Glucose derived inhibitors of glycogen phosphorylase

László Somsák

doi:10.1016/j.crci.2010.09.004

Account/Revue

Glucose derived inhibitors of glycogen phosphorylase

László Somsák ¹

¹ Department of Organic Chemistry, University of Debrecen, POB 20, 4010 Debrecen, Hungary

Comptes Rendus. Chimie, Chimie et biochimie des hydrates de carbone - seconde partie, Volume 14 (2011) no. 2-3, pp. 211-223.

Résumé

Design, synthesis, and structure–activity relationships of glucose analogue inhibitors of glycogen phosphorylase are surveyed.

Métadonnées

Reçu le : 2010-01-24
Accepté le : 2010-09-08
Publié le : 2010-11-05

DOI : 10.1016/j.crci.2010.09.004

Mots-clés : Type 2 diabetes mellitus, Glycogen phosphorylase, Inhibitor, Glucose derivatives

Affiliations des auteurs :

László Somsák ¹

¹ Department of Organic Chemistry, University of Debrecen, POB 20, 4010 Debrecen, Hungary

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László Somsák. Glucose derived inhibitors of glycogen phosphorylase. Comptes Rendus. Chimie, Chimie et biochimie des hydrates de carbone - seconde partie, Volume 14 (2011) no. 2-3, pp. 211-223. doi : 10.1016/j.crci.2010.09.004. https://comptes-rendus.academie-sciences.fr/chimie/articles/10.1016/j.crci.2010.09.004/

Version originale du texte intégral

Le texte intégral ci-dessous peut contenir quelques erreurs de conversion par rapport à la version officielle de l'article publié.

1 Introduction

One of the major aims of chemical biology [1], the young and developing scientific field between chemistry and biology, is to find matches between the biological and chemical space [2]. The chemical space comprises (small) molecules, some of which show complementary features to certain points of the biological space constituted by the structure of binding sites of biomacromolecules (mainly but not only proteins). Good matches may result in efficient agonists/antagonists of receptors or activators/inhibitors of enzymes. Such interactions contribute to the basic understanding of the way of biological action of the macromolecule, and may ultimately be utilised in drug design and discovery.

In the context of this survey, the biological space is represented by glycogen phosphorylase (GP), the main regulatory enzyme of glycogen metabolism. GP, catalysing the rate-determining step of glycogen degradation in the liver by phosphorolysis, is directly responsible for the regulation of blood glucose levels. Thus, the enzyme has become a validated target in combatting non-insulin-dependent, or type 2, diabetes mellitus (NIDDM or T2DM), and its inhibitors are considered as potential antidiabetic agents. The biochemical and pharmacological background of this research has been amply summarized in several reviews of the past decade, therefore, the reader is kindly referred to those papers [3–8].

Diverse classes of compounds [4,9–12] can be found among inhibitors of GP binding to one (or in specific cases more) of the so far discovered binding sites of the enzyme (Fig. 1). The most populated class of compounds is that of glucose derivatives, first proposed and investigated [4,13,14] by Fleet, Johnson, and Oikonomakos,¹ which bind primarily to the active site of GP. This article highlights the most important “historical” moments of GP inhibitor design among glucose analogues, and the main emphasis is put on developments of the past couple of years, not, or not fully, included in the last comprehensive reviews [11,12]. Although the design of compounds was heavily based on and supported by results of crystallographic investigations of enzyme–inhibitor complexes and molecular dockings, the syntheses and structure–activity relationships of the inhibitors are pointed out in this overview.

2 Early glucose analogue inhibitors of glycogen phosphorylase

The weak binding of d-glucose anomers 1 and 2 to the catalytic site of GP to act as the physiological regulator of the enzyme [15] raised the possibility to design glucose derivatives with much higher affinity to the active site. Enzymatic tests of a large series of α- and β-d-glucopyranosides, 1-thio-d-glucopyranosides, N-acyl-β-d-glucopyranosylamines and related compounds [13] revealed 1-deoxy-d-gluco-heptulopyranose 2-phosphate (3) and N-acetyl-β-d-glucopyranosylamine (4) as the first glucose derivatives with an inhibitor constant (K_i) in the low micromolar range. Anhydro-heptonamides 5 and 6 were less effective, however, a formal combination of 6 with an anomeric substituent similar to that of 4 gave again a low micromolar inhibitor 7. Ring closure of 7 to glucopyranosylidene-spiro-hydantoin 8 strengthened the binding by a factor of ∼5. The spiro-epimeric hydantoin 9 proved much less efficient, indicating that the presence of a β-d-anomeric NH was very important to make a good inhibitor. This was rationalized by crystallographic investigation of the enzyme–inhibitor complex [16] to show the presence of a specific H-bridge between NH and His377 next to the catalytic site also present in N-acyl-β-d-glucopyranosylamine type inhibitors (Fig. 2a for an illustration). The synthetic problems with the stereoselective preparation of the properly configured spiro-hydantion 8 [17–19] were essentially overcome by the highly stereoselective synthesis of spiro-thiohydantoin 10 [20] which proved equipotent with 8 (Fig. 3).

Fig. 2
Outline of binding of glucose analogues at the active site of glycogen phosphorylase (GP) highlighting (a) important H-bonds between N-acyl-β-d-glucopyranosylamine type inhibitors and His377 and (b) binding modes of N-acyl-N’-β-d-glucopyranosyl ureas as observed by X-ray crystallography.

Fig. 3
Inhibition of glycogen phosphorylase (GP) by d-glucose and the most efficient inhibitors of early glucose analogue derivatives (K_i [μM] against RMGPb) [21–26].

3 Glucose derivatives tested recently as inhibitors of glycogen phosphorylase

3.1 N-Acyl-β-d-glucopyranosylamines and related compounds

Following the success of the first N-acyl-β-d-glucopyranosylamine type inhibitors like 4, several modifications of the acyl group were carried out. A widely applied general method for the preparation of such compounds starts with the reaction of per-O-acetylated β-d-glucopyranosyl azide 11 with triaryl- or trialkyl phosphanes (PMe₃ proved the most advantageous [27]) and the intermediate phosphinimine is then reacted with a carboxylic acid or acid chloride or anhydride to get protected amides 14 (Scheme 1; for an exhaustive review see [28]). Reduction of 11 to 15 followed by acylation can be an alternative synthetic route. Subsequent deprotection yields test compounds of type 14 (R = H), and several recent examples as inhibitors of rabbit muscle GP b (RMGPb) are shown in Fig. 4.

