Synthesis and Photolysis Properties of a New Chloroquine Photoaffinity Probe.

A new chloroquine-derived photoaffinity probe has been prepared by a convergent synthesis from derivative of 4,7-dichloroquinoline and N1,N1-diethyl-N4-methylpentane. The features of this probe are a unique 3-azido photolabel, the pyridine ring of the quinoline, and the presence of a secondary amine at the 4-position of the quinoline. These features, particularly the 4-amino methylation, prevent triazole formation through combination of the 3-azide and the 4-amine.

Soluble meso and deuteroporphyrin analogs of the malaria pigment hematin anhydride.

Two soluble heme analogs of the insoluble malaria pigment hematin anhydride (HA, or β-hematin), [Fe(III)(protoporphyrin)], with either mesoporphyrin (MHA) or deuteroporphyrin (DHA) are characterized by elemental analysis, SEM, IR spectroscopy, electronic spectroscopy, paramagnetic H NMR spectroscopy and solution magnetic susceptibility. While prior single crystal and X-ray powder diffraction results indicate all three have a common propionate linked dimer motif, there is considerable solid state variation in the conformation. This is associated with enhanced solubility of MHA and DHA.

Fluorotrithiophosphate Abstraction from the Difluoropentathiodiphosphate Dianion: d and d Complexes of [η-SPF].

Coordinative heterolysis of the difluoropentathiodiphosphate dianion [SPF] results in the formal elimination of [SPF] by complexes of the group 10 divalent metals nickel, palladium, and platinum. The remaining fragment of this cleavage, [SPF] coordinates as an η-ligand. Several complexes with this novel fluorotrithiophosphate were characterized structurally and spectroscopically with X-ray diffraction (XRD), infrared (IR) spectroscopy, and P and F nuclear magnetic resonance (NMR).

The Sulfur Rich Fluorothiophosphate Dianions [S P F ] and [S PF] : Cluster and Chelation Control of P-S Heterolysis.

The sulfur rich difluoropentathiodiphosphate dianion [S P F ] , from fluoride addition to P S , has a somewhat checkered history and proves to be the main product of the reaction in acetonitrile. Its optimized synthesis, and structural characterization, as either a tetraphenylphosphonium or a tetrapropylammonium salt, [N Pr ] [S P F ] allows for the first coordination chemistry for this dianion. Reactions of [S P F ] with d metal ions of zinc(II), and cadmium(II), and d copper(II) resulted in a surprising diverse array of binding modes and structural motifs.

Quantification of local zinc and tungsten deposits in bone with LA-ICP-MS using novel hydroxyapatite-collagen calibration standards.

Tungsten has recently emerged as a potential toxicant and is known to heterogeneously deposit in bone as reactive polytungstates. Zinc, which accumulates in regions of bone remodeling, also has a heterogenous distribution in bone. Determining the local concentrations of these metals will provide valuable information about their mechanisms of uptake and action.

Coordination Chemistry of the Parent Dithiocarbamate HNCS: Organometallic Chemistry and Tris-Chelates of Group 9 Metals.

Two tris-chelate complexes of cobalt and rhodium and two complexes of Ru(II) of dithiocarbamate, [SCNH], were synthesized. The complexes were spectroscopically characterized by IR, NMR, UV-vis, and MS and structurally characterized by X-ray diffraction. The structural features of the rhodium complex were compared to those of other tris-chelate Rh(III) dithiocarbamate complexes and are characterized by a change in the ground-state geometry in comparison to expected octahedral tris-chelate complexes.

Arsenic 3 methyltransferase (AS3MT) automethylates on cysteine residues in vitro.

Arsenic toxicity is a global concern to human health causing increased incidences of cancer, bronchopulmonary, and cardiovascular diseases. In human and mouse, inorganic arsenic (iAs) is metabolized in a series of methylation steps catalyzed by arsenic (3) methyltransferase (AS3MT), forming methylated arsenite (MAsIII), dimethylarsenite (DMAIII) and the volatile trimethylarsine (TMA). The methylation of arsenic is coordinated by four conserved cysteines proposed to participate in catalysis, namely C33, C62, C157, and C207 in mouse AS3MT.

Synthesis and Structural and Spectroscopic Studies of a pH-Neutral Argentic Chelate Complex: Tribasic Silver (III) Bisperiodate.

The preparation of stable hypervalent metal complexes containing Ag(III) has historically been challenging due to their propensity for reduction under ambient conditions. This work explores the preparation of a tripotassium silver bisperiodate complex as a tetrahydrate via chemical oxidation of the central silver atom and orthoperiodate chelation. The isolation of the chelate complex in high yield and purity was achieved via acidimetric titration.

Separation of Isomers and Mechanisms of Inversion of Stereochemistry of Group 9 d Tris-Chelate Complexes of Hinokitiol.

