Conformationally-locked C-glycosides: tuning aglycone interactions for optimal chaperone behaviour in Gaucher fibroblasts.

A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver ß-glucosidase/ß-galactosidase and specific inhibition of human ß-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location. Molecular dynamics simulations highlighted the paramount importance of an optimal orientation of the hydrophobic substituent to warrant efficient non-glycone interactions, which are critical for the binding affinity. The results provide a rationale for the strong decrease of the inhibition potency of APP compounds on going from neutral to acidic pH. The best candidate was found to behave as pharmacological chaperone in Gaucher fibroblasts with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound Ambroxol.

Regioselective ring-opening metathesis-cross metathesis of bridgehead-substituted 7-azanorbornene.

[structure: see text]. In this paper we describe a highly regioselective ring-opening metathesis-cross metathesis (ROM-CM) process between methyl N-Boc-7-azabicyclo[2.2.1]hept-2-en-1-carboxylate, a bridgehead-substituted 7-azanorbornene system, and electron-poor olefins. The reaction opens the way to the synthesis of interesting alpha-amino diacids and pyrrolizinone derivatives that incorporate quaternary stereocenters.

Synthesis of azabicyclo[2.2.n]alkane systems as analogues of 3-[1-methyl-2-(S)-pyrrolidinyl- methoxy]pyridine (A-84543).

This work is connected with the epibatidine field and describes the synthesis of several analogues of compounds that present affinity for nicotinic acetylcholine receptors, such as 3-[1-methyl-2-(S)-pyrrolidinylmethoxy]pyridine (A-84543). These analogues bear a 3-pyridyl ether substituent at the bridgehead carbon of the azabicyclo[2.2.n]alkane system. Particularly, in the case of the 1-substituted 2-azabicyclo[2.2.2]octane system, a new synthetic route has been developed, which involves the synthesis of a novel rigid sulfamidate that allows the straightforward introduction of nucleophiles.

Effect of beta-O-glucosylation on L-Ser and L-Thr diamides: a bias toward alpha-helical conformations.

Beta-D-O-glucosylation produces a remarkable effect on the peptide backbone of the model peptides derived from serine and threonine. Consequently, this type of glycosylation is responsible for the experimentally observed shift from extended conformations (model peptides) towards the folded conformations (model glycopeptides). The conclusion has been solidly assessed by a combined NMR/MD protocol. Interestingly, the MD (molecular dynamics) results for the glycopeptides point towards the existence of water-bridging molecules between the sugar and peptide moieties, which could explain the stabilization of the folded conformers in aqueous solution.

Synthesis of conformationally constrained hydroxy-alpha-amino acids by intramolecular conjugate addition.

An efficient and easily applicable method for the synthesis of a variety of hydroxy-alpha-amino acids analogues of serine and phenylalanine has been established. The method involves the stereoselective intramolecular conjugate addition of the benzamide group to cyclohexenone promoted by Lewis acid. Subsequent transformations of functional groups provide the conformationally constrained 2-hydroxy- and 2,4-dihydroxy-6-phenylcyclohexane-alpha-amino acids.