Fig. 4
Inhibition of rabbit muscle glycogen phosphorylase b (RMGPb) by N-acyl-β-d-glucopyranosylamines and related compounds. Illustrative examples of the most efficient members of larger series of compounds detailed in the referred papers [29–37].

Substitution in the methyl group of N-acetyl-β-d-glucopyranosylamine makes the inhibition weaker (Fig. 4, compare 4 and 14a,b). The α-anomeric trifluoroacetamide 17 proved configurationally stable (for a discussion on the stability of N-acyl-glycosylamine anomers, see ref. [27]) but showed no inhibition. From a larger collection of monoamides of dicarboxylic acids, 14c showed similar inhibition to that of 4, while its methylester 14d proved significantly weaker. In the series of oxamic acid derivatives, the efficiencies of acid 14e and ester 14f were reversed, both being much less effective than 4. Introduction of a large side chain as in 14g made a weak inhibitor. Among aromatic amides, the 2-naphthoyl derivative 14h proved the most efficient, and in this series, the position occupied by the aromatic moiety becomes also important (Fig. 5 also). Necessity of the intact homoaromatic system is indicated by 1,4-benzodioxane carboxamide 14i. Changing the acyl part to a dimethoxyphosphoryl residue (18) resulted in a practical loss of inhibition.

Fig. 5
Comparison of inhibition of rabbit muscle glycogen phosphorylase b (RMGPb) (K_i [μM]) by N-acyl-β-d-glucopyranosylamines, N-substituted-N’-β-d-glucopyranosyl ureas and related compounds. Against rat liver glycogen phosphorylase (GP) [48–51].

Syntheses of analogues 19 of spiro-hydantoins 8-10 were envisaged by photocyclization of acyl urea derivatives 20 outlined in Scheme 2a. To this end, reported cyclizations of 3-oxoalkyl glycosides [38,39] 23 resulting in stereoselective formation of spiro-acetals 24 (Scheme 2b) served as analogies. Thus, a photoexcitation of 20 might have resulted in intermediate 22 which, upon intramolecular hydrogen abstraction to give 21 and subsequent radical combination could have given the target compounds 19.

To test this hypothesis, N-acyl-N’-β-d-glucopyranosyl ureas of type 27 (Scheme 3) were needed. Only two examples of this class of compounds were known in the literature [40] which were obtained by a modification of the original synthesis. Azide 11 was transformed to urea 26 by Pintér et al.’s method [41] and then acylation was carried out to give 27 (R = Ac, R’ = Me or Ph). Irradiation of 27 under various conditions brought about a Norrish I type cleavage of the R’CO moieities leading back to 26 instead of the expected Norrish II type cyclization [42]. Quite unexpectedly, the deprotected compounds 27 (R = H, R’ = Me K_i = 305 μM; R’ = Ph K_i = 4.6 μM) proved efficient inhibitors of GP [43] and the benzoyl derivative had similar potency to those of spiro-hydantoins 8 and 10. Initiated by this serendipitous finding, synthetic and enzymatic studies were started to get insight in structure–activity relationships of β-d-glucopyranosyl derivatives attached to aromatic rings by linkers of 3-6 atoms analogous to amide groups.

N-Aryl-N’-β-d-glucopyranosyl ureas 13 were obtained (Scheme 1) either via acid catalysed hydration of carbodiimide 12 obtained from azide 11 by a Staudinger type transformation, or by reacting glucosylamine 15 with isocyanates, or by in situ conversion of 15 into glucosylisocyanate 16 [44] followed by amine addition. Removal of the protecting groups was straightforward under Zemplén conditions. Further compounds of the protected N-acyl-N’-β-d-glucopyranosyl urea series 27 (Scheme 3) were obtained in reactions of glucosylamine 15 with acyl-isocyanates or from glucosylisocyanate 16 upon treatment with arenecarboxamides. During these syntheses, anomerization was observed in almost every cases thereby diminishing the yield of the target compounds [45]. Furthermore, deprotection of acyl ureas 27 was always accompanied by the cleavage of the R’CO group, both under base or acid catalysed transesterification conditions. These side reactions could be circumvented by the addition of unprotected β-d-glucopyranosylamine obtained in situ from β-d-glucopyranosylammonium carbamate [46] (25) to various acyl-isocyanates to give directly the unprotected 27 ureas [45]. Biurets 28 [47] and 29 [42] were prepared in reactions of urea 26 with phenyl and 2-naphthoyl isocyanates, respectively.

Most important results of the enzyme kinetic studies are collected in Fig. 5. Comparison of entries 1, 2, 4, 13, and 14 shows that the inhibition is strongest for the acyl urea type compounds (entry 4). Introduction of a tetrahedral element into the linker makes weaker inhibitors (compare entries 2–3, 4–6). Replacement of one NHCO by a more rigid bond (entries 4, 7, 9) seems less detrimental, although the inhibition is weakened, showing the necessity of a polar part capable for participation in H-bonds as well. Entries 7 and 8 indicate again that higher flexibility due to a rotatable element of the linker is not advantageous (of course, the absence of the H-bond donor amide moiety from the anomeric carbon must also contribute to the weaker binding). Constitutional isomers of the NHCONHCO moiety (entries 10–12) also make significantly less efficient inhibitors. Comparison of columns A–C demonstrate the importance of the size and orientation of the aromatic appendage the 2-naphthyl derivatives exhibiting the strongest binding. Accordingly, N-2-naphthoyl-N’-β-d-glucopyranosyl urea (entry 4C) was the first nanomolar glucose analogue inhibitor of GP. Protein crystallography showed acyl ureas of entries 4A and 4C to bind also to the new allosteric site of the enzyme [43].

