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Abstract: This paper describes a convenient and efficient synthesis of new complexing surfactants from d-galacturonic acid and n-octanol as renewable raw materials in a two-step sequence. In the first step, simultaneous O-glycosidation–esterification under Fischer conditions was achieved. The anomeric ratio of the products was studied based on the main experimental parameters and the activation mode (thermal or microwave). In the second step, aminolysis of the n-octyl ester was achieved with various functionalized primary amines under standard thermal or microwave activation. The physico-chemical properties of these new amphiphilic ligands were measured and these compounds were found to exhibit interesting surface properties. Complexing abilities of one uronamide ligand functionalized with a pyridine moiety toward Cu(II) ions was investigated in solution by EPR titrations. A solid compound was also synthesized and characterized, its relative structure was deduced from spectroscopic data. [Copyright &y& Elsevier]

Abstract: The synthesis of a series of aryl-substituted cyclic sugar imines was performed via a tandem nucleophilic addition/substitution reaction. The so-obtained ketimines displayed fucosidase inhibitory activities (IC50 =46–556μM). Their reduced counterparts were prepared and assayed after addition of sodium borohydride to the enzymatic assay stock solution. The pyrrolidines strongly inhibit fucosidase (IC50 =0.65–150μM). [Copyright &y& Elsevier]

Abstract: The synthesis of a fully deprotected ketimine-type iminosugar is reported, starting from commercial d-mannose diacetonide. An appropriate solvent system was critical for the success of the key tandem addition/cyclization reaction. Reduction of the imine was also achieved to yield the corresponding pyrrolidine in a stereoselective manner. The cyclic sugar imine displayed modest fucosidase inhibitory activity when compared to the saturated analogue. [Copyright &y& Elsevier]

Abstract: A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP. [Copyright &y& Elsevier]

Abstract: Polyhydroxy 4-azaspiro[2.4]heptane derivatives (spirocyclopropyl iminosugars) were prepared in four to six steps from readily available protected aldoses. The key step of the reaction sequence involves a titanium-mediated aminocyclopropanation of glycononitriles with subsequent cyclization. Five new polyhydroxypyrrolidines so-obtained have been evaluated for their ability to inhibit 16 glycosidases. One of them exhibits selective inhibition of α-l-fucosidase from bovine kidney (K i =1.6μM, competitive). [Copyright &y& Elsevier]

Abstract: Chitin synthase is an enzyme involved in the biosynthesis of chitin, a major structural component of the cell wall of many fungi. Since chitin is absent in vertebrates, chitin synthase has been envisaged as a valuable target in the search for new antifungal agents. In this report, a series of C-2 substituted polyhydroxypyrrolidines were designed and synthesized with the aim of mimicking the glycosylcation involved at the transition state of the enzymatic reaction governed by chitin synthase. Some of these models displayed chitin synthase inhibition in the millimolar range. However, no significant antifungal activity was noted on a panel of fungal strains. [Copyright &y& Elsevier]

Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino-l-erythrose and 4-amino-5-deoxy-l-ribose series were synthesised by asymmetric hetero-Diels–Alder reaction followed by chemical transformations. 4-Amino-4-deoxy-l-erythrose and 4-amino-4,5-dideoxy-l-ribose were potent β-d-glucosidase, α-d-mannosidase, α- and β-d-galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α-d-mannosidase. [Copyright &y& Elsevier]

Resin-bound α-keto mesylates were cleaved under acidic conditions (TFA/CH2Cl2) in the presence of a variety of aryl or alkyl thiols to give the corresponding thioethers. Access to the target compounds via standard nucleophilic displacement proved to be much less efficient. The stereochemical outcome of the reaction suggested formation of a highly reactive α-keto carbocation trapped in situ by the thiol acting as a scavenger. [Copyright &y& Elsevier]

A concise enantioselective synthesis of 2,5-imino-2,5,6-trideoxy-d-manno-heptitol (6-deoxy-homoDMDP) and 2,5-imino-2,5,6-trideoxy-l-gulo-heptitol has been achieved. These compounds were used as stereochemical references to establish the absolute configuration of the corresponding naturally occurring stereoisomers, recently isolated from Hyacinthus orientalis. [Copyright &y& Elsevier]

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1′,2′)-dihydroxyethyl substituent of homoDMDP with –C 4 F 9 proved detrimental for enzyme binding, introduction of a –C 3 F 7 moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast. [ABSTRACT FROM AUTHOR]

The synthesis and the biological evaluation of a new ferrocenyl-iminosugar conjugate designed for fucosidase inhibitory and anticancer activity is described. The compound showed strong affinity for fucosidase from bovine kidney ( K i = 23 nM) and from Bacteroides thetaiotaomicron ( K i = 150 nM), displaying a 10-fold tighter binding affinity for these enzymes than the previous analogs. The interaction pattern that improves binding has been evaluated through structural analysis of the inhibitor–enzyme complex. The ferrocenyl-iminosugar exhibits significant anticancer activity on MDA-MB-231 and SK-MEL28 cell lines at 100 μM. [ABSTRACT FROM AUTHOR]

