Next Article in Journal
Asymmetric Total Synthesis of Four Stereoisomers of the Sex Pheromone of the Western Corn Rootworm
Next Article in Special Issue
Potent GH20 N-Acetyl-β-d-hexosaminidase Inhibitors: N-Substituted 3-acetamido-4-amino-5-hydroxymethyl-cyclopentanediols
Previous Article in Journal
Silyl Ketene Acetals/B(C6F5)3 Lewis Pair-Catalyzed Living Group Transfer Polymerization of Renewable Cyclic Acrylic Monomers
Previous Article in Special Issue
Synthesis of O-Amino Sugars and Nucleosides
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 23
Issue 3
10.3390/molecules23030666
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

by
Sándor Kun
1,
Éva Bokor
1,
Ádám Sipos
2,
Tibor Docsa
2 and
László Somsák
1,*
1
Department of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, Hungary
2
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(3), 666; https://doi.org/10.3390/molecules23030666
Submission received: 27 February 2018 / Revised: 7 March 2018 / Accepted: 13 March 2018 / Published: 15 March 2018
(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)
Browse Figures
Versions Notes

Abstract

:
The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-β-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-β-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-d-glucopyranosyl-5-phenyltetrazole (IC50 600 μM). These studies extended the structure-activity relationships of β-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety.

Graphical Abstract

1. Introduction

Glycogen phosphorylase inhibitors (GPIs) attract considerable scientific interest [1,2,3] since such compounds may be applied in finding new therapies against type two diabetes [4,5,6], myocardial [7,8] and cerebral [9,10] ischemias, and tumors [11,12,13,14,15,16]. In addition to demonstrating in vivo antihyperglycemic activities [17,18,19,20,21], physiological studies with several GPIs revealed unprecedented effects on hepatic metabolism [22] and improvement of pancreatic β-cell function [23].
A large variety of compounds have been designed and synthesized for the inhibition of GP [24,25]. Among them different derivatives of d-glucose represent the largest class of inhibitors. Within glucose-derived compounds N-acyl-β-d-glucopyranosylamines (I in Table 1) [26,27,28,29] were among the first low micromolar inhibitors of rabbit muscle GP b (RMGPb), the prototype of these enzymes [30]. Based on the concept of bioisosterism [31,32,33] many sorts of N- and C-β-d-gluco-pyranosyl heterocycles, wherein the hetero-ring replaced the NHCO moiety of I as its bioisostere, were synthesized and tested against RMGPb. Thus, N-β-d-glucopyranosyl 1,2,3-triazoles II [29,34] had comparable inhibitory effects to those of amides I. Among C-β-d-glucopyranosyl derivatives three isomeric oxadiazoles III–V were studied to show that the constitution of the heterocycle had a decisive bearing on the efficiency. Thus, 1,3,4-oxadiazoles III [35,36,37] proved to be rather weak inhibitors, the 3-glucosyl-5-substituted isomers IV [38] were somewhat more efficient (especially the 2-naphthyl derivative IVc) and the 5-glucosyl-3-substituted counterparts V [37,39] showed low micromolar inhibition. C-Glucosyl 1,2,4-triazoles VI [40,41] and imidazoles VII [42,43] featuring hydrogen bond donor heterocycles were significantly more effective.
Actually, these compounds are the best glucose analogue inhibitors of GP known to date. Their efficiency, among other factors, is due to the formation of a H-bridge between the heterocycle and the His-377 main chain carbonyl group in the active site of the enzyme. 5-Glucosyltetrazole VIII [35], although capable of H-bond formation, proved inactive. It is remarkable that, besides the properties of the heterocycle, also the nature and the size of the substituent of the azole moiety had a very significant influence on the activity of the inhibitors. While methyl substituted derivatives in column a were practically inactive, a phenyl appendage (column b) made much more efficient compounds and the 2-naphthyl derivatives (column c) proved to be the strongest inhibitors. With these preliminaries in mind, in order to make the structure-activity relationship of N- and C-β-d-glucopyranosyl azole type compounds more complete, we envisaged to synthesize the “missing” counterparts of the above glucose derivatives. In this paper the syntheses and enzymatic evaluation of 4-β-d-glucopyranosyl-1-substituted-1,2,3-triazoles IX, 1-β-d-glucopyranosyl-4-substituted imidazoles X, 5-β-d-glucopyranosyl-2-substituted tetrazoles XI, and 2-β-d-glucopyranosyl-5-substituted tetrazoles XII are presented.

