Linked Life Data

3254299

Source:http://linkedlifedata.com/resource/pubmed/id/3254299

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1989-9-7
pubmed:abstractText
Ambient temperature incubation of the anticancer agent mitoxantrone with horseradish peroxidase and hydrogen peroxide converts it into a hexahydronaphtho[2,3-f]quinoxaline-7,12-dione in which one side chain has cyclized to the chromophore. The structure of this cyclic metabolite was secured by independent synthesis. This peroxidative conversion of mitoxantrone, the progress of which can be followed spectrophotometrically, is accompanied by formation of a free radical species. The EPR characteristics, and dependence on pH of the latter, suggest it exists as a radical cation. The enzymatic oxidation of mitoxantrone is totally irreversible. The purified cyclic metabolite is a substrate for the peroxidase affording the unstable fully oxidized diimino compound and this reaction is fully reversible upon addition of ascorbate or other biological reductants. Admixture of the fully oxidized diimino product with the reduced cyclic metabolite generates the corresponding radical cation species by disproportionation-comproportionation processes. Independent kinetic studies confirm that reaction of the peroxidase with the cyclic metabolite proceeds more rapidly than with mitoxantrone itself. A derivative of mitoxantrone, in which the side-chain secondary amine functions are acylated, generates a radical cation upon treatment with the peroxidase-H2O2 system but does not cyclize subsequently. Derivatives without phenolic hydroxyls or those in which the phenolic hydroxyls are blocked also undergo peroxidative reaction. These observations suggest that initial peroxidative attack occurs at the aromatic nitrogens of mitoxantrone. The possible relevance of these results to the anticancer action of mitoxantrone and the implications for suppression of lipid peroxidation in vivo are discussed.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0891-5849
pubmed:author
pubmed:issnType
Print
pubmed:volume
5
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
13-25
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1988
pubmed:articleTitle
Enzymatic oxidative activation and transformation of the antitumor agent mitoxantrone.
pubmed:affiliation
Department of Chemistry, University of Alberta, Edmonton, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't