The moderate-to-high in vitro cytotoxicity against ovarian A2780 (IC50 = 4.7-14.4 μM), prostate LNCaP (IC50 = 18.7-30.8 μM) and prostate PC-3 (IC50 = 17.6-42.3 μM) human cancer cell lines of the platinum(II) cyclobutane-1,1'-dicarboxylato complexes [Pt(cbdc)(naza)2] (1-6; cbdc = cyclobutane-1,1'-dicarboxylate(2-); naza = halogeno-substituted 7-azaindoles), derived from the anticancer metallodrug carboplatin, are reported. The complexes containing the chloro- and bromo-substituted 7-azaindoles (1, 2, and 4-6) showed a significantly higher (p < 0.05) cytotoxicity against A2780 cell line as compared to cisplatin used as a reference drug. Addition of the non-toxic concentration (5.0 μM) of L-buthionine sulfoximine (L-BSO, an effective inhibitor of γ-glutamylcysteine synthase) markedly increases the in vitro cytotoxicity of the selected complex 3 against A2780 cancer cell line by a factor of about 4.4. The cytotoxicity against A2780 and LNCaP cells, as well as the DNA platination, were effectively enhanced by UVA light irradiation (λmax = 365 nm) of the complexes, with the highest phototoxicity determined for compound 3, resulting in a 4-fold decline in the A2780 cells viability from 25.1% to 6.1%. The 1H NMR and ESI-MS experiments suggested that the complexes did not interact with glutathione as well as their ability to interact with guanosine monophosphate. The studies also confirmed UVA light induced the formation of the cis [Pt(H2O)2(cbdc`)(naza)] intermediate, where cbdc` represents monodentate-coordinated cbdc ligand, which is thought to be responsible for the enhanced cytotoxicity. This is further supported by the results of transcription mapping experiments showing that the studied complexes preferentially form the bifunctional adducts with DNA under UVA irradiation, in contrast to the formation of the less effective monofunctional adducts in dark.

• MeSH
• adukty DNA chemie   genetika   MeSH
• buthionin sulfoximin farmakologie   MeSH
• dvouřetězcové zlomy DNA účinky léků   účinky záření   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• indoly chemie   farmakologie   MeSH
• karboplatina chemie   farmakologie   MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory genetika   patologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• synergismus léků MeSH
• ultrafialové záření * MeSH
• viabilita buněk účinky léků   genetika   účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-azaindole dimer MeSH Prohlížeč
• adukty DNA MeSH
• buthionin sulfoximin MeSH
• indoly MeSH
• karboplatina MeSH
• protinádorové látky MeSH

Effects of adducts of [PtCl(NH3)3]Cl or chlorodiethylenetriamineplatinum(II) on DNA stability were studied with emphasis on thermodynamic origins of that stability. Oligodeoxyribonucleotide duplexes (15-bp) containing the single, site-specific monofunctional adduct at G-residues of the central sequences TGT/ACA or 5'-AGT/5'-ACT were prepared and analyzed by differential scanning calorimetry, temperature-dependent ultraviolet absorption and circular dichroism. The unfolding of the platinated duplexes was accompanied by relatively small unfavorable free energy terms. This destabilization was enthalpic in origin. On the other hand, a relatively large reduction of melting temperature (T(m)) was observed as a consequence of the monofunctional adduct in the TGT sequence, whereas T(m) due to the adduct in the AGT sequence was reduced only slightly. We also examined the efficiency of the mammalian nucleotide excision repair system to remove from DNA the monofunctional adducts and found that these lesions were not recognized by this repair system. Thus, rather thermodynamic than thermal characterization of DNA adducts of monofunctional platinum compounds is a property implicated in the modulation of downstream effects such as protein recognition and repair.

• MeSH
• adukty DNA analýza   chemie   MeSH
• denaturace nukleových kyselin MeSH
• DNA analýza   chemie   MeSH
• kinetika MeSH
• oprava DNA * MeSH
• platina analýza   chemie   MeSH
• přenos energie MeSH
• teplota MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• DNA MeSH
• platina MeSH

Modifications of natural DNA and synthetic oligodeoxyribonucleotide duplexes in a cell-free medium by analogs of antitumor cisplatin containing enantiomeric amine ligands, such as cis-[PtCl(2)(RR-DAB)] and cis-[PtCl(2)(SS-DAB)] (DAB = 2,3-diaminobutane), were studied by various methods of molecular biophysics and biophysical chemistry. These methods include DNA binding studies by pulse polarography and atomic absorption spectrophotometry, mapping of DNA adducts using transcription assay, interstrand cross-linking assay using gel electrophoresis under denaturing conditions, differential scanning calorimetry, chemical probing, and bending and unwinding studies of the duplexes containing single, site-specific cross-link. The major differences resulting from the modification of DNA by the two enantiomers are the thermodynamical destabilization and conformational distortions induced in DNA by the 1,2-d(GpG) intrastrand cross-link. It has been suggested that these differences are associated with a different biological activity of the two enantiomers observed previously. In addition, the results of the present work are also consistent with the view that formation of hydrogen bonds between the carbonyl oxygen of the guanine residues and the "quasi equatorial" hydrogen of the cis amine in the 1, 2-d(GpG) intrastrand cross-link plays an important role in determining the character of the distortion induced in DNA by this lesion.

• MeSH
• adukty DNA chemie   MeSH
• aminy chemie   MeSH
• biofyzika MeSH
• biofyzikální jevy MeSH
• cisplatina analogy a deriváty   chemie   farmakologie   MeSH
• diferenciální skenovací kalorimetrie MeSH
• DNA chemie   účinky léků   genetika   MeSH
• genetická transkripce MeSH
• konformace nukleové kyseliny MeSH
• ligandy MeSH
• molekulární sekvence - údaje MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reagencia zkříženě vázaná MeSH
• sekvence nukleotidů MeSH
• skot MeSH
• stereoizomerie MeSH
• techniky in vitro MeSH
• termodynamika MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• aminy MeSH
• cisplatina MeSH
• DNA MeSH
• ligandy MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH