One of the major advances in medical science has been the development of antimicrobials; however, a consequence of their widespread use has been the emergence of drug-resistant populations of microorganisms. There is clearly a need for the development of new antimicrobials--but more importantly, there is the need for the development of new classes of antimicrobials, rather than drugs based upon analogues of known scaffolds. Due to the success of the platinum anticancer agents, there has been considerable interest in the development of therapeutic agents based upon other transition metals--and in particular ruthenium(II/III) complexes, due to their well known interaction with DNA. There have been many studies of the anticancer properties and cellular localisation of a range of ruthenium complexes in eukaryotic cells over the last decade. However, only very recently has there been significant interest in their antimicrobial properties. This review highlights the types of ruthenium complexes that have exhibited significant antimicrobial activity and discusses the relationship between chemical structure and biological processing--including site(s) of intracellular accumulation--of the ruthenium complexes in both bacterial and eukaryotic cells.
1H NMR spectroscopy was used to study the
oligonucleotide binding of the Δ enantiomers of
[Ru(phen)2L]2+
where the bidentate ligand L is 1,10-phenanthroline (phen),
dipyrido[3,2-d:2‘,3‘-f]quinoxaline
(dpq) or dipyrido[3,2-a:2‘,3‘-c](6,7,8,9-tetrahydro)phenazine
(dpqC). The data from one- and two-dimensional NMR
experiments
of the oligonucleotide−metal complex binding suggest that all three
ruthenium(II) polypyridyl complexes bind in
the DNA minor groove. While a minimally intercalated
oligonucleotide binding mode may be proposed for
Δ-[Ru(phen)3]2+, the NMR data
clearly indicate that
Δ-[Ru(phen)2dpq]2+ binds the
hexanucleotide d(GTCGAC)2
by intercalation, of the dpq ligand, from the minor groove. This
demonstrates that metallointercalators can
intercalate from the DNA minor groove. Molecular modeling of the
metal complex in the intercalation site
suggests that Δ-[Ru(phen)2dpq]2+
binds in a “head-on” fashion with the phenanthroline rings in the
minor groove
and the dpq ligand inserted into the nucleotide base stack. NOESY
experiments of the binding of Δ-[Ru(phen)2dpq]2+ with d(GTCGAC)2 and
d(TCGGGATCCCGA)2 suggest that intercalation from the minor
groove
is favored at purine−purine/pyrimidine−pyrimidine sequences for
this complex. The syntheses of Δ-[Ru(phen)2dpq]2+ and
Δ-[Ru(phen)2dpqC]2+ are reported
along with crystal structure of
[Ru(phen)2dpq](PF6)2
(monoclinic crystal system, space group
P21
/c, Z = 4,
a = 9.483(2) Å, b = 33.374(6) Å,
c = 12.900(3) Å, β =
110.05(2)°, V = 3835(2)
Å3).
The encapsulation of cisplatin by cucurbit [7]uril (Q[7]) and multinuclear platinum complexes linked via a 4,4 -dipyrazolylmethane (dpzm) ligand by Q [7] and cucurbit [8] 4+ (tri-Pt) provide a barrier to the on and off movement of cucurbituril, resulting in binding kinetics that are slow on the NMR timescale for the metal complex. Although the dpzm ligand has relatively few rotamers, encapsulation by the larger Q[8] resulted in a more compact di-Pt conformation with each platinum centre retracted further into each Q[8] portal. Encapsulation of the hydrolysed forms of di-Pt and tri-Pt is considerably slower than for the corresponding Cl forms, presumably due to the high-energy cost of passing the +2 platinum centres through the cucurbituril portals. The results of this study suggest that cucurbiturils could be suitable hosts for the pharmacological delivery of multinuclear platinum complexes.
The minimum inhibitory concentrations (MIC) of a series of synthetic inert polypyridylruthenium(II) complexes 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)--have been determined. The results demonstrate that for the dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)(2)}(2){μ-bb(n)}](4+) {where phen = 1,10-phenanthroline; bb(n) = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n = 2, 5, 7, 10, 12 or 16)} the complexes linked by the bb(12), bb(14) and bb(16) ligands are highly active, with MIC values of 1 μg mL(-1) against both S. aureus and MRSA, and 2-4 and 8-16 μg mL(-1) against E. coli and P. aeruginosa, respectively. The mononuclear complex [Ru(Me(4)phen)(3)](2+) showed equal activity (on a mole basis) against S. aureus compared with the Rubb(12), Rubb(14) and Rubb(16), but was considerably less active against MRSA and the two Gram negative bacteria. For the dinuclear Rubb(n) family of complexes, the antimicrobial activity was related to the octanol-water partition coefficient (logP). However, the highly lipophilic mononuclear complex Δ-[Ru(phen)(2)(bb(16))](2+) was significantly less active than Rubb(16), highlighting the importance of the dinuclear structure. Preliminary toxicity assays were also carried out for the ΔΔ isomers of Rubb(7), Rubb(10), Rubb(12) and Rubb(16) against two human cells lines, fresh red blood cells and THP-1 cells. The results showed that the dinuclear ruthenium complexes are significantly less toxic to human cells compared to bacterial cells, with the HC(50) and IC(50) values 100-fold higher than the MIC for the complex that showed the best potential--ΔΔ-Rubb(12).
Mitoxantrone was efficiently encapsulated within cucurbit[8]uril in a 2:1 complex where the two mitoxantrone molecules were symmetrically located through both portals of a cucurbit[8]uril cage. The novel complex facilitates increased mitoxantrone uptake in mouse breast cancer cells and decreases the toxicity of the drug in healthy mice. In an orthotopic mouse model of metastatic breast cancer the complex still maintains anticancer activity compared to the free drug, yet provides a statistically significant increase in the survival of these mice compared to conventional mitoxantrone treatment. This new low toxicity formulation offers the possibility to increase mitoxantrone dose and thus maximize efficacy while managing the dose limiting side effects.
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