Observation of a single-stranded DNA/pyrrolobenzodiazepine adduct.
J Am Chem Soc
; 133(48): 19376-85, 2011 Dec 07.
Article
em En
| MEDLINE
| ID: mdl-21928841
ABSTRACT
Pyrrolobenzodiazepine (PBD) antitumor agents have, to date, only been observed to bind to duplex DNA, apparently requiring a minor groove environment for covalent bond formation between their C11-position and the C2-NH(2) functionality of a guanine base. Using an HPLC/MS assay we have now observed and isolated for the first time PBD adducts with single-stranded DNA fragments. Surprisingly, these adducts could only be formed through dissociation of duplex DNA adducts and not by direct interaction of PBDs with single-stranded DNA. They were sufficiently stable for characterization by MALDI-TOF-MS and remained intact after storing at -20 °C for at least 20 days, although the PBD became detached from the DNA within 7 days if stored at room temperature. Furthermore, addition of a complementary strand allowed the duplex adduct to reform. The relative stability of single-stranded PBD/DNA adducts despite a complete loss of minor groove structure was further confirmed by CD spectroscopic analysis. The CD signal induced by the presence of a PBD molecule in the single-stranded adducts remained prominent despite heating for 2 h at 50-60 °C, thus indicating their relatively robust nature.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Benzodiazepinas
/
DNA de Cadeia Simples
/
Adutos de DNA
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Antineoplásicos
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article