A novel μ-oxo-diruthenium(III,III)-ibuprofen-(4-aminopyridine) chloride derived from the diruthenium(II,III)-ibuprofen paddlewheel metallodrug shows anticancer properties

• Published in: Journal of inorganic biochemistry 2021-12, Vol.225, p.111596-111596, Article 111596
• Main Authors: Alves, Samara R., Santos, Rodrigo L.S.R., Fornaciari, Bárbara, Colquhoun, Alison, de Oliveira Silva, Denise
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - pharmacology; Diruthenium; Drug Screening Assays, Antitumor; Humans; Ibuprofen; Ibuprofen - analogs & derivatives; Ibuprofen - pharmacology; Kinetics; Metallodrug; Oxo-bridged compounds; Ruthenium - chemistry
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2021.111596

Diruthenium(II,III) metal-metal multiply bonded paddlewheel complexes bearing non-steroidal anti-inflammatory drugs are promising anticancer metallodrugs. The [Ru2(Ibp)4Cl] (Ibp, ibuprofenate anion from HIbp ibuprofen drug), free or encapsulated, shows anticancer activity against glioblastoma (in vitro, in vivo), and against human breast and prostate cancer cells. Herein we report the interaction of [Ru2(Ibp)4Cl] and of [Ru2(Ac)4(H2O)2]PF6 (Ac, acetate) with the 4-aminopyridine (4Apy) drug. The N-ligand was capable of cleaving the paddlewheel unit with oxidation of Ru2(II,III) to Ru2(III,III)O μ-oxo core in the ibuprofen complex while the acetate complex underwent axial substitution of water by 4Apy. Carefully designed synthetic and chromatographic methods succeeded in giving the novel [Ru2O(Ibp)2(4Apy)6]Cl2 metallodrug, the first diruthenium(III,III) μ-oxo having chloride as counterion. Characterization was performed by elemental analysis, mass spectrometry, thermogravimetric analysis, electronic absorption and vibrational spectroscopies, molar conductivity and cyclic voltammetry. Kinetic studies for the μ-oxo complex (in 50:50 v/v ethanol:water) suggested an aquation/complexation equilibrium in consecutive step reactions with the exchange of the two 4Apy trans to the μ-oxo bridge by water (aquation) and the back coordination of 4Apy in excess of the N-ligand (complexation). Trypan blue assays for the novel compound showed time- and dose- dependent antiproliferative effects (at 5–50 μmol L−1) and cytotoxicity (> 20 μmol L−1), and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays gave IC50 value of 7.6 ± 1.5 μmol L−1 (at 48 h, 1–20 μmol L−1) against U87MG human glioblastoma cells (aggressive brain glioma cancer) pointing the metallodrug as potential candidate for novel therapies in gliomas. The interaction of diruthenium(II,III)-tetracarboxylate metal-metal multiply bonded complexes with the 4- aminopyridine (4Apy) drug is reported. A novel μ-oxo diruthenium(III,III)-ibuprofen-(4Apy) chloride metallodrug was prepared, characterized, investigated for ligand substitution kinetics and screened for anticancer effects in U87MG human glioblastoma cells. [Display omitted] •Interaction of diruthenium(II,III)-tetracarboxylate with 4-aminopyridine.•A novel μ-oxo-diruthenium(III,III)-ibuprofen-(4-aminopyridine) chloride metallodrug.•Synthesis, characterization and ligand exchange kinetic studies.•Biological activity against U87MG human gli