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

Author(s)

Alves, Samara R. ^[1] ; Santos, Rodrigo L. S. R. ^{[2, 1]} ; Fornaciari, Barbara ^[1] ; Colquhoun, Alison ^[3] ; Silva, Denise de Oliveira ^[1]

Affiliation

^[1] Univ Sao Paulo, Lab Synthet & Struct Inorgan Chem Bioinorgan & Me, Dept Fundamental Chem, Inst Chem, Ave Prof Lineu Prestes 748, B2T, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Estadual Santa Cruz, Dept Exact & Technol Sci, Rod Jorge Amado, Km 16, BR-45662900 Ilheus, BA - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Ave Prof Lineu Prestes 1524, BR-05508000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Journal of Inorganic Biochemistry; v. 225, DEC 2021.
• Web of Science Citations: 0

Abstract

Diruthenium(II,III) metal-metal multiply bonded paddlewheel complexes bearing non-steroidal anti-inflammatory drugs are promising anticancer metallodrugs. The {[}Ru-2(Ibp)(4)Cl] (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 {[}Ru-2(Ibp)(4)Cl] and of {[}Ru-2(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 Ru-2(II,III) to Ru-2 (III,III)O mu-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)]Cl-2 metallodrug, the first diruthenium(III, III) mu-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 mu-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 mu-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 mu mol L-1) and cytotoxicity (> 20 mu mol 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 mu mol L-1 (at 48 h, 1-20 mu mol L-1) against U87MG human glioblastoma cells (aggressive brain glioma cancer) pointing the metallodrug as potential candidate for novel therapies in gliomas. (AU)

• FAPESP's process: 14/23481-7 - Study of lipid-based nanoparticles as carriers for anticancer ruthenium metallodrugs
• Grantee: Samara Rodrigues Alves
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/23047-5 - Anticancer metallodrugs of ruthenium containing bioactive ligands: synthesis, interaction with biomolecules and preparation of biocompatible nanoparticle drug delivery systems
• Grantee: Denise de Oliveira Silva
• Support Opportunities: Regular Research Grants