Synthesis, isomerisation and biological properties of mononuclear ruthenium complexes containing the bis[4(4 '-methyl-2,2 '-bipyridyl)]-1,7-heptane ligand

A series of mononuclear ruthenium(II) complexes containing the tetradentate ligand bis[4(4’-methyl-2,2’- bipyridyl)]-1,7-heptane have been synthesised and their biological properties examined. In the synthesis of the [Ru(phen’)(bb7)]2+ complexes (where phen’ = 1,10-phenanthroline and its 5-nitro-, 4,7-dimethyland 3,4,7,8-tetramethyl- derivatives), both the symmetric cis-α and non-symmetric cis-β isomers were formed. However, upon standing for a number of days (or more quickly under harsh conditions) the cis-β isomer converted to the more thermodynamically stable cis-α isomer. The minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) of the ruthenium(II) complexes were determined against six strains of bacteria: Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA); and the Gram-negative Escherichia coli (E. coli) strains MG1655, APEC, UPEC and Pseudomonas aeruginosa (P. aeruginosa). The results showed that the [Ru(5-NO2phen)- (bb7)]2+ complex had little or no activity against any of the bacterial strains. By contrast, for the other cisα-[Ru(phen’)(bb7)]2+ complexes, the antimicrobial activity increased with the degree of methylation. In particular, the cis-α-[Ru(Me4phen)(bb7)]2+ complex showed excellent and uniform MIC activity against all bacteria. By contrast, the MBC values for the cis-α-[Ru(Me4phen)(bb7)]2+ complex varied considerably across the bacteria and even within S. aureus and E. coli strains. In order to gain an understanding of the relative antimicrobial activities, the DNA-binding affinity, cellular accumulation and water–octanol partition coefficients (log P) of the ruthenium complexes were determined. Interestingly, all the [Ru(phen’)- (bb7)]2+ complexes exhibited stronger DNA binding affinity (Ka ≈ 1 × 107 M−1 ) than the well-known DNAintercalating complex [Ru(phen)2(dppz)]2+ (where dppz = dipyrido[3,2-a:2’,3’-c]phenazine)

Occurrence and stability of lone pair-π and OH-π interactions between water and nucleobases in functional RNAs

We identified over 1000 instances of water-nucleobase stacking contacts in a variety of RNA molecules from a non-redundant set of crystal structures with resolution ≤3.0 Å. Such contacts may be of either the lone pair-π (lp-π) or the OH-π type, in nature. The distribution of the distances of the water oxygen from the nucleobase plane peaks at 3.5 Å for A, G and C, and approximately at 3.1-3.2 Å for U. Quantum mechanics (QM) calculations confirm, as expected, that the optimal energy is reached at a shorter distance for the lp-π interaction as compared to the OH-π one (3.0 versus 3.5 Å). The preference of each nucleobase for either type of interaction closely correlates with its electrostatic potential map. Furthermore, QM calculations show that for all the nucleobases a favorable interaction, of either the lp-π or the OH-π type, can be established at virtually any position of the water molecule above the nucleobase skeleton, which is consistent with the uniform projection of the OW atoms over the nucleobases ring we observed in the experimental occurrences. Finally, molecular dynamics simulations of a model system for the characterization of water-nucleobase stacking contacts confirm the stability of these interactions also under dynamic conditions

Tri- and tetra-nuclear polypyridyl ruthenium(II) complexes as antimicrobial agents

A series of inert tri- and tetra-nuclear polypyridylruthenium(II) complexes that are linked by the bis[4(4'- methyl-2,2'-bipyridyl)]-1,n-alkane ligand ("bbn" for n = 10, 12 and 16) have been synthesised and their potential as antimicrobial agents examined. Due to the modular nature of the synthesis of the oligonuclear complexes, it was possible to make both linear and non-linear tetra nuclear ruthenium species. 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). In order to gain an understanding of the relative antimicrobial activities, the cellular uptake and water–octanol partition coefficients (log P) were determined for a selection of the ruthenium complexes. Although the trinuclear complexes were the most lipophilic based upon log P values and showed the greatest cellular uptake, the linear tetranuclear complexes were generally more active, with MIC values <1 μM against the Gram positive bacteria. Similarly, although the non-linear tetranuclear complexes were slightly more lipophilic and were taken up to a greater extent by the bacteria, they were consistently less active than their linear counterparts. Of particular note, the cellular accumulation of the oligonuclear ruthenium complexes was greater in the Gram negative strains compared to that in the Gram positive S. aureus and MRSA. The results demonstrate that the lower antimicrobial activity of polypyridylruthenium(II) complexes towards Gram negative bacteria, particularly P. aeruginosa, is not strongly correlated to the cellular accumulation but rather to a lower intrinsic ability to kill the Gram negative cells

Probing the pharmacokinetics of cucurbit[7, 8 and 10]uril: and a dinuclear ruthenium antimicrobial complex encapsulated in cucurbit[10]uril

The relatively non-toxic family of cucurbit[n]uril, Q[n], have shown considerable potential in vitro as drug delivery agents, with only a few examples of pharmacokinetic (PK) studies for drug⊂Q[n]. Drug-free Q[n] PK studies are the next step in determining the pharmacological applicability in their drug delivery potential. The results for the first PK and bio-distribution of drug-free ¹⁴C-Q[7] are described for administration via intravenous (i.v.) and intraperitoneal (i.p.) dosing. A study of oral administration of drug-free ¹⁴C-Q[8] has also been undertaken to determine the time course for the gastrointestinal tract (GIT), absorption and subsequent bio-distribution. Q[10], a potential drug carrier for larger drugs, was evaluated for its effect on the PK profile of a dinuclear ruthenium complex (Rubb₁₂), a potential antimicrobial agent. The Rubb₁₂⊂Q[10] complex and free Rubb₁₂ were administered by i.v. to determine differences in Rubb₁₂ plasma concentrations and organ accumulation. Interestingly, the PK profiles and bio-distribution observed for Q[7] showed similarities to those of Rubb₁₂⊂Q[10]. Drug-free Q[7] has a relatively fast plasma clearance and a generally low organ accumulation except for the kidneys. Drug-free Q[8] showed a low absorption from the GIT into the blood stream but the small percentage absorbed reflected the organ accumulation of Q[7]. These results provide a better understanding of the probable PK profile and bio-distribution for a drug⊂Q[n] through the influence of the drug delivery vehicle and the positive clearance of drug-free Q[n] via the kidneys supports its potential value in future drug delivery applications.Fangfei Li, Anil K. Gorle, Marie Ranson, Kara L. Vine, Robert Kinobe, Marshall Feterl, Jeffrey M. Warner, F. Richard Keene, J. Grant Collins and Anthony I. Da

Mononuclear polypyridylruthenium(II) complexes with high membrane permeability in gram-negative bacteria—in particular Pseudomonas aeruginosa

Ruthenium(II) complexes containing the tetra dentate ligand bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane ("bb(n)"; n=10 and 12) have been synthesised and their geometric isomers separated. All [Ru(phen)(bb(n))]²⁺ (phen=1,10-phenanthroline) complexes exhibited excellent activity against Gram-positive bacteria, but only the cis-a-[Ru(phen)(bb₁₂)]²⁺ species showed good activity against Gram-negative species. In particular, the cis-a-[Ru(phen)(bb₁₂)]²⁺ complex was two to four times more active than the cis-b-[Ru(phen)(bb₁₂)]²⁺complex against the Gram-negative strains. The cis-a- and cis-b-[Ru(phen)(bb₁₂)]²⁺ complexes readily accumulated in the bacteria but, significantly, showed the highest level of uptake in Pseudomonas aeruginosa. Furthermore, the accumulation of the cis-a- and cis-b-[Ru(phen)(bb₁₂)]²⁺ complexes in P. aeruginosa was considerably greater than in Escherichia coli. The uptake of the cis-a-[Ru(phen)(bb₁₂)]²⁺ complex into live P. aeruginosa was confirmed by using fluorescence microscopy. The water/octanol partition coefficients (log P) were determined to gain understanding of the relative cellular uptake. The cis-a- and cis-b-[Ru(phen)(bb(n))]²⁺ complexes exhibited relatively strong binding to DNA (Kb≈10⁶M⁻¹ ), but no significant difference between the geometricisomers was observed