One-Pot Stereospecific Synthesis of 1,4-Oligosaccharides by Glycal-Derived Vinyl Epoxides Assembly.

Recently, naturally occurring linear 1,4-glycans have attracted remarkable attention for their activity in cancer and neurodegenerative disease treatment. Classical chemical synthetic strategies for linear 1,4-oligosaccharides are considerably time-consuming due to orthogonal protection/deprotection, the introduction of leaving groups, and various forms of activation of the glycosylation reaction. Herein, we present a new one-pot microwave-activated reiterative assembly of glycal-derived vinyl epoxides in an uncatalyzed substrate-dependent stereospecific process for the preparation of both β-1,4-d-Gulo and α-1,4-d-Manno oligosaccharides.

Ring-Opening Reactions of Imidazolidines and Hexahydropyrimidines with Grignard Reagents.

We herein report an unprecedented ring-opening of unstrained cyclic aminals such as imidazolidines and hexahydropyrimidines by the use of Grignard and cuprate reagents to give secondary sulfonamides bearing diversely substituted tertiary amines in the β- or γ-position. This synthetic procedure can be carried out in a one-pot fashion without collateral reactions that are commonly associated with sp-organometallic multicomponent Mannich-type reactions, indicating the fundamental role of sulfonamide protection of the second nitrogen atom in the generation of the cyclic aminal and in the ring-opening process. Computational density functional theory (DFT) data point to the formation of a transient iminium ion intermediate, in which the Lewis acidity of the cationic component of the organometallic reagent triggers the ring-opening process by coordination.

Glycoconjugate coumarins exploiting metabolism-enhanced fluorescence and preferential uptake: New optical tools for tumor cell staining.

The possibility to visually discriminate cells based on their metabolism and capability to uptake exogenous molecules is an important topic with exciting fallback on translational and precision medicine. To this end, probes that combine several complementary features are necessary. The ideal probe is selectively uptaken and activated in tumor cells compared with control ones and is not fluorescent in the extracellular medium.

Development of an asymmetric formal synthesis of (-)-quinagolide enzymatic resolution and stereoselective iminium ion reduction.

The stereoselective reduction of a diastereoisomeric mixture of benzo[]octahydroquinolinium ion was examined in detail. A diastereoselective borohydride reduction in combination with an efficient deacylative enzymatic resolution of its β-aminoester precursor are the key steps for a stereoselective installation of the three chiral centres present in the (3,4a,10a)-eutomer of the medicinal drug quinagolide. The obtained data paves the way for an easy and practical attainment of chiral 3-substituted octahydrobenzo[]quinolines that are privileged structures in medicinal chemistry.

Functionalized aliphatic polyketones with germicide activity.

The COVID-19 pandemic has further confirmed to the community that direct contact with contaminated surfaces and objects represents an important source of pathogen spreading among humans. Therefore, it is of paramount importance to design effective germicidal paints to ensure a rapid and potent disinfectant action of surfaces. In this work, we design novel germicide polymeric coatings by inserting quaternary ammonium and sugar groups on the macromolecular backbone, thus respectively endowing the polymer with germicide features and hydrophilicity to interact with the surfaces.

New glycoconjugation strategies for Ruthenium(II) arene complexes via phosphane ligands and assessment of their antiproliferative activity.

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEβ and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1β and 1α.

Tethering Carbohydrates to the Vinyliminium Ligand of Antiproliferative Organometallic Diiron Complexes.

Four propargyl -glycosides derivatized with mannose, glucose, and fructose moieties were synthesized and then incorporated within a diiron structure as part of a vinyliminium ligand. Hence, six glycoconjugated diiron complexes, []CFSO (see Scheme 1) and the nonglycosylated analogues []CFSO, were obtained in high yields and unambiguously characterized by elemental analysis, mass spectrometry, and IR and multinuclear NMR spectroscopies. All compounds exhibited a significant stability in DMSO- /DO solution, with 63-89% of the complexes unaltered after 72 h at 37 °C and also in the cell culture medium.

Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with Bpin: Experimental and Computational Studies.

The possibility to form new C-B bonds with aziridines using diboron derivatives continues to be a particularly challenging field in view of the direct preparation of functionalized β-aminoboronates, which are important compounds in drug discovery, being a bioisostere of β-aminoacids. We now report experimental and computational data that allows the individuation of the structural requisites and of reaction conditions necessary to open alkyl aziridines using bis(pinacolate)diboron (Bpin) in a regioselective nucleophilic addition reaction under copper catalysis.