X-Ray crystallographic studies of GP–N-acyl-N’-β-d-glucopyranosyl urea complexes revealed that, contrary to the N-acyl-β-d-glucopyranosylamines, there is no H-bond between the β-anomeric NH and His377 (Fig. 2b) [43]. As the acyl ureas are much more inhibitory than the corresponding glucosylamines (Fig. 5, entries 1 and 4), the stronger binding must be due to extended interactions of the urea and especially the aromatic parts of the molecules in the β-channel² of the enzyme. This observation was utilized in further inhibitor design discussed in Section 3.4.

Very recently, a new series of aldehyde 4-(β-d-glucopyranosyl)-thiosemicarbazones [52,53] was prepared from per-O-acetylated β-d-glucopyranosylisothiocyanate (Fig. 6) and several of them showed micromolar inhibition.

Fig. 6
Synthesis of aldehyde 4-(β-d-glucopyranosyl)thiosemicarbazones and their enzymatic evaluation against rabbit muscle glycogen phosphorylase b (RMGPb) [54,55].

3.2 N-β-d-glucopyranosyl heterocycles

The problems encountered in the synthesis of N-acyl-β-d-glucopyranosyl ureas necessitated a quest for more stable compounds. To this end, bioisosteric replacement of NHCO moieties in acyl ureas and related compounds was envisaged. As the first example of such studies, the NHCO unit of N-acyl-β-d-glucopyranosylamines was changed to 1,2,3-triazole because some literature examples indicated similarities [56] of these two moieties. Three series of 1-d-glucopyranosyl-4-substituted-1,2,3-triazoles [51] were prepared by copper(I) catalysed azide-alkyne cycloaddition (CuAAC) [57] outlined in Scheme 4. From β-d-glucopyranosyl azide 11 conditions 1a, frequently applied in the literature, proved to be a straightforward way to the per-O-acetylated 1-β-d-glucopyranosyl-4-substituted-1,2,3-triazoles in 58–96% yields. Transformations of the α-azide 30 required higher catalyst loads (conditions 1b) and the yields for the corresponding per-O-acetylated 1-α-d-glucopyranosyl-4-substituted-1,2,3-triazoles were lower (36–72%). The aqueous conditions were unsatisfactory for the reactions of (hept-2-ulopyranosylazide)onamide 31 for which conditions 1c were found the best to give 75–87% of the corresponding O-protected glucosyl triazoles with 51–73% conversion of the starting 31 in one day. Removal of the protecting groups was effected by the Zemplén protocol to give triazoles 32-34 in generally very good yields.

From these 1,2,3-triazoles, only compounds 32 showed significant inhibition (e.g. R = CH₂OH K_i = 26 μM [51] or 14 μM; [35]). Inhibitor constants for other members of this series can be found in Fig. 5, entry 15 to show acceptable similarity with those of glucosyl amides in entry 1. Comparative crystallographic studies of the amide and triazole series revealed that pairs of the compounds with the same aglycon bound to the enzyme in essentially the same way in most cases [35]. Thereby, the bioisosteric relationship for NHCO-1,2,3-triazole was proven for the GP case as well.

Investigations of some N-β-d-glucopyranosyl derivatives of pyrimidine and purine heterocycles (“glucosyl nucleosides”) showed these compounds to have inhibitory effect towards GP, and the best inhibitors are collected in Fig. 7.

Fig. 7
Inhibitory effect of β-d- glucopyranosyl nucleosides against rabbit muscle glycogen phosphorylase b (RMGPb) [58] (K_i [μM]) [58].

3.3 C-β-d-glucopyranosyl derivatives

The first C-β-d-glucopyranosyl heterocycles tested as inhibitors of GP were methyl-1,3,4-oxadiazole 38, tetrazole 39, benzothiazole 40, and benzimidazole 41 (Scheme 5, R = H in each) [59]. Common starting material for the syntheses of these compounds was the per-O-acetylated or -benzoylated 2,6-anhydro-aldononitrile (β-d-glucopyranosyl cyanide) 36. 1,3-Dipolar cycloaddition of protected 36 with azide ion gave 5-β-d-glucopyranosyl tetrazole 39 which was transformed into 2-β-d-glucopyranosyl-5-substituted-1,3,4-oxadiazoles 38 via an N-acyl-nitrilimine intermediate obtained by acylation of 39 [59,60]. Oxadiazoles 38 could also be prepared by oxidation [60] of 2,6-anhydro-aldose acylhydrazones [61] 35, and the two pathways proved comparable with respect to yields and operational difficulties. Nitrile 36 was ring-closed to benzothiazole 40 with 2-aminothiophenol. The analogous reaction with 1,2-diaminobenzene was unsuccessful, therefore, benzimidazole 41 was obtained via thioimidate 37. Deprotection was carried out by the Zemplén method.

Per-O-benzoylated or -benzylated nitriles 36 were also transformed into two other series of 1,2,4-oxadiazoles (Scheme 6). 1,3-dipolar cycloaddition with nitrile-oxides generated in situ furnished 5-β-d-Glucopyranosyl-3-substituted-1,2,4-oxadiazoles 43 [60,62]. Addition of hydroxylamine to 36 produced amidoxime 42 which upon O-acylation with either carboxylic acids or acid chlorides followed by cyclodehydration gave 3-β-d-glucopyranosyl-5-substituted-1,2,4-oxadiazoles 44 [63]. The protecting groups were removed by standard methods.

Results of enzyme kinetic studies are presented in Fig. 8. β-d-Glucopyranosyl cyanide 36 is a somewhat better inhibitor than anhydro-aldonamide 5, while tetrazole 39 and amidoxime 42 are inactive. Benzimidazole 41 binds stronger than benzothiazole 40, and this can be attributed to the H-bond between the NH of the heterocycle and His377 which is necessarily absent for 40. X-ray crystallography has shown 41 also to be present at the new allosteric site and the new “benzimidazole site” has been discovered by investigating this compound (Fig. 1) [64]. From the three oxadiazole series (38, 43, 44), compounds 43 are the most active. The tendency of strengthening the inhibition by a large and properly oriented aromatic substituent can be observed in the oxadiazoles, too: compounds with a 2-naphthyl appendage (43d, 44d) are the best inhibitors. Although all three oxadiazoles could be considered as bioisosteric replacements [65,66] of NHCO, these results suggest that in the case of GP, 5-β-d-glucopyranosyl-3-substituted-1,2,4-oxadiazoles 43 are the best choice.

