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Titolo:
SYNTHESIS OF (-DYNEMICIN-A AND ANALOGS OF WIDE STRUCTURAL VARIABILITY- ESTABLISHMENT OF THE ABSOLUTE-CONFIGURATION OF NATURAL DYNEMICIN-A())
Autore:
MYERS AG; FRALEY ME; TOM NJ; COHEN SB; MADAR DJ;
Indirizzi:
CALTECH,ARNOLD & MABEL BECKMAN LABS CHEM SYNTHESIS PASADENA CA 91125
Titolo Testata:
Chemistry & biology
fascicolo: 1, volume: 2, anno: 1995,
pagine: 33 - 43
SICI:
1074-5521(1995)2:1<33:SO(AAO>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
DIELS-ALDER REACTION; A MODELS; METHYL; 1,5-DIYN-3-ENE; ANTIBIOTICS; CHEMISTRY; CLEAVAGE; SYSTEMS;
Keywords:
ANTHRACYCLINE ANTIBIOTICS; CHEMICAL SYNTHESIS; DNA CLEAVAGE; DYNEMICIN A; ENEDIYNE ANTIBIOTICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
29
Recensione:
Indirizzi per estratti:
Citazione:
A.G. Myers et al., "SYNTHESIS OF (-DYNEMICIN-A AND ANALOGS OF WIDE STRUCTURAL VARIABILITY- ESTABLISHMENT OF THE ABSOLUTE-CONFIGURATION OF NATURAL DYNEMICIN-A())", Chemistry & biology, 2(1), 1995, pp. 33-43

Abstract

Background: Dynemicin A is an exceedingly potent antitumor antibioticderived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH orglutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modifythe structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product. Results: Amultistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed. The absolute configuration of natural dynemicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation. The route that uas developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to nonnatural dynemicins of wide structural variability by modifications of these fragments. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH. Conclusions: Enantiomerically pure dynemicin A is now available by laboratory synthesis. The natural, (+)-enantiomer of dynemicin A is shown to possessthe 2S, 3S, 4S, 7R, 8R configuration. A wide variety of heretofore unavailable, active analogs of dynemicin A have been prepared and are found to produce subtle variations in sequence specificity of DNA cleavage compared to the natural product and, of potentially greater significance, display variations in the efficiency of DNA cleavage as a function of the activating agent.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/08/20 alle ore 00:52:54