Abstract
C60-based ebselen derivative 3 was synthesized through Bingel cyclopropanation of C60 with the ebselen malonate 2. Compound 3 was obtained in 42% yield (based on consumed C60) in a three-step synthesis starting from 2-(chloroseleno)benzoyl chloride and 2-(2aminoethoxy)ethanol. Its structure was confirmed by ¹H NMR, 13C NMR, IR, UV and FAB-MS spectroscopy analyses. In order to verify the enhanced antioxidative and neuroprotective activity of 3, a C60 derivative (4), an ebselen derivative (2), and their mixture (4 plus 2 in equimolar ratio) were employed to treat cortical neuronal cells, following the same procedure used with 3 and at the same final concentration (30 µmol L-1). Cell viabilities of the four treated groups were estimated by LDH (lactic dehydrogenase) leakage and MTT (3-(4, 5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assays. Results showed that the antioxidative and protective activities of C60-based ebselen derivative 3 against H2O2-mediated neuronal injury (MTT(OD) 0.364 ± 0.028; LDH release (UL-1) 4.66 ± 0.28) were significantly higher than those of C60 derivative 4 (MTT(OD) 0.324 ± 0.025; LDH release (UL-1) 5.39 ± 0.17), ebselen derivative 2 (MTT(OD) 0.294 ± 0.021; LDH release (UL-1) 5.71 ± 0.27), and the mixture of 4 and 2 (MTT(OD) 0.310 ± 0.018; LDH release (UL-1) 5.54 ± 0.39). These findings demonstrated that the combination of two molecular units with similar biological activities (C60 and ebselen) may be a desirable way of obtaining new and more biologically effective C60-based compounds.
Highlights
The investigation of modern medical sciences has suggested that free radicals are associated with a number of neurodegenerative diseases,[1] such as Parkinson and Huntington’s diseases and Alzheimer’s dementia
The same carboxyfullerenes were reportedly able to inhibit cerebellar granule cell apoptosis, possibly by reducing the generation of reactive oxygen species (ROS).[7]. Other fullerene derivatives, such as fullerenol, hexasulfobutylated C60 (FC4S) and C60(glucosamine)[6], showed neuroprotective activity related to their antioxidative property
C60(glucosamine)[6] has been found to prevent renal I/Rinduced apoptosis formation and superoxide generation.[10]. All these results reveal that fullerene and its derivatives possess antioxidative activity and may be useful as neuroprotective agents in several acute or chronic neurodegenerative diseases
Summary
The investigation of modern medical sciences has suggested that free radicals are associated with a number of neurodegenerative diseases,[1] such as Parkinson and Huntington’s diseases and Alzheimer’s dementia. Carboxyfullerenes prevent apoptotic injury of cultured cortical neurons evoked by N-methyl-D-aspartate and β-amyloid peptide,[5] and inhibit iron-induced oxidative stress in rat brain.[6] The same carboxyfullerenes were reportedly able to inhibit cerebellar granule cell apoptosis, possibly by reducing the generation of ROS.[7] Other fullerene derivatives, such as fullerenol, hexasulfobutylated C60 (FC4S) and C60(glucosamine)[6], showed neuroprotective activity related to their antioxidative property. Oxidative injury was induced by adding H2O2 (final concentration 150 μmol L-1) to the serum-free DMEM culture medium containing 0.2% DMSO and incubating at 37 °C for 2 h.18. Control cells were not exposed to H2O2 nor to the various compounds, but cultured in serum-free DMEM medium supplemented with 0.2% DMSO for 24 h. LDH contents in the extracellular medium were determined using the LDH assay kit according to the kit instructions
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