2. Results and Discussion

For the syntheses of C-glucosyl 1,2,3-triazoles of type IX several methods were published and this chemistry was reviewed last year [44]. Our work, summarized in Table 2, started with O-perbenzylated C-glucosyl acetylene 1 described in the literature [45]. Copper catalyzed azide-alkyne cycloaddition (CuAAC) [46] was effected from 1 either by pre-formed aryl azides with CuO(CO)C3H7(PPh3)2 as the catalyst [47] (method a) or azides obtained in situ from areneboronic acids [48,49] (method b) to give 1,2,3-triazoles 2a–c in very good yields. Removal of the O-benzyl protecting groups from 2a by usual catalytic hydrogenation (method c) gave excellent yield of 5a, however, under the same conditions 2c gave an inseparable product mixture. After O-peracetylation (method e) of the mixture the products could be separated and identified as 4c and a partially saturated derivative 4d. Since the formation of a tetrahydronaphthyl by-product under catalytic hydrogenation was observed previously with a 2-naphthyl substituted C-glucopyranosyl 1,2,4-triazole [50] hydrogenolytic deprotection of 2b was not attempted. Instead, the protecting groups were exchanged to acetate esters as reported to get O-peracetylated acetylene 3 [51]. CuAAC from 3 produced triazoles 4b and 4c in very good yields. Formation of 4b was also effected from 2b by a direct exchange of protective groups by method d [51]. Removal of the O-acetyl groups from 4b,c under Zemplén conditions (method f) gave the targeted 5b,c in excellent yields.
For the preparation of an imidazole of type X a literature method [52] was adapted. Thus, acetobromoglucose 6 was reacted with 4-phenyl-imidazole in the presence of Hg(CN)2 in acetonitrile to give 1-glucopyranosyl-4-phenyl-imidazole 7 (Scheme 1). Due to the tautomerism of imidazoles the formation of the isomeric 1-glucopyranosyl-5-phenyl-imidazole would also be possible, however, this was excluded on the basis of a HMBC measurement. Specifically, the observation of cross peaks between H-1’–C-2, H-1’‒C-5, C-1’‒H-2, and C-1’‒H-5 clearly indicated the formation of 7. O-Deacetylation of 7 by the Zemplén method gave 8 in good yield.
Next we turned to the synthesis of C-glucopyranosyl tetrazoles of type XI. While 5-(β-d-gluco-pyranosyl)tetrazoles (e.g., 9) are long known compounds ([35,49] and references cited therein), no N-substituted derivatives could be located in the literature. For the preparation of the phenyl substituted derivatives a copper catalyzed reaction [53] of 9 and benzeneboronic acid was applied (Table 3, conditions a). Although the tautomerism of the tetrazole moiety could have facilitated the formation of regioisomers, only 10a was obtained in excellent yield as it was claimed in the cited paper. By modifying a literature procedure [54], compound 10a was also prepared, albeit in lower yield, from tosylhydrazone 12 [55,56] and benzenediazonium tetrafluoroborate [57,58] (conditions c). For the methylation of 9 a method [59] applied for the synthesis of C-glycofuranosyl tetrazoles was adapted. Thus, 9 was reacted with diazomethane to give a 1:1 mixture of the regioisomeric tetrazoles 10e and 11e in very good overall yield (conditions b). Removal of the ester protecting groups by the Zemplén protocol gave the test compounds 13 and 14 in very good yields (conditions d). The regioisomers of the formed C,N-disubstituted tetrazoles could easily be identified by the 13C-NMR signal of the C-5 carbons. It is well known that the tetrazole carbon of 2,5-disubstituted derivatives (162–167 ppm) is shifted downfield by ~10 ppm in comparison to that of the 1,5-disubstituted counterparts (152–156 ppm) [60], and this is clearly visible in the obtained data shown in Table 3. In addition, for 11e 1H-1H NOEs were observed between the CH3 protons and the pyranose H-1’ and H-2’, while for 10e the NOE spectrum did not indicate proximity between the substituents of the tetrazole.
For the synthesis of N-(β-d-glucopyranosyl)-5-substituted-tetrazoles a literature protocol was applied to give 15a and 16a [61] in the reaction of acetobromoglucose 6 and 5-phenyltetrazole [62] (Table 4). From a similar transformation of 6 with 5-methyltetrazole [62] only the 2,5-disubstituted 15e could be isolated in moderate yield and the formation of the HBr elimination product 2-acetoxy-d-glucal 17 was observed in a significant amount. Protecting group removal was effected by the Zemplén method to furnish the test compounds 18 and 19 in very good yields. The regioisomeric tetrazoles 15, 18 vs. 16, 19 were identified on the basis of the C-5 chemical shifts as described above (see respective data in Table 4).
The new compounds were assayed against rabbit muscle glycogen phosphorylase b enzyme (RMGPb) as described earlier [27] and the results are collected in Table 5. The inefficiency of C-glucopyranosyl 1,2,3-triazoles 5 (entries 4–6) as compared to the micromolar inhibition of the N-glucopyranosyl counterparts II in Table 2 came as a surprise, since the size of the heterocycle and the position of the H-bond donor and acceptor sites of the ring must not have been altered by the interchange of the substituents. A comparison of the inhibitory efficiency of N-benzoyl-β-d-gluco-pyranosylamine Ib (entry 1) with its “reversed” counterpart N-phenyl-2,6-anhydro-d-glycero-d-gulo-heptonamide 20 (shown in entry 3) results in a ratio of 38–67 (~53 as an average). Multiplication of the inhibition constants of IIb (entry 2) with this average factor to predict the efficiency of 5a (entry 4) gives values of ~7900–8500 μM, a range being well beyond the concentrations investigated in this study (max 625 μM). Nevertheless, our observations may refer to a strong directionality in the amide-1,2,3-triazole bioisosterism (mostly ignored in related studies [63,64]) indicating that the proper replacement must correspond to the pairs Ib–IIb and 20–5a in entries 1–2 and 3–4, respectively.
N-Glucosylimidazole 8 (entry 7) as well as N-substituted-5-glucopyranosyltetrazoles 13 and 14 (entries 8–10) proved non-inhibitory in the investigated concentration range. From the N-glucopyranosyl-5-substituted tetrazoles 18 and 19 (entries 11–13) only the 5-phenyl derivative 18a showed very weak inhibition (entry 11). This study has corroborated that the inhibition of glycogen phosphorylase by N- and C-glucopyranosyl azole type compounds is extremely sensitive to the properties of the heterocycle.

