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Titolo:
Abasic site recognition in DNA as a new strategy to potentiate the action of anticancer alkylating drugs?
Autore:
Belmont, P; Jourdan, M; Demeunynck, M; Constant, JF; Garcia, J; Lhomme, J; Carez, D; Croisy, A;
Indirizzi:
Univ Grenoble 1, CNRS, UMR 5616, LEDSS, F-38041 Grenoble 9, France Univ Grenoble 1 Grenoble France 9 616, LEDSS, F-38041 Grenoble 9, France Ctr Univ Orsay, Lab Raymond Latarjet, Inst Curie Rech, INSERM U350, F-91405 Orsay, France Ctr Univ Orsay Orsay France F-91405 , INSERM U350, F-91405 Orsay, France
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 25, volume: 42, anno: 1999,
pagine: 5153 - 5159
SICI:
0022-2623(199912)42:25<5153:ASRIDA>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
CLEAVE APURINIC SITES; TOPOISOMERASE-II; EXCISION-REPAIR; INHIBITION; AGENTS; OLIGODEOXYNUCLEOTIDES; ENDONUCLEASES; CYTOTOXICITY; RELIGATION; MOLECULES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Demeunynck, M Univ Grenoble 1, CNRS, UMR 5616, LEDSS, BP 53, F-38041 Grenoble 9, France Univ Grenoble 1 BP 53 Grenoble France 9 Grenoble 9, France
Citazione:
P. Belmont et al., "Abasic site recognition in DNA as a new strategy to potentiate the action of anticancer alkylating drugs?", J MED CHEM, 42(25), 1999, pp. 5153-5159

Abstract

Inhibition of abasic site repair in the cell seems an attractive strategy to potentiate the action of antitumor DNA alkylating drugs. Molecules that bind specifically and strongly to the abasic site are possible candidates to achieve such inhibition. We explored this strategy by preparing molecule 4 that incorporates (1) an aminoacridine intercalator for DNA binding, (2) an adenine moiety for abasic site recognition, and (3) a linker containing two guanidinium functions to increase binding to DNA without inducing cleavage at the base-sensitive abasic site. Compound 4 was compared to analoguescontaining secondary amines, i.e., 1. We report on synthesis of the new heterodimer 4. We show by physicochemical studies-including determination of association constants with calf-thymus DNA, T-m measurements, and high-field NMR examination of the complexes formed with abasic DNA duplexes-that 4 binds specifically and more strongly to the abasic site than the analogues. Compound 4 does not cleave abasic plasmid DNA. Compound 4 shows apparent synergy with the anticancer bischloroethylnitrosourea (BCNU) in L1210 and A549 cell lines in vitro. It potentiates BCNU in the in vivo tests. The results favor the pertinence of the strategy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 04:44:09