Conformational analysis of site-specific DNA cross-links of cisplatin-distamycin conjugates
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
11027144
DOI
10.1021/bi000710h
PII: bi000710h
Knihovny.cz E-resources
- MeSH
- DNA Adducts chemistry MeSH
- Bromine chemistry MeSH
- Circular Dichroism MeSH
- Cisplatin chemistry MeSH
- Diethyl Pyrocarbonate chemistry MeSH
- Dinucleoside Phosphates chemistry MeSH
- Distamycins chemistry MeSH
- DNA chemistry MeSH
- Nucleic Acid Heteroduplexes chemical synthesis chemistry MeSH
- DNA, Single-Stranded chemistry MeSH
- Nucleic Acid Conformation * MeSH
- Potassium Permanganate chemistry MeSH
- Oligodeoxyribonucleotides chemical synthesis chemistry MeSH
- Pyrimidine Nucleotides chemical synthesis chemistry MeSH
- Cross-Linking Reagents chemistry MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Bromine MeSH
- cisplatin-deoxy(guanosine monophosphate guanosine) adduct MeSH Browser
- cisplatin-DNA adduct MeSH Browser
- Cisplatin MeSH
- deoxyguanylyl-(3'-5')-guanosine MeSH Browser
- Diethyl Pyrocarbonate MeSH
- Dinucleoside Phosphates MeSH
- Distamycins MeSH
- DNA MeSH
- Nucleic Acid Heteroduplexes MeSH
- DNA, Single-Stranded MeSH
- Potassium Permanganate MeSH
- Oligodeoxyribonucleotides MeSH
- Pyrimidine Nucleotides MeSH
- Cross-Linking Reagents MeSH
- stallimycin MeSH Browser
The requirement for novel platinum antitumor drugs led to the concept of synthesis of novel platinum drugs based on targeting cisplatin to various carrier molecules. We have shown [Loskotova, H., and Brabec, V. (1999) Eur. J. Biochem. 266, 392-402] that attachment of DNA minor-groove-binder distamycin to cisplatin changes several features of DNA-binding mode of the parent platinum drug. Major differences comprise different conformational changes in DNA and a considerably higher interstrand cross-linking efficiency. The studies of the present work have been directed to the analysis of oligodeoxyribonucleotide duplexes containing single, site-specific adducts of platinum-distamycin conjugates. These uniquely modified duplexes were analyzed by Maxam-Gilbert footprinting, phase-sensitive gel electrophoresis bending assay and chemical probes of DNA conformation. The results have indicated that the attachment of distamycin to cisplatin mainly affects the sites involved in the interstrand cross-links so that these adducts are preferentially formed between complementary guanine and cytosine residues. This interstrand cross-link bends the helix axis by approximately 35 degrees toward minor groove, unwinds DNA by approximately 95 degrees and distorts DNA symmetrically around the adduct. In addition, CD spectra of restriction fragments modified by the cisplatin-distamycin conjugates have demonstrated that distamycin moiety in the interstrand cross-links of these compounds interacts with DNA. This interaction facilitates the formation of these adducts. Hence, the structural impact of the specific interstrand cross-link detected in this study deserves attention when biological behavior of cisplatin derivatives targeted by oligopeptide DNA minor-groove-binders is evaluated.
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