Significant increase in iron occurs in the substantia nigra pars compacta of Parkinsonian subjects, and in 6-hydroxydopamine (6-OHDA) treated rats and monkeys. This increase in iron has been ...attributed to its release from ferritin and is associated with the generation of reactive oxygen species and the onset of oxidative stress-induced neurodegeneration. Several iron chelators with hydroxyquinoline backbone were synthesized and their ability to inhibit basal as well as iron-induced mitochondrial lipid peroxidation was examined. The neuroprotective potential of the brain permeable iron chelator, VK-28 (5-4-(2-hydroxyethyl) piperazine-1-ylmethyl-quinoline-8-ol), injected either intraventricularly (ICV) or intraperitoneally (IP), to 6-OHDA lesioned rats was investigated. VK-28 inhibited both basal and Fe/ascorbate induced mitochondrial membrane lipid peroxidation, with an IC
50 (12.7 μM) value comparable to that of the prototype iron chelator, desferal, which does not cross the blood brain barrier. At an ICV pretreatment dose as low as 1 μg, VK-28 was able to completely protect against ICV 6-OHDA (250 μg) induced striatal dopaminergic lesion, as measured by dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) levels. IP injection of rats with VK-28 (1 and 5 mg/kg) daily for 10 and 7 days, respectively, demonstrated significant neuroprotection against ICV 6-OHDA at the higher dose, with 68% protection against loss of dopamine at 5mg/kg dosage of VK-28. The present study is the first to show neuroprotection with a brain permeable iron chelator. The latter can have implications for the treatment of Parkinson’s disease and other neurodegenerative diseases (Alzheimer’s disease, Friedreich ataxia, aceruloplasminemia, Hallervorden Spatz syndrome) where abnormal iron accumulation in the brain is thought to be associated with the degenerative processes.
Iron‐dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)‐B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson's disease, ...Alzheimer's disease and related neurodegenerative diseases. Accordingly, iron chelators, antioxidants and MAO‐B inhibitors have shown efficacy in a variety of cellular and animal models of CNS injury. In searching for novel antioxidant iron chelators with potential MAO‐B inhibitory activity, a series of new iron chelators has been designed, synthesized and investigated. In this study, the novel chelators were further examined for their activity as antioxidants, MAO‐B inhibitors and neuroprotective agents in vitro. Three of the selected chelators (M30, HLA20 and M32) were the most effective in inhibiting iron‐dependent lipid peroxidation in rat brain homogenates with IC50 values (12–16 µm), which is comparable with that of desferal, a prototype iron chelator that is not has orally active. Their antioxidant activities were further confirmed using electron paramagnetic resonance spectroscopy. In PC12 cell culture, the three novel chelators at 0.1 µm were able to attenuate cell death induced by serum deprivation and by 6‐hydroxydopamine. M30 possessing propargyl, the MAO inhibitory moiety of the anti‐Parkinson drug rasagiline, displayed greater neuroprotective potency than that of rasagiline. In addition, in vitro, M30 was a highly potent non‐selective MAO‐A and MAO‐B inhibitor (IC50 < 0.1 µm). However, HLA20 was more selective for MAO‐B but had poor MAO inhibition, with an IC50 value of 64.2 µm. The data suggest that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for the treatment of various neurodegenerative disorders.
Several novel antioxidant iron chelators bearing 8-hydroxyoxyquinoline moiety were synthesized, and their various properties related to neuroprotective action were investigated.
Several novel ...antioxidant-iron chelators bearing 8-hydroxyoxyquinoline moiety were synthesized, and various properties related to their iron chelation, and neuroprotective action were investigated. All the chelators exhibited strong iron(III) chelating and high antioxidant properties. Chelator
9 (HLA20), having good permeability into K562 cells and moderate selective MAO-B inhibitory activity (IC
50 110
μM), displayed the hightest protective effects against differentiated P19 cell death induced by 6-hydroxydopamine. EPR studies suggested that Chelator
9 also act as radical scavenger to directly scavenge hydroxyl radical.
Ion Exchange Dimitri Muraviev, Vladimir Gorshkov, Abraham Warshawsky / Dimitri Muraviev, Vladimir Gorshkov, Abraham Warshawsky
1999
eBook
This text offers the best of ion exchange science conducted in the countries of the former Soviet Union. It reviews the multidisciplinary study at the nexus of physical, organic, inorganic and ...biological chemistries, and progresses from theoretical fundamentals to practical applications in manufacturing, mineral refining and environmental clean-up. The text examines advances and phenomena observed in ion-exchange systems.
