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The hypothesis was tested that flavonoids may scavenge singlet oxygen (¹O₂) in mesophyll cells of Phillyrea latifolia exposed to excess-light stress. In cross-sections taken from leaves developed at 10% (shade) or 100% (sun) solar irradiance, we evaluated the excess photosynthetically active radiation (PAR)-induced accumulation of ¹O₂ in mesophyll cells by imaging the fluorescence quenching of the specific ¹O₂ probe N-[2-(diethylamino)ethyl]-N-[(2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)methyl]-5-(dimethylamino)-1-naphthalenesulfonamide (DanePy). The intracellular location of flavonoids was also analyzed using three-dimensional deconvolution microscopy. Photo-induced quenching of DanePy fluorescence was markedly greater in the mesophyll of shade leaves than in that of sun leaves, the former showing a negligible accumulation of mesophyll flavonoids. The photo-induced generation of ¹O₂ was inversely related to the content of flavonoids in the mesophyll cells of sun leaves. Flavonoids were located in the chloroplasts, and were likely associated with the chloroplast envelope. Here we provide relevant evidence for the potential scavenger activity of chloroplast-located flavonoids against ¹O₂ and new insights into the photo-protective role of flavonoids in higher plants.

Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM® (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC50 in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy.

A general method for the synthesis of pyrrolizidine derivatives using an intramolecular hydroaminomethylation protocol (HAM) under microwave (MW) dielectric heating is reported. Starting from a 3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-vinylpyrrolidine, MW-assisted intramolecular HAM in the presence of gaseous H2 and CO gave the natural alkaloid hyacinthacine A2 protected as benzyl ether. The same approach gave a lentiginosine analogue starting from the corresponding vinyl N-hydroxypyrrolidine. The nature of the reaction products and the yields were strongly influenced by the relative stereochemistry of the starting pyrrolidines, as well as by the catalyst/ligand employed. The use of ethanol as a solvent provides environmentally friendly conditions, while the ligand/catalyst system can be recovered by separating the alkaloid product with an SCX column and recycling the ethanolic solution. HAM worked up to three times with the recycled catalyst solution without any significant impact on yield.

GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.

The 1,2-diamine motif is found in a number of bioactive natural products, pharmaceuticals, and ligands for organometallic chemistry. Here, the recent advances in the synthesis of such structures by direct metal-catalysed diamination of alkenes are considered, and opportunities for future research in the area identified. The 1,2-diamine motif is present in a number of natural products with interesting biological activity and in many important pharmaceutical agents. Chiral 1,2-diamines are also widely used as the control elements in asymmetric synthesis and catalysis. Such compounds are thus an attractive target for the synthetic chemist. Although the diamination of an alkene seems an obvious route to these structures, far less research has been devoted to it than to the analogous dihydroxylation or aminohydroxylation reactions that are well-established processes in asymmetric synthesis. Here, we examine recent advances in metal-catalysed diamination reactions and their asymmetric variants. Given the prevalence of these structures, it seems likely that they will find extensive application in the construction of natural products and drug molecules in the near future.

Among carbohydrate-processing enzymes, Jack bean α-mannosidase (JBα-man) is the glycosidase with the best responsiveness to the multivalent presentation of iminosugar inhitopes. We report, in this work, the preparation of water dispersible gold nanoparticles simultaneously coated with the iminosugar deoxynojirimycin (DNJ) inhitope and simple monosaccharides (β-d-gluco- or α-d-mannosides). The display of DNJ at the gold surface has been modulated (i) by using an amphiphilic linker longer than the aliphatic chain used for the monosaccharides and (ii) by presenting the inhitope, not only in monomeric form, but also in a trimeric fashion through combination of a dendron approach with glyconanotechnology. The latter strategy resulted in a strong enhancement of the inhibitory activity towards JBα-man, with a Ki in the nanomolar range (Ki = 84 nM), i.e., more than three orders of magnitude higher than the monovalent reference compound.

1,3-Dipolar cycloadditions on nitrone dipoles are key reactions to access five-membered heterocycles, which are useful intermediates in the synthesis of biologically relevant glycomimetics. The good atomic balance and high stereoselectivity characteristic of such reactions make them good candidates for the development of green protocols. In the present work, these features were maximized by avoiding the use of organic solvents and considering starting materials derived from biomass. Reactions involving (acyclic and cyclic) carbohydrate-derived nitrones as dipoles and levoglucosenone as dipolarophile were considered. Performing selected 1,3-dipolar cycloadditions in neat conditions showed reduced reaction times, maintaining similar selectivity and yields with respect to the classical protocols. The use of microwave irradiation and orbital shaking were also exploited to increase the sustainability of the synthetic protocols. The collected results highlight the potential of solvent-free 1,3-dipolar cycloadditions in the design of efficient synthetic routes according to green chemistry principles, such as prevention, atom economy, safer solvents and auxiliaries, and use of renewable feedstocks.

Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new β-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative “all-cis” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal β-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.

The synthesis of new multivalent architectures based on a trihydroxypiperidine α-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC) between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases.

The oxidation of imines may give several products, such as oxaziridines, nitrones, amides, and other rearranged compounds. Therefore, its selectivity is a challenge that various methods have to face. The controversial selectivity of the oxidation of imines using urea hydrogen peroxide (UHP) catalyzed by methyltrioxorhenium (MTO) is addressed by varying the solvent, temperature, reaction time, amount of oxidant, and catalyst used. The reactivity and selectivity of the oxidation of imines proved to be particularly sensitive to the type of solvent. The use of methanol furnished the corresponding nitrones as the exclusive products, except for very hindered N-tert-alkyl substituted substrates. Using the ionic liquid [bmim]BF4 as a solvent resulted in a complete switch in reactivity and selectivity. N-methyl substituted imines gave the corresponding amides, while imines with bulkier substituents at nitrogen did not show any reactivity. An exception was the C-phenyl,N-tert-butyl imine—the only substrate that was oxidized to the corresponding oxaziridine, albeit with low conversion. The results reported herein reaffirm the oxidation of imines with UHP/MTO in MeOH as the method of choice for their interconversion to nitrones.