Publications by authors named "Leticia Monjas"

17 Publications

  • Page 1 of 1

Unveiling Adatoms in On-Surface Reactions: Combining Scanning Probe Microscopy with van't Hoff Plots.

J Phys Chem C Nanomater Interfaces 2021 May 30;125(18):9847-9854. Epub 2021 Apr 30.

Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.

Scanning probe microscopy has become an essential tool to not only study pristine surfaces but also on-surface reactions and molecular self-assembly. Nonetheless, due to inherent limitations, some atoms or (parts of) molecules are either not imaged or cannot be unambiguously identified. Herein, we discuss the arrangement of two different nonplanar molecular assemblies of -hexaphenyl-dicarbonitrile (Ph(CN)) on Au(111) based on a combined theoretical and experimental approach. For deposition of Ph(CN) on Au(111) kept at room temperature, a rhombic nanoporous network stabilized by a combination of hydrogen bonding and antiparallel dipolar coupling is formed. Annealing at 575 K resulted in an irreversible thermal transformation into a hexagonal nanoporous network stabilized by native gold adatoms. However, the Au adatoms could neither be unequivocally identified by scanning tunneling microscopy nor by noncontact atomic force microscopy. By combining van't Hoff plots derived from our scanning probe images with our density functional theory calculations, we were able to confirm the presence of the elusive Au adatoms in the hexagonal molecular network.
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http://dx.doi.org/10.1021/acs.jpcc.1c03134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279638PMC
May 2021

"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.

Bioorg Med Chem 2021 Jul 7;42:116269. Epub 2021 Jun 7.

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland; National Centre for Nuclear Research, 05-400 Otwock-Świerk, Poland.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.
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http://dx.doi.org/10.1016/j.bmc.2021.116269DOI Listing
July 2021

Surface state tunable energy and mass renormalization from homothetic quantum dot arrays.

Nanoscale 2019 Dec 3;11(48):23132-23138. Epub 2019 Dec 3.

Instituto de Ciencia de Materiales de Aragón (ICMA), CSIC-Universidad de Zaragoza, E-50009 Zaragoza, Spain. and Departamento de Física de la Materia Condensada, Universidad de Zaragoza, E-50009 Zaragoza, Spain.

Quantum dot arrays in the form of molecular nanoporous networks are renowned for modifying the electronic surface properties through quantum confinement. Here we show that, compared to the pristine surface state, the band bottom of the confined states can exhibit downward shifts accompanied by a lowering of the effective masses simultaneous to the appearance of tiny gaps at the Brillouin zone boundaries. We observed these effects by angle resolved photoemission for two self-assembled homothetic (scalable) Co-coordinated metal-organic networks. Complementary scanning tunneling spectroscopy measurements confirmed these findings. Electron plane wave expansion simulations and density functional theory calculations provide insight into the nature of this phenomenon, which we assign to metal-organic overlayer-substrate interactions in the form of adatom-substrate hybridization. To date, the absence of the experimental band structure resulting from single metal adatom coordinated nanoporous networks has precluded the observation of the significant surface state renormalization reported here, which we infer to be general for low interacting and well-defined adatom arrays.
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http://dx.doi.org/10.1039/c9nr07365eDOI Listing
December 2019

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents.

Beilstein J Org Chem 2019 2;15:1468-1474. Epub 2019 Jul 2.

Department of Chemistry and Molecular Biology, University of Gothenburg, Kemigården 4, 412 96, Gothenburg, Sweden.

The synthesis and antibacterial activity of two new highly truncated derivatives of the natural product abyssomicin C are reported. This work outlines the limits of structural truncation of the natural product and consequently provides insights for further structure-activity relationship studies towards novel antibiotics targeting 4-amino-4-deoxychorismate (ADC) synthase. Specifically, it is demonstrated that the synthetically challenging bicyclic motif is essential for activity towards methicillin-resistant (MRSA).
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http://dx.doi.org/10.3762/bjoc.15.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633193PMC
July 2019

Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists.

ChemMedChem 2019 08 22;14(15):1444-1456. Epub 2019 Jul 22.

Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada.

Chromobox homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low-molecular-weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors that had previously been reported to be inactive against Cbx7. We evaluated each new inhibitor for Cbx7 inhibition by fluorescence polarization assay, and also confirmed the binding of selected inhibitors to Cbx7 by saturation-transfer difference NMR spectroscopy. This work identified multiple small-molecule inhibitors with modest (IC : 257-500 μm) potency.
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http://dx.doi.org/10.1002/cmdc.201900021DOI Listing
August 2019

Low-Dimensional Metal-Organic Coordination Structures on Graphene.

J Phys Chem C Nanomater Interfaces 2019 May 30;123(20):12730-12735. Epub 2019 Apr 30.

Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.

