Glycoclusters presenting lactose on calix[4]arene cores display trypanocidal activity

A new series of water-soluble tetravalent glycoclusters incorporating β-lactosyl residues attached to a central calix[4]arene core was synthesised using azide-alkyne Cu(I)-catalysed cycloaddition (‘click chemistry’). Carbohydrate moieties were attached either to the upper or lower rim of rigid cone-shaped or partial cone macrocycles via 14-21 atom spacer arms. The glycoclusters with a C₄-symmetrical arrangement of β-lactosyl residues showed trypanocidal activity, with one of them showing comparable activity to established anti-trypanosomal drug benznidazole in in vitro anti-parasite assays.     

Stereocontrolled spirocyclization of exo-glucal derivatives for stereodivergent synthesis of spiro[5.5]ketals

This Letter describes a stereoselective synthetic approach to spiro[5.5]ketals from the exo-glucals, constructed from 1-(4-hydroxyalkylidene)-1,5-anhydro-d-glucitol, by spirocyclization based on intramolecular α- and β-selective glycosylation. Stereodivergent synthesis of both α- and β-glucoside of spiro[5.5]ketals was attained by combination of chiral d-glucopyranose environment and C-4′ chiral center on the side chain.     

Influence of an 8-trifluoroacetyl group on flavanol couplings

The effect of an electron attracting substituent in the Lewis acid catalyzed oligomerization of flavanols was investigated. The results showed that the presence of a COCF₃, at the 8 position of a (+)-catechin unit strongly influenced the attack of the 6 free nucleophile flavanol position by the electrophile generated from a 4-O-alkyloxy protected catechin unit. This was observed either with TiCl₄ or TMSOTf as Lewis acids in which the carbon-carbon bond formation was inhibited and the corresponding dimer was detected in small amount. On the contrary, the formation of a carbon-oxygen bond was observed and the corresponding C-4→O→C-3 ether linked procyanidin dimer was isolated in a good yield. In order to avoid the participation of the C-3 hydroxyl group in the dimerization reaction, the two flavanol units were forced into C-4→C-8 coupling by use of an internal link. The structural elucidation of the isolated compounds was achieved through MS and NMR spectroscopy.     

Substituent effects in the ring-chain tautomerism of 4-aryl-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines

By condensation of 1-(2′-aminoethyl)-1,2,3,4-tetrahydroisoquinoline derivatives with substituted benzaldehydes, 1,6-unsubstituted and diastereomers of 1-methyl- or 6-methyl-substituted 4-aryl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines were prepared. The ring-chain tautomeric equilibria of most of these compounds in CDCl₃ at 300 K were found to be shifted nearly totally towards either the cyclic or the open tautomeric forms, while the (6R*,11bR*)-6-methyl substituted compounds proved to be three-component tautomeric mixtures, the equilibria of which could be characterized by a Hammett-type equation. The conformational equilibria of the cyclic forms turned out to be strongly influenced by the 1- and 6-methyl substituents and the configurations of the substituted carbons (C-1 or C-6 and C-4) relative to C-11b.     

Coordination of pertechnetate [TcO4]- to actinides

The ability of [TcO(4)](-) to coordinate directly to tetra- and hexa-valent actinides in the presence of organic P[double bond, length as m-dash]O ligands is confirmed in the crystallographically characterised complexes [UO(2)(TcO(4))(2)(Ph(3)PO)(3)] and [Th(TcO(4))(4)((n)Bu(3)PO)(4)].     

Toward the Rational Design of Galactosylated Glycoclusters That Target Pseudomonas aeruginosa Lectin A (LecA): Influence of Linker Arms That Lead to Low‐Nanomolar Multivalent Ligands

Anti‐infectious strategies against pathogen infections can be achieved through antiadhesive strategies by using multivalent ligands of bacterial virulence factors. LecA and LecB are lectins of Pseudomonas aeruginosa implicated in biofilm formation. A series of 27 LecA‐targeting glycoclusters have been synthesized. Nine aromatic galactose aglycons were investigated with three different linker arms that connect the central mannopyranoside core. A low‐nanomolar (K_d=19 nm , microarray) ligand with a tyrosine‐based linker arm could be identified in a structure–activity relationship study. Molecular modeling of the glycoclusters bound to the lectin tetramer was also used to rationalize the binding properties observed.     

