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Titolo:
Sequence selectivity, cross-linking efficiency and cytotoxicity of DNA-targeted 4-anilinoquinoline aniline mustards
Autore:
McClean, S; Costelloe, C; Denny, WA; Searcey, M; Wakelin, LPG;
Indirizzi:
Natl Univ Ireland Univ Coll Dublin, Dept Chem, Dublin 4, Ireland Natl UnivIreland Univ Coll Dublin Dublin Ireland 4 m, Dublin 4, Ireland Univ Auckland, Auckland Canc Soc Res Ctr, Res Ctr, Fac Med & Hlth Sci, Auckland 1, New Zealand Univ Auckland Auckland New Zealand 1 & Hlth Sci, Auckland 1, New Zealand
Titolo Testata:
ANTI-CANCER DRUG DESIGN
fascicolo: 3, volume: 14, anno: 1999,
pagine: 187 - 204
SICI:
0266-9536(199906)14:3<187:SSCEAC>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
MINOR-GROOVE-BINDING; DIRECTED ALKYLATING-AGENTS; BENZOIC-ACID MUSTARD; BISQUATERNARY AMMONIUM HETEROCYCLES; DISTAMYCIN DERIVATIVE TALLIMUSTINE; ANTI-TUMOR COMPOUNDS; BIOLOGICAL EVALUATION; ANTITUMOR-ACTIVITY; NITROGEN MUSTARDS; CONTAINING ANALOGS;
Keywords:
alkylating agent; 4-anilinoquinoline aniline mustards; cross-linking; cytotoxicity; DNA binding; minor groove binder; sequence selectivity;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
61
Recensione:
Indirizzi per estratti:
Indirizzo: Wakelin, LPG Univ New S Wales, Sch Chem, Sydney, NSW 2052, Australia Univ New S Wales Sydney NSW Australia 2052 W 2052, Australia
Citazione:
S. McClean et al., "Sequence selectivity, cross-linking efficiency and cytotoxicity of DNA-targeted 4-anilinoquinoline aniline mustards", ANTI-CAN DR, 14(3), 1999, pp. 187-204

Abstract

We have investigated the sequence selectivity, DNA binding site characteristics, interstrand cross-linking ability and cytotoxicity of four 4-anilinoquinoline aniline mustards related to the AT-selective minor groove-bindingbisquaternary ammonium heterocycles. The compounds studied include two full mustards that differ in alkylating power, a half mustard and a quaternaryanilinoquinolinium bismustard. We have also compared their cytotoxitity with their precursor diols and their toxicity and cross-linking ability with the classical alkylating agents melphalan and chlorambucil. We find that the anilinoquinaline aniline mustards weakly and non-specifically alkylate guanines in the major groove and that they bind strongly to AT-rich sequencesin the minor groove, where they alkylate both adenines and guanines at theN3 position. The most preferred sites are classical minor groove binder AT-tracts to which all four ligands bind equally well, The remaining sites are AT-rich, but include GC base pairs, to which the ligands bind with preferences depending on their structure, The full mustards alkylate at the 3' ends of the binding site in an orientation that depends on the spatial disposition of the purines within the two strands. Generally speaking guanines are found to be much less reactive than adenines, The anilinoquinoline aniline mustards are interstrand cross-linking agents that are 60- to 100-fold more effective than melphalan, with the quaternary compound being the most efficacious. However, the type of binding site at which the cross-links occuris not clear, since distamycin challenge fails to antagonize them fully. The full mustards are 20- to 50-fold more cytotoxic than their diol precursors, are more cytotoxic than the half mustard and are 20- to 30-fold more active than melphalan and chlorambucil, The quaternary ligand is the most potent. Given the evidence to hand, it appears that antitumour activity correlates with capacity to cause interstrand cross-links at classical or near-classical AT-minor groove binder sites, rather than with ability to discriminate between the subsets of potential anilinoquinoline aniline mustard binding sites.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 20:07:41