We report the formation of one- and two-dimensional metal-organic coordination structures from -hexaphenyl-dicarbonitrile (NC-Ph-CN) molecules and Cu atoms on graphene epitaxially grown on Ir(111). By varying the stoichiometry between the NC-Ph-CN molecules and Cu atoms, the dimensionality of the metal-organic coordination structures could be tuned: for a 3:2 ratio, a two-dimensional hexagonal porous network based on threefold Cu coordination was observed, while for a 1:1 ratio, one-dimensional chains based on twofold Cu coordination were formed. The formation of metal-ligand bonds was supported by imaging the Cu atoms within the metal-organic coordination structures with scanning tunneling microscopy. Scanning tunneling spectroscopy measurements demonstrated that the electronic properties of NC-Ph-CN molecules and Cu atoms were different between the two-dimensional porous network and one-dimensional molecular chains.
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http://dx.doi.org/10.1021/acs.jpcc.9b00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541427PMC
May 2019

A combinatorial approach for the discovery of drug-like inhibitors of 15-lipoxygenase-1.

Eur J Med Chem 2019 Jul 12;174:45-55. Epub 2019 Apr 12.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Department of Drug Design and Optimization, Campus Building E8.1, 66123, Saarbrücken, Germany; Department of Pharmacy, Saarland University, 66123, Saarbrücken, Germany. Electronic address:

Human 15-lipoxygenase-1 (15-LOX-1) is a mammalian lipoxygenase which plays an important regulatory role in several CNS and inflammatory lung diseases. To further explore the role of this enzyme in drug discovery, novel potent inhibitors with favorable physicochemical properties are required. In order to identify such new inhibitors, we established a combinatorial screening method based on acylhydrazone chemistry. This represents a novel application of combinatorial chemistry focusing on the improvement of physicochemical properties, rather than on potency. This strategy allowed us to efficiently screen 44 reaction mixtures of different hydrazides and our previously reported indole aldehyde core structure, without the need for individual synthesis of all possible combinations of building blocks. Our approach afforded three new inhibitors with IC values in the nanomolar range and improved lipophilic ligand efficiency.
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http://dx.doi.org/10.1016/j.ejmech.2019.04.021DOI Listing
July 2019

Comparing the Self-Assembly of Sexiphenyl-Dicarbonitrile on Graphite and Graphene on Cu(111).

Chemistry 2019 Apr 12;25(19):5065-5070. Epub 2019 Mar 12.

Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.

A comparative study on the self-assembly of sexiphenyl-dicarbonitrile on highly oriented pyrolytic graphite and single-layer graphene on Cu(111) is presented. Despite an overall low molecule-substrate interaction, the close-packed structures exhibit a peculiar shift repeating every four to five molecules. This shift has hitherto not been reported for similar systems and is hence a unique feature induced by the graphitic substrates.
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http://dx.doi.org/10.1002/chem.201806312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519158PMC
April 2019

Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine.

ChemMedChem 2017 10 6;12(20):1693-1696. Epub 2017 Oct 6.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747, AG, Groningen, The Netherlands.

We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.
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http://dx.doi.org/10.1002/cmdc.201700440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698757PMC
October 2017

Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia.

Eur J Med Chem 2017 Apr 22;130:60-72. Epub 2017 Feb 22.

Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006, Madrid, Spain. Electronic address:

Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.
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http://dx.doi.org/10.1016/j.ejmech.2017.02.034DOI Listing
April 2017

Harnessing dynamic combinatorial chemistry in the search for new ligands for protein targets.

Future Med Chem 2015 29;7(16):2095-8. Epub 2015 Oct 29.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG, Groningen, The Netherlands.

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http://dx.doi.org/10.4155/fmc.15.146DOI Listing
September 2016

Structure-based design of potent small-molecule binders to the S-component of the ECF transporter for thiamine.

Chembiochem 2015 Mar 12;16(5):819-26. Epub 2015 Feb 12.

Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen (The Netherlands) http://www.rug.nl/research/membrane-enzymology/

Energy-coupling factor (ECF) transporters are membrane-protein complexes that mediate vitamin uptake in prokaryotes. They bind the substrate through the action of a specific integral membrane subunit (S-component) and power transport by hydrolysis of ATP in the three-subunit ECF module. Here, we have studied the binding of thiamine derivatives to ThiT, a thiamine-specific S-component. We designed and synthesized derivatives of thiamine that bind to ThiT with high affinity; this allowed us to evaluate the contribution of the functional groups to the binding affinity. We determined six crystal structures of ThiT in complex with our derivatives. The structure of the substrate-binding site in ThiT remains almost unchanged despite substantial differences in affinity. This work indicates that the structural organization of the binding site is robust and suggests that substrate release, which is required for transport, requires additional changes in conformation in ThiT that might be imposed by the ECF module.
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http://dx.doi.org/10.1002/cbic.201402673DOI Listing
March 2015

Multipotent, permeable drug ASS234 inhibits Aβ aggregation, possesses antioxidant properties and protects from Aβ-induced apoptosis in vitro.

