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

Hanif-Ur-Rehman; Tatiana E Freitas; Renata N Gomes; Alison Colquhoun; Denise de Oliveira Silva

doi:10.1016/j.jinorgbio.2016.10.003

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

J Inorg Biochem. 2016 Dec:165:181-191. doi: 10.1016/j.jinorgbio.2016.10.003. Epub 2016 Oct 14.

Authors

Hanif-Ur-Rehman¹, Tatiana E Freitas², Renata N Gomes², Alison Colquhoun², Denise de Oliveira Silva³

Affiliations

¹ Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, Av. Prof. Lineu Prestes, 748, 05508-000 São Paulo, SP, Brazil.
² 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.
³ 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.

PMID: 28340940
DOI: 10.1016/j.jinorgbio.2016.10.003

Abstract

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.

Keywords: Diruthenium; Human glioma cells; Ibuprofen; Metal-metal bond; Metallodrug; Non-steroidal anti-inflammatory drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects*
Cell Line, Tumor
Cell Movement / drug effects*
Glioma / drug therapy*
Glioma / metabolism
Humans
Ibuprofen* / chemistry
Ibuprofen* / pharmacology
Mitosis / drug effects*
Molecular Structure
Organometallic Compounds* / chemical synthesis
Organometallic Compounds* / chemistry
Organometallic Compounds* / pharmacology
Ruthenium* / chemistry
Ruthenium* / pharmacology

Substances

Antineoplastic Agents
Organometallic Compounds
Ruthenium
Ibuprofen