Fig. 8
C-β-d-glucopyranosyl heterocycles and their precursors as inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb) (K_i [μM]).

β-d-Glucopyranosyl hydroquinone derivative 46 in its O-acetyl protected form was prepared by aromatic electrophilic substitution in 1,4-dimethoxybenze using penta-O-acetyl-β-d-glucopyranose as a source of glucosylium ion. Subsequent oxidation gave protected benzoquinone 47 which was reduced to 45 [67]. The deprotected compounds were moderately inhibitory against GP (Fig. 9). Cyclopropane 48 was obtained from per-O-benzoylated nitrile 36 by EtMgBr–Ti(OiPr)₄ followed by Zemplén deprotection [68]. This compound had no inhibition of GP.

Fig. 9
β-d-Glucopyranosyl carbocycles as inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb) (K_i [μM]).

3.4 Glucopyranosylidene-spiro-heterocycles

Studies on N-acyl-β-d-glucopyranosylamines and N-acyl-N’-β-d-glucopyranosyl ureas allowed one to conclude that it is possible to make very efficient inhibitors even in the absence of a H-bond to His377, provided that interactions in the β-channel are strong enough. Combining these facts with the spirobicyclic structure of hydantoins, a novel design principle for efficient glucose-based inhibitors of GP could be set up [69,70]:

• such molecules should have a rigid spirobicyclic scaffold in which a (preferably five-membered hetero) cycle is attached to the anomeric carbon of d-glucopyranose;
• this cycle, although it may, should not necessarily be a H-bond donor towards His 377;
• a suitably oriented, large aromatic appendage must be present on this cycle to fit into the β-channel.

This principle was first verified by spiro-oxathiazolines 53, the synthesis of which followed well elaborated pathways [71] (Scheme 7): per-O-acetylated 1-thio-β-d-glucopyranose 49 was reacted with in situ generated nitrile-oxides to give hydroximothioates 50 which underwent a ring-closure upon oxidation by NBS to yield the target compounds 53 after Zemplén deprotection. Synthesis of the analogous spiro-oxadiazoline 54 was also attempted. To this end, glucosyl azide 11 was transformed in a Staudinger type reaction into N-β-d-glucopyranosyl amidoxime 51. Oxidative treatment of 51 gave oxadiazole 52 probably via 54. The driving force for the tautomeric ring opening must be the aromatization of the heterocycle.

A series of glucopyranosylidene-spiro-isoxazolines 58 was prepared by 1,3-dipolar cycloaddition of nitrile-oxides to exo-glycals 57 (Scheme 8) [62]. The exomethylene sugars were made by Julia olefination of per-O-benzylated or -silylated lactone 55. Protecting group exchange to get the per-O-acetylated 57 was necessary because upon hydrogenolytic debenzylation of 58, the isoxazoline ring also opened up due to a cleavage of the N–O bond. O-deacetylation of 58 could be achieved by the Zemplén protocol. Another way to 57 was reported by transforming per-O-acylated nitriles 36 to 2,6-anhydro-aldose tosylhydrazones followed by a Bamford-Stevens type carbene generation to yield the target exo-glycals [72,73].

Enzyme kinetic investigation of these spirocycles (Fig. 10) indicated low micromolar inhibition of GP by the phenyl substituted derivatives 53a and 58a. Substitution in the para-position of the aromatic ring gave somewhat better inhibitors (53c, 58b,c). The 2-naphthyl derivatives (53d, 58d) were nanomolar inhibitors, thereby fully validating the design principles.

Fig. 10
Inhibition of rabbit muscle glycogen phosphorylase b (RMGPb) (K_i [μM]) by glucopyranosylidene-spiro-heterocycles [74].

3.5 Miscellaneous compounds

Several O-, S-, and N-glucosides (Fig. 11, 59-63) of β-d-gluco-hept-2-ulopyranosonamide were prepared by nucleophilic substitutions of the corresponding glycosyl bromide [75]. These compounds can be regarded as anomerically extended variants of amide 6 for which a β-anomeric carbamate moiety (7) significantly improved the inhibitory efficiency. On the other hand, the new substitution patterns of 59-63 weakened the inhibition.

Fig. 11
Inhibition of rabbit muscle glycogen phosphorylase b (RMGPb) by various monosaccharide derivatives [78].

Sulfonamide 64 prepared recently by two different methods [76,77] had no inhibition against RMGPb.

Very recently, multivalent molecules have been designed and proposed for inhibition of GP [79]. Compound 65 (Fig. 12) was prepared by acylation of amidoxime 42 with trimesic acid chloride. To get compound 67 containing a spacer, 42 was acylated with 4-pentynoic acid followed by CuAAC with 1,3,5-tris(azidomethyl)benzene. These compounds have three glucose units, each potentially capable to bind to an active site of GP. It was found that the homotrivalent derivatives 65 and 67 had slightly better inhibitory activity than the corresponding monovalent compounds 44b and 66, respectively. Homobivalent compounds 68 were made by CuAAC from N-ω-azidoalkanoyl-β-d-glucopyranosylamines and 1,7-octadiyne, but had no effect on the enzyme [80].

Fig. 12
Probing multivalency for the inhibition of rabbit muscle glycogen phosphorylase (RMGP).

Potentially heterobivalent compounds were designed by tethering pentacyclic triterpenes and d-glucose derivatives [80]: C-28 propargyl esters of oleanolic, ursolic, or maslinic acids were coupled by CuAAC with β-d-glucopyranosyl azide and N-ω-azidoalkanoyl-β-d-glucopyranosylamines to give compounds 69 and 70, respectively. Derivatives with both per-O-acetylated and unprotected sugar parts were tested against GP and the best inhibitors are shown in Fig. 12. Micromolar inhibitors could be identified among both protected and unprotected glucose derivatives, and also the triterpene part and, in some cases, the linker length had a bearing on the efficiency of the compounds.

