transplatin Dotaz Zobrazit nápovědu
Clinically ineffective transplatin [trans-diamminedichloridoplatinum(II)] is used in the studies of the structure-pharmacological activity relationship of platinum compounds. In addition, a number of transplatin analogs exhibit promising toxic effects in several tumor cell lines including those resistant to conventional antitumor cisplatin. Moreover, transplatin-modified oligonucleotides have been shown to be effective modulators of gene expression. Owing to these facts and because DNA is also considered the major pharmacological target of platinum complexes, interactions between transplatin and DNA are of great interest. We examined, using biophysical and biochemical methods, the stability of 1,3-GNG intrastrand cross-links (CLs) formed by transplatin in short synthetic oligodeoxyribonucleotide duplexes and natural double-helical DNA. We have found that transplatin forms in double-helical DNA 1,3-GNG intrastrand CLs, but their stability depends on the sequence context. In some sequences the 1,3-GNG intrastrand CLs formed by transplatin in double-helical DNA readily rearrange into interstrand CLs. On the other hand, in a number of other sequences these intrastrand CLs are relatively stable. We show that the stability of 1,3-GNG intrastrand CLs of transplatin correlates with the extent of conformational distortion and thermodynamic destabilization induced in double-helical DNA by this adduct.
- MeSH
- biofyzikální jevy MeSH
- cisplatina metabolismus MeSH
- DNA genetika chemie metabolismus MeSH
- financování organizované MeSH
- kalorimetrie MeSH
- konformace nukleové kyseliny MeSH
- oligodeoxyribonukleotidy genetika chemie metabolismus MeSH
- reagencia zkříženě vázaná metabolismus MeSH
- sekvence nukleotidů MeSH
- termodynamika MeSH
It is well-known that although cisplatin, [cis-[PtCl2(NH3)2], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm-2). Chemical studies show that light activates both chloride ligands of transplatin, and experiments on pSP73 plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark). Comet assays showed that UVA irradiation of transplatin-treated cells resulted in an increased inhibition of H2O2-induced DNA migration, supporting the conclusion that the cytotoxicity of photoactivated transplatin is mainly due to formation of DNA interstrand and DNA-protein cross-links.
- MeSH
- antitumorózní látky * farmakologie MeSH
- cisplatina * farmakologie MeSH
- DNA footprinting MeSH
- DNA metabolismus účinky léků účinky záření MeSH
- keratinocyty účinky léků účinky záření MeSH
- kometový test MeSH
- kultivované buňky účinky léků účinky záření MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- nádory vaječníků farmakoterapie patologie radioterapie MeSH
- poškození DNA účinky léků účinky záření MeSH
- proteiny metabolismus MeSH
- reagencia zkříženě vázaná * farmakologie MeSH
- stereoizomerie MeSH
- ultrafialové záření * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Oligonucleotides modified by clinically ineffective trans-diamminedichloridoplatinum(II) (transplatin) have been shown to be effective modulators of gene expression. This is so because in some nucleotide sequences the 1,3-GNG intrastrand adducts formed by transplatin in double-helical DNA readily rearrange into interstrand cross-links so that they can cross-link the oligonucleotides to their targets. On the other hand, in a number of other sequences these intrastrand adducts are relatively stable, which represents the major difficulty in the clinical use of the antisense transplatin-modified oligonucleotides. Therefore, we examined in this study, the stability of 1,3-GNG intrastrand adducts in double-helical DNA formed by a new antitumor derivative of transplatin, trans-[Pt(CH3NH2)2Cl2], in the sequence contexts in which transplatin formed relatively stable intrastrand cross-links which did not readily rearranged into interstrand cross-links. We have found that 1,3-GNG intrastrand adducts in double-helical DNA formed by trans-[Pt(CH3NH2)2Cl2] even in such sequences readily rearrange into interstrand cross-links. This work also suggests that an enhanced frequency of intrastrand cross-links yielded by trans-[Pt(CH3NH2)2Cl2] is a consequence of the fact that these DNA lesions considerably distort double-helical DNA in far more sequence contexts than parent transplatin. Our results suggest that trans-[Pt(CH3NH2)2Cl2]-modified oligonucleotides represent promising candidates for new agents in antisense or antigene approach.
- MeSH
- adukty DNA chemie MeSH
- antitumorózní látky chemie farmakologie MeSH
- cisplatina chemie farmakologie MeSH
- DNA chemie MeSH
- lidé MeSH
- ligandy MeSH
- methylaminy chemie farmakologie MeSH
- oligonukleotidy chemie farmakologie MeSH
- reagencia zkříženě vázaná chemie farmakologie MeSH
- sekvence nukleotidů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The effects of the two representatives of the antitumor transplatinum agents, trans-[PtCl2(methylamine)2] and trans-[PtCl2(NH3)(1-methyl-7-azaindole)] on bacterial growth were examined. The results show that these antitumor transplatinum agents can be grouped with the coordination Pt(II) compounds exhibiting antitumor activity and capable of inducing bacterial filamentation and initiate lysis in lysogenic bacteria. The results corroborate the thesis that DNA is the potential cellular target also for a class of antitumor derivatives of transplatin.
