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Titolo:
The relevance of enzymatic oxidation by horseradish peroxidase to antitumour potency of imidazoacridinone derivatives
Autore:
Mazerska, Z; Gorlewska, K; Kraciuk, A; Konopa, J;
Indirizzi:
GdanskdTech Univ, Dept Pharmaceut Technol & Biochem, PL-80952 Gdansk, Polan Gdansk Tech Univ Gdansk Poland PL-80952 Biochem, PL-80952 Gdansk, Polan
Titolo Testata:
CHEMICO-BIOLOGICAL INTERACTIONS
fascicolo: 1, volume: 115, anno: 1998,
pagine: 1 - 22
SICI:
0009-2797(19980814)115:1<1:TROEOB>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA CROSS-LINKING; ANTI-TUMOR; ANTINEOPLASTIC IMIDAZOACRIDINONES; BIOLOGICAL-ACTIVITY; COVALENT BINDING; IN-VIVO; CELLS; MITOXANTRONE; AGENTS; RAT;
Keywords:
antitumour imidazoacridinones; enzymatic oxidation; metabolic activation of drugs; peroxidase-mediated metabolism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
29
Recensione:
Indirizzi per estratti:
Indirizzo: Mazerska, Z GdanskdTech Univ, Dept Pharmaceut Technol & Biochem, PL-80952 Gdansk, Polan Gdansk Tech Univ Gdansk Poland PL-80952 -80952 Gdansk, Polan
Citazione:
Z. Mazerska et al., "The relevance of enzymatic oxidation by horseradish peroxidase to antitumour potency of imidazoacridinone derivatives", CHEM-BIO IN, 115(1), 1998, pp. 1-22

Abstract

The presented study concentrated on the oxidative enzymatic transformationof six imidazoacridinone derivatives exhibiting different antitumour activity. Horseradish peroxidase was applied as an enzymatic model system. The investigations aimed to evaluate: (1) whether the studied compounds can undergo oxidative biotransformation; (2) whether the susceptibility to such biotransformation relates to the structure and antitumour activity of these compounds; and (3) which elements of imidazoacridinone structure are involvedin this kind of transformation. The reaction courses were followed by three methods: UV-VIS spectroscopy, electron paramagnetic resonance and high-performance liquid chromatography, It was shown that all the imidazoacridinones studied underwent enzymatic oxidation resulting in the formation of several products, spectra of which revealed that imidazoacridinone chromophore as well as alkylamino side-chain were involved in these biotransformations. The susceptibility to enzymatic oxidation turned out to be well correlatedwith antitumour activity of these compounds. It was demonstrated that the highly active antitumour 8-hydroxy derivatives underwent oxidative transformation far more readily than the less active 8-methoxy derivatives and analogues without substituent in position 8. The results indicated that the oxidation pathway of 8-hydroxy compounds was different from those observed forthe remaining imidazoacridinones studied. It also differed from the pathway proposed earlier for mitoxantrone. Moreover, it was find out that not only the rate but also the mechanism of horseradish oxidation of 8-hydroxy derivatives depended on the reaction conditions. In the presence of excess of hydrogen peroxide, the drugs were exceptionally reactive giving rise to themixture of many unstable products, among which compounds with both changedand unchanged chromophore structure were formed. However, the equimolar ratio of drug and hydrogen peroxide led to stable products, which resulted from the oxidation in aminoalkyl side-chain. The possible structures of products of imidazoacridinone enzymatic oxidation are discussed. In conclusion, the results presented in this paper indicate that the oxidative metabolic activation of imidazoacridinones may represent the crucial step in their biological action. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/12/20 alle ore 10:41:14