Oleanolic acid and d-glucose were also conjugated via C-6 ethers and glucuronic esters in several ways [81]. Most efficient compounds are 71b and 72a (Fig. 13) interestingly with an unprotected and a protected sugar unit, respectively. Based on molecular docking, 71b was proposed to bind at the allosteric site of GP. Per-O-benzylated precursor sugars 73 and 74 containing a propargyl group also exhibited inhibition of GP, the latter in the low micromolar range.

Fig. 13
Triterpene–glucose conjugates and protected monosaccharide derivatives [81] as inhibitors of rabbit muscle glycogen phosphorylase a (RMGPa) (IC₅₀ [μM]).

4 Conclusion

Extensive synthetic efforts supported by crystallographic studies on enzyme–inhibitor complexes have resulted in several new types of glucose analogue inhibitors of GP. Among them, N-acyl-N’-β-d-glucopyranosyl ureas, glucopyranosylidene-spiro-oxathiazolines and -isoxazolines represent novel scaffolds which, in the presence of suitable substituents, exhibit nanomolar efficiency. Further increase in the binding strength of glucose analogues may be expected from a better exploitation of interactions of the molecules in the β-channel of the enzyme. This will need a strong collaboration between synthetic and computational chemists, as well as crystallographers and biochemists. Nevertheless, due to the extremely high flexibility of the catalytic site of GP, synthesis and enzyme kinetic study of a large number of compounds will be inevitable.

5 Note added in proof

While this manuscript was under review, an interesting paper appeared on enzyme kinetic and crystallographic investigations of a series of 3-deoxy-3-fluoro-β-d-glucopyranosyl pyrimidine derivatives [82].

Acknowledgement

This work was supported by the Hungarian Scientific Research Fund (OTKA CK 77712) and an ongoing bilateral project of the Hungarian Academy of Sciences and Centre national de la recherche scientifique (PICS 4576). Sincere thanks are due to coworkers in the author's laboratory (V. Nagy, M. Tóth, K. Czifrák, Zs. Hadady, N. Felföldi, E. Berzsényi, É. Bokor, B. Kónya, S. Kun, L. Kóder, C. Hüse, K. Telepó) participating in the syntheses of the compounds, as well as P. Gergely and T. Docsa (Debrecen) for the kinetic studies. Cooperations with J.-P. Praly and S. Vidal (Lyon), H.-B. Sun (Nanjing), D. Postel (Amiens) in the field of organic synthesis, N.-G. Oikonomakos and E.-D. Chrysina (Athens, protein crystallography, enzyme kinetics), I. Tvaroška (Bratislava, computational chemistry) continuously gave new impetus and ideas for the work. These collaborations were supported by the Hungarian Academy of Sciences, the National Office for Research and Technology and the relevant funding organizations of the partner countries.

¹ Passed away on Aug 31, 2008.

Fig. 1A schematic diagram of the muscle GPb dimeric molecule viewed down the molecular dyad. The positions are shown for the catalytic, allosteric, glycogen storage, the caffeine, the indole site, and the novel binding site for benzimidazole. The catalytic site, marked by 2-β-d-glucopyranosyl benzimidazole, is buried at the centre of the subunit and is accessible to the bulk solvent through a 15 Å-long channel. Binding of the competitive inhibitor benzimidazole promotes the less active T state through stabilization of the closed position of the 280 s loop (shown in white). The allosteric site, which binds the activator AMP (indicated in the figure), is situated at the subunit–subunit interface some 30 Å from the catalytic site. The inhibitor site or caffeine binding site, which binds purine compounds, such as caffeine and flavopiridol (indicated), is located on the surface of the enzyme some 12 Å from the catalytic site and, in the T state, obstructs the entrance to the catalytic site tunnel. The glycogen storage site (with bound maltopentaose) is on the surface of the molecule some 30 Å from the catalytic site, 40 Å from the allosteric site and 50 Å from the new allosteric inhibitor site. The new allosteric or indole binding site, located inside the central cavity, formed an association of the two subunits, bound indole-2 carboxamide analogues, N-benzoyl-N’-β-d-glucopyranosyl urea, and benzimidazole (indicated). The novel binding site with bound benzimidazole, also located on the surface of the molecule, is some 31 Å from the catalytic site, 32 Å from the allosteric site, and 32 Å from the indole site (figure by courtesy of N.-G. Oikonomakos and E.-D. Chrysina).

² The β-channel or β-pocket is an empty space next to the catalytic site of GP in the direction of the β-anomeric substituent of bound d-glucose surrounded by amino acid side chains of mixed character.

