Photolabile Ru Model Complexes with Chelating Diimine Ligands for Light-Triggered Drug Release

A series of water-soluble photolabile model complexes of the general formula [Ru([9]aneS3)(chel)(py)]Cl2 ([9]aneS3 = 1,4,7-trithiacyclononane, chel = chelating diimine) was prepared and fully characterized. The photo-triggered release of pyridine with visible light as a function of the nature of the diimine (chel = 2,2\u2032-bipyridine (6) 1,10-phenanthroline (7), 4,7-diphenil-1,10-phenanthroline (8), dipyrido-[3,2-a:2\u2032,3\u2032-c]phenazine (dppz, 9), 2,2\u2032-biquinoline (bq, 10)) was investigated. Our aim is that of establishing if this type of complexes in the future might be realistically used in the photo-uncaging strategy of photoactivated chemotherapy (PACT). Compounds 6 \u2013 9 present a MLCT absorption in the blue region of the visible spectrum. When irradiated with light at 470 nm, they rapidly and quantitatively release the coordinated pyridine. Complex 10 turned out to be quite different from to the others in the series. Structure-wise, in 10 the average plane of coordinated bq \u2013 owing to its steric demand \u2013 is remarkably tilted relative to the equatorial coordination plane (37.43 (4)\ub0, with the \u201cfront\u201d of the ligand pointing towards the axial py) and the orientation of py is ca. orthogonal compared to that found in 6 and 7 for minimizing steric clashes with bq. The low-lying acceptor orbitals of bq induce a red-shift of the MLCT absorption maximum to ca. 500 nm. Contrary to the expectations, complex 10 is more photo-stable compared to 6 \u2013 9 and photo-dissociation of both py and bq, in ca. equal amounts, occurs. A detailed theoretical investigation was performed on 10 (and on 6 for comparison), for explaining its peculiar spectral features and photochemical behavior

An exploration of the experiences and utility of functional electrical stimulation for foot drop in people with multiple sclerosis

Purpose: Functional electrical stimulation (FES) is effective in improving walking in people with multiple sclerosis (MS) with foot drop. There is limited research exploring people’s experiences of using this device. This study aims to explore the utility, efficacy, acceptability, and impact on daily life of the device in people with MS. Methods: An interpretative phenomenological approach was employed. Ten participants who had used FES for 12 months were interviewed. Transcripts were analysed, and emergent themes identified. Results: Nine participants continued to use the device. Three relevant super-ordinate themes were identified; impact of functional electrical stimulation, sticking with functional electrical stimulation, and autonomy and control. Participants reported challenges using the device; however, all reported positive physical and psychological benefits. Intrinsic and external influences such as; access to professional help, the influence of others, an individual’s ability to adapt, and experiences using the device, influenced their decisions to continue with the device. A thematic model of these factors was developed. Conclusions: This study has contributed to our understanding of people with MS experiences of using the device and will help inform prescribing decisions and support the continued, appropriate use of FES over the longer term

A comparison of the initial orthotic effects of functional electrical stimulation and ankle-foot orthoses on the speed and oxygen cost of gait in multiple sclerosis

Foot drop affects walking in people with multiple sclerosis (pwMS). This study compares the initial orthotic effects of two treatments for foot drop: ankle-foot orthoses (AFO) and functional electrical stimulation (FES), on the speed and oxygen cost of walking in MS. Method and materials: Seventy-eight pwMS were randomised to receive AFO or FES (ODFS PACE (OML, Salisbury, UK)). Participants completed the 25-ft walk test (25ftWT) and 5-min self-selected walk test (5minSSWT), from which oxygen cost was determined, with and without their device. Between-, within- and sub-group analyses (based on baseline walking speed of <0.8 m/s (slow) or ≥0.8 m/s (fast)) were undertaken. Results: No significant differences between baseline measures were observed. The AFO group walked significantly slower than the FES group (5minSSWT, p = 0.037, 0.11 m/s). The AFO group walked significantly slower with than without AFO (25ftWT, p = 0.037), particularly in the fast-walking group ( p = 0.011). The slow-walking FES group walked significantly faster with FES than without (25ftWT; p = 0.029, 5minSSWT; p = 0.037). There were no differences in the fast-walking FES group or in the oxygen cost for either device. Conclusion: AFO reduced walking speed, particularly in fast walkers. FES increased walking speed in slow, but not fast walkers

Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand

The anticancer ruthenium-arene compd. [Ru(η6-C6H5CF3)(pta)Cl2] (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing α,α,α-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compds. known. To rationalize the high obsd. cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5'-GTATTGGCACGTA-3') were studied using NMR spectroscopy, high-resoln. Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium-chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concn., which is a special property of the compd. not obsd. for other ruthenium-arene complexes with relatively stable ruthenium-arene bonds. Accordingly, the mass spectra of the biomol. reaction mixts. contained mostly [Ru(pta)]-biomol. adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compds. were not obsd. in the protein or DNA binding studies. Gel electrophoresis expts. revealed a significant degree of decompn. of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3. Graphical abstr.: RAPTA-CF3 is a fast-acting cytotoxic compd. that degrades DNA and has a mode of action fundamentally different from that of other ruthenium(II)-arene compds

Correction: Metal complexes as a promising source for new antibiotics

Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem. Sci., 2020, 11, 2627–2639

Metal complexes as a promising source for new antibiotics

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance