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Transplatin-modified oligonucleotides as modulators of gene expression
1Centre de Biophysique Moléculaire, CNRS, Rue Charles Sadron, 45071, Orléans, France.
Abstract:
Transplatin [trans-diamminedichloroplatinum(II)], contrary to its stereoisomer cisplatin, is clinically inactive. However, like cisplatin, it binds to DNA. In the first part of this review, some results on the interactions between transplatin and double-stranded DNA are presented. The major bifunctional adducts are interstrand cross-links. Intrastrand cross-links are not formed. On the other hand, intrastrand cross-links are formed in the reaction between single-stranded DNA and transplatin. Some properties of the intrastrand cross-links at GNG sites (N is a nucleotide) are described. The (G1,G3)-intrastrand cross-links rearrange into interstrand cross-links as soon as the platinated oligonucleotides are paired with their complementary strands. The linkage isomerization reaction is exclusively triggered by the formation of a double helix. The potential use of these platinated oligonucleotides to block the cellular machinery specifically and irreversibly is discussed.
Insights
Transplatin, unlike cisplatin, is clinically inactive but binds DNA. It forms interstrand cross-links with double-stranded DNA and intrastrand cross-links with single-stranded DNA, which can rearrange into interstrand cross-links.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biochemistry
Background:
- Cisplatin is a clinically effective platinum-based chemotherapy drug.
- Transplatin, a stereoisomer of cisplatin, is clinically inactive.
- Both cisplatin and transplatin interact with DNA.
Purpose of the Study:
- To investigate the DNA binding interactions of transplatin.
- To compare the adducts formed by transplatin with double-stranded and single-stranded DNA.
- To explore the potential therapeutic applications of transplatin-DNA adducts.
Main Methods:
- Review of existing literature on transplatin-DNA interactions.
- Analysis of DNA adduct formation in double-stranded and single-stranded DNA.
- Characterization of intrastrand cross-links at GNG sites.
- Investigation of adduct rearrangement upon DNA duplex formation.
Main Results:
- Transplatin predominantly forms interstrand cross-links with double-stranded DNA.
- Intrastrand cross-links are formed with single-stranded DNA at GNG sites.
- These intrastrand cross-links can isomerize into interstrand cross-links upon formation of a complementary DNA strand.
- This isomerization is triggered by double helix formation.
Conclusions:
- Transplatin's DNA binding mechanism differs significantly from cisplatin.
- The ability of transplatin adducts to rearrange suggests potential for targeted cellular machinery inhibition.
- Further research into transplatin-DNA adducts may yield novel therapeutic strategies.