Dendri-RAFTs: a second generation of cyclopeptide-based glycoclusters

Synthetic glycoclusters and their related biological applications have stimulated increasing interest over the last decade. As a prerequisite to discovering active and selective therapeuticals, the development of multivalent glycoconjugates with diverse topologies is faced with inherent synthetic and structural characterisation difficulties. Here we describe a new series of molecularly-defined glycoclusters that were synthesized in a controlled manner using a robust and versatile divergent protocol. Starting from a Regioselectively Addressable Functionalized Template (RAFT) carrier, either a polylysine dendritic framework or a second RAFT, then 16 copies of βGal, αMan, βLac or cancer-related Thomsen-Freidenreich (αTF) antigen were successively conjugated within the same molecule using oxime chemistry. We thus obtained a new generation of dendri-RAFTs glycoclusters with high glycosidic density and variable spatial organizations. These compounds displaying 16 endgroups were unambiguously characterized by NMR spectroscopy and mass spectrometry. Further biological assays between a model lectin from Canavalia ensiformis (ConA) and mannosylated glycoclusters revealed a higher inhibition potency than the tetravalent counterpart, in particular for the hexadecavalent polylysine skeleton. Together with the efficiency of the synthetic and characterisation processes, this preliminary biological study provided clear evidence of promising properties that make the second generation of cyclopeptide-based glycoclusters attractive for biomedical applications.     

Regioselective iodination of flavonoids by N-iodosuccinimide under neutral conditions

Regioselective synthesis of C-6 and C-8 monoiodo flavonoids, which are important intermediates for the synthesis of flavonoid natural products and drug molecules, was achieved by iodination of suitably alkylated flavonoids with N-iodosuccinimide (NIS) in DMF. The iodination gives either a C-6 or C-8 iodo flavonoid in high yield, depending on the protection pattern of the C-5 and C-7 OH groups. The mild and neutral conditions render this novel protocol particularly useful for the regioselective iodination of acid-sensitive substrates.     

Suberitine A-D, four new cytotoxic dimeric aaptamine alkaloids from the marine sponge Aaptos suberitoides

Suberitine A-D (1-4), four new bis-aaptamine alkaloids with two aaptamine skeleton units, 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine and demethyl(oxy)-aaptamine, linked through a rare C-3-C-3' or C-3-C-6' σ-bond between the 1,6-naphthyridine rings, together with two known monomers 5 and 6, were isolated from the marine sponge Aaptos suberitoides. Their structures were elucidated using NMR spectroscopy. Compounds 2 and 4 showed potent cytotoxicity against P388 cell lines, with IC(50) values of 1.8 and 3.5 μM, respectively.     

Rim-differentiation vs. mixture of constitutional isomers: A binding study between pillar[5]arene-based glycoclusters and lectins from pathogenic bacteria

Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria, are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strategy. In this study, a series of constitutionally-pure pentavalent glycoclusters was prepared by conjugating assorted azido-carbohydrates onto a penta-propargyl rim-differentiated pillar[5]arene (RD-P[5]) scaffold through Cu(I)-catalyzed azide–alkyne cycloaddition “click” reactions. Their binding towards therapeutically relevant bacterial lectins, such as LecA and LecB from Pseudomonas aeruginosa and concanavalin A (ConA), were evaluated subsequently by isothermal titration calorimetric studies. Most of these isomer-free RD-P[5] pentavalent glycoclusters, except the fucosylated ones, display good affinities to lectins. Nonetheless, the dissociation constants observed are similar to those displayed by an analogous pentavalent glycocluster consisting of four P[5] constitutional isomers, in which the RD-P[5] component merely accounts for 7% in the mixture. Our results revealed that high constitutional purity is not essential for achieving effective multivalent interactions between P[5]-based glycoclusters and lectins, presumably as a result of the conformationally labile nature of the P[5] scaffold. This information provides valuable design principles for low-cost and facile syntheses of glycosylated P[5]s for biomedical applications.     

Synthetic cation transporters incorporating crown ethers and calixarenes as headgroups and central relays: a comparison of sodium and chloride selectivity

An earlier study showed that a calix[4]arene could function as a central relay unit to form an ion conductance pathway through a phospholipid bilayer membrane. The present study expands the range of compounds from calix[4]arene to calix[6]arene and incorporates them either as central units or as headgroups, substituting one or more diaza-18-crown-6 residues in functioning hydraphiles. Ion release was assayed by detecting either Na(+) or Cl(-) release from phospholipid vesicles. The ion transport activity for calix[4]arenes in either position is modest, but is almost non-existent when calix[6] residues were incorporated either as head groups or central relay units. The poor activity of the calix[6]arenes may result from an inability to penetrate to the midplane of the bilayer or pass entirely through it to form a conductance pathway. The transmembrane "flip-flop" may result from high polarity or steric bulk, or both. A hydraphile incorporating a single -NHCOC(6)H(4)OCH(2)CONH- as a central relay proved to be an excellent Na(+) conductor, but less selective for Cl(-). The fact that this new hydraphile molecule shows selectivity for Na (+) over Cl(-) transport and possesses two secondary amide residues in the central relay suggests a means to control ion selectivity in synthetic ion transporters.     

