Sequence-specific DNA alkylation targeting for Kras codon 13 mutation by pyrrole-imidazole polyamide seco-CBI conjugates.
Chemistry
; 20(5): 1310-7, 2014 Jan 27.
Article
en En
| MEDLINE
| ID: mdl-24382626
ABSTRACT
Hairpin N-methylpyrrole-N-methylimidazole polyamide seco-CBI conjugates 2-6 were designed for synthesis by Fmoc solid-phase synthesis, and their DNA-alkylating activities against the Kras codonâ
13 mutation were compared by high-resolution denaturing gel electrophoresis with 225 base pair (bp) DNA fragments. Conjugate 5 had high reactivity towards the Kras codonâ
13 mutation site, with alkylation occurring at the A of the sequence 5'-ACGTCACCA-3' (siteâ
2), including minor 1â
bp-mismatch alkylation against wild type 5'-ACGCCACCA-3' (siteâ
3). Conjugate 6, which differs from conjugate 5 by exchanging one Py unit with a ß unit, showed high selectivity but only weakly alkylated the A of 5'-ACGTCACCA-3' (siteâ
2). The hairpin polyamide seco-CBI conjugate 5 thus alkylates according to Dervan's pairing rule with the pairing recognition which ß/ß pair targets T-A and A-T pairs. SPR and a computer-minimized model suggest that 5 binds to the target sequence with high affinity in a hairpin conformation, allowing for efficient DNA alkylation.
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Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Pirroles
/
ADN
/
Proteínas ras
/
Imidazoles
/
Nylons
Límite:
Humans
Idioma:
En
Revista:
Chemistry
Asunto de la revista:
QUIMICA
Año:
2014
Tipo del documento:
Article