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Wendy A. Loughlin; Ian D. Jenkins; N. David Karis; Peter C. Healy Discovery of new nanomolar inhibitors of GPa: Extension of 2-oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors, European Journal of Medicinal Chemistry, Volume 127 (2017), p. 341 | DOI:10.1016/j.ejmech.2016.12.049
Éva Bokor; Efthimios Kyriakis; Theodora G.A. Solovou; Csenge Koppány; Anastassia L. Kantsadi; Katalin E. Szabó; Andrea Szakács; George A. Stravodimos; Tibor Docsa; Vassiliki T. Skamnaki; Spyros E. Zographos; Pál Gergely; Demetres D. Leonidas; László Somsák Nanomolar Inhibitors of Glycogen Phosphorylase Based on β-d-Glucosaminyl Heterocycles: A Combined Synthetic, Enzyme Kinetic, and Protein Crystallography Study, Journal of Medicinal Chemistry, Volume 60 (2017) no. 22, p. 9251 | DOI:10.1021/acs.jmedchem.7b01056
Anastassia L. Kantsadi; George A. Stravodimos; Efthimios Kyriakis; Demetra S.M. Chatzileontiadou; Theodora G.A. Solovou; Sándor Kun; Éva Bokor; László Somsák; Demetres D. Leonidas van der Waals interactions govern C-β-d-glucopyranosyl triazoles’ nM inhibitory potency in human liver glycogen phosphorylase, Journal of Structural Biology, Volume 199 (2017) no. 1, p. 57 | DOI:10.1016/j.jsb.2017.05.001
Shadia A. Galal; Muhammad Khattab; Fotini Andreadaki; Evangelia D. Chrysina; Jean-Pierre Praly; Fatma A.F. Ragab; Hoda I. El Diwani Synthesis of (benzimidazol-2-yl)aniline derivatives as glycogen phosphorylase inhibitors, Bioorganic Medicinal Chemistry, Volume 24 (2016) no. 21, p. 5423 | DOI:10.1016/j.bmc.2016.08.069
Éva Bokor; Zsolt Széles; Tibor Docsa; Pál Gergely; László Somsák C-Glucopyranosyl-1,2,4-triazol-5-ones: synthesis and inhibition of glycogen phosphorylase, Carbohydrate Research, Volume 429 (2016), p. 128 | DOI:10.1016/j.carres.2015.12.005
David Goyard; Bálint Kónya; Aikaterini S. Chajistamatiou; Evangelia D. Chrysina; Jérémy Leroy; Sophie Balzarin; Michel Tournier; Didier Tousch; Pierre Petit; Cédric Duret; Patrick Maurel; László Somsák; Tibor Docsa; Pál Gergely; Jean-Pierre Praly; Jacqueline Azay-Milhau; Sébastien Vidal Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition, European Journal of Medicinal Chemistry, Volume 108 (2016), p. 444 | DOI:10.1016/j.ejmech.2015.12.004
Wendy A. Loughlin; Ian D. Jenkins; N. David Karis; Stephanie S. Schweiker; Peter C. Healy 2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study, European Journal of Medicinal Chemistry, Volume 111 (2016), p. 1 | DOI:10.1016/j.ejmech.2016.01.031
Anastassia L. Kantsadi; Éva Bokor; Sándor Kun; George A. Stravodimos; Demetra S.M. Chatzileontiadou; Demetres D. Leonidas; Éva Juhász-Tóth; Andrea Szakács; Gyula Batta; Tibor Docsa; Pál Gergely; László Somsák Synthetic, enzyme kinetic, and protein crystallographic studies of C -β- d -glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase, European Journal of Medicinal Chemistry, Volume 123 (2016), p. 737 | DOI:10.1016/j.ejmech.2016.06.049
Luz M. Rosado; Terence J. Meyerhoefer; Saqib M. Bett; Saba. Ilyas; Lubabalo. Bululu; Carla A. Martin; Troy W. Joseph; Michael De Castro Direct Coupling of Amides and Urea to Glycosyl Halides Using Silver Triflate, European Journal of Organic Chemistry, Volume 2016 (2016) no. 16, p. 2778 | DOI:10.1002/ejoc.201600350
Marion Donnier-Maréchal; Sébastien Vidal Glycogen phosphorylase inhibitors: a patent review (2013 - 2015), Expert Opinion on Therapeutic Patents, Volume 26 (2016) no. 2, p. 199 | DOI:10.1517/13543776.2016.1131268
S. Mirabella; F. Cardona; A. Goti From glycals to aminosugars: a challenging test for new stereoselective aminohydroxylation and related methodologies, Organic Biomolecular Chemistry, Volume 14 (2016) no. 23, p. 5186 | DOI:10.1039/c6ob00649c
A. A. Spasov; N. I. Chepljaeva; E. S. Vorob’ev Glycogen phosphorylase inhibitors in the regulation of carbohydrate metabolism in type 2 diabetes, Russian Journal of Bioorganic Chemistry, Volume 42 (2016) no. 2, p. 133 | DOI:10.1134/s1068162016020138
Mária Petrušová; Hana Smrtičová; Božena Pribulová; Silvia Vlčková; Iveta Uhliariková; Tibor Docsa; László Somsák; Ladislav Petruš One pot InCl3-catalyzed synthesis of 1-glycosylmethyl-1H-imidazoles, Tetrahedron, Volume 72 (2016) no. 17, p. 2116 | DOI:10.1016/j.tet.2016.03.010
Éva Bokor; Sándor Kun; Tibor Docsa; Pál Gergely; László Somsák 4(5)-Aryl-2-C-glucopyranosyl-imidazoles as New Nanomolar Glucose Analogue Inhibitors of Glycogen Phosphorylase, ACS Medicinal Chemistry Letters, Volume 6 (2015) no. 12, p. 1215 | DOI:10.1021/acsmedchemlett.5b00361
Marion Donnier-Maréchal; David Goyard; Vincent Folliard; Tibor Docsa; Pal Gergely; Jean-Pierre Praly; Sébastien Vidal 3-Glucosylated 5-amino-1,2,4-oxadiazoles: synthesis and evaluation as glycogen phosphorylase inhibitors, Beilstein Journal of Organic Chemistry, Volume 11 (2015), p. 499 | DOI:10.3762/bjoc.11.56
David Goyard; Tibor Docsa; Pál Gergely; Jean-Pierre Praly; Sébastien Vidal Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles and evaluation as glycogen phosphorylase inhibitors, Carbohydrate Research, Volume 402 (2015), p. 245 | DOI:10.1016/j.carres.2014.10.009