Chukvelutilides A-F, phragmalin limonoids from the stem barks of Chukrasia tabularis var. velutina

Chukvelutilides A-F (1-6), a new class of C-15-acyl phragmalin type limonoids, featuring a C-16/C-30 δ-lactone ring, were isolated from Chukrasia tabularis var. velutina. These compounds are suggested to possess a three- or four-carbon enolized acyl substituent at C-15 through a plausible biosynthetic origin. Their structures were elucidated by extensive spectroscopic means, and that of 1 was confirmed by single-crystal X-ray diffraction.     

Atropdiastereoisomers of ellagitannin model compounds: configuration,conformation, and relative stability of d-glucose diphenoyl derivatives

Conformational analysis reveals a remarkable rigidity of 2,3-, 4,6-, 3,6-, and 2,4-O-(S)- and (R)-diphenoyl (DP) bridged methyl β-d-glucosides, which were used as model compounds to evaluate the atropisomeric features of the natural ellagitannins, which possess at least one hexahydroxydiphenoyl (HHDP) moiety. The 2,3- and 4,6-O-(S)-DP bridged glucosides with ⁴C₁ pyranose geometries are thermodynamically more stable than their (R)-DP counterparts, whilst in the 3,6- and 2,4-O-linked series with ¹C₄ glucopyranose geometries the (R)-DP configuration is preferred. The chiral scaffold of glucose exerts a strong atropdiastereoselective effect onto the diphenoyl units, which is mediated through 10- to 12-membered rings via ester linkages. The calculated results not only explain the observed (S)-diastereoselectivity of di-esterification reactions of suitably protected racemic hexaoxydiphenic acids with 4,6-unsubstituted d-glucopyranose derivatives, but also correlate the observed configuration of axially chiral HHDP-moieties of natural ellagitannins with conformational parameters.     

Enantioselectivities of yeast epoxide hydrolases for 1,2-epoxides

Kinetic resolution of homologous series of unbranched 1,2-epoxyalkanes (C-4 to C-12), 1,2-epoxyalkenes (C-4, C-6 and C-8), a 2,2-dialkylsubstituted epoxide (2-methyl-1,2-epoxyheptane) and a benzyloxy-substituted epoxide (benzyl glycidyl ether) was investigated using resting cells of 10 different yeast strains. Biocatalysts with excellent enantioselectivity (E>100) and high initial reaction rates (>300 nmol/min/mg dry weight) were found for the 2-monosubstituted aliphatic epoxides C-6 to C-8. Yeast strains belonging to the genera Rhodotorula, Rhodosporidium and Trichosporon all preferentially hydrolyzed (R)-1,2-epoxides with retention of configuration. The epoxide hydrolases of all the yeast strains are membrane-associated.     

Stereoselective construction of the pyrrolizidine bridgehead stereochemistry by the adjacent hydroxyl group in the synthesis of (+)-heliotridine and (−)-retronecine

Formal total synthesis of (+)-heliotridine (4) and total synthesis of (−)-retronecine (5) were accomplished by using (S)-3-acetoxysuccinimide (6) as the common starting material. The stereogenic center of 6 ended up as C-1 in both alkaloids. The chiral centers at C-7a of the alkaloids were stereoselectively constructed through the help of the adjacent functionality at C-1. The B-rings of the alkaloids were formed through α-sulfonyl radical cyclizations.     

Iterative multifunctionalization of unactivated C-H bonds in piperidines by way of intramolecular Rh(II)-catalyzed aminations

Efficient stereocontrolled synthesis of di-, tri-, tetra-, and pentasubstituted piperidines from simple 2-sulfamoyloxymethyl piperidine derivatives has been performed by way of intramolecular Rh-catalyzed amination of saturated C-H bonds. In this process, the sulfamoyloxymethyl arm was directly or indirectly involved in the functionalization of every saturated methylene group of the piperidine ring at C-3, C-4, C-5, and C-6. Direct application to the total synthesis of iminosugars and related compounds demonstrated the synthetic potential of this strategy.     