Tris-chelate complexes of Co(III), Rh(III), and Ir(III) with 4-isopropyltropolone (hinokitiol or β-thujaplicin) form by the substitution of carbonate and chloride ligands from group 9 trivalent metal salts. The new complexes are neutral, are readily soluble in most organic solvents, and are brightly colored with strong charge transfer bands. The isomers of Co(hino) and Rh(hino) were isolated from the mixture by fractional recrystallization from ethanol.

2,3,5-Metallotriazoles: Amphoteric Mesoionic Chelates from Nitrosoguanidines.

Soluble nitrosoguanidine- and -methylnitrosoguanidine-based metallotriazole complexes of ruthenium(II) monocarbonyls have been prepared and characterized. Both nitrosoguanidines prove to be strong chelates with the formally π-accepting nitroso nitrogen binding to carbon monoxide and a π-donating amide to the CO. The resulting ensemble consists of ruthenium examples of 1-metallo-2,3,5-triazoles.

Sex-Specific Effects of Prenatal and Early Life Inorganic and Methylated Arsenic Exposure on Atherosclerotic Plaque Development and Composition in Adult Mice.

Background: Epidemiologic studies indicate that early life arsenic exposures are linked to an increased risk of cardiovascular diseases. Different oxidation and methylation states of arsenic exist in the environment and are formed via the action of arsenic ( oxidation state) methyltransferase (As3MT). Methylated arsenicals are pro-atherogenic postnatally, but pre- and perinatal effects are unclear.

Fluxionality in the Tropolone Hinokitiol Chelate.

Tropolonate complexes of Ru(II), Ru(III), and Os(II) with hinokitiol, also termed β-thuljaplicin, or 4-isopropyltropolone, readily formed by chloride and triarylphosphine substitution in RuCl(PPh) and MHCl(CO)(PR) (M = Ru, R = Ph; M = Os, R = Ph and -tolyl). The resulting colorful complexes have variable and strong charge transfer bands and also have a surprising combination of stereochemical selectivity and lability. For the Os(II) d examples, the tropolone chelate has a fluxionality with a barrier of only 90 kJ/mol for the R = aryl examples, as determined by variable-temperature P NMR.

Topical combination of meldonium and N-acetyl cysteine relieves allodynia in rat models of CRPS-1 and peripheral neuropathic pain by enhancing NO-mediated tissue oxygenation.

Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain.

Addressing K/L-edge overlap in elemental analysis from micro-X-ray fluorescence: bioimaging of tungsten and zinc in bone tissue using synchrotron radiation and laser ablation inductively coupled plasma mass spectrometry.

Synchrotron radiation micro-X-ray fluorescence (SR-μXRF) is a powerful elemental mapping technique that has been used to map tungsten and zinc distribution in bone tissue. However, the heterogeneity of the bone samples along with overlap of the tungsten L-edge with the zinc K-edge signals complicates SR-μXRF data analysis, introduces minor artefacts into the resulting element maps, and decreases image sensitivity and resolution. To confirm and more carefully delineate these SR-μXRF results, we have employed laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to untangle the problem created by the K/L-edge overlap of the tungsten/zinc pair.

Inorganic ions on hemozoin surface provide a glimpse into Plasmodium biology.

In malaria, Plasmodium parasites produce hemozoin (Hz) as a route to detoxify free heme released from the catabolism of hemoglobin. Hz isolated from the parasites is encapsulated in an organic layer constituted by parasite and host components. This organic coating may play a role in Hz formation and in the immunomodulatory properties attributed to Hz, and they may influence the mode of action of antimalarials that block Hz formation.

What is pure hemozoin? A close look at the surface of the malaria pigment.

The malaria parasite, Plasmodium spp., produces hemozoin (Hz) crystals as a by-product of hemoglobin digestion. Purification methods used to remove host or parasite products adsorbed on Hz surface lead to variable and undetermined residues.

Hydrating the Bispropionate Notch in Malaria Pigment: A New Structural Motif in the Iron(III)(deuteroporphyrin) Dimer.

Treating deuterohemin, chloro(deuteroporphyrinato)iron(III), with a non-coordinating base in DMSO/methanol allows for the isolation of [(deuteroporphyrinato)iron(III)] , deuterohematin anhydride (DHA), an analogue of malaria pigment, the natural product of heme detoxification by malaria. The structure of DHA obtained from this solvent system has been solved by X-ray powder diffraction analysis and displays many similarities, yet important structural differences, to malaria pigment. Most notably, a water molecule of solvation occupies a notch created by the propionate side chains and stabilizes a markedly bent propionate ligand coordinated with a long Fe-O bond, and a carboxylate cluster associated with water molecules is generated.

Micro-Raman high-pressure investigation on the malaria pigment hematin anhydride (β-hematin).

The effect of pressure on the Raman and fluorescence spectra of hematin anhydride (β-hematin) is reported. In a diamond-anvil cell, DAC, with applied pressures up to 41 kbar, the Raman spectrum undergoes a series of intensity enhancements and increases in energy for many of the Raman-active bands up to a pressure of ~27 kbar. At higher pressures, there is either a leveling out or a decrease in the energies of these vibrational modes.

