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Titolo:
ENZYMATIC ACTIVATION OF DNA CLEAVAGE BY DYNEMICIN-A AND SYNTHETIC ANALOGS
Autore:
MYERS AG; KORT ME; COHEN SB; TOM NJ;
Indirizzi:
CALTECH,DIV CHEM & CHEM ENGN PASADENA CA 91125
Titolo Testata:
Biochemistry
fascicolo: 13, volume: 36, anno: 1997,
pagine: 3903 - 3908
SICI:
0006-2960(1997)36:13<3903:EAODCB>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTITUMOR ANTIBIOTIC DYNEMICIN; ONE-ELECTRON REDUCTION; WIDE STRUCTURAL VARIABILITY; HYDROXYL RADICAL PRODUCTION; FERREDOXIN-NADP+ REDUCTASE; ANTI-CANCER AGENTS; MITOMYCIN-C; DT-DIAPHORASE; BIOREDUCTIVE ALKYLATION; XANTHINE DEHYDROGENASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
86
Recensione:
Indirizzi per estratti:
Citazione:
A.G. Myers et al., "ENZYMATIC ACTIVATION OF DNA CLEAVAGE BY DYNEMICIN-A AND SYNTHETIC ANALOGS", Biochemistry, 36(13), 1997, pp. 3903-3908

Abstract

Dynemicin A (1), a member of the enediyne family of natural products,binds to double stranded DNA (K-B similar to 10(4) M(-1)) and in the presence of millimolar concentrations of a reducing cofactor such as NADPH or GSH reacts to cleave DNA. In this work, we show that the two flavin-based enzymes ferredoxin-NADP(+) reductase and xanthine oxidase catalyze the reductive activation of 1 by NADPH and NADH, respectively. The enzyme-catalyzed reductive activation of 1 leads to more rapid and efficient cleavage of DNA, even with 10-20-fold lower concentrations of the stoichiometric reductant. Significantly, the enzymatic systems are also found to activate the tight-binding (K-B greater than or equal to 10(6) M(-1)) synthetic dynemicin analogs 3 and 5 toward DNA cleavage. These same analogs do not undergo reductive activation with NADPH or NADH alone, where evidence has been obtained to support the proposal that the DNA-bound drugs are protected from reductive activation. The new enzymatic activation processes described may have important implications for chemistry occurring with 1 and synthetic analogs in vivo, as well as for the future development of dynemicin-based anticancer agents.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/07/20 alle ore 11:31:53