Stereodirecting Effect of Esters at the 4-Position of Galacto- and Glucopyranosyl Donors: Effect of 4-C-Methylation on Side-Chain Conformation and Donor Reactivity, and Influence of Concentration and Stoichiometry on Distal Group Participation.

When generated in a mass spectrometer bridged bicyclic 1,3-dioxenium ions derived from 4-O-acylgalactopyranosyl, donors can be observed by infrared spectroscopy at cryogenic temperatures, but they are not seen in the solution phase in contrast to the fused bicyclic 1,3-dioxalenium ions of neighboring group participation. The inclusion of a 4-C-methyl group into a 4-O-benzoyl galactopyranosyl donor enables nuclear magnetic resonance observation of the bicyclic ion arising from participation by the distal ester, with the methyl group influence attributed to ester ground state conformation destabilization. We show that a 4-C-methyl group also influences the side-chain conformation, enforcing a gauche,trans conformation in gluco and galactopyranosides. Competition experiments reveal that the 4-C-methyl group has only a minor influence on the rate of reaction of 4-O-benzoyl or 4-O-benzyl-galacto and glucopyranosyl donors and, consequently, that participation by the distal ester does not result in kinetic acceleration (anchimeric assistance). We demonstrate that the stereoselectivity of the 4-O-benzoyl-4-C-methyl galactopyranosyl donor depends on reaction concentration and additive (diphenyl sulfoxide) stoichiometry and hence that participation by the distal ester is a borderline phenomenon in competition with standard glycosylation mechanisms. An analysis of a recent paper affirming participation by a remote pivalate ester is presented with alternative explanations for the observed phenomena.

Synthesis of 4-O-(4-Amino-4-deoxy-ß-D-xylopyranosyl)paromomycin and 4-S-(ß-D-Xylopyranosyl)-4-deoxy-4'-thio-paromomycin and Evaluation of their Antiribosomal and Antibacterial Activity.

The design, synthesis and antiribosomal and antibacterial activity of two novel glycosides of the aminoglycoside antibiotic paromomycin are described. The first carries of 4-amino-4-deoxy-ß-D-xylopyranosyl moiety at the paromomycin 4'-position and is approximately two-fold more active than the corresponding ß-D-xylopyranosyl derivative. The second is a 4'-(ß-D-xylopyranosylthio) derivative of 4'-deoxyparomomycin that is unexpectedly less active than the simple ß-D-xylopyranosyl derivative, perhaps because of the insertion of the conformationally more mobile thioglycosidic linkage.

Synthesis and evaluation of 1,5-dithialaminaribiose and -triose tetravalent constructs.

We report the synthesis of novel tetravalent glucoclusters containing 1,5-dithia mimetics of laminaribiose and triose. The new constructs were evaluated for their ability to inhibit anti-CR3 fluorescent staining of human neutrophils, for which they showed moderate affinity. Evaluation of the synthesized glycoclusters for their ability to inhibit anti-Dectin-1 fluorescent staining of mouse macrophages revealed little to no affinity for Dectin-1.

Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors.

Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6- to 10-fold more potent than isosteric compounds with the gauche,trans conformation; a manno-configured iminosugar with the gauche,gauche conformation is a 27-fold better inhibitor than 1-deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.

Importance of Co-operative Hydrogen Bonding in the Apramycin-Ribosomal Decoding A-Site Interaction.

An intramolecular hydrogen bond between the protonated equatorial 7'-methylamino group of apramycin and the vicinal axial 6'-hydroxy group acidifies the 6'-hydroxy group leading to a strong hydrogen bond to A1408 in the ribosomal drug binding pocket in the decoding A site of the small ribosomal subunit. In 6'-epiapramycin, the trans-nature of the 6'-hydroxy group and the 7'-methylamino group results in a much weaker intramolecular hydrogen bond, and a consequently weaker cooperative hydrogen bonding network with A1408, resulting overall in reduced inhibition of protein synthesis and antibacterial activity.