Nanoscale synchrotron x-ray analysis of intranuclear iron in melanised neurons of Parkinson's substantia nigra.

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson's disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Animal models of Parkinson's have evidenced iron loading inside the nucleoli of nigral neurons, however the nature of intranuclear iron deposition in the melanised neurons of the human substantia nigra is not understood.

Photosubstitution and photoreduction of a diazido platinum(IV) anticancer complex.

The hyphenation of HPLC with its high separation ability and ICP-MS with its excellent sensitivity, allows the analysis of Pt drugs in biological samples at the low nanomolar concentration levels. On the other hand, LC-MS provides molecular structural confirmation for each species. Using a combination of these methods, we have investigated the speciation of the photoactive anticancer complex diazido Pt(IV) complex , , -[Pt(N)(OH)(py)] (FM-190) in aqueous solution and biofluids at single-digit nanomolar concentrations before and after irradiation.

A Photodynamic and Photochemotherapeutic Platinum-Iridium Charge-Transfer Conjugate for Anticancer Therapy.

The novel hetero-dinuclear complex trans,trans,trans-[Pt(py)(N)(OH)(μ-OOCCHCHCONHCH-bpyMe)Ir(ppy)]Cl (Pt-Ir), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) (Pt-OH) and donor photodynamic Ir(III) (Ir-NH) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex (Pt-OH) to generate Pt(II) species, an azidyl radical and O. The Ir(III)* excited state, formed after irradiation, can oxidise NADH to NAD⋅ radicals and NAD.

Experimental and theoretical evidence for unprecedented strong interactions of gold atoms with boron on boron/sulfur-doped carbon surfaces.

The 16e square-planar bis-thiolato-Au(iii) complexes [Au(1,2-dicarba--dodecarborane-1,2-dithiolato)][NBu] (Au-1) and [Au(4-methyl-1,2-benzenedithiolato)][NBu] (Au-2) have been synthesized and fully characterized. Au-1 and Au-2 were encapsulated in the symmetrical triblock copolymer poloxamer (Pluronic®) P123 containing blocks of poly(ethylene oxide) and poly(propylene oxide), giving micelles AuMs-1 and AuMs-2. High electron flux in scanning transmission electron microscopy (STEM) was used to generate single gold atoms and gold nanocrystals on B/S-doped graphitic surfaces, or S-doped amorphous carbon surfaces from AuMs-1 and AuMs-2, respectively.

Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues.

The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date.

Tuning the photoactivated anticancer activity of Pt(iv) compounds distant ferrocene conjugation.

Photoactive prodrugs offer potential for spatially-selective antitumour activity with minimal effects on normal tissues. Excited-state chemistry can induce novel effects on biochemical pathways and combat resistance to conventional drugs. Photoactive metal complexes in particular, have a rich and relatively unexplored photochemistry, especially an ability to undergo facile intersystem crossing and populate triplet states.

Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy.

A novel photoactivatable Pt(IV) diazido anticancer agent, , bearing a pendant deferoxamine (DFO) siderophore for radiometal chelation, has been synthesized for the study of its behavior with radionuclide imaging. complexation of Fe(III) and Ga(III) ions yielded new heterobimetallic complexes that maintain the photoactivation properties and photocytotoxicity of the parent Pt complex in human cancer cell lines. Radiolabeled ( = 68 min, positron emitter) was readily prepared under mild conditions and was stable in the dark upon incubation with human serum.

Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors.

Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring.

A Concerted Redox- and Light-Activated Agent for Controlled Multimodal Therapy against Hypoxic Cancer Cells.

Hypoxia represents a remarkably exploitable target for cancer therapy, is encountered only in solid human tumors, and is highly associated with cancer resistance and recurrence. Here, a hypoxia-activated mitochondria-accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported. This prodrug has multimodal theranostic properties toward hypoxic cancer cells.

Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First Experiments.

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents.

