Nitracrine - an experimental hypoxia selective cytotoxin

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dc.contributor.author Sutton, Bridget Mary en
dc.date.accessioned 2007-09-10T05:31:14Z en
dc.date.available 2007-09-10T05:31:14Z en
dc.date.issued 1989 en
dc.identifier THESIS 90-022 en
dc.identifier.citation Thesis (PhD--Chemistry)--University of Auckland, 1989 en
dc.identifier.uri http://hdl.handle.net/2292/1774 en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Nitracrine, 9-(3-dimethylaminopropylamino)-1-nitroacridine, is a hypoxia selective cytotoxin in mammalian cell culture but it does not demonstrate hypoxia selective activity in vivo. In this investigation some of the physico-chemical properties of nitracrine are examined. Hydrolysis of 4-substituted-1-nitroacridines has been examined and attempts have been made to fit the rate constants of hydrolysis and the acid dissociation constants of these compounds to linear free energy and dual substituent parameter relationships. The compounds most resistant to hydrolytic breakdown are those bearing electron donating substituents. New chromatographic methods have been developed which have differing selectivity and have been used to examine the products of reduction of nitracrine. The major hypoxic metabolite from AA8 cells has been prepared synthetically using NaBH4 reduction under neutral conditions, catalysed by Pd/C. The compound has been identified as 1-amino-9-(3-dimethylaminopropylamino)acridine. γ-Radiolysis has been used to determine the stoichiometry of reduction of the 4-substituted nitracrines. Structure activity relationships for the kinetics of nitro reduction have been defined using the enzyme xanthine oxidase and reduced flavin mononucleotide, the latter acting as a model of the enzyme's active site. Vmax and Km have been determined for the reduction of a series of nitroheterocycles catalysed by xanthine oxidase. Km shows significant variation among the compounds tested. Marcus theory has been used to determine ΔG◦‡ for the reduction reactions. Results from both reduction methods show that ΔG◦‡ ≈ 2 kJ mol-1, suggesting that the enzymatic and non-enzymatic reductions occur by a similar mechanism. A correlation is observed between the reduction potential and the logarithm of the rate of reduction, measured as Vmax in the case of xanthine oxidase and k2 in the case of reduced flavin mononucleotide. These correlations have led to the selection of 4-OMe-nitracrine for testing in vivo. en
dc.language.iso en en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA9911445214002091 en
dc.rights Restricted Item. Available to authenticated members of The University of Auckland. en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Nitracrine - an experimental hypoxia selective cytotoxin en
dc.type Thesis en
thesis.degree.discipline Chemistry en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The author en


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