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
• DNA Adducts chemistry   genetics   MeSH
• Buthionine Sulfoximine pharmacology   MeSH
• DNA Breaks, Double-Stranded drug effects   radiation effects   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Indoles chemistry   pharmacology   MeSH
• Carboplatin chemistry   pharmacology   MeSH
• Nucleic Acid Conformation MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Neoplasms genetics   pathology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Drug Synergism MeSH
• Ultraviolet Rays * MeSH
• Cell Survival drug effects   genetics   radiation effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 7-azaindole dimer MeSH Browser
• DNA Adducts MeSH
• Buthionine Sulfoximine MeSH
• Indoles MeSH
• Carboplatin MeSH
• Antineoplastic Agents MeSH

The global modification of mammalian and plasmid DNAs by the novel platinum compounds cis-[PtCl(2)(isopropylamine)(1-methylimidazole)] and trans-[PtCl(2)(isopropylamine)(1-methylimidazole)] and the reactivity of these compounds with reduced glutathione (GSH) were investigated in cell-free media using various biochemical and biophysical methods. Earlier cytotoxicity studies had revealed that the replacement of the NH(3) groups in cisplatin by the azole and isopropylamine ligands lowers the activity of cisplatin in both sensitive and resistant cell lines. The results of the present work show that this replacement does not considerably affect the DNA modifications by this drug, recognition of these modifications by HMGB1 protein, their repair, and reactivity of the platinum complex with GSH. These results were interpreted to mean that the reduced activity of this analog of cisplatin in tumor cell lines is due to factors that do not operate at the level of the target DNA. In contrast, earlier studies had shown that the replacement of the NH(3) groups in the clinically ineffective trans isomer (transplatin) by the azole and isopropylamine ligands results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin, which is distinctly different from that of cisplatin, but does not affect reactivity with GSH. Hence, the results of the present work are consistent with the view and support the hypothesis systematically tested by us and others that platinum drugs that bind to DNA in a fundamentally different manner from that of conventional cisplatin may have altered pharmacological properties.

• MeSH
• Cell-Free System MeSH
• Circular Dichroism MeSH
• DNA chemistry   drug effects   MeSH
• Glutathione chemistry   drug effects   MeSH
• Culture Media chemistry   MeSH
• Humans MeSH
• Organoplatinum Compounds chemistry   pharmacology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Spectrophotometry, Ultraviolet MeSH
• Stereoisomerism MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• dichloro(isopropylamine)(1-methylimidazole)diplatinum(II) MeSH Browser
• DNA MeSH
• Glutathione MeSH
• Culture Media MeSH
• Organoplatinum Compounds MeSH
• Antineoplastic Agents MeSH