Reactions of cisplatin and oxaliplatin with penicillin G: implications for drug inactivation and biological activity.

Determination of the toxicity of compounds toward cancer cells is a frequent procedure in drug discovery. For metal complexes, which are often reactive prodrugs, care has to be taken to consider reactions with components of the cell culture medium that might change the speciation of the metal complex before it is taken up by the cells. Here, we consider possible reactions between the clinical platinum drugs cisplatin and oxaliplatin with penicillin G, an antibiotic added routinely to cell culture media to prevent bacterial contamination.

Kinetics and mechanism of sequential ring methyl C-H activation in cyclopentadienyl rhodium(III) complexes.

We have studied activation of the methyl C-H bonds in the cyclopentadienyl ligands of half-sandwich Rh(III) complexes [-CpRh(N,N')Cl] by observing the dependence of sequential H/D exchange on variations in Cp = Cp* (complexes 1 and 2), MePhCp (Cp, 3) or MePhPhCp (Cp, 4), and chelated ligand ,' (bpy, 1; phen, 2-4). H/D exchange was fastest in d-MeOD ( = 10 min, 37 °C, complex 1), no H/D exchange was observed in DMSO/DO, and d-MeOD enhanced the rate in CDCN. The proposed Rh(I)-fulvene intermediate was trapped by [4 + 2] Diels-Alder reactions with conjugated dienes and characterized.

Light Triggers the Antiproliferative Activity of Naphthalimide-Conjugated (η-arene)ruthenium(II) Complexes.

We report the synthesis and characterization of three half-sandwich Ru(II) arene complexes [(η-arene)Ru(N,N')L][PF] containing arene = p-cymene, N,N' = bipyridine, and L = pyridine meta- with methylenenaphthalimide (C1), methylene(nitro)naphthalimide (C2), or methylene(piperidinyl)naphthalimide (C3). The naphthalimide acts as an antenna for photoactivation. After 3 h of irradiation with blue light, the monodentate pyridyl ligand had almost completely dissociated from complex C3, which contains an electron donor on the naphthalimide ring, whereas only 50% dissociation was observed for C1 and C2.

Photocatalytic glucose-appended bio-compatible Ir(III) anticancer complexes.

Rationally-designed glucose-appended Ir(III) photo-catalysts ([Ir(,)(,-Glc)], Ir1-Ir3) show visible light-induced catalytic NAD(P)H oxidation in aqueous solution. The highly biocompatible complex, Ir3, shows lysosome and mitochondria targeting necro-apoptotic photo-cytotoxicity against various cancer cell lines and multicellular spheroids, while remaining non-toxic in the dark.

Effect of cysteine thiols on the catalytic and anticancer activity of Ru(II) sulfonyl-ethylenediamine complexes.

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) Ru arene complexes 1-8 of [(η-arene)Ru(R-SO-EnBz)X], where the arene is benzene, HO(CH)O-phenyl or biphenyl (biph), X = Cl or I, and R is phenyl, 4-Me-phenyl, 4-NO-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η-biph)Ru(4-Me-phenyl-SO-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.

Density functional theory investigation of Ru(II) and Os(II) asymmetric transfer hydrogenation catalysts.

Transition metal ions have a unique ability to organise and control the steric and electronic effects around a substrate in the active site of a catalyst. We consider half-sandwich Ru(II) (Noyori-type) and Os(II) sulfonyldiamine 16-electron active catalysts [Ru/Os(η--cymene)(TsDPEN-H)], where TsDPEN is -tosyl-1,2-diphenylethylenediamine containing , or , chiral centres, which catalyse the highly efficient asymmetric transfer hydrogenation of aromatic ketones to chiral alcohols using formic acid as a hydride source. We discuss the recognition of the prochiral ketone acetophenone by the catalyst, the protonation of a ligand NH and transfer of hydride from formate to the metal, subsequent transfer of hydride to one enantiotopic face of the ketone, followed by proton transfer from metal-bound NH, and regeneration of the catalyst.

