Yves Le Merrer

Synthesis of azasugars as potent inhibitors of glycosidases

A series of enantiomerically pure azasugars (2,5-dideoxy-2, 5-imino-D-mannitol, 1-deoxynojirimycin, 1-deoxymannojirimycin, and related compounds) was synthesized from D-mannitol via aminoheterocyclization of C2-symmetric bis-epoxides and subsequently followed by ring isomerization in few cases. These compounds have been evaluated as inhibitors of several glycosidases (alpha- and beta-D-glucosidases, alpha-D-mannosidase and alpha-L-fucosidase). Inhibition studies indicate notably that the polyhydroxylated azepanes are inhibitors of glycosidases, with Ki in the micromolar range.

Polyhydroxylated piperidines and azepanes from D-mannitol synthesis of 1-deoxynojirimycin and analogues

Abstract D -mannitol and L -iditol bis-epoxides, easily obtained from D -mannitol, are convenient substrates for the synthesis of polyhydroxylated piperidines and azepanes, via a nucleophilic opening of one epoxy function followed by a spontaneous intramolecular ring closure. Using this strategy 1-deoxynojirimycin and analogues were prepared.

Synthesis of thiosugars as weak inhibitors of glycosidases

Abstract A series of enantiomerically pure thiosugars (1,6-dideoxy-1,6-thio-D-mannitol or L-iditol, 1,5-dideoxy-1,5-thio-L-gulitol or D-glucitol and 2,5-dideoxy-2,5-thio-L-iditol or D-mannitol, and their corresponding sulfoxide or sulfone) was synthesized via thiocyclization of C2-symmetric bis-epoxides, and subsequently followed by ring isomerization in few cases. These compounds have been evaluated as inhibitors of several glycosidases (α- and β-D-glucosidases, α-D-mannosidase and α-L-fucosidase).

Synthesis of sugar-like amino-carboxylic acids from D-mannitol

Abstract 6-Amino-2,5-anhydro-6-deoxy- D -gluconic and L -gulonic acid derivatives, conformationally restricted sugar-like amino-carboxylic acids which mimic dipeptides, have been synthesized by a silica gel assisted azidolysis of enantiomerically pure bis-epoxides.

Design, synthesis and binding affinities of novel non-peptide mimics of somatostatin/sandostatin®

Abstract Based on molecular modelling studies of Sandostatin®, sugar-based derivatives I-VI were prepared as potential non-peptide mimics of somatostatin/Sandostatin®. These compounds displaced 3-[ 125 I]-Tyr 11 -SRIF-14 from the somatostatin receptor on membranes of rat cerebral cortex with IC 50 values between 10 and 15 μM.

Synthesis of (-)-Muricatacin and (-)-(5R,6S)-6-acetoxy-5-hexadecanolide, the Mosquito oviposition attractant pheromone, from D-isoascorbic acid

Abstract From D -isoascorbic acid, a general approach to enantiomerically pure hydroxy γ-butyro and δ-valero lactones, (-)-Muricatacin and (-)-(5 R ,6 S )-6-acetoxy-5-hexadecanolide, via a four carbon atoms bis-epoxide equivalent, is reported.

Thiosugars from D-mannitol

Abstract Enantiomerically pure thiosugars, with a thiepan, tetrahydrothiopyran or tetrahydrothiophene backbone, have been synthesized by thio-heterocyclization of enantiopure C 2 -symmetric bis-epoxides and possibly ring contraction.

Synthesis of azasugars. Part 2 isomerization of polyhydroxylated azepanes

Abstract Isomerization of enantiopure C2-symmetric 3,5-dihydroxyazepane derivatives has been studied. The neighboring nitrogen participation occurs during mesylation to give a chloromethylpiperidine, whereas from the l -ido- azepane a chiral bridged morpholine structure (1R-(6endo, 7exo)-8-oxa-3-azabicyclo[3.2.1]octane-6,7-diol) is obtained under Mitsunobu conditions.

A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model

Activating germline fibroblast growth factor receptor 3 (FGFR3) mutations cause achondroplasia (ACH), the most common form of human dwarfism and a spectrum of skeletal dysplasias. FGFR3 is a tyrosine kinase receptor and constitutive FGFR3 activation impairs endochondral ossification and triggers severe disorganization of the cartilage with shortening of long bones. To decipher the role of FGFR3 in endochondral ossification, we analyzed the impact of a novel tyrosine kinase inhibitor (TKI), A31, on both human and mouse mutant FGFR3-expressing cells and on the skeleton of Fgfr3(Y367C/+) dwarf mice. We found that A31 inhibited constitutive FGFR3 phosphorylation and restored the size of embryonic dwarf femurs using an ex vivo culture system. The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. Premature cell cycle exit and defective chondrocyte differentiation were observed in the Fgfr3(Y367C/+) growth plate. A31 restored normal expression of cell cycle regulators (proliferating cell nuclear antigen, KI67, cyclin D1 and p57) and allowed pre-hypertrophic chondrocytes to properly differentiate into hypertrophic chondocytes. Our data reveal a specific role for FGFR3 in the cell cycle and chondrocyte differentiation and support the development of TKIs for the treatment of FGFR3-related chondrodysplasias.

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and (3R,4R)-3-amino-4-hydroxyazepane from D-isoascorbic acid

Abstract Taking advantage of the high functionality of an enantiopure protected syn -2 R -amino-1,3,4-triol derivative, easily available on a multigram scale from D-isoascorbic acid, several biologically active compounds have been synthesized such as the (2 S ,3 R )-3-amino-2-hydroxydecanoic acid (AHDA), the N -terminal moiety of microginin, and the (3 R ,4 R )-3-amino-4-hydroxyazepane, the ophiocordin and balanol core structure.