peroxynitrite, nitric oxide derivatives, and NO/superoxide will be carried out.
The kinetics, energetics and mechanism of peroxynitrite reactions with different substrates will be investigated. Dimethylsulfoxide and phenols will be used as the major substrates, and the effect of pH, CO2, solvents, and the effect of different transition metal complexes, metalloproteins, and models of active sites of metalloproteins will be studied in detail.
New hydroxamic acids and their derivatives based on natural hydroxycarbonic acids will be synthesised, and their antioxidant and chelating properties will be studied. Methods to assess their antioxidant activities will be further developed. Special emphasis will be given to mixtures of antioxidants to determine synergism and the mechanism of their interaction. An algorithm based on a technique developed to evaluate antioxidant properties towards peroxynitrite will be used. New methods to evaluate antioxidants - simple tube assays and selective electrodes - will be developed
Thus, the emphasis of proposed work is to synthesize new antioxidants and models of Cu- and Fe metalloproteins; to study their reactions with peroxynitrite; and to develop new methods of antioxidants evaluations.
The major results expected are: novel basic knowledge regarding mechanisms of peroxynitrite reactions; new efficient antioxidants; new chemical models of metalloproteins; new methods of antioxidant evaluations, and new approaches for peroxynitrite detoxification with antioxidants and chelating agents
Topic(s)
Call for proposal
Data not availableFunding Scheme
Data not availableCoordinator
27100 Pavia
Italy