Search

The use of unprotected carbohydrate-derived nitrones as partners in strain-promoted alkyne-nitrone cycloadditions was investigated as a new tool for bioconjugation. The observed second-order reactions displayed rate constants of 3.4 × 10 -4 -5.8 × 10 -2 M -1 s -1 , which is the common order of magnitude of reaction kinetics with other simple aliphatic or aromatic nitrones. Applicability of this method to aqueous media was demonstrated by performing a one-pot protocol, which combines sequential formation of the nitrone and cycloaddition with cyclooctyne in water.

A straightforward synthesis of carbohydrate templated isoxazolidines is described, by reaction of unprotected glycosylhydroxylamines (operating as 1,3-dipoles) with methyl acrylate using microwave activation. Rhamno- and erythro-isoxazolidines are recognized by plant cells, resulting in a strong ROS-production as a plant immune response, and exert a high antifungal activity against Botrytis cinerea., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Trifluoromethyl analogues of methylerythritol phosphate (MEP) and 2- C -methyl-erythritol 2,4-cyclodiphosphate (MEcPP), natural substrates of key enzymes from the MEP pathway, were prepared starting from d-glucose as the chiral template to secure absolute configurations. The obligate trifluoromethyl group was inserted with complete diastereoselectivity using the Ruppert-Prakash nucleophile. Target compounds were assayed against the corresponding enzymes showing that trifluoro-MEP did not disrupt IspD activity, whereas trifluoro-MEcPP induced 40% inhibition of IspG at 1 mM.

Access to 5-bromopentanal and 6-bromohexanal derivatives from Weinreb amides is described. The method relies on the sequential C-bromination/zircona-aminal hydrolysis of bis-C,O-zirconocenes, which are generated in situ from unsaturated Weinreb amides using Schwartz's reagent. Synthetic illustrations of such bromo-aldehydes, which can act as carbocycle and heterocycle precursors, are also presented.

IspG (also called GcpE) is an oxygen-sensitive [4Fe-4S] enzyme catalyzing the penultimate step of the methylerythritol phosphate (MEP) pathway, a validated target for drug development. It converts 2-C-methyl-d-erythritol-2,4-cyclo-diphosphate (MEcPP) into (E)-4-hydroxy-3-methyl-but-2-enyl-1-diphosphate (HMBPP). The reaction, assimilated to a reductive dehydration, involves redox partners responsible for the formal transfer of two electrons to substrate MEcPP. The 2-vinyl analogue of MEcPP was designed to generate conjugated species during enzyme catalysis, with the aim of providing new reactive centers to be covalently trapped by neighboring amino acid residues. The synthesized substrate analogue displayed irreversible inhibition towards IspG. Furthermore, we have shown that electron transfer occurs prior to inhibition; this might designate conjugated intermediates as probable affinity tags through covalent interaction at the catalytic site. This is the first report of an irreversible inhibitor of the IspG metalloenzyme., (© 2022 Wiley-VCH GmbH.)

The diastereoselective access to cyclopentanols and N,O-dimethylcyclopentylhydroxylamines from 4-pentenoic acid-derived Weinreb amides is described. Based on the concomitant generation of both the nucleophilic and the electrophilic poles by hydrozirconation of the amide and the C=C double bond, the cyclisation may be tuned towards cyclopentanols or N,O-dimethylcyclopentylhydroxylamines depending on the ring-closure promotor. An extension to cis 3-substituted N,O-dimethylcyclohexylhydroxylamines is also presented., (© 2021 Wiley-VCH GmbH.)

A new myo-inositol pentakisphosphate was synthesized, which featured a dansyl group at position C-5. The fluorescent tag was removed from the inositol by a 6-atom spacer to prevent detrimental steric interactions in the catalytic site of phytases. The PEG linker was used in order to enhance hydrophilicity and biocompatibility of the new artificial substrate. Computational studies showed a favorable positioning in the catalytic site of phytases. Enzymatic assays demonstrated that the tethered myo-inositol was processed by two recombinant phytases Phy-A and Phy-C, classified respectively as acid and alkaline phytases, with similar rates of phosphate release compared to their natural substrate., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The development of new fluorine-containing building blocks and their efficient synthetic access is currently a challenging research field. Herein, the highly regio- and stereoselective addition of a large range of aldehydes onto trifluoromethylated benzofulvenes was achieved using a simple La/I 2 /DIBAL-Cl system via a selective C-F bond activation process. This versatile methodology provided homodienyl alcohols bearing a terminal CF 2 -alkene with potential further applications, as shown by the dehydration to the first benzofulvenes carrying a difluorovinyl group. In addition, for certain electron-poor aldehydes, unprecedented ipso substitution of the CF 3 group in a diene was observed, which, according to DFT studies, is related to the presence of the large, Lewis-acidic lanthanum metal., (© 2021 Wiley-VCH GmbH.)

The access to 1,2- and 1,1,2-substituted trans cyclopentanes via a sequential hydrozirconation/TMSOTf-mediated cyclization applied to 5-methoxypent-1-enes is presented. Involving a transient carbocation, the reaction was shown to be diastereo-convergent. Possibly performed in a nonracemic version, the reaction proved compatible with a range of functional groups affording a large panel of cyclopentanes.

Condensation reactions of unprotected tetroses and pentoses with hydroxylamines afforded nitrones, which were easily converted to densely functionalized isoxazolidines in the presence of electron-poor alkenes. The 1,3-dipolar cycloaddition occurred with good facial discrimination of the chiral nitrone but under rather low endo/exo control. Stereochemistry of isomers was ascertained by chemical correlation with known derivatives from the literature. Microwave activation appeared as the most efficient reaction mode, affording the expected adducts within several minutes whereas hours were needed under standard heating. Alternatively, the transformation proved also possible under high pressure conditions by using a hand pump system, avoiding any energy source. Although water could not be used as the solvent, leading to hydrolysis of the nitrone substrate, a large variety of organic solvents proved efficient. The method has potential use in the preparation of non-ionic carbohydrate-based amphiphiles.

The diastereoselective conjugate addition of secondary homoallylamines, obtained in the enantioenriched form via allylmetallation of imines, to α,β-unsaturated esters is reported. This method allows access to valuable building blocks as well as heterocyclic skeletons, providing tertiary amines bearing two chains integrating a stereogenic center adjacent to the nitrogen atom.

The synthesis of unprecedented branched pyrrolizidines and indolizidines was accomplished via nitrone chemistry. The required ketonitrone, a known intermediate usually obtained as a mixture of regioisomers, was prepared in a pure form from d-arabinose by a sequence of oximation/reduction/oxidation steps. Nucleophilic vinylation or allylation followed by ring-closing metathesis of the corresponding N-allylpyrrolidines furnished the targeted iminosugars, which proved potent and selective inhibitors of alpha-glucosidase from rice (GH31 family).

Access to 1,3-disubstituted cyclohexenes from zirconocenes containing a latent electrophilic allylic fragment is described. Requiring a specific conformation, 6-endo-trig cyclisation is based on the TMSOTf-mediated generation of a stabilized carbocation.

The selective activation of one carbon-fluorine bond in polyfluorinated aromatic molecules or in trifluoromethyl-containing substrates offers the possibility of accessing unique fluorine-containing molecules, which are difficult to obtain by other synthetic pathways. Among various metals, which can undergo C-F activation, lanthanides (Ln) are good candidates as they form strong Ln-F bonds. Lanthanide metals are strong reducing agents with a redox potential Ln 3+ /Ln of approximately -2.3 V, which is comparable to the value of the Mg 2+ /Mg redox couple. In addition, lanthanide metals display a promising functional group tolerance and their reactivity can vary along the lanthanide series, making them suitable reagents for fine-tuning reaction conditions in organic and organometallic transformations. However, due to their oxophilicity, lanthanides react readily with oxygen and water and therefore require special conditions for storage, handling, preparation, and activation. These factors have limited a more widespread use in organic synthesis. We herein present how dysprosium metal - and by analogy all lanthanide metals - can be freshly prepared under anhydrous conditions using glovebox and Schlenk techniques. The freshly filed metal, in combination with aluminum chloride, initiates the selective C-F activation in trifluoromethylated benzofulvenes. The resulting reaction intermediates react with nitroalkenes to obtain a new family of difluoroalkenes.

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Two strategies based on kinetic resolution(s) of chiral alanes and providing enantioenriched syn homoallylamines are reported. The first implies a single kinetic resolution of the alane using camphor; the second requires two sequential kinetic resolutions using the synergistic combination of (-)-camphor/(R)-tert-butylsulfinamide-derived imines. This syn selectivity, specific to the use of allyaluminum, opens the way to the preparation of valuable building blocks as illustrated by the synthesis of (+)-epilupinamine.

