Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

Baráth, Marek; Koóš, Miroslav; Tvaroŝka, Igor; Hirsch, Ján

doi:10.1515/chempap-2015-0017

Cited by 5 publications

(6 citation statements)

References 11 publications

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“…Recently, alkyl or aryl 3‐acetamido‐3‐deoxy‐1‐ O ‐phosphono‐2‐thio‐ β ‐ d ‐psicofuranosyl sulfone derivatives have been designed, synthesized and biologically evaluated as GnT‐I inhibitors . Our research group presented precursors of potential inhibitors of GnT‐I bearing d ‐psicofuranose, d ‐tagatofuranose as well as d ‐fructofuranose scaffolds . This work is an extension of our previous research in which corresponding 1‐ O ‐phosphono‐2‐thio‐ d ‐fructofuranosides were prepared.…”

Section: Introductionmentioning

confidence: 73%

“…The furanose formation of hexoses contains two primary hydroxyl groups with similar reactivity. However, primary hydroxyl group on position C‐1 is more sterically hindered by the presence of anomeric substituent and therefore bulky protective groups like tert ‐buthyldimethylsilyl predominantly react on the position C‐6 to produce silylated thioglycosides ( 11 – 13 ) (Scheme ). To minimize the presence of disilylated thioglycosides a slight excess of TBDMSCl (1.25 eq.)…”

Section: Resultsmentioning

confidence: 99%

“…Our research group presented precursors of potential inhibitors of GnT‐I bearing d ‐psicofuranose, d ‐tagatofuranose as well as d ‐fructofuranose scaffolds . This work is an extension of our previous research in which corresponding 1‐ O ‐phosphono‐2‐thio‐ d ‐fructofuranosides were prepared. In this contribution we present a computational docking, synthesis and biological assays of 1‐ O ‐sulfono‐ d ‐fructofuranosyl sulfones 1 – 3 as possible GnT‐I inhibitors (Figure ).…”

Section: Introductionmentioning

confidence: 85%

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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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Section: Introductionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

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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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“…A deformed six-membered hexopyranose ring was replaced with a five-membered furanose ring. Several potential inhibitors based on these scaffolds have been synthesized [ 458 , 459 , 460 ]. Two examples of potential inhibitors are given in Figure 23 d,e.…”

Section: Carbohydrate Processing Inhibitorsmentioning

confidence: 99%

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

2020

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Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological processes. The sialylated and fucosylated tetrasaccharide sLex is an essential glycan recognized by selectins. Several glycosyltransferases are responsible for the biosynthesis of the sLex tetrasaccharide. Selectins are involved in a sequence of interactions of circulated leukocytes with endothelial cells in the blood called the adhesion cascade. Recently, it has become evident that cancer cells utilize a similar adhesion cascade to promote metastases. However, like Dr. Jekyll and Mr. Hyde’s two faces, selectins also contribute to tissue destruction during some infections and inflammatory diseases. The most prominent function of selectins is associated with the initial stage of the leukocyte adhesion cascade, in which selectin binding enables tethering and rolling. The first adhesive event occurs through specific non-covalent interactions between selectins and their ligands, with glycans functioning as an interface between leukocytes or cancer cells and the endothelium. Targeting these interactions remains a principal strategy aimed at developing new therapies for the treatment of immune and inflammatory disorders and cancer. In this review, we will survey the significant contributions to and the current status of the understanding of the structure of selectins and the role of selectins in various biological processes. The potential of selectins and their ligands as therapeutic targets in chronic and acute inflammatory diseases and cancer will also be discussed. We will emphasize the structural characteristic of selectins and the catalytic mechanisms of glycosyltransferases involved in the biosynthesis of glycan recognition determinants. Furthermore, recent achievements in the synthesis of selectin inhibitors will be reviewed with a focus on the various strategies used for the development of glycosyltransferase inhibitors, including substrate analog inhibitors and transition state analog inhibitors, which are based on knowledge of the catalytic mechanism.

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“…To date, the catalytic mechanism of GnTs is not completely understood, although mechanistic studies on inverting GnTs using ab‐initio calculations have shed some light on the reaction pathway and the determination of the TS structure . Recently, based on the results of molecular modeling, 2‐thio‐ d ‐psico‐ and 2‐thio‐ d ‐tagatofuranosides were prepared as TS analogs of the enzymatic reaction . TS analogs are stable compounds that resemble the three‐dimensional structural arrangement as well as the charge distribution as seen in an unstable TS of an enzymatic reaction.…”

Section: Introductionmentioning

confidence: 99%

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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Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

Cited by 5 publications

References 11 publications

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

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

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

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

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