Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters.

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms.

Wood Metabolomic Responses of Wild and Cultivated Grapevine to Infection with , a Trunk Disease Pathogen.

Grapevine trunk diseases (GTDs), which are associated with complex of xylem-inhabiting fungi, represent one of the major threats to vineyard sustainability currently. Botryosphaeria dieback, one of the major GTDs, is associated with wood colonization by Botryosphaeriaceae fungi, especially . We used GC-MS and HPLC-MS to compare the wood metabolomic responses of the susceptible subsp.

Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation.

Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC values of 6.5-11.

Sodium arsenite effect on Vitis vinifera L. Physiology.

Sodium arsenite (NaAsO) was especially used as a dormant spray to control grapevine trunk diseases (GTDs) in European vineyards until 2003 when it was banned. It was an efficient product but it was banned due to high risk for human health and the environment. Now, as one of the consequences with climatic changes, GTDs threaten the sustainability of vineyards since no similar and efficacious sprays are presently available to reduce the impact of GTDs.

Grapevine Botryosphaeria dieback fungi have specific aggressiveness factor repertory involved in wood decay and stilbene metabolization.

Grapevine trunk diseases: Eutypa dieback, esca and Botryosphaeria dieback, which incidence has increased recently, are associated with several symptoms finally leading to the plant death. In the absence of efficient treatments, these diseases are a major problem for the viticulture; however, the factors involved in disease progression are not still fully identified. In order to get a better understanding of Botryosphaeria dieback development in grapevine, we have investigated different factors involved in Botryosphaeriaceae fungi aggressiveness.

Secreted proteins produced by fungi associated with Botryosphaeria dieback trigger distinct defense responses in Vitis vinifera and Vitis rupestris cells.

Grapevine trunk diseases (Eutypa dieback, esca and Botryosphaeria dieback) are caused by a complex of xylem-inhabiting fungi, which severely reduce yields in vineyards. Botryosphaeria dieback is associated with Botryosphaeriaceae. In order to develop effective strategies against Botryosphaeria dieback, we investigated the molecular basis of grapevine interactions with a virulent species, Neofusicoccum parvum, and a weak pathogen, Diplodia seriata.

Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis.

Aminopeptidases are ubiquitous hydrolases that cleave the N-terminal residues of proteins and oligopeptides. They are broadly distributed throughout all kingdoms of life and have been implicated in a wide variety of physiological processes, including viral infection, parasite metabolism, protein processing, regulation of peptide hormones, and cancer cell proliferation. Members of the M1 family, also termed gluzincins, are defined by two highly conserved motifs in the catalytic domain: a zinc-binding motif, HEXXH-(X18)-E; and an exopeptidase motif, GXMEN.

Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels.

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

Exploring S1 plasticity and probing S1' subsite of mammalian aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors.

In order to probe the S1 and S1' mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with Ki values in the nanomolar range.

Toxicity of extracellular proteins from Diplodia seriata and Neofusicoccum parvum involved in grapevine Botryosphaeria dieback.

Botryosphaeria dieback, esca and Eutypa dieback are three economic major grapevine trunk diseases that cause severe yield reduction in vineyards worldwide. The frequency of disease symptoms has increased considerably over the past decade, and no efficient treatment is currently available to control these diseases. The different fungi associated with grapevine trunk diseases mainly induce necrotic wood and characteristic foliar symptoms.

Synthesis of amino-hydroxy-benzocycloheptenones as potent, selective, non-peptidic dinuclear zinc metalloaminopeptidase inhibitors.

Racemic trisubstituted benzocycloheptanes were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. A highly selective nanomolar inhibitor of a prototypical 'two zinc' aminopeptidase from the M28 family was observed with these tridentate species, while bidentate analogs proved to be highly selective for the 'one zinc' M1 family of enzymes. The selectivity profile of these new, low molecular weight structures may guide the design of specific, non-peptidic inhibitors of binuclear aminopeptidases.

Selective aminopeptidase-N (CD13) inhibitors with relevance to cancer chemotherapy.

Aminopeptidase-N (APN/CD13) is highly expressed on the surface of numerous types of cancer cells and particularly on the endothelial cells of neoangiogenic vessels during tumourigenesis. This metallo-aminopeptidase has been identified as a potential target for cancer chemotherapy. In this work, we evaluated the efficacy of a novel series of benzosuberone analogues, which were previously reported to be highly potent, selective APN inhibitors with Ki values in the micromolar to sub-nanomolar range.

Rapid and efficient synthesis of a novel series of substituted aminobenzosuberone derivatives as potent, selective, non-peptidic neutral aminopeptidase inhibitors.

Racemic 5-substituted 7-aminobenzocyclohepten-6-one were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. Unexpectedly, 5-thio substituted compounds showed enhanced inhibition potency with K(i) values in the nanomolar range against the 'one zinc' aminopeptidases from the M1 family, while most of them were rather poor inhibitors of the 'two zincs' enzymes from the M17 family. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.

A diverted total synthesis of mycolactone analogues: an insight into Buruli ulcer toxins.

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts.

A novel amino-benzosuberone derivative is a picomolar inhibitor of mammalian aminopeptidase N/CD13.

A new class of low molecular weight, highly potent and selective non peptidic inhibitors of aminopeptidase N (APN/CD13) is described. We report the synthesis and in vitro evaluation of racemic substituted analogues of 7-amino-benzocyclohepten-6-one 1a. We investigated various substitutions on the aromatic ring with phenyl and halogen groups.

Synthesis of 4-amino-4,5-dideoxy-L-lyxofuranose derivatives and their evaluation as fucosidase inhibitors.

The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-L-lyxofuranose (3).

Amino-benzosuberone: a novel warhead for selective inhibition of human aminopeptidase-N/CD13.

This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.

Synthesis of all-cis 2,5-imino-2,5-dideoxy-fucitol and its evaluation as a potent fucosidase and galactosidase inhibitor.

We here describe a simple and efficient synthetic method for a non-hydrolysable precursor of a GDP-fucose analogue: The synthesis of the racemic aminofuranofucitol 3 from sorbic alcohol by nitroso-Diels-Alder reaction. This 'all-cis-pyrrolidine', with all substituents occupying a cis position, has been determined as a potent inhibitor of α-L-fucosidase and a moderate inhibitor of α- and β-D-galactosidase. The good recognition of this fucose moiety analogue by specific enzymes is thus confirmed.

Synthesis and evaluation of amino-threoses in D- and L-series: are five membered ring amino-sugars more potent glycosidase inhibitors than the six membered ones?

Cyclic D- and L-4-aminothreose were synthesised from ethyl D- and L-tartrate, respectively. D-aminothreose was a potent inhibitor of alpha-glucosidase and of alpha-mannosidase. From the glycosidase inhibition potencies of the four 4-amino-4-deoxy-tetroses, the contribution of binding of each functionality of the 5 and 6 membered ring amino-sugars towards the various glycosidases is discussed.

Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors.

Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C.

Asymmetric synthesis of the L-fuco-nojirimycin, a nanomolar alpha-L-fucosidase inhibitor.

We describe the asymmetric synthesis of the 5-amino-5-deoxy-l-fucose (l-fuco-nojirimycin) which appears as a very potent fucosidase inhibitor with a K(i) value of 1 nM.