Heavy metal on Lewis acid: The combination of lanthanide metals and AlCl 3 has been employed for selective single C-F activation in benzofulvenes comprising an exocyclic CF 3 substituent. Intermediate ϵ,ϵ-difluorinated metal-dienyl species react with a large variety of aldehydes in a highly regio- and diastereoselective fashion to afford 1,1-disubstituted indenes bearing a difluorovinyl group. These new building blocks have been further transformed through a hydrogenation-cyclization process into fluorinated heterocyclic spiro compounds., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polyhydroxylated quinolizidines bearing a hydroxymethyl group at the ring junction were synthesized from a readily available l-sorbose-derived ketonitrone. Evaluated as glycoside hydrolase inhibitors, these quinolizidines revealed to be potent and selective α-glucosidase inhibitors. Quinolizidine 9a is the first quinolizidine-scaffolded iminosugar exhibiting nanomolar inhibition of a glycoenzyme.

Eleven compounds were isolated from Poraqueiba sericea stems and identified as niga-ichigoside-F1 (1), trachelosperoside B1 (2), 4-epi-niga-ichigoside (7), 19α-hydroxyasiatic acid (3), myrianthic acid (4), hyptatic acid (5), trachelosperogenin B (6), arjunolic acid (8), and trachelosperogenin E (9), secologanoside (10) and secoxyloganin (11). Compounds 1-11 were tested for their antileishmanial activities against Leishmania infantum promastigotes, 1-6 and 8-11 were tested for their cytotoxic activities on fibroblasts, 1-3, 5-6, 8-11 were evaluated for their anti-elastase and anti-acetylcholinesterase assays activities by a spectrophotometric method and 1-2, 5 and 7-10 were tested using bioautography for their β-glucosidase. No antileishmanial activity was detected; compounds 1, 2 and 11 showed a moderate cytotoxic activity with IC 50 17.7, 20.5 and 10.9 μg/mL, respectively; compounds 2, 8, 9 and 10 gave a percentage of inhibition ranging from 13 to 16% (at 50 μg/mL) and compounds 1 and 2 showed an inhibition zone on β-glucosidase and anti-acetylcholinesterase assays.

An efficient (+)-camphor-mediated kinetic resolution of racemic cyclohex-2-en-1-ylalane is described. This approach provides an enantiomerically enriched form of the alane, in situ available for synthetic uses. Applied to the allylation of aldehydes, this protocol leads to the corresponding homoallylalcohols in a highly enantioselective manner.

Multi-valent inhibitors offer promise for the enhancement of therapeutic compounds across a range of chemical and biological processes. Here, a significant increase in enzyme-inhibition potencies was observed with a dimeric iminosugar-templated fucosidase inhibitor (IC50 = 0.108 μM) when compared to its monovalent equivalent (IC50 = 2.0 μM). Such a gain in binding is often attributed to a "multivalent effect" rising from alternative recapture of the scaffolded binding epitopes. The use of control molecules such as the meso analogue (IC50 = 0.365 μM) or the enantiomer (IC50 = 569 μM), as well as structural analysis of the fucosidase-inhibitor complex, allowed a detailed analysis of the possible mechanism of action, at the molecular level. Here, the enhanced binding affinity of the dimer over the monomer can be attributed to additional interactions in non-catalytic sites as also revealed in the 3-D structure of a bacterial fucosidase inhibitor complex.

A small library of divalent fucosidase inhibitors containing pyrrolidine motifs and separated by polyamino and triazole-benzylated spacers was prepared and evaluated as α-fucosidase inhibitors. Although a weak multivalent effect was observed in polyamino derived dimers, useful structural information can be deduced about the length of the bridge, the number of nitrogen atoms present and the moieties close to the pyrrolidine. Within these investigations one of the best α-fucosidase inhibitors containing a pyrrolidine framework was obtained (18, Ki = 3.7 nM).

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 (Ki=23 nM) and from Bacteroides thetaiotaomicron (Ki=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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound 9b exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding.

A series of diastereomeric tetrahydroxylated azepanes featuring a carboxymethyl group at the pseudo-anomeric position have been synthesized from a common unsaturated intermediate. Syn- and anti-dihydroxylation reactions were achieved to yield the target compounds after efficient one-step deprotection of carbamate, ester and acetonide groups simultaneously. Screening of these polyhydroxylated azepanes toward a range of commercially available glycosidases was performed and one of the stereoisomers showed potent and selective inhibition toward β-galactosidase (IC50=21 μM)., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Fucosidase inhibition shows potential in numerous therapeutic contexts. Substitution of fucose-like iminosugars with hydrophobic "aglycons" yields significant improvements in potency of fucosidase inhibition. Here we have prepared three new 2-aryl-3,4-dihydroxy-5-methylpyrrolidines featuring phenyl substituents in variable orientations with respect to the iminocyclitol core and at various distances from it to explore the key binding interactions that stabilise the enzyme-inhibitor complex. The presence of a triazole linker in one structure resulted in nanomolar inhibition of the fucosidase from bovine kidney (Ki =4.8 nM), thus giving rise to one of the most potent pyrrolidine-type inhibitors of this enzyme known to date., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 A1-A4 (1, 2, 5, 6), 1-deoxygalactonojirimycin in glyphaeaside B1-B5 (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 IC50 values ranging from 0.15 to 68μM. Compound 10 with an 1-deoxynojirimycin backbone was the most active and was found to act as a competitive inhibitor with Ki=31nM, 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)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