An Overview of the Potential Therapeutic Applications of CO-Releasing Molecules.

Carbon monoxide (CO) has long been known as the "silent killer" owing to its ability to form carboxyhemoglobin-the main cause of CO poisoning in humans. Its role as an endogenous neurotransmitter, however, was suggested in the early 1990s. Since then, the biological activity of CO has been widely examined via both the direct administration of CO and in the form of so-called "carbon monoxide releasing molecules (CORMs).

Generation of a Mn(IV)-Peroxo or Mn(III)-Oxo-Mn(III) Species upon Oxygenation of Mono- and Binuclear Thiolate-Ligated Mn(II) Complexes.

A thiolate-bridged binuclear complex [PPN][(Mn(PS3))] (1, PPN = bis(triphenylphosphine)iminium and PS3H = (2,2',2″-trimercapto-3,3',3″-tris(trimethylsilyl)triphenylphosphine)), prepared from the reaction of MnCl/[PPN]Cl and Li[PS3], converts into a mononuclear complex [PPN][Mn(PS3)(DABCO)] (2) in the presence of excess amounts of DABCO (DABCO = 1,4-diazabicyclo[2.2.2]octane).

Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the Mouse Model and the Role of As3mt-Mediated Methylation.

Background: Arsenic is metabolized through a series of oxidative methylation reactions by arsenic (3) methyltransferase (As3MT) to yield methylated intermediates. Although arsenic exposure is known to increase the risk of atherosclerosis, the contribution of arsenic methylation and As3MT remains undefined.

Objectives: Our objective was to define whether methylated arsenic intermediates were proatherogenic and whether arsenic biotransformation by As3MT was required for arsenic-enhanced atherosclerosis.

Solution and Solid State Correlations of Antimalarial Drug Actions: NMR and Crystallographic Studies of Drug Interactions with a Heme Model.

Solution NMR has been used in tandem with a diamagnetic non-iron heme model compound as a simple and effective tool to rapidly probe the structures of the bound complexes formed between the metalloporphyrin and antimalarial drugs from the 4-aminoquinoline, 4-methylenehydroxylquinoline, and 8-aminoquinoline subfamilies. The ability of gallium(III) protoporphyrin IX to mimic heme chemistry is exploited. The 4-aminoquinolines quinacrine and amodiaquine and two novel 3-halo chloroquine analogues are found to bind to the metalloporphyrin through hydrogen-bonding and stacking interactions, while halofantrine and the 4-methylenehydroxylquinolines, quinine and mefloquine bind through the alcohol group of the drug.

{Fe(NO)(2)(9) Dinitrosyl Iron Complex Acting as a Vehicle for the NO Radical.

To carry and deliver nitric oxide with a controlled redox state and rate is crucial for its pharmaceutical/medicinal applications. In this study, the capability of cationic {Fe(NO)} dinitrosyl iron complexes (DNICs) [(DDB)Fe(NO)] (R = Me, Et, Iso; DDB = N,N'-bis(2,6-dialkylphenyl)-1,4-diaza-2,3-dimethyl-1,3-butadiene) carrying nearly unperturbed nitric oxide radical to form [(DDB)Fe(NO)(NO)] was demonstrated and characterized by IR, UV-vis, EPR, NMR, and single-crystal X-ray diffractions. The unique triplet ground state of [(DDB)Fe(NO)(NO)] results from the ferromagnetic coupling between two strictly orthogonal orbitals, one from Fe d and the other a π* orbital of a unique bent axial NO ligand, which is responsible for the growth of a half-field transition (ΔM = 2) from 70 to 4 K in variable-temperature EPR measurements.

Crystal Structure Analysis of the Repair of Iron Centers Protein YtfE and Its Interaction with NO.

Molecular mechanisms underlying the repair of nitrosylated [Fe-S] clusters by the microbial protein YtfE remain poorly understood. The X-ray crystal structure of YtfE, in combination with EPR, magnetic circular dichroism (MCD), UV, and (17) O-labeling electron spin echo envelope modulation measurements, show that each iron of the oxo-bridged Fe(II) -Fe(III) diiron core is coordinatively unsaturated with each iron bound to two bridging carboxylates and two terminal histidines in addition to an oxo-bridge. Structural analysis reveals that there are two solvent-accessible tunnels, both of which converge to the diiron center and are critical for capturing substrates.

3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine.

Chloroquine (CQ), the first cost-effective synthetic antimalarial, is rendered ineffective in malaria-endemic regions owing to the rise and spread of CQ-resistant Plasmodium falciparum. In this report, we show that a halogen derivative of CQ, namely 3-iodo-CQ, inhibits the proliferation of CQ-sensitive and -resistant P. falciparum in a verapamil-insensitive manner.