Influence of Divalent Cations in the Protein Crystallization Process Assisted by Lanthanide-Based Additives.

The use of lanthanide complexes as powerful auxiliaries for biocrystallography prompted us to systematically analyze the influence of the commercial crystallization kit composition on the efficiency of two lanthanide additives: [Eu(DPA)] and Tb-Xo4. This study reveals that the tris(dipicolinate) complex presents a lower chemical stability and a strong tendency toward false positives, which are detrimental for its use in a high-throughput robotized crystallization platform. In particular, the crystal structures of (Mg(HO))[Eu(DPA)]·7HO (), {(Ca(HO))[Eu(DPA)]}·10HO (), and {Cu(DPA)(HO)} (), resulting from spontaneous crystallization in the presence of a divalent alkaline-earth cation and transmetalation, are reported.

Stereoselective synthesis of new pyran-dioxane based polycycles from glycal derived vinyl epoxide.

Chiral heteropolycyclic structures are widespread in compounds of high pharmaceutical relevance. In particular, linear fused pyran-dioxane based polycycles can be found in several naturally occurring molecules, and among them, cardiac glycosides and antibiotic spectinomycin are characterized by a -- geometry. Then, the stereocontrol in the synthesis of this type of polycyclic scaffold is of primary importance.

Combining Dextran Conjugates with Stimuli-Responsive and Folate-Targeting Activity: A New Class of Multifunctional Nanoparticles for Cancer Therapy.

Nanoparticles with active-targeting and stimuli-responsive behavior are a promising class of engineered materials able to recognize the site of cancer disease, targeting the drug release and limiting side effects in the healthy organs. In this work, new dual pH/redox-responsive nanoparticles with affinity for folate receptors were prepared by the combination of two amphiphilic dextran (DEX) derivatives. DEXFA conjugate was obtained by covalent coupling of the polysaccharide with folic acid (FA), whereas DEXssPEGCOOH derived from a reductive amination step of DEX was followed by condensation with polyethylene glycol 600.

New Coumarin Dipicolinate Europium Complexes with a Rich Chemical Speciation and Tunable Luminescence.

Europium (III) luminescent chelates possess intrinsic photophysical properties that are extremely useful in a wide range of applications. The lack of examples of coumarin-based lanthanide complexes is mainly due to poor photo-sensitization attempts. However, with the appeal of using such a versatile scaffold as antenna, especially in the development of responsive molecular probes, it is worth the effort to research new structural motifs.

New lipophilic glycomimetic DC-SIGN ligands: Stereoselective synthesis and SPR-based binding inhibition assays.

The design and synthesis of efficient ligands for DC-SIGN is a topic of high interest, because this C-type lectin has been implicated in the early stages of many infection processes. DC-SIGN membrane-protein presents four carbohydrate-binding domains (CRD) that specifically recognize mannose and fucose. Therefore, antagonists of minimal disaccharide epitope Manα(1,2)Man, represent potentially interesting antibacterial and antiviral agents.

New 1,3-Disubstituted Benzo[]Isoquinoline Cyclen-Based Ligand Platform: Synthesis, Eu Multiphoton Sensitization and Imaging Applications.

The development of lanthanide-based luminescent probes with a long emission lifetime has the potential to revolutionize imaging-based diagnostic techniques. By a rational design strategy taking advantage of computational predictions, a novel, water-soluble Eu complex from a cyclen-based ligand bearing 1,3-disubstituted benzo[h]isoquinoline arms was realized. The ligand has been obtained overcoming the lack of reactivity of position 3 of the isoquinoline moiety.

Coumarin-based fluorescent biosensor with large linear range for ratiometric measurement of intracellular pH.

Intracellular pH is a critical parameter involved in cell machinery, and its dysregulation can either cause or signal pathologic states. Currently described fluorescent pH probes are based on single acid-base equilibria, and for this reason are intrinsically unable to capture the wide range of cell pH, usually spanning over more than four units. Here we describe a fluorescent pH biosensor based on a conjugated coumarin-triazine scaffold that is excitable in the visible range, shows pseudo-linear ratiometric response over more than 6 pH units with a single fluorogenic unit, and allows imaging of the whole endo-lysosomal pH landscape of living cells with a single acquisition.

Glycoconjugated Metal Complexes as Cancer Diagnostic and Therapeutic Agents.

The possibility of selectively delivering metal complexes to a defined cohort of cells on the basis of their metabolic features is a highly challenging goal, which may be extremely useful for a series of purposes, including diagnosis and therapy of pathological states, such as cancer. Tumor cells display augmented requests for carbohydrates and, in particular, for glucose in order to sustain their high proliferation rate, which causes an increased glycolytic process (Warburg effect). Since several metal complexes display diagnostic and/or therapeutic properties, their conjugation to carbohydrate portions often induce their preferential accumulation in cancer cells, similarly to what is observed with fluorodeoxyglucose (FDG).

Uranium-free X solution: a new generation contrast agent for biological samples ultrastructure.

Biological samples are mainly composed of elements with a low atomic number which show a relatively low electron scattering power. For Transmission Electron Microscopy analysis, biological samples are generally embedded in resins, which allow thin sectioning of the specimen. Embedding resins are also composed by light atoms, thus the contrast difference between the biological sample and the surrounding resin is minimal.

Experimental and Computational Studies Unraveling the Peculiarity of Enolizable Oxoesters in the Organocatalyzed Mannich-Type Addition to Cyclic -Acyl Iminium Ions.

γ- and δ-Oxoesters are easily available starting materials that have been sparingly used in some organocatalyzed reactions proceeding with a high enantioselectivity. In our experimentation we found that the use of these compounds as the enolizable (nucleophilic) component in organocatalyzed Mannich-type reactions using in situ-generated cyclic -acyl iminium ions gave low diastereoselectivity and low to moderate values of enantioselectivity. This significant drop of facial selectivity with respect to simple aliphatic aldehydes has been rationalized by means of density functional theory (DFT) calculations.

Remarkable Effect of [Li(G4)]TFSI Solvate Ionic Liquid (SIL) on the Regio- and Stereoselective Ring Opening of α-Gluco Carbasugar 1,2-Epoxides.

Carba analogues of biologically relevant natural carbohydrates are promising structures for the development of future drugs endowed with enhanced hydrolytic stability. An open synthetic challenge in this field is the optimization of new methodologies for the stereo- and regioselective opening of α-gluco carbasugar 1,2-epoxides that allow for the preparation of pseudo mono- and disaccharides of great interest. Therefore, we investigated the effect of Lewis acids and solvate ionic liquids (SILs) on the epoxide ring opening of a model substrate.

First Examples of HS-Releasing Glycoconjugates: Stereoselective Synthesis and Anticancer Activities.

HS donors are currently emerging as promising therapeutic agents in a wide variety of pathologies, including tumors. Cancer cells are characterized by an enhanced uptake of sugars, such as glucose. Therefore, novel glycoconjugated HS donors were synthesized so that high concentrations of HS can be selectively achieved therein.

Organocatalytic alkylation of carbohydrate-containing aldehydes with dihydroquinoline N,O-acetals: Absolute configuration of 1,2-dihydroquinolines.

The direct catalytic α-amidoalkylation of dihydroquinolines with aldehydes bearing oxygen functionalities at different positions in a Mannich-type reaction has been studied. β-Alkoxy-aldehyde 1d gave high enantioselectivity, albeit with an inherently poor diastereoselectivity, while the use of α-alkoxy aldehydes 1c was detrimental also to enantioselectivity. Mannich-type reactions have been studied for the first time using new chiral carbohydrate-derived aldehydes 1a,b showing a reactivity markedly influenced by the presence of water.

Unveiling the Binding Modes of the Crystallophore, a Terbium-based Nucleating and Phasing Molecular Agent for Protein Crystallography.

Crystallophores are lanthanide complexes that act as powerful auxiliary for protein crystallography due to their strong nucleating and phasing effects. To get first insights on the mechanisms behind nucleation induced by Crystallophore, we systematically identified various elaborated networks of supramolecular interactions between Tb-Xo4 and subset of 6 protein structures determined by X-ray diffraction in complex with terbium-Crystallophore (Tb-Xo4). Such interaction mapping analyses demonstrate the versatile binding behavior of the Crystallophore and pave the way to a better understanding of its unique properties.

Crystallophore: a versatile lanthanide complex for protein crystallography combining nucleating effects, phasing properties, and luminescence.

Macromolecular crystallography suffers from two major issues: getting well-diffracting crystals and solving the phase problem inherent to large macromolecules. Here, we describe the first example of a lanthanide complex family named "crystallophore" (Xo4), which contributes to tackling both bottlenecks. This terbium complex, Tb-Xo4, is an appealing agent for biocrystallography, combining the exceptional phasing power of the Tb(iii) heavy atom with powerful nucleating properties, providing ready-to-use crystals for structure determination.