Single-Cell Chemistry of Photoactivatable Platinum Anticancer Complexes.

The Pt(IV) prodrug -[Pt(pyridine)(N)(OH)] () and its coumarin derivative -[Pt(pyridine)(N)(OH)(coumarin-3-carboxylate)] () are promising agents for photoactivated chemotherapy. These complexes are inert in the dark but release Pt(II) species and radicals upon visible light irradiation, resulting in photocytotoxicity toward cancer cells. Here, we have used synchrotron techniques to investigate the in-cell behavior of these prodrugs and visualize, for the first time, changes in cellular morphology and Pt localization upon treatment with and without light irradiation.

NMR studies of group 8 metallodrugs: Os-enriched organo-osmium half-sandwich anticancer complex.

We report the synthesis of the organo-osmium anticancer complex [Os(η--cym)(,-azpy-NMe)Br]PF (1) containing natural abundance Os (1.96%), and isotopically-enriched (98%) [Os]-1. Complex 1 and [Os]-1 contain a π-bonded -cymene (-cym), a chelated 4-(2-pyridylazo)-,-dimethylaniline (azpy-NMe), and a monodentate bromide as ligands.

Induction of immunogenic cell death in cancer cells by a photoactivated platinum(IV) prodrug.

The platinum() prodrug trans,trans,trans-[Pt(N)(OH)(py)] (1) is stable and non-toxic in the dark, but potently cytotoxic to cancer cells when irradiated by visible light, including cisplatin-resistant cells. On irradiation with visible light, it generates reactive Pt(II) species which can attack DNA, and produces reactive oxygen species (ROS) and reactive nitrogen species (RNS) which exert unusual effects on biochemical pathways. We now show that its novel mechanism of action includes induction of immunogenic cell death (ICD).

Photoactivated Osmium Arene Anticancer Complexes.

Half-sandwich Os-arene complexes exhibit promising anticancer activity, but their photochemistry has hardly been explored. To exploit the photocytotoxicity and photochemistry of Os-arenes, -chelated complexes [Os(η--cymene)(Curc)Cl] (, Curc = curcumin) and [Os(η-biphenyl)(Curc)Cl] (), and -chelated complexes [Os(η-biphenyl)(dpq)I]PF (, dpq = pyrazino[2,3-][1,10]phenanthroline) and [Os(η-biphenyl)(bpy)I]PF (, bpy = 2,2'-bipyridine), have been investigated. The Os-arene curcumin complexes showed remarkable photocytotoxicity toward a range of cancer cell lines (blue light IC: 2.

Transfer hydrogenation catalysis in cells.

Hydrogenation reactions in biology are usually carried out by enzymes with nicotinamide adenine dinucleotide (NAD(P)H) or flavin mononucleotide (FAMH)/flavinadenine dinucleotide (FADH) as cofactors and hydride sources. Industrial scale chemical transfer hydrogenation uses small molecules such as formic acid or alcohols ( propanol) as hydride sources and transition metal complexes as catalysts. We focus here on organometallic half-sandwich Ru and Os η-arene complexes and Rh and Ir η-Cp complexes which catalyse hydrogenation of biomolecules such as pyruvate and quinones in aqueous media, and generate biologically important species such as H and HO.

Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

Complexes trans,trans,trans-[Pt(N3)2(OH)(OCOR)(py)2] where py = pyridine and where OCOR = succinate (1); 4-oxo-4-propoxybutanoate (2) and N-methylisatoate (3) have been synthesized by derivation of trans,trans,trans-[Pt(OH)2(N3)2(py)2] (4) and characterised by NMR and EPR spectroscopy, ESI-MS and X-ray crystallography. Irradiation of 1-3 with green (517 nm) light initiated photoreduction to Pt(ii) and release of the axial ligands at a 3-fold faster rate than for 4. TD-DFT calculations showed dissociative transitions at longer wavelengths for 1 compared to 4.