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)

Iridium(III) complexes containing 1,10-phenanthroline and derivatives: Synthetic, stereochemical, and structural studies, and their antimicrobial activity

A convenient synthetic strategy is reported for the series of complexes [Ir(pp)3]3+ (where pp = phen, Me2phen and Me4phen) through the intermediacy of the appropriate [Ir(pp)2(CF3SO3)2]+ species. In the case of [Ir(phen)3]3+, the cation was resolved into its enantiomeric forms, for which the absolute configurations were determined by X-ray diffraction. The availability for the first time of the CD spectra allowed comparison with computed CD spectra. Measurement of the antimicrobial activity of the [Ir(pp)3]3+ species {and the [Ir(pp)2X2]+ (X = Cl–, CF3SO3–) precursors involved in their synthesis}, as well as cell uptake studies with the four bacterial strains S. aureus, methicillin-resistant S. aureus (MRSA), E. coli, and P. aeruginosa, indicated that they showed little activity compared with their Ru(ii) analogues. The results suggest that it is unfavourable for an individual metal centre with a 3+ charge to pass across the bacterial cell membrane. Mallesh Pandrala, Fangfei Li, Lynne Wallace, Peter J. Steel, Barry Moore II, Jochen Autschbach, J. Grant Collins, and F. Richard Keen

PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84

Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology

Chlorido-containing ruthenium(II) and iridium(III) complexes as antimicrobial agents

A series of polypyridyl-ruthenium(II) and -iridium(III) complexes that contain labile chlorido ligands, [{M(tpy)Cl}₂{μ-bbn}]^2/4+ {Cl-Mbbn; where M = Ru or Ir; tpy = 2,2':6',2''-terpyridine; and bbn = bis[4(4'-methyl-2,2'-bipyridyl)]⁻¹,n-alkane (n = 7, 12 or 16)} have been synthesised and their potential as antimicrobial agents examined. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of the series of metal 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. All the ruthenium complexes were highly active and bactericidal. In particular, the Cl-Rubb₁₂ complex showed excellent activity against all bacterial cell lines with MIC values of 1 μg mL⁻¹ against the Gram positive bacteria and 2 and 8 μg mL⁻¹ against E. coli and P. aeruginosa, respectively. The corresponding iridium(III) complexes also showed significant antimicrobial activity in terms of MIC values; however and surprisingly, the iridium complexes were bacteriostatic rather than bactericidal. The inert iridium(III) complex, [{Ir(phen)₂}₂{μ-bb12}]⁶⁺ {where phen = 1,10-phenanthroline) exhibited no antimicrobial activity, suggesting that it could not cross the bacterial membrane. The mononuclear model complex, [Ir(tpy)(Me₂bpy)Cl]Cl₂ (where Me₂bpy = 4,4'-dimethyl-2,2'-bipyridine), was found to aquate very rapidly, with the pKₐ of the iridium-bound water in the corresponding aqua complex determined to be 6.0. This suggests the dinuclear complexes [Ir(tpy)Cl}₂{μ-bbn}]⁴⁺ aquate and deprotonate rapidly and enter the bacterial cells as 4+ charged hydroxo species

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer.

Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens