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Titolo:
THE MECHANISM OF DECOMPOSITION OF N-METHYL-N-NITROSOUREA (MNU) IN WATER AND A STUDY OF ITS REACTIONS WITH 2'-DEOXYGUANOSINE, 2'-DEOXYGUANOSINE 5'-MONOPHOSPHATE AND D(GTGCAC)
Autore:
GOLDING BT; BLEASDALE C; MCGINNIS J; MULLER S; REES HT; REES NH; FARMER PB; WATSON WP;
Indirizzi:
UNIV NEWCASTLE UPON TYNE,DEPT CHEM,BEDSON BLDG NEWCASTLE TYNE NE1 7RUTYNE & WEAR ENGLAND TEESSIDE POLYTECH,SCH SCI & TECHNOL MIDDLESBROUGH TS1 3BA CLEVELAND ENGLAND UNIV LEICESTER,MRC,TOXICOL UNIT LEICESTER LE1 9HN LEICS ENGLAND SHELL RES LTD,SITTINGBOURNE RES CTR SITTINGBOURNE ME9 8AG KENT ENGLAND
Titolo Testata:
Tetrahedron
fascicolo: 11, volume: 53, anno: 1997,
pagine: 4063 - 4082
SICI:
0040-4020(1997)53:11<4063:TMODON>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTITUMOR DRUG TEMOZOLOMIDE; AQUEOUS-SOLUTION; DNA; ALKYLATION; ALKYLUREAS; EXCHANGE; CANCER; NMR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
60
Recensione:
Indirizzi per estratti:
Citazione:
B.T. Golding et al., "THE MECHANISM OF DECOMPOSITION OF N-METHYL-N-NITROSOUREA (MNU) IN WATER AND A STUDY OF ITS REACTIONS WITH 2'-DEOXYGUANOSINE, 2'-DEOXYGUANOSINE 5'-MONOPHOSPHATE AND D(GTGCAC)", Tetrahedron, 53(11), 1997, pp. 4063-4082

Abstract

The carcinogenicity of N-methyl-N-nitrosourea (MNU) arises from its ability to methylate DNA. This occurs in an aqueous environment and therefore an appreciation of the mode of decomposition of MNU in water isessential to understanding the mechanism of DNA methylation and its base sequence dependence. The kinetics of MNU hydrolyses are shown to be first order in MNU with a steep rise in rate above pH 8. Using NMR for in situ monitoring of reaction intermediates and products from hydrolyses of [(CO)-C-13]MNU, [(NH2)-N-15]MNU and [(CH3)-C-13]MNU, it is proved that base-induced hydrolysis of MNU is initiated by deprotonation at the carbamoyl group. The critical reactive species are shown to be the methyldiazonium ion (Me-N-2(+)) and cyanate (NCO-). Investigations of reactions of [(CH3)-C-13]MNU with 2'-deoxyguanosine (dGuo) and 2'-deoxyguanosine 5'-monophosphate (dGuo-5P) showed that: a) the site of methylation of dGuo is highly pH-dependent (relatively more N-1 and O-6-methylation compared to N-7 occurs at higher pH); b) the principalsite of methylation of dGuo-5P by MNU is at phosphate: c) incorporation of deuterium into methyl groups occurs in D2O at higher pH. Methylation of the oligonucleotide d(GT[N-15]GCAC) by MNU in D2O showed partial deuteriation of the N-7-methyl groups of the guanines, whilst methylation by MNU in water indicated no significant preference for either guanine with respect to N-7-methylation. (C) 1997 Elsevier Science Ltd.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 10:09:57