DNA double helix promotes a linkage isomerization reaction in trans-diamminedichloroplatinum(II)-modified DNA.

Abstract

In the reaction between trans-diamminedichloroplatinum(II) and a single-stranded pyrimidinerich oligodeoxyribonucleotide (22-mer) containing the central sequence TGAGT, the 1,3-trans-{Pt(NH3)2[d(GAG)J} crosslink is formed. The 1,3-intrastrand cross-link is inert within the single-stranded oligonucleotide. In contrast, it rearranges to an interstrand cross-link when the platinated oligonucleotide is paired with its complementary deoxyribo-or ribonucleotide strand. The half-life of the 1,3-intrastrand cross-link, -6 h at 370C, is independent of the nature and concentration of the salt (NaCl or NaCI04). It is not dramatically affected when the intervening adenine residue between the chelated guanine residues is replaced by a cytosine or a thymine residue or when the TA base pair adjacent to the 5' or 3' side of the adduct is replaced by a C-G base pair. On the other hand, a mismatch on the 3' or 5' side of the adduct prevents the rearrangement. We propose that the linkage isomerization reaction results from a direct nucleophilic attack of the cytosine residue complementary to the platinated 5' guanine residue on the platinum residue. Among others, the potential use of the DNA RNApromoted reaction is discussed in the context of the antisense strategy to irreversibly cross-link the antisense oligonucleotides to their targets. cis-Diamminedichloroplatinum(II) (cis-DDP) is a chemotherapeutic agent used largely in the clinical treatment of tumors. It is generally accepted that the cytotoxic action of cis-DDP is related to its ability to bind to cellular DNA and form covalent adducts. Although the major lesion is an intrastrand cross-link between two guanine (G) residues, it is not yet established that this lesion is responsible for the antitumor activity of cis-DDP (for general reviews, see refs. 1-4). Acquired resistance to cis-DDP may be associated with the increased gene-specific DNA repair efficiency of the interstrand adducts (5), a minor lesion in which the two G residues in the d(GC)-d(GC) site are cross-linked (6, 7).A question still under debate concerns trans-dichlorodiammineplatinum(II) (trans-DDP), the stereoisomer of cis-DDP. This compound is less mutagenic and less cytotoxic than cis-DDP and is ineffective as an antitumor drug (1)(2)(3)(4). In their reaction with DNA, the two isomers present similarities and differences (for general reviews, see refs. 8 and 9). The DNA modification by cis-or trans-DDP is controlled kinetically and the adducts are formed in two solvent-assisted reactions. The exchange of the chloro groups of both isomers is rate-limiting in both the initial attack of DNA and the closure of monofunctional adducts to bifunctional crosslinks. The preferred site of initial binding of the isomers is the N7 atom of G residues. Subsequently, the monofunctional adducts react with the neighboring bases to form intrastrand and interstrand cross-links. Among the differences between the two isomers, one is that stereochemical limitations preclude trans-DDP from forming intrastrand cross-links b...

DNA Interstrand Cross-links of the Novel Antitumor Trinuclear Platinum Complex BBR3464

“…It was no longer reactive in all three cross-linked duplexes. This observation confirms that the unique G residue in the top strands remained platinated and was involved in the interstrand CL contained in the single fraction of interstrand cross-linked duplexes (10,29,43).…”

“…The samples of duplexes [1,2], [1,4], and [1,6] interstrand cross-linked by BBR3464 in which the top strand was only 5Ј-end-labeled with 32 P were reacted with DMS, which does not react with platinated G residues because N-7 is no longer accessible (10,29,43). The adducts were removed by NaCN (29,30), and then the sample was treated with piperidine.…”

“…2A). After a 24-h reaction period, the bands or FPLC peaks corresponding to the interstrand cross-linked duplexes were cut off from the gel or collected after FPLC separation, respectively; the duplexes were isolated (eluted from the bands and precipitated or only precipitated from the FPLC fractions) and further characterized by Maxam-Gilbert footprinting (10,29,43).…”

Coordination of 9-Ethylguanine to the Mixed-Ligand Compound α-[Ru(azpy)(bpy)Cl2] (azpy = 2-Phenylazopyridine and bpy = 2,2‘-Bipyridine). An Unprecedented Ligand Positional Shift, Correlated to the Cytotoxicity of This Type of [RuL2Cl2] (with L = azpy or bpy) Complex

“…Furthermore, linkage isomerization processes of cis-and trans-[PtCl 2 (NH 3 ) 2 ]-like species in oligonucleotides are driven by strained initial structures. [30][31][32] Figure 7. 2D 1 H-1 H NOESY spectrum (600 MHz) and some assignments (proton numbering as in Figures 1 and 8) of the aromatic region of R′-[Ru-(azpy)(bpy)(9-EtGua)(H2O)](PF6)2 in acetone-d6 at 263 K. This measurement has been performed using an old sample of 2 (three weeks in acetone-d6).…”

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5′-GMP

“…More specifically the activity of cisplatin is thought to be related to its ability to form 1,2-intrastrand cross-links between two adjacent guanines [11][12][13]. On the other hand, if transplatin, binds a guanine base, it is more likely to transform into an interstrand adduct involving the complementary cytosine, than to bind the adjacent base on the same strand of DNA [12,14]. It is this difference in DNA-platinum adducts formation that may be the reason for the difference in antitumor activity observed between cis-and transplatin.…”