Stereospecific synthesis of methyl 2-amino-2-deoxy-(6S)-deuterio-α,β-d-glucopyranoside and methyl 2,6-diamino-2,6-dideoxy-(6R)-deuterio-α,β-d-glucopyranoside: Side chain conformations of the 2-amino-2-deoxy and 2,6-diamino-2,6-dideoxyglucopyranosides

Kato, Takayuki; Vasella, Andrea; Crich, David

doi:10.1016/j.carres.2017.05.015

Cited by 11 publications

(13 citation statements)

References 29 publications

(31 reference statements)

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“…Thus, adopting literature data on the side chain conformations of methyl 2-amino-2-deoxy-α-D-glucopyranoside and of methyl 2,6-diamino-2,6-dideoxy-α-D-glucopyranoside, 49,66 the hydroxymethyl and protonated aminomethyl side chains of paromomycin 2 and neomycin 3 are approximately 60:40:0 and 10:90:0 mixtures, respectively, of the gg , gt and tg conformers. Thus, on binding to the decoding A site in the gt conformation, paromomycin pays a penalty for restricting the side chain to a higher energy conformer.…”

Section: Discussionmentioning

confidence: 88%

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

et al. 2017

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The preparation of a series of four analogues of the aminoglycoside antibiotics neomycin and paromomycin is described in which ring I, involved in critical binding interactions with the ribosomal target, is replaced by an apramycin-like dioxabicyclo[4.4.0]octane system. The effect of this modification is to lock the hydroxymethyl side chain of the neomycin or paromomycin ring I, as part of the dioxabicyclooctane ring, into either the gauche-gauche or the gauche-trans conformation (respectively axial or equatorial to the bicyclic system). The antiribosomal activity of these compounds is investigated with cell-free translation assays using both bacterial ribosomes and recombinant hybrid ribosomes carrying eukaryotic decoding A site cassettes. Compounds substituted with an equatorial hydroxyl or amino group in the newly formed ring are considerably more active than their axial diastereomers, lending strong support to crystallographically-derived models of aminoglycoside-ribosome interactions. One such bicyclic compound carrying an equatorial hydroxyl group has activity equal to that of the parent, yet displays better ribosomal selectivity, predictive of an enhanced therapeutic index. A paromomycin analog lacking the hydroxymethyl ring I side chain is considerably less active than the parent. Antibacterial activity against model Gram negative and Gram positive bacteria is reported, for selected compounds, as is activity against ESKAPE pathogens and recombinant bacteria carrying specific resistance determinants. Analogues with a bicyclic ring I carrying equatorial amino or hydroxyl groups mimicking the bound side chains of neomycin and paromomcyin, respectively, show excellent activity and, by virtue of their novel structure, retain this activity in strains that are insensitive to the parent compounds.

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Section: Discussionmentioning

confidence: 88%

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

et al. 2017

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“…This transformation follows the literature description 36 with the exception that the original solvent, tetrachloromethane, was replaced by the more environmentally friendly α,α,α-trifluoromethylbenzene 42 as described previously for the gluco series. 43 Reductive debromination with tributyltin deuteride, prepared according to Neumann, 44 then gave the 6 S -deuterio anhydrogalactose ( 6 ) in 77% yield. A series of standard transformations were then applied to convert 6 via intermediates 7 – 10 to the desired 6 S - d -1 uneventfully (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

2018

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The synthesis and conformational analysis of a series of phenyl 2,3,6-tri-O-benzyl-β-d-thio galacto- and glucopyranosides and their 6S-deuterio isotopomers, with systematic variation of the protecting group at the 4-position, are described. For the galactopyranosides, replacement of a 4-O-benzyl ether by a 4-O-alkanoyl or aroyl ester results in a small but measurable shift in side chain population away from the trans,gauche conformation and in favor of the gauche,trans conformer. In the glucopyranoside series on the other hand, replacement of a 4-O-benzyl ether by a 4-O-alkanoyl or aroyl ester results in a small but measurable increase in the population of the trans,gauche conformer at the expense of the gauche,gauche conformer. The possible modulating effect of these conformational changes on the well-known changes in the anomeric reactivity of glycosyl donors as a function of protecting group is discussed, raising the possibility that larger changes may be observed at the transition state for glycosylation. A comparable study with a series of ethyl 2,3,4-tri-O-benzyl-β-d-thioglucopyranosides reveals that no significant influence in side chain population is observed on changing the O6 protecting group.

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“…A critical interaction between ring I of the 2-deoxystreptamine AGAs and the ribosome is the pseudobase pair interaction with residue A1408 involving hydrogen bonds from both the side chain heteroatom and the ring oxygen of the AGA ring I to the adenine residue (Figure ). Crystal structures of AGAs bound to the ribosome show that participation in this interaction enforces the gt conformation of the side chain despite the approximately equal population of the gg and gt conformations in the unbound drug . Preorganization of the exocyclic bonds into the gt conformation can therefore be expected to increase affinity for the ribosomal decoding A site, as was borne out with paromomycin 9 and its bicyclic analogue 11 .…”

Section: Results and Discussionmentioning

confidence: 99%

Predictive Analysis of the Side Chain Conformation of the Higher Carbon Sugars: Application to the Preorganization of the Aminoglycoside Ring 1 Side Chain for Binding to the Bacterial Ribosomal Decoding A Site

et al. 2020

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With a view to facilitating prediction of the exocyclic bond to the pyranoside ring in higher carbon sugars, a model is advanced that relates the relative configuration of the three stereogenic centers comprised of the branchpoint and of the two flanking centers (C4−C5−C6 in aldoheptoses and higher and C5−C6−C7 in sialic and ulosonic acids) to that of the simple ringopened pentoses. Assignment of a given stereotriad as arabino, lxyo, ribo, or xylo by inspection of the Fischer projection formulas permits prediction of conformation of the exocyclic bond by comparison with the known solution (= crystal in all cases) conformations of the simple pentitols. More remote stereogenic centers in the side chain, as in the 8-position of N-acetylneuraminic acid, have little impact on the conformation of the exocyclic bond. On the basis of this model the conformation of the exocyclic bond in ring I of 6′-homologated 4,5-disubstituted 2-deoxystreptamine class aminoglycoside antibiotics was predicted and was borne out by NMR analysis of newly synthesized derivatives in D 2 O at pD5. The antiribosomal and antibacterial activity of these derivatives is briefly presented and discussed in terms of preorganization of the side chain for binding to the ribosomal decoding A site. It is anticipated that this predictive analysis will also find use in the prediction of the conformation of the exocyclic bonds in other 2-(1hydroxyalkyl)-3-hydroxytetrahydropyrans and tetrahydrofurans.

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Stereospecific synthesis of methyl 2-amino-2-deoxy-(6S)-deuterio-α,β-d-glucopyranoside and methyl 2,6-diamino-2,6-dideoxy-(6R)-deuterio-α,β-d-glucopyranoside: Side chain conformations of the 2-amino-2-deoxy and 2,6-diamino-2,6-dideoxyglucopyranosides

Cited by 11 publications

References 29 publications

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

Structure-Based Design and Synthesis of Apramycin–Paromomycin Analogues: Importance of the Configuration at the 6′-Position and Differences between the 6′-Amino and Hydroxy Series

Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

Predictive Analysis of the Side Chain Conformation of the Higher Carbon Sugars: Application to the Preorganization of the Aminoglycoside Ring 1 Side Chain for Binding to the Bacterial Ribosomal Decoding A Site

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