We report in the present work new analogues of clinically ineffective transplatin in which one ammine group was replaced by aliphatic and the other by a planar heterocyclic ligand, namely trans-[PtCl(2)(isopropylamine)(3-(hydroxymethyl)-pyridine)], 1, and trans-[PtCl(2)(isopropylamine)(4-(hydroxymethyl)-pyridine)], 2. The new compounds, in comparison with parent transplatin, exhibit radically enhanced activity in tumor cell lines both sensitive and in particular resistant to cisplatin. Concomitantly, the DNA binding mode of 1 and 2 compared to parent transplatin and other antitumor analogues of transplatin in which only one ammine group was replaced is also different. The results also suggest that the reactions of glutathione and metallothionein-2 with compounds 1 and 2 do not play a crucial role in their overall biological effects. In addition, the monofunctional adducts of 1 and 2 are quenched by glutathione considerably less than the adducts of transplatin, which may potentiate cytotoxic effects of these new platinum complexes.
- MeSH
- aminy chemie MeSH
- cirkulární dichroismus MeSH
- cisplatina farmakologie chemická syntéza chemie MeSH
- DNA chemie účinky léků MeSH
- financování organizované MeSH
- heterocyklické sloučeniny monocyklické farmakologie chemická syntéza chemie MeSH
- krystalografie rentgenová MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- molekulární sekvence - údaje MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- sekvence nukleotidů MeSH
- thiomočovina chemie MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active tag.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- cisplatina analogy a deriváty MeSH
- DNA metabolismus MeSH
- indoly chemie MeSH
- lidé MeSH
- nádorový supresorový protein p53 fyziologie MeSH
- organoplatinové sloučeniny chemická syntéza chemie farmakologie MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
trans-Diaminedicholoroplatinum(II) complexes with one planar and one non-planar heterocyclic amine ligand were designed as new potential antitumor drugs. The X-ray crystallographic structures of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl revealed that the piperidine and piperazine ligands bind to the platinum through the equatorial position and that the ligands adopt the chair conformation. The nonplatinated amine of the piperazine can form hydrogen bonds with atoms that are approximately 7.5 A away from the Pt binding site. DNA is considered a major pharmacological target of platinum compounds. Hence, to expand the database correlating structural features of platinum compounds and DNA distortions induced by these compounds, which may facilitate identification of more effective anticancer platinum drugs, we describe the DNA binding mode in a cell-free medium of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl. Interestingly, the overall impact of the replacement of the second ammine group in transplatin by the heterocyclic ligands appears to change the character of the global conformational changes induced in DNA towards that induced by cisplatin. The clinical ineffectiveness of the parent transplatin has been proposed to be also associated with its reduced capability to form bifunctional adducts in double-helical DNA. The results of the present work support the view that replacement of both ammine groups of transplatin by heterocyclic ligands enhances cytotoxicity probably due to the marked enhancement of the stability of intrastrand cross-links in double-helical DNA.
- MeSH
- antitumorózní látky farmakologie chemie MeSH
- cisplatina farmakologie chemie MeSH
- DNA-helikasy MeSH
- DNA * metabolismus účinky léků MeSH
- heterocyklické sloučeniny farmakologie chemická syntéza MeSH
- indikátory a reagencie MeSH
- krystalografie rentgenová MeSH
- ligandy MeSH
- molekulární modely MeSH
- platina chemie MeSH
- reagencia zkříženě vázaná farmakologie chemie MeSH
- superhelikální DNA chemie účinky léků MeSH
- thiomočovina chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- práce podpořená grantem MeSH
The thermodynamics of cisplatin and transplatin hydration is studied within the model of constant pH solution. Several implicit solvation models were chosen for the determination of pK(a) and pK constants of the hydration reactions. The polarizable dielectric model (DPCM), integral equation formalism polarizable model (IEFPCM), and polarizable conductor model (CPCM) were combined with the 'united atom model for Hartree-Fock' (UAHF) method for cavity construction and the B3LYP/6-31++G(2dp,2pd) level of calculations for the determination of electronic energies. The results were compared with the COSMO-RS and SM8 model developed by Truhlar (with M06 and MPWX functionals and the charge model CM4). The RMS difference between experimental and calculated pK(a) values of cis/transplatin, water, HCl, and NH (4) (+) was used to evaluate accuracy of calculations. The DPCM model was confirmed to perform the best. The predicted pK(a) constants were used in Legendre transformation for the estimation of the ΔG' energies in the constant-pH model. The dependence of the pK constant on pH is plotted and compared with experimental value at pH=7.4. The influence of various chloride concentrations on the molar fractions of dissolved forms of cisplatin is examined for the DPCM model. The increased ratio of cisplatin active aqua-forms is clearly visible for 4 mM chloride solution in comparison with 104 mM Cl(-) concentration.