Ten phenylalkyl-substituted iminosugars ( 1 – 10 ) and a cinnamic acid derived glucoside ( 11 ) were isolated from the roots of Glyphaea brevis (Malvaceae). Their structures were elucidated by 1D and 2D NMR analysis, as well as by HR-ESIMS. Compounds 1 – 10 retain an unprecedented structure composed of an iminosugar-like core identified as 1-deoxyfuconojirimycin in glyphaeaside A 1 –A 4 ( 1 , 2 , 5 , 6 ), 1-deoxygalactonojirimycin in glyphaeaside B 1 –B 5 ( 3 , 4 , 7 – 9 ) or 1-deoxynojirimycin in glyphaeaside C ( 10 ), substituted by a β - d -glucopyranose in compounds 2 , 4 , 6 and 9 . These compounds feature a di-, tri- or tetra-hydroxylated nine-carbon chain at the pseudo-anomeric position, substituted by a terminal phenyl group. All alkyl C -iminosugars displayed potent and selective inhibition towards β -glucosidase with IC 50 values ranging from 0.15 to 68 μM. Compound 10 with an 1-deoxynojirimycin backbone was the most active and was found to act as a competitive inhibitor with K i = 31 nM, therefore emerging as one of the most potent inhibitor of β -glucosidase reported to date. Inhibition of β -mannosidase was observed with compounds 1 , 3 , 7 and 10 , but only weak inhibition could be detected with the alkyl- C -iminosugars on the other tested glycosidases ( α -glucosidase, α -fucosidase, α - and β -galactosidase). [ABSTRACT FROM AUTHOR]

Abstract: A convenient approach to the construction of dihydroxylated unsaturated azepanes featuring a functional group (ethoxycarbonyl)methyl or (cyano)methyl at C-2 was achieved from a pent-4-enal synthon obtained in four steps from d-xylose. The key step of the sequence relied on the conjugate addition of allylamine to α,β-unsaturated ester or nitrile, prepared by Wadsworth–Emmons olefination. Subsequent RCM afforded the target unsaturated azepanes. [Copyright &y& Elsevier]

Abstract: Nitrogen-in-the-ring analogues of l-fucose and l-rhamnose were prepared, which feature a spirocyclopropyl moiety in place of the methyl group of the natural sugar. The synthetic route involved a titanium-mediated aminocyclopropanation of a glycononitrile as the key step. Four new spirocyclopropyl iminosugar analogues were generated, which displayed some activity towards l-fucosidase and l-rhamnosidase. [Copyright &y& Elsevier]

Abstract: The interactions between a new proline–threonine dipeptide ligand with two metallic cations were investigated in aqueous solution. The metallic cations studied were the copper(II) and the nickel(II), which are involved in many biological processes. The combination of potentiometry, UV–visible spectrophotometry, EPR, and mass spectrometry was used to determine the formation constants of the complexes and their structure in solution. The complexation sites were identified using electronic absorption and EPR spectroscopies. Copper complexes were obtained as square planar or square pyramidal mononuclear species, whereas nickel complexes were obtained as dinuclear species with an octahedral geometry. [Copyright &y& Elsevier]

The methionine salvage pathway is ubiquitous in all organisms, but metabolic variations exist between bacteria and mammals. 5-Methylthioribose (MTR) kinase is a key enzyme in methionine salvage in bacteria and the absence of a mammalian homolog suggests that it is a good target for the design of novel antibiotics, The structures of the apo-form of Bacillus subtilis MTR kinase, as well as its ADP, ADP-PO4, AMP-PCP, and AMPPCP-MTR complexes have been determined. MTR kinase has a bilobal eukaryotic protein kinase fold but exhibits a number of unique features. The protein lacks the DFG motif typically found at the beginning of the activation loop and instead coordinates magnesium via a DXE motif (Asp250-Glu252). In addition, the glycine-rich loop of the protein, analogous to the "Gly triad" in protein kinases, does not interact extensively with the nucleotide. The MTR substrate-binding site consists of Asp233 of the catalytic HGD motif, a novel twin arginine motif (Arg340/Arg341), and a semi-conserved W-loop, which appears to regulate MTR binding specificity. No lobe closure is observed for MTR kinase upon substrate binding. This is probably because the enzyme lacks the lobe closure/inducing interactions between the C-lobe of the protein and the ribosyl moiety of the nucleotide that are typically responsible for lobe closure in protein kinases. The current structures suggest that MTR kinase has a dissociative mechanism. [ABSTRACT FROM AUTHOR]