Axially-modified paddlewheel diruthenium(II,III)-ibuprofenato metallodrugs and the influence of the structural modification on U87MG and A172 human glioma cell proliferation, apoptosis, mitosis and migration.
The metallodrug chloridotetrakis(ibuprofenato)diruthenium(II,III) ([Ru2(Ibp)4Cl] or RuIbpCl (1), Ibp=carboxylate anion derived from the non-steroidal anti-inflammatory drug ibuprofen) has shown promising results in vitro and in vivo, which point to its potential as an inhibitor of glioma tumour growth in vivo. In order to get insight into the influence of structural changes on the biological response of the metallodrug, the [Ru2(Ibp)4] metal-metal multiply bonded paddlewheel unit was modified for the axial ligand. Two new analogues, [Ru2(Ibp)4(CF3SO3)] (2) and [Ru2(Ibp)4(EtOH)2]PF6(3), were synthesized and fully characterized by elemental analysis, ESI-MS, vibrational (FTIR, Raman) and electronic (UV/VIS/NIR) spectroscopy, magnetic susceptibility, molar conductivity measurements, and thermal analysis. RuIbpCl was re-prepared and complementary characterization to previous work was performed. The three axially-modified RuIbp metallodrugs were compared for their effects on U87MG and A172 human glioma cell proliferation, apoptosis, mitosis, and cell migration in vitro. The results provide evidence that the chloride ligand in RuIbpCl may play key role in the mode of action of the metallodrug, since the best results for antiproliferative activity were found for (1) in both types of human glioma cells. All the metallodrugs, (1), (2) and (3), were uptaken by the cells, and were shown to cause increase on number of apoptotic cells and decrease on number of mitotic cells. Additionally, the RuIbp metallodrugs were capable of inhibiting cell migration process in both human glioma cell lines. These data are extremely promising as drugs which can inhibit both cell proliferation/mitosis and inhibit cell migration could target two major chemotherapeutic targets in high grade gliomas.
Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748, 05508-000 São Paulo, SP, Brazil.
Hanif-Ur-Rehman
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, 05508-000 São Paulo, SP, Brazil.
Tatiana E
TE
Freitas
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, 05508-000 São Paulo, SP, Brazil.
Renata N
RN
Gomes
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, 05508-000 São Paulo, SP, Brazil.
Alison
A
Colquhoun
Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748, 05508-000 São Paulo, SP, Brazil. Electronic address: deosilva@iq.usp.br.
Denise
D
de Oliveira Silva
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D012428:Ruthenium; D007052:Ibuprofen
Diruthenium; Human glioma cells; Ibuprofen; Metal-metal bond; Metallodrug; Non-steroidal anti-inflammatory drugs