András Páhi; Katalin Czifrák; Katalin E. Kövér; László Somsák Anomeric spirocycles by solvent incorporation: reactions of O-peracylated (glyculopyranose and glyculopyranosyl bromide)onamide derivatives with ketones, Carbohydrate Research, Volume 403 (2015), p. 192 | DOI:10.1016/j.carres.2014.04.003
Éva Bokor; Eszter Szennyes; Tibor Csupász; Nóra Tóth; Tibor Docsa; Pál Gergely; László Somsák C-(2-Deoxy-d-arabino-hex-1-enopyranosyl)-oxadiazoles: synthesis of possible isomers and their evaluation as glycogen phosphorylase inhibitors, Carbohydrate Research, Volume 412 (2015), p. 71 | DOI:10.1016/j.carres.2015.04.016
Terence J. Meyerhoefer; Sonia Kershaw; Nadia Caliendo; Sumeia Eltayeb; Emi Hanawa‐Romero; Polina Bykovskaya; Victor Huang; Cecilia H. Marzabadi; Michael De Castro A Practical Synthesis of Various 2‐Deoxy‐N‐glycosides by Using D‐Glucal, European Journal of Organic Chemistry, Volume 2015 (2015) no. 11, p. 2457 | DOI:10.1002/ejoc.201500001
Efthimios Kyriakis; George A. Stravodimos; Anastassia L. Kantsadi; Demetra S.M. Chatzileontiadou; Vassiliki T. Skamnaki; Demetres D. Leonidas Natural flavonoids as antidiabetic agents. The binding of gallic and ellagic acids to glycogen phosphorylase b, FEBS Letters, Volume 589 (2015) no. 15, p. 1787 | DOI:10.1016/j.febslet.2015.05.013
Jaida Begum; Gergely Varga; Tibor Docsa; Pál Gergely; Joseph M. Hayes; László Juhász; László Somsák Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-d-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors, MedChemComm, Volume 6 (2015) no. 1, p. 80 | DOI:10.1039/c4md00335g
Anup Kumar Misra; Éva Bokor; Sándor Kun; Evelin Bolyog-Nagy; Ágnes Kathó; Ferenc Joó; László Somsák Chemoselective hydration of glycosyl cyanides to C-glycosyl formamides using ruthenium complexes in aqueous media, Tetrahedron Letters, Volume 56 (2015) no. 44, p. 5995 | DOI:10.1016/j.tetlet.2015.09.040
Katalin Czifrák; András Páhi; Szabina Deák; Attila Kiss-Szikszai; Katalin E. Kövér; Tibor Docsa; Pál Gergely; Kyra-Melinda Alexacou; Maria Papakonstantinou; Demetres D. Leonidas; Spyros E. Zographos; Evangelia D. Chrysina; László Somsák Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: Synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods, Bioorganic Medicinal Chemistry, Volume 22 (2014) no. 15, p. 4028 | DOI:10.1016/j.bmc.2014.05.076
Vanessa Parmenopoulou; Anastassia L. Kantsadi; Vicky G. Tsirkone; Demetra S.M. Chatzileontiadou; Stella Manta; Spyros E. Zographos; Christina Molfeta; Georgios Archontis; Loranne Agius; Joseph M. Hayes; Demetres D. Leonidas; Dimitri Komiotis Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines, Bioorganic Medicinal Chemistry, Volume 22 (2014) no. 17, p. 4810 | DOI:10.1016/j.bmc.2014.06.058
László Somsák; Éva Bokor; Beáta Czibere; Katalin Czifrák; Csenge Koppány; László Kulcsár; Sándor Kun; Enikő Szilágyi; Marietta Tóth; Tibor Docsa; Pál Gergely Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as potential inhibitors of glycogen phosphorylase, Carbohydrate Research, Volume 399 (2014), p. 38 | DOI:10.1016/j.carres.2014.05.020
Sándor Kun; Éva Bokor; Gergely Varga; Béla Szőcs; András Páhi; Katalin Czifrák; Marietta Tóth; László Juhász; Tibor Docsa; Pál Gergely; László Somsák New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase, European Journal of Medicinal Chemistry, Volume 76 (2014), p. 567 | DOI:10.1016/j.ejmech.2014.02.041
Anastassia L. Kantsadi; Anna Apostolou; Stavroula Theofanous; George A. Stravodimos; Efthimios Kyriakis; Vyron A. Gorgogietas; Demetra S.M. Chatzileontiadou; Kalliope Pegiou; Vassiliki T. Skamnaki; Dimitrios Stagos; Dimitrios Kouretas; Anna-Maria G. Psarra; Serkos A. Haroutounian; Demetres D. Leonidas Biochemical and biological assessment of the inhibitory potency of extracts from vinification byproducts of Vitis vinifera extracts against glycogen phosphorylase, Food and Chemical Toxicology, Volume 67 (2014), p. 35 | DOI:10.1016/j.fct.2014.01.055
Joseph M. Hayes; Anastassia L. Kantsadi; Demetres D. Leonidas Natural products and their derivatives as inhibitors of glycogen phosphorylase: potential treatment for type 2 diabetes, Phytochemistry Reviews, Volume 13 (2014) no. 2, p. 471 | DOI:10.1007/s11101-014-9360-6
Éva Bokor; Tibor Docsa; Pál Gergely; László Somsák C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase, ACS Medicinal Chemistry Letters, Volume 4 (2013) no. 7, p. 612 | DOI:10.1021/ml4001529
Mária Polyák; Gergely Varga; Bence Szilágyi; László Juhász; Tibor Docsa; Pál Gergely; Jaida Begum; Joseph M. Hayes; László Somsák Synthesis, enzyme kinetics and computational evaluation of N-(β-d-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors, Bioorganic Medicinal Chemistry, Volume 21 (2013) no. 18, p. 5738 | DOI:10.1016/j.bmc.2013.07.024
Māris Turks; Vitalijs Rodins; Evija Rolava; Pāvels Ostrovskis; Sergey Belyakov A practical access to glucose- and allose-based (5+5) 3-spiropseudonucleosides from a common intermediate, Carbohydrate Research, Volume 375 (2013), p. 5 | DOI:10.1016/j.carres.2013.04.008
Éva Bokor; Enikő Szilágyi; Tibor Docsa; Pál Gergely; László Somsák Synthesis of substituted 2-(β-d-glucopyranosyl)-benzimidazoles and their evaluation as inhibitors of glycogen phosphorylase, Carbohydrate Research, Volume 381 (2013), p. 179 | DOI:10.1016/j.carres.2013.01.011
