Jean-Bernard Behr

Design, synthesis and biological evaluation of hetaryl-nucleoside derivatives as inhibitors of chitin synthase.

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.

Synthesis and fucosidase inhibitory study of unnatural pyrrolidine alkaloid 4-epi-(+)-codonopsinine.

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.

α‐L‐Fucosidase Inhibition by Pyrrolidine–Ferrocene Hybrids: Rationalization of Ligand‐Binding Properties by Structural Studies

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.

Hydroxymethyl-Branched Polyhydroxylated Indolizidines: Novel Selective α-Glucosidase Inhibitors

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.

The spirocyclopropyl moiety as a methyl surrogate in the structure of L-fucosidase and L-rhamnosidase inhibitors

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.

Synthesis of new (difluoromethylphosphono)azadisaccharides designed as bisubstrate analogue inhibitors for GlcNAc:β-1,4 glycosyltransferases

We report here the design, synthesis and antifungal evaluation of a new model of bisubstrate analogue inhibitor for glycosyltransferases. The synthetic strategy relies on the reductive amination between the aldehyde derived from an N-allylphosphono-pyrrolidine and an aminosugar.

Highly Selective Indium Mediated Allylation of Unprotected Pentosylamines

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.

Synthesis of 6-deoxy-homoDMDP and its C(5)-epimer: absolute stereochemistry of natural products from Hyacinthus orientalis

Abstract 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.

Exploiting the Hydrophobic Terrain in Fucosidases with Aryl-Substituted Pyrrolidine Iminosugars.

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.

Tandem Nucleophilic Addition/Cyclization Reaction in the Synthesis of Ketimine-Type Iminosugars

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.