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Background:GSK-3β activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer’s disease is the most studied neurodegenerative disease, but GSK-3β seems to be involved in almost all neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, and the autoimmune disease multiple sclerosis.Objective:This review aims to help researchers both working on this research topic or not to have a comprehensive overview of GSK-3β in the context of neuroinflammation and neurodegeneration.Method:Literature has been searched using PubMed and SciFinder databases by inserting specific keywords. A total of more than 500 articles have been discussed.Results:First of all, the structure and regulation of the kinase were briefly discussed, and then, specific GSK-3β implications in neuroinflammation and neurodegenerative diseases were illustrated with the help of figures, to conclude with a comprehensive overview on the most important GSK-3β and multitarget inhibitors. The structure and IC50 values at the target kinase have been reported for all the discussed compounds.Conclusion:GSK-3β is involved in several signaling pathways in neurons, glial cells and immune cells. The fine regulation and interconnection of all these pathways are at the base of the rationale use of GSK-3β inhibitors in neuroinflammation and neurodegeneration. Some compounds are now under clinical trials. Despite this, the compounds’ pharmacodynamic and ADME/Tox profiles were often not fully characterized which is deleterious in such a complex system.

In the search for alternative photosensitizers for use in photodynamic therapy (PDT), herein we describe two new water-soluble porphyrins, a neutral fourfold-symmetric compound and a +3-charged tris-methylpyridinium derivative, in which either four or one [1,4,7]-triazacyclononane (TACN) units are connected to the porphyrin macrocycle through a hydrophilic linker; we also report their corresponding tetracationic Re(I) conjugates. The in vitro (photo)toxic effects of the compounds toward the human cell lines HeLa (cervical cancer), H460M2 (non-small-cell lung carcinoma), and HBL-100 (non-tumorigenic epithelial cells) are reported. Three of the compounds are not cytotoxic in the dark up to 100 μm, and the fourfold-symmetric couple revealed very good phototoxic indexes (PIs). The intracellular localization of all derivatives was studied in HeLa cells by confocal fluorescence microscopy. Although low nuclear localization was observed for some of them, it still prompted us to investigate their capacity to bind both quadruplex and duplex DNA; we observed significant selectivity in the tris-methylpyridinium derivatives for G-quadruplex interactions.

We recently prepared two novel water soluble porphyrins bearing a single peripheral chelator, either diethylenetriamine (1) or bipyridyl (2), tethered to one meso position. The preparation of their conjugates with a fac-{(99m) Tc(CO)3 }(+) fragment and the potential of these resulting conjugates as fluorescence and radio imaging tools were also described. In this work, we focused on the corresponding non-radioactive analogues that bear the fac-{Re(CO)3 }(+) fragment (diethylenetriamine 3 and bipyridyl 4). We report on the uptake, in vitro PDT activity, and cellular localization of Re(I) conjugates 3 and 4 in comparison to the parent porphyrins 1 and 2. Compounds 1-4 have modest or negligible cytotoxicity in the dark against HeLa human cervical cancer cells but become remarkably cytotoxic after exposure to moderate doses of red visible light (590-700 nm). This phototoxicity was found to be directly proportional to the total light dose. Although the four compounds show distinct uptake patterns, they have comparable PDT activity. Confocal fluorescence measurements showed that porphyrin 1 and its Re(I) conjugate 3 have different cellular localization patterns in HeLa cells.

A quantitative study on the effect of ring size in the intramolecular ring opening of epoxides by carbanions is described. Two series of substrates were examined a,a-bis-sulfonyl w-epoxides 1 and a-cyano-a-sulfonyl w-epoxides 2; in each series the carbanion is tethered to the epoxide by a chain of variable length from one to four methylene groups. The nucleophile can attack either electrophilic position of the oxirane ring, or both; exo ring opening of cyano sulfonyl epoxides 2 is followed by a second cyclization leading eventually to bicyclic, fused y-lactones. Both series of epoxides show the same trend of reactivity as a function of ring size, in the formation of three- to seven-membered rings, with reactivity maxima corresponding to the formation of cyclopropane and cyclopentane derivatives. Unlike 8 N 2 ring closure of w-halogeno carbanions, cyclization to a five-membered ring is the fastest process in this case. The ratio kdk5 between formation of three- and five-membered rings drops from over 100, in the SN2 cyclization of w-iodo bis-sulfones, to less than 0.5, in the cyclization of w-epoxy bis-sulfones 1. The difference is discussed in terms of trajectory of approach of the carbanion to the nucleophilic center. Cyclization of cyano sulfonyl epoxide 2a, in which the nucleophilic center and the epoxide are spaced by a single methylene group, is diastereoselective and leads to a bicyclic product with a cis fusion between the y-lactone and the cyclopropane ring.

Lipase catalyzed stereoselective acylation of butyl mandelate was studied. The determining role of solvent and acylating agent was pointed out and a considerable inhibitory effect due to mandelic acid was observed by screening different lipases. Finally, the performance of the reaction was appreciably improved thank to a multivariate approach.

A quantitative study on the effects of methyl and gem-dimethyl groups in the intramolecular ring opening of epoxides by bis-sulfonyl carbanions is reported for the formation of cyclopropanes. Reaction rates are increased by methyl groups on the chain connecting the nucleophile with the oxirane and depressed by methyl substitution in the epoxide ring. When gem-dimethyl groups are present on the epoxide, ring opening is apparently inhibited. It will be shown that in this case the reaction is reversible and the apparent stabilization of the gem-dimethyl- substituted oxirane is actually due to a combination of effects on both the forward and the reverse reactions. On the basis of current theories on intramolecular reactions, it is suggested that release of ground-state strain and van der Waals repulsions in the transition state can account for the observed reactivity.

The effect of substituents on 13C and 1H NMR chemical shifts in 2- and 3-substituted furans, thiophenes, seleno-phenes and tellurophenes was studied by means of principal components analysis (PCA) and partial least squares (PLS) analysis. The analysis of the data by PCA showed that for both series the substituents are grouped into four different classes depending on the heteroatom present in the ring, and that the substituent-heteroatom interaction has the same nature for all the rings. PLS analysis of the data sets allowed the prediction of the chemical shift values of a different ring having the same substituents.

The isomerization of 1,5-cyclooctadiene to 1,3-cyclooctadiene and 1,4-cyclooctadiene catalyzed by silica-supported Ir 4 (CO) 12 was investigated by means of statistical methods, and the yield in 1,4-cyclooctadiene was optimized. A complete factorial design was developed in order to evaluate the effects of five experimental variables and their interactions. Response surface methodology was employed to study the experimental domain (level of variables) and to determine the values of the independent variables for which the responses assume optimum values. By this method optimum yield in 1,4-isomer (50%) was obtained with the highest selectivity (>97%) so far obtained in this reaction.

Treatment of non-aqueous spherical beads of calcium alginate, or alginic acid gel, with acetic anhydride in pyridine results in acetylation without degradation. The degree and pattern of substitution were investigated using n.m.r. spectroscopy and degradation with specific enzymes. At low degrees of acetylation, substitution occurred almost exclusively on the mannosyluronic acid residues. At high degrees of acetylation, only a minor proportion of the isolated guluronic acid residues was substituted. The presence of O -acetyl groups inhibited depolymerisation by alginate lyases.