An unprecedented reactivity of CF3-TMS has been revealed, which exploits the basic character of the generated [CF3(-)] capable of delivering dichloromethide from dichloromethane with subsequent transfer to nitrones under smooth conditions. The proton-abstraction pathway was demonstrated through isotopic labeling experiments in CD2Cl2. The same reaction was achieved in acetonitrile with the introduction of a cyanomethyl group onto the nitrones.

Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking (3)E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100% inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μM., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We prepared a series of new iminosugar-ferrocene hybrids displaying potent inhibition of fucosidase (bovine kidney) and inactivation of MDA-MB-231 breast cancer cells proliferation at low micromolar concentrations. The synthetic route brought to light an unprecedented isomerisation of a 2-ethanalylpyrrolidine.

A straightforward functionalization of D-pentoses is reported, which affords homoallylaminopolyols in two steps and uses ion exchange chromatography as the only purification operation. The key indium-mediated allylation is effected on unprotected glycosylamines and occurs with good to excellent syn stereoselection. Validation of the synthetic utility of the method was exemplified by a 3-step synthesis of an optically active 1,2,3,6-tetrahydropyridine from D-xylose.

The total synthesis of enantiopure 4-epi-(+)-codonopsinine was achieved in 10 steps starting from D-ribose as a chiral building block. The key step involved a highly stereoselective nucleophilic addition of a Grignard reagent to a protected ribosylamine. Synthesis of the N-desmethyl derivative and its p-tolyl analogue was also accomplished, and the compounds were assayed against α-fucosidase.

During the last 30 past years, more life-threatening fungal infections have appeared due to the increasing frequency of patients with weakened immune systems. Inhibition of fungal enzymes involved in the biosynthesis of sterols is considered to be a safe and effective option for antifungal therapy. However, the intensive use of sterol-biosynthesis inhibitors for years has resulted in resistance development. Consequently, the search for alternative therapeutics must be intensified. In this context, the biosynthesis of chitin, an essential component of the fungal cell wall that is absent in mammalian cells, was envisioned as a safe and selective therapeutic target. We present here recent successes in the inhibition of chitin synthase, the enzyme involved in the last step of the biosynthesis of chitin.

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 (c) 2010 Elsevier Ltd. All rights reserved.)

3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-D-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited beta-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1mM)., (Copyright 2009 Elsevier Inc. All rights reserved.)

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.

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.

The biological activity of unsaturated iminosugars has not yet been extensively studied because of a lack of general synthetic methods. A practical synthesis of these cyclic ketimine sugars was developed, which was based on a tandem addition-cyclization reaction of a Grignard reagent to a omega-methanesulfonylglycononitrile.

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-PO(4), AMPPCP, 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 (Asp(250)-Glu(252)). 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 Asp(233) of the catalytic HGD motif, a novel twin arginine motif (Arg(340)/Arg(341)), 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.

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 alpha-L-fucosidase from bovine kidney (Ki=1.6 microM, competitive).

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 glycosylation 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.

[reaction: see text] We describe the Fmoc solid-phase synthesis of peptide thioesters based on the alkylation of the safety-catch sulfonamide linker with a protected 2-mercaptoethanol derivative. The thioester is generated on the solid phase after the peptide chain assembly as a consequence of an intramolecular N,S-acyl shift. Depending on the stability of the spacer separating the sulfonamide linker from the resin toward TFA, treatment of the peptidyl resin with TFA led to a soluble or supported deprotected thioester.

We identified 6-deoxy-homoDMDP as a potent inhibitor of chitin synthase (Ki = 38 microM), displaying an uncompetitive inhibition pattern. Dual inhibition was also performed with the enzymatic reaction product uridine 5'-diphosphate in order to evaluate the concurrent effect of both inhibitors. An interaction coefficient alpha of 0.9 was found, revealing synergistic inhibition.

We report here the design, synthesis and biological evaluation of new models of sugar analogues for chitin synthase. These UDP-GlcNAc mimetics associate a sugar-mimicking hetaryl group and uridine, linked with different pyrophosphate bioisosteres. The compounds displayed weak inhibition activity on chitin synthase and their antifungal potencies have been assayed against a large variety of pathogenic fungi.