Controlled inhibition of the enzyme Cu/Zn superoxide dismutase (SOD), one of the most important enzymes of the antioxidant defense system of aerobic organisms, is the subject of this paper. It is ...desirable in several noted medical and agricultural applications. This paper describes the synthesis of a very limited “sublibrary” of bifunctional metal chelators. The first function is the metal chelator DTC (sodium diethyldithiocarbamate (Et2DTC)), which has the sole chemical function of specific metal binding. An amphiphile (more precisely, an oligoether) is the second function and has a sole physical function: changing the physical properties of the molecule. The paper discusses novel copper chelators with variable amphiphilic properties: disubstituted dithiocarbamates (DTCs, R1(CH2CH2O)2NR2CS2Na) with one alkyl (R2 = hexyl, octyl, decyl, or dodecyl) and one oligoether (R1(CH2CH2O)2, where R1 = Et or Bu) substituent. The octanol−water distribution ratios of the dithiocarbamates (partition measurements by the shake-flask method) and their penetration through the liposome bilayer were measured to predict their transport behavior through biological membranes. The comparative copper binding constants and the stepwise transformation of Fe(DTC)3 to Cu(DTC)2 were measured and show the selectivity of the ligands for copper over iron. Differential effects of dithiocarbamates on the rates of copper removal from SOD are shown. The influence of DTCs on SOD superoxide dismutation activity was measured by the cytochrome C/xanthine/xanthine oxidase assay. The SOD dismutation activity was recovered after incubation of inactivated SOD with copper. Inhibition of peroxidase activity of SOD by different DTCs was determined using electron paramagnetic resonance spectra of the DMPO−•OH adduct formed in solutions containing H2O2 and CuZnSOD and in the presence of the spin trap compound. The conclusions are that the addition of an oligoether chain of up to eight aliphatic carbon atoms to the structure of dithiocarbamates leads to an increase in the hydrophobicity (relative to Et2DTC) of more than 1000-fold but only a 2.3-fold decrease in the ability to inhibit SOD dismutation activity. However, the rates of decomposition of Na, K, and Li salts are tremendously enhanced. These unexpectedly high rates of hydrolysis may be due to high interfacial activity as may be deduced from the preliminary interfacial tension and critical micelle concentration data. DTCs have close similarity in their ability to transport through bilayer membranes when the rates of substitution of Cu2+ by DTCs from calcein−copper complex in buffer solution and in liposomes are compared. Structural attenuation leads to a balance in desired properties. Library members with decyl and dodecyl groups are poor inhibitors of SOD dismutase activity. Amphiphilic dithiocarbamates (hexyl and octyl substituted) reduce the peroxidase activity of SOD. Amphiphilic DTCs and their copper complexes do not cause damage to a tested membrane model (liposome system) and, hence, are not expected to damage biological membranes.
Laboratory studies were conducted to investigate the feasibility of using ion-exchange resins in permeable reactive barriers (PRBs) for the remediation of groundwater contaminated by heavy and ...transition metals. Ion-exchange resins represent an essentially neglected class of materials which may, in addition to iron, activated carbon, and zeolites, prove effective for use in PRBs. Four resins were considered: two commercially available resins, Duolite GT-73 (Rohm and Haas) and Amberlite IRC-748 (Rohm and Haas), and two solvent-impregnated resins (SIRs). The SIRs were prepared from Amberlite IRA-96 (Rohm and Haas) and two different thiophosphoric extractants. All four resins are able to reduce cadmium, lead, and copper concentrations from 1000 μg/L (typical for contaminated groundwaters) to below 5 μg/L. Significantly, all of the resins are effective for the capture of cadmium, copper, and lead, even in the presence of CaCl2 and clay. Because of their high hydraulic conductivity, the use of these resins in clusters of wells, as an alternative to continuous walls, is considered in the design of effective PRBs. Numerical solution of the groundwater flow equations shows that, depending on the well configuration, most (or all) of the contaminated groundwater can pass through the resins. These results demonstrate the possibility of using selective ion-exchange resins as an effective, active material in PRBs for in situ groundwater remediation.
Photochromes, bound to polysulfone via carboxyamide bonds and physically blended in a polymeric matrix, were prepared and their physical and photochromic properties investigated. In order to express ...the photochromic activity, plasticization is required; this is readily achieved by using the swelling solvent, N-methylpyrrolidone (NMP). The photochromic activity is repressed in the presence of carboxylic groups, and this requires complex blocking of any acidity, e.g., by esterification or amidation. The photochromic activity was expressed in membranes made from functional and blended polysulfones, yet the photoresponsive membranes did not produce a significant electroresponse or, if they did, this decayed rapidly. Obviously, membranes with a much higher degree of covalent binding are needed.
Infection by many fungi activates a variety of calcium dependent defenses in the hosts, slowing or suppressing the attacker and limiting the efficacy of mycoherbicides. The calcium requirement for ...fungal growth is so low that it could only be implied based on fungi containing calcium-dependent signaling enzymes. Analytical grade media contain <2 μM calcium, and the addition of specific chelators does not affect fungal growth. Hydrophobic derivatives of the calcium-specific chelator BAPTA designed to traverse plant cuticles were synthesized in order to chelate calcium internally during fungal attack. Some chelators as well as calcium precipitating oxalate and channel blocker verapamil were applied with a weakly mycoherbicidal Colletotrichum coccodes to cotyledons of compatible Abutilon threophrasti. They suppressed calcium dependent callose biosynthesis in the weed and increased virulence but may have affected other calcium-dependent processes that facilitate virulence. The low calcium requirement of fungi, and their high affinity for calcium, allows the application of calcium-regulating agents as synergists for mycoherbicides where the weed uses calcium-dependent defenses. Keywords: Abutilon theophrasti; BAPTA; Colletotrichum coccodes, calcium chelators; calcium requirements; callose; EGTA; infection; mycoherbicides; oxalate; synergists; virulence
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