Potential transition-state analogs for glycosyltransferases. Design and DFT calculations of conformational behavior

Raab, Michal; Kozmon, Stanislav; Tvaroŝka, Igor

doi:10.1016/j.carres.2005.01.041

Cited by 25 publications

(17 citation statements)

References 29 publications

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“…They represent the precursors of model mimetics of the saccharide part of donor UDPGlcNAc in TS, where the benzyl and/or ethyl groups mimic the acceptor part of the molecule and the "1-thio" linker provides the approximately 1.9Å distance between the "donor" and the "acceptor" part of the molecule as well as the charge distribution as in TS (Fig. 3) (Raab et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, some carbohydrate mimetics have been suspected to be representatives of a new generation of potential inhibitors of GTs; however, only a few of them exhibited significant activity. Compounds of this family are structurally altered analogs of carbohydrate designed to simulate their shape and functionalities of the natural substrates in the ground or transition state (TS) with the goal of modulating their biological activities (Sears & Wong, 1999). Carbohydrate mimetics related to GTs inhibitors are often used to imitate the TS of the enzymatic reaction (Waldscheck et al, 2001) rather than the ground state, promising a better inhibition than the natural carbohydrate substrate.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

et al. 2015

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Based on rational design of the transition state analog inhibitors of glycosyltransferases, four model glycomimetics of this type, viz. benzyl 2-thio-α-D-fructofuranoside 1-diethylphosphate (XIa), its β-anomer (XIb), and their ethyl 2-thio analogs -α-anomer (XIIa) and β-anomer (XIIb), were synthesized. In addition, fourteen precursors arising during the synthesis of the desired final model compounds (XI and XII), partially or fully acetylated benzyl and/or ethyl 2-thiofructofuranoside 1-diethyl phosphates, were isolated and characterized with the aim to prepare complete series of glycomimetics, representing donor UDP-GlcNAc designated for biological assays on human GnT's, viz. GnT-I, Core2GnT, and GnT-V.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

et al. 2015

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“…To see how the presence of the SO 2 group, as opposed to the sulfur atom originally intended for 1 , can influence the binding to the GnT‐I active site, docking of compound 2 into the GnT‐I structure was carried out. During the docking procedure, the best 20 poses of compound 2 were kept.…”

Section: Resultsmentioning

confidence: 99%

“…The DFT/6‐31+G* optimized structures of 2 and UMP‐ 2 were docked into the structure of GnT‐I [PDB (Protein Data Bank) ID: 1FOA]. The GnT‐I structure, the docking grids, and parameters were prepared as described in our previous publications , . B3LYP/6‐31+G* ESP (electrostatic potential) charges were associated to the 2 and UMP‐ 2 structures before docking.…”

Section: Methodsmentioning

confidence: 99%

“…The phosphoric acid residue simulates the leaving UDP (uridine diphosphate) group, the 3‐acetamido‐3‐deoxy‐ d ‐psicofuranose ring resembles the GlcNAc donor moiety, and the alkylsulfanyl or arylsulfanyl group represents an approaching nucleophilic acceptor in the course of the enzymatic reaction. As calculated for the TS by molecular modeling, a β configuration at the anomeric centre is crucial for the inhibition activity of the proposed inhibitors 1 …”

Section: Introductionmentioning

confidence: 99%

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Synthesis of a β‐d‐Psicofuranosyl Sulfone and Inhibitory‐Activity Evaluation Against N‐Acetylglucosaminyltransferase I

et al. 2017

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Alkyl or aryl 3‐acetamido‐3‐deoxy‐2‐thio‐β‐d‐psicofuranosides bearing a phosphate group at C‐1, which were originally designed as potential GnT‐I inhibitors (GnT = N‐acetylglucosaminyltransferase) by computational methods, were found to be unstable. Therefore their structure was slightly modified to stable 3‐acetamido‐3‐deoxy‐β‐d‐psicofuranosyl sulfones. A model inhibitor of GnT‐I, namely ethyl 3‐acetamido‐3‐deoxy‐1‐O‐phosphono‐β‐d‐psicofuranosyl sulfone, was synthesized based on the transformation of d‐mannose into 3‐azido‐3‐deoxy‐d‐psicofuranose as the key intermediate. Thioglycosylation of 1,2‐O‐diisopropylidene‐protected 3‐azido‐ or 3‐amino‐3‐deoxy‐d‐psicofuranose derivatives with thiols in the presence of BF3·OEt2 was found to be a crucial step in the synthesis of the predicted inhibitor. Biochemical evaluation of the proposed inhibitor revealed only a very weak inhibition of GnT‐I. Additional molecular modeling showed that further modifications of the UDP‐mimicking part of the synthesized inhibitor are necessary to improve its inhibitory activity against GnT‐I.

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Novel 1‐O‐Sulfono‐α‐d‐Fructofuranosyl Sulfones as Possible Inhibitors of Human GnT‐I Enzyme

et al. 2020

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The present work is dedicated to Professor Ladislav Petruš on the occasion of his 70th birthday.Library of a new class of C-1 monosulfated saccharide derivatives derived from D-fructofuranose have been synthesized as potential GnT-I inhibitors. To increase stability of originally proposed thioglycosides, the compounds were oxi-dized to sulfones bearing three different aglycons; ethyl, 2methyl propyl (isopropyl) and phenyl. Here we present molecular modelling, synthesis and biological assays of prepared compounds. Scheme 2. Reagent and Conditions: a) TBDMSCl, pyridine, À 20°C!r.t., overnight; b) DMTrCl, DMAP, pyridine, r.t. overnight; c) 1 M TBAF in THF, THF, r.t., 90 min; d) BnBr, DMF, NaH, 0°C!r.t., 2 h; e) CF 3 COOH, DCM, triethylsilane, r.t., 1.5-4 h. Scheme 3. Reagent and Conditions: a) SO 3 ⋅py complex, DCM, r.t., 48 h; b) 3chloroperbenzoic acid, DCM, 0°C!r.t., 0.5-1.5 h. Scheme 4. Reagent and Conditions: a) SO 3 .py complex, DCM, r.t., 48 h; b) cat. 10 % Pd/C, H 2 , MeOH, 2 h.

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Potential transition-state analogs for glycosyltransferases. Design and DFT calculations of conformational behavior

Cited by 25 publications

References 29 publications

Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

Synthesis of a β‐d‐Psicofuranosyl Sulfone and Inhibitory‐Activity Evaluation Against N‐Acetylglucosaminyltransferase I

Novel 1‐O‐Sulfono‐α‐d‐Fructofuranosyl Sulfones as Possible Inhibitors of Human GnT‐I Enzyme

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