Curr Alzheimer Res 2013 Oct;10(8):797-808

Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.

Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ1-42 self-aggregation more efficiently than that of Aβ1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ1-42 and Aβ1-40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Aβ1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.
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http://dx.doi.org/10.2174/15672050113109990151DOI Listing
October 2013

Benzothiazepine CGP37157 and its isosteric 2'-methyl analogue provide neuroprotection and block cell calcium entry.

ACS Chem Neurosci 2012 Jul 26;3(7):519-29. Epub 2012 Mar 26.

Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, C/Diego de León, 62, 28006 Madrid, Spain; Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispro Morcillo, 4, 28029, Madrid, Spain.

Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca(2+) handling, by its blocking effect of the mitochondria Na(+)/Ca(2+) exchanger. Recently, CGP37157 has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2' of the phenyl ring. ITH12505 has exerted neuroprotective properties similar to CGP37157 in chromaffin cells and hippocampal slices stressed with veratridine. Also, both compounds afforded neuroprotection in hippocampal slices stressed with glutamate. However, while ITH12505 elicited protection in SH-SY5Y cells stressed with oligomycin A/rotenone, CGP37157 was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3-30 μM, while CGP37157 only protected at 30 μM. Both compounds caused blockade of Ca(2+) channels in high K(+)-depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervous system penetration (PAMPA-BBB; parallel artificial membrane permeability assay for blood-brain barrier) revealed that both compounds could cross the blood-brain barrier, thus reaching their biological targets in the central nervous system. In conclusion, by causing a mild isosteric replacement in the benzothiazepine CGP37157, we have obtained ITH12505, with improved neuroprotective properties. These findings may inspire the design and synthesis of new benzothiazepines targeting mitochondrial Na(+)/Ca(2+) exchanger and L-type voltage-dependent Ca(2+) channels, having antioxidant properties.
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http://dx.doi.org/10.1021/cn300009eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399582PMC
July 2012

Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease.

Eur J Med Chem 2012 Aug 28;54:750-63. Epub 2012 Jun 28.

Laboratoire de Chimie Appliquée, Hétérocycles, Corps Gras et Polymères Faculté des Sciences de Sfax, Université de Sfax, 3018 Sfax, Tunisia.

The synthesis, pharmacological analysis and molecular modeling of the readily available racemic tacrine analogs 21-30, bearing the 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amine heterocyclic ring system (II), prepared by Friedländer reaction of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (11-20) with cyclohexanone, are described in this paper. Molecules 21-30 are potent and selective inhibitors of hAChE, in the low micromolar range, one of the most potent inhibitors, 4-(8-amino-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-7-yl)-2-methoxyphenol (25), showing a IC(50) (hAChE) = 0.33 ± 0.04 μM. Kinetic studies of compound 25 proved that this compound is a mixed type inhibitor for EeAChE (K(i) = 81 nM). Accordingly, molecular modeling of inhibitor 25 showed that both enantiomers have two major predicted binding modes at the active and at the peripheral anionic sites of AChE. Inhibitor 25 has an excellent antioxidant profile as determined in the ORAC experiment (1.47 ± 0.10 Trolox equiv). Inhibitors 26-28 and 30 are permeable to BBB as determined in the PAMPA assay. Compared to tacrine, selected compounds 26-28 and 30 showed less hepatic toxicity in HepG2 cells. Moreover, cell viability-related studies in cortical neurons in primary cultures show that compounds 26-28 and 30 (0.1-50 μM) have significant neuroprotective effects against mitochondrial chain blockers-induced cell death, and, unlike tacrine, are not neurotoxic at concentrations lower than 50 μM. It is worth highlighting that compound 27 has the best neuroprotective properties out of all assayed compounds and shows no neurotoxicity. To sum up, these tacrine analogs can be considered as attractive multipotent therapeutic molecules on pharmacological receptors playing key roles in the progress of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.ejmech.2012.06.038DOI Listing
August 2012

New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and β-amyloid-reducing properties.

J Med Chem 2012 Feb 27;55(3):1303-17. Epub 2012 Jan 27.

Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.
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http://dx.doi.org/10.1021/jm201460yDOI Listing
February 2012

Α-aryl-N-alkyl nitrones, as potential agents for stroke treatment: synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties.

J Med Chem 2012 Jan 21;55(1):153-68. Epub 2011 Dec 21.

Laboratorio de Radicales Libres y Química Computacional, Instituto de Química Orgánica General (CSIC), Juan de la Cierva, 3, 28006-Madrid, Spain.

We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection. When compounds 1-11 were tested for necrotic cell death (LDH release test) nitrones 1-3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.
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http://dx.doi.org/10.1021/jm201105aDOI Listing
January 2012
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