Béla Szőcs; Marietta Tóth; Tibor Docsa; Pál Gergely; László Somsák Synthesis of 2-(β-d-glucopyranosyl)-5-(substituted-amino)-1,3,4-oxa- and -thiadiazoles for the inhibition of glycogen phosphorylase, Carbohydrate Research, Volume 381 (2013), p. 187 | DOI:10.1016/j.carres.2013.03.009
Marietta Tóth; Béla Szőcs; Tímea Kaszás; Tibor Docsa; Pál Gergely; László Somsák Synthesis of 2-(β-d-glucopyranosylamino)-5-substituted-1,3,4-oxadiazoles for inhibition of glycogen phosphorylase, Carbohydrate Research, Volume 381 (2013), p. 196 | DOI:10.1016/j.carres.2013.04.025
Nicolas Gaboriaud-Kolar; Alexios-Leandros Skaltsounis Glycogen phosphorylase inhibitors: a patent review (2008 – 2012), Expert Opinion on Therapeutic Patents, Volume 23 (2013) no. 8, p. 1017 | DOI:10.1517/13543776.2013.794790
Lilla Nagy; Tibor Docsa; Magdolna Szántó; Attila Brunyánszki; Csaba Hegedűs; Judit Márton; Bálint Kónya; László Virág; László Somsák; Pál Gergely; Péter Bai; Laszlo Buday Glycogen Phosphorylase Inhibitor N-(3,5-Dimethyl-Benzoyl)-N’-(β-D-Glucopyranosyl)Urea Improves Glucose Tolerance under Normoglycemic and Diabetic Conditions and Rearranges Hepatic Metabolism, PLoS ONE, Volume 8 (2013) no. 7, p. e69420 | DOI:10.1371/journal.pone.0069420
Éva Bokor; Attila Fekete; Gergely Varga; Béla Szőcs; Katalin Czifrák; István Komáromi; László Somsák C-(β-d-Glucopyranosyl)formamidrazones, formic acid hydrazides and their transformations into 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles: a synthetic and computational study, Tetrahedron, Volume 69 (2013) no. 48, p. 10391 | DOI:10.1016/j.tet.2013.09.099
Jevgeņija Lugiņina; Vitālijs Rjabovs; Sergey Belyakov; Māris Turks A concise synthesis of sugar isoxazole conjugates, Tetrahedron Letters, Volume 54 (2013) no. 39, p. 5328 | DOI:10.1016/j.tetlet.2013.07.103
Sophie Feuillastre; Aikaterini S. Chajistamatiou; Constantinos Potamitis; Maria Zervou; Panagiotis Zoumpoulakis; Evangelia D. Chrysina; Jean-Pierre Praly; Sébastien Vidal C-Glucosylated malonitrile as a key intermediate towards carbohydrate-based glycogen phosphorylase inhibitors, Bioorganic Medicinal Chemistry, Volume 20 (2012) no. 18, p. 5592 | DOI:10.1016/j.bmc.2012.07.033
Veronika Nagy; Nóra Felföldi; Bálint Kónya; Jean-Pierre Praly; Tibor Docsa; Pál Gergely; Evangelia D. Chrysina; Costas Tiraidis; Magda N. Kosmopoulou; Kyra-Melinda Alexacou; Maria Konstantakaki; Demetres D. Leonidas; Spyros E. Zographos; Nikos G. Oikonomakos; Stanislav Kozmon; Igor Tvaroška; László Somsák N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods, Bioorganic Medicinal Chemistry, Volume 20 (2012) no. 5, p. 1801 | DOI:10.1016/j.bmc.2011.12.059
Bálint Kónya; Tibor Docsa; Pál Gergely; László Somsák Synthesis of heterocyclic N-(β-d-glucopyranosyl)carboxamides for inhibition of glycogen phosphorylase, Carbohydrate Research, Volume 351 (2012), p. 56 | DOI:10.1016/j.carres.2012.01.020
David Goyard; Marc Baron; Paraskevi V. Skourti; Aikaterini S. Chajistamatiou; Tibor Docsa; Pál Gergely; Evangelia D. Chrysina; Jean-Pierre Praly; Sébastien Vidal Synthesis of 1,2,3-triazoles from xylosyl and 5-thioxylosyl azides: evaluation of the xylose scaffold for the design of potential glycogen phosphorylase inhibitors, Carbohydrate Research, Volume 364 (2012), p. 28 | DOI:10.1016/j.carres.2012.09.020
Anastasia L. Kantsadi; Joseph M. Hayes; Stella Manta; Vicky T. Skamnaki; Christos Kiritsis; Anna‐Maria G. Psarra; Zissis Koutsogiannis; Athina Dimopoulou; Stavroula Theofanous; Nikolaos Nikoleousakos; Panagiotis Zoumpoulakis; Maria Kontou; George Papadopoulos; Spyros E. Zographos; Dimitris Komiotis; Demetres D. Leonidas The σ‐Hole Phenomenon of Halogen Atoms Forms the Structural Basis of the Strong Inhibitory Potency of C5 Halogen Substituted Glucopyranosyl Nucleosides towards Glycogen Phosphorylase b, ChemMedChem, Volume 7 (2012) no. 4, p. 722 | DOI:10.1002/cmdc.201100533
Stella Manta; Andromachi Xipnitou; Christos Kiritsis; Anastassia L. Kantsadi; Joseph M. Hayes; Vicky T. Skamnaki; Christos Lamprakis; Maria Kontou; Panagiotis Zoumpoulakis; Spyridon E. Zographos; Demetres D. Leonidas; Dimitri Komiotis 3′‐Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why, Chemical Biology Drug Design, Volume 79 (2012) no. 5, p. 663 | DOI:10.1111/j.1747-0285.2012.01349.x
Sándor Kun; Gergő Z. Nagy; Marietta Tóth; Laura Czecze; Albert Nguyen Van Nhien; Tibor Docsa; Pál Gergely; Maria-Despoina Charavgi; Paraskevi V. Skourti; Evangelia D. Chrysina; Tamás Patonay; László Somsák Synthesis of variously coupled conjugates of d-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase, Carbohydrate Research, Volume 346 (2011) no. 12, p. 1427 | DOI:10.1016/j.carres.2011.03.004
Laszlo Somsak ChemInform Abstract: Glucose‐Derived Inhibitors of Glycogen Phosphorylase, ChemInform, Volume 42 (2011) no. 34 | DOI:10.1002/chin.201134238

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^☆ Dedicated to Professor András Lipták on the occasion of his 75th birthday.

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