Probing the reactivity of nebularine N1-oxide. A novel approach to C-6 C-substituted purine nucleosides

A novel approach to the synthesis of purine nucleoside analogues, featuring the reaction of the C6-N1-O⁻ aldonitrone moiety of 9-ribosyl-purine (nebularine) N1-oxide with some representative dipolarophiles, as well as Grignard reagents, is reported. Addition of Grignard reagents to the electrophilic C-6 carbon of the substrate allows a facile access to C-6 C-substituted purine nucleosides without using metal catalysts. 1,3-Dipolar cycloaddition processes lead to novel nucleoside analogues via opening, degradation or ring-enlargement of the pyrimidine ring of the base system of the first-formed isoxazoline or isoxazolidine cycloadduct.     

A general strategy to the intracellular sensing of glycosidases using AIE-based glycoclusters

Glycosidases, which are the enzymes responsible for the removal of residual monosaccharides from glycoconjugates, are involved in many different biological and pathological events. The ability to detect sensitively the activity and spatiotemporal distribution of glycosidases in cells will provide useful tools for disease diagnosis. However, the currently developed fluorogenic probes for glycosidases are generally based on the glycosylation of the phenol group of a donor–acceptor type fluorogen. This molecular scaffold has potential drawbacks in terms of substrate scope, sensitivity because of aggregation-caused quenching (ACQ), and the inability for long-term cell tracking. Here, we developed glycoclusters characterized by aggregation-induced emission (AIE) properties as a general platform for the sensing of a variety of glycosidases. To overcome the low chemical reactivity associated with phenol glycosylation, here we developed an AIE-based scaffold, which is composed of tetraphenylethylene conjugated with dicyanomethylene-4H-pyran (TPE–DCM) with a red fluorescence emission. Subsequently, a pair of dendritic linkages was introduced to both sides of the fluorophore, to which six copies of monosaccharides (d-glucose, d-galactose or l-fucose) were introduced through azide–alkyne click chemistry. The resulting AIE-active glycoclusters were shown to be capable of (1) fluorogenic sensing of a diverse range of glycosidases including β-d-galactosidase, β-d-glucosidase and α-l-fucosidase through the AIE mechanism, (2) fluorescence imaging of the endogenous glycosidase activities in healthy and cancer cells, and during cell senescence, and (3) glycosidase-activated, long-term imaging of cells. The present study provides a general strategy to the functional, in situ imaging of glycosidase activities through the multivalent display of sugar epitopes of interest onto properly designed AIE-active fluorogens.

We report a general strategy for the fluorogenic sensing of glycosidases in cells based on aggregation-induced emission of glycoclusters.     

Mycopyranone: A 8,8ˈ-binaphthopyranone with potent anti-MRSA activity from the fungus Phialemoniopsis sp.

A new 8,8?-binaphthopyranone (mycopyranone, 1) was isolated from a solid fermentation of Phialemoniopsis sp. (fungal strain MSX61662), and the structure was elucidated via analysis of the NMR and HRESIMS data. The axial chirality of 1 was determined to be M by ECD. The central chirality at C-4/C-4? was assigned through a modified Mosher’s method, while the absolute configuration at C-3/C-3? was deduced based on analysis of the ³J_H-3-H-4 values and NOESY correlations. Compound 1 was evaluated for its antimicrobial properties against Staphylococcus aureus SA1199 and a clinically relevant methicillin-resistant S. aureus strain (MRSA USA300 LAC strain AH1263). Compound 1 inhibited the growth of both strains in a concentration dependent manner with IC₅₀ values in the low μM range. Molecular docking indicated that compound 1 binds to the FtsZ (tubulin-like) protein in the same pocket as viriditoxin (2), suggesting that 1 targets bacterial cell division.     

Aspergilazine A,a diketopiperazine dimer with a rare N-1 to C-6 linkage,from a marine-derived fungus Aspergillus taichungensis

A novel diketopiperazine (DKP) dimer, aspergilazine A (1), dimerized by two DKP units via a rare N-1 to C-6 linkage, was isolated from the marine-derived fungus Aspergillus taichungensis ZHN-7-07. The structure was determined by the combination of spectroscopic and Marfey’s methods. Biological evaluation indicated that aspergilazine A (1) had a weak activity against influenza A (H₁N₁) virus.