Effect of the amine non-leaving group on the structure and stability of DNA complexes with cis-[Pt(R-NH2)2(NO3)2].
The antitumor compound cis-[Pt(NH3)2Cl2] (cisplatin), conserves two ammine ligands during the reaction with its cellular target DNA. Modifications of these non-leaving groups change the antineoplastic properties of this compound and its genotoxic effects. It is therefore of interest to determine the influence of non-leaving groups on the structure and stability of DNA in vitro. We have investigated platinum-DNA adducts formed by cis-[Pt(R-NH2)2(NO3)2] (where R-NH2 = NH3, methylamine, cyclobutylamine, cyclopentylamine and cyclohexylamine) as a function of DNA binding. All compounds quantitatively reacted with DNA in less than 1 h at 37 degrees C. They formed bifunctional adducts with adjacent nucleotides judging from the displacement of the intercalating molecule ethidium bromide, ultraviolet absorption spectroscopy and circular dichroism. Substitution of a H on the NH3 ligand by alkyl groups dramatically destabilized the platinum-DNA complex. Thermal stability decreased progressively with an increasing number of carbon atoms, delta tm = -4.4 degrees C for 3 cyclohexylamine-platinum-DNA adducts/1000 nucleotides, conditions where cisplatin had no effect. DNA adducts with cyclobutylamine and cyclohexylamine ligands inhibited the hydrolysis of platinum-DNA complexes by S1 nuclease. Km for the digestion of DNA containing these lesions was 2.3 times greater than for cisplatin, indicating steric inhibition of enzyme-substrate complex formation. These results show that the non-leaving groups of substituted cis-Pt(II) compounds may destabilize DNA and interfere with protein-DNA interactions. These perturbations may have consequences for the genotoxic and antitumor activities of platinum compounds.
Butour
J L
JL
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Centre National de la Recherche Scientifique, Toulouse, France.
Alvinerie
P
P
Souchard
J P
JP
Colson
P
P
Houssier
C
C
Johnson
N P
NP
D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D004279:DNA, Viral / Q000737:chemistry; D004355:Drug Stability; D007364:Intercalating Agents; D007700:Kinetics; D009691:Nucleic Acid Denaturation; D009944:Organoplatinum Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000970:Antineoplastic Agents; D004279:DNA, Viral; D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin