RESUMO
A series of non-symmetric dinuclear polypyridylruthenium(ii) complexes (Rubbn-Cl) that contain one inert metal centre and one coordinatively-labile metal centre, linked by the bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane ligand ("bbn" for n = 7, 12 and 16), have been synthesised and their potential as antimicrobial agents examined. The minimum inhibitory concentrations (MIC) of the ruthenium(II) complexes were determined against four strains of bacteria--Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram-negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). The Rubbn-Cl complexes displayed good antimicrobial activity, with Rubb12-Cl being the most active complex against both Gram-positive and Gram-negative strains. Interestingly, Rubb7-Cl was found to be eight- and sixteen-fold more active towards E. coli than against S. aureus and MRSA, respectively. The cytotoxicities of the Rubbn-Cl complexes against three eukaryotic cell lines--two kidney cell lines (BHK and HEK-293) and one liver cell line (HepG2)--were examined. The Rubbn-Cl complexes were found to be considerably less toxic towards eukaryotic cells than S. aureus, MRSA and E. coli, with Rubb12-Cl being thirty- to eighty-times more toxic to the bacteria than to BHK, HEK-293 or HepG2 cells. Unexpectedly, Rubb7-Cl was far more toxic to HepG2 cells (24 h-IC50 = 3.7 µM) and far less toxic to BHK cells (24 h-IC50 = 238 µM) than the Rubb12-Cl and Rubb16-Cl complexes. In order to understand the unexpected large differences in the cytotoxicities of the Rubbn-Cl complexes towards eukaryotic cells, a confocal microscopic study of their intracellular localisation was undertaken. The results suggest that the observed cytotoxicity might be related to the extent of DNA binding.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Rutênio/química , Antibacterianos/metabolismo , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Transporte Biológico , Técnicas de Química Sintética , Células HEK293 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/metabolismo , Compostos Organometálicos/toxicidadeRESUMO
This paper is a focused review of our recent efforts to produce multi-nuclear platinum anti-cancer complexes that preferentially target adenine residues in DNA. Multi-nuclear platinum complexes, like cisplatin, predominantly form covalent adducts with guanine bases; however, controlling the pre-covalent binding association of the metal complex may modify this preference. NMR experiments, using oligonucleotides, indicate that multi-nuclear complexes linked by flexible diaminoalkanes will pre-associate in the DNA minor groove at A/T rich regions. Despite this pre-covalent binding preference, these complexes still predominantly covalently bind guanine residues. However, using 4,4'-dipyrazolylmethane (dpzm) as a linking ligand produces a dinuclear platinum complex, trans-[[PtCl(NH(3))(2)](2)mu-dpzm](2+), that covalently binds DNA with a preference for adenine bases. In vitro transcription assays also demonstrate that the dpzm-based complex covalently binds within an A/T rich region of the 512 base-pair segment of DNA used for the study.