Publication Type Journal Article
Title Screening organometallic binuclear thiosemicarbazone ruthenium complexes as potential anti-tumour agents: cytotoxic activity and human serum albumin binding mechanism
Authors Bruno Demoro R. F. M. de Almeida Fernanda M. Marques Cristina P. Matos Lucia Otero J.C. Pessoa Isabel Santos Alejandra Rodriguez Virtudes Moreno Julia Lorenzo Dinorah Gambino Ana Isabel Tomaz
Groups BIOIN
Journal DALTON TRANSACTIONS
Year 2013
Month
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Volume 42
Number 19
Pages 7131-7146
Abstract Four complexes combining the \Ru(p-cym)\ moiety (p-cym = para-cymene) with thiosemicarbazone (TSC) ligands containing the 5-nitrofuryl pharmacophore were investigated in vitro for their properties as prospective anti-tumour agents. The compounds are dimeric structures of general formula [Ru-2(p-cym)(2)(L)(2)]-X-2 where X = Cl-, PF6- and L = deprotonated 5-nitrofuraldehyde TSC (L1), and the N-methyl (L2), N-ethyl (L3) and N-phenyl (L4) derivatives. The precursor [RuCl2(p-cym)](2), all TSC ligands L1-L4 and their corresponding complexes 1-4 were screened in vitro for their cytotoxicity against a range of human cancer cell lines (HL-60 acute promyelocytic leukemia, A2780 ovarian adenocarcinoma, MCF7 breast adenocarcinoma and PC3 grade IV prostate carcinoma). While the precursor complex was found to be inactive and L4 exhibited moderate activity only in the MCF7 cell line, the coordination of L4 to the \Ru(p-cym)\ moiety remarkably enhanced the activity of the whole complex. In fact, complex 4 [Ru-2(p-cym)(2)(L4)(2)]Cl-2 was found to be the most active agent of the whole series, and was studied further (as well as complex 1 for comparison). Concerning the mode of action, the mechanism of cell death for both 1 and 4 seemed to be related to apoptotic processes, and they strongly interacted with tubulin (involved in the cell cycle) and with integrin (involved in the cytoskeleton formation). As an approach to their pharmacokinetics, the interaction of 1 and 4 with human serum albumin (HSA) was assessed. A quantitative model for the binding of 4 to HSA is proposed from Circular Dichroism data, and validated by fluorescence results. Models of Forster resonance energy transfer and fluorescence quenching afforded the distance of 4 to the lone Trp214 residue. Importantly, HSA binding enhanced the cytotoxicity of 4 and correlated well with the HSA binding data. Our results consistently indicate that [Ru-2(p-cymene)(2)(L4)(2)]Cl-2 is quite promising as a prospective metallodrug for cancer chemotherapy.
DOI http://dx.doi.org/10.1039/c3dt00028a
ISBN
Publisher
Book Title
ISSN 1477-9226
EISSN 1477-9234
Conference Name
Bibtex ID ISI:000317981700052
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