3. Experimental

3.1. General Methods

Anhydrous solvents were prepared by standard methods. CH2Cl2, CHCl3 and EtOAc were distilled from P4O10 and stored over 4 Å molecular sieves. MeOH was distilled over Mg turnings and iodine. Acetone was dried by distillation from CaSO4. Anhydrous pyridine (VWR, Vienna, Austia) and EtOH (Molar Chemicals, Halásztelek, Hungary) were used as received. Melting points were measured on a Kofler hot stage and are uncorrected. Optical rotations were determined on a P-2000 polarimeter (Jasco, Easton, MD, USA) at room temperature. NMR spectra were recorded with DRX360 (360/90 MHz for 1H/13C) and DRX400 (400/100 MHz for 1H/13C) spectrometers (Bruker, Karlsruhe, Germany). Chemical shifts are referenced to internal Me4Si (1H) or the residual solvent signal (13C). HRMS spectra were recorded with a Bruker maXis II spectrometer with electrospray ionization technique. TLC was performed on DC Alurolle Kieselgel 60 F254 (Merck, Darmstadt, Germany), the plates were visualized by gentle heating. For column chromatography Kieselgel 60, 63–200 µm (Molar Chemicals) was used. Organic solutions were dried over anhydrous MgSO4 and concentrated in vacuo at 40–50 °C (water bath). Alkynes 1 [45] and 3 [51], tetrazole 9 [49], tosylhydrazone 12 [55,56], 5-phenyltetrazole [62], 5-methyltetrazole [62], and benzenediazonium tetrafluoroborate [57,58] were prepared according to literature procedures.

3.1.1. General Procedure 1 for the Synthesis of O-Peracetylated or O-Perbenzylated 1-aryl-4-β-d-Glucopyranosyl-1,2,3-triazoles from Azido-Arenes

To the solution of the corresponding alkyne (1 or 3) in anhydr. CH2Cl2 (0.1 mmol/mL) the azido-arene and CuO(CO)C3H7(PPh3)2 were added and the mixture was stirred at rt for the given time (20 min–5 h) while the reaction was monitored by TLC (eluent: hexane-EtOAc 4:1 for O-benzylated cmpounds, 1:1 for O-acetylated compounds). After total consumption of the alkyne the solvent was evaporated and the residue purified by column chromatography.

3.1.2. General Procedure 2 for the Synthesis of O-Peracetylated or O-Perbenzylated 1-aryl-4-β-d-Glucopyranosyl-1,2,3-triazoles from Arylboronic Acids by Using CuSO4/L-Ascorbic Acid Catalytic System

Arylboronic acid (1 equiv.) was dissolved in MeOH (5 mL/mmol), NaN3 (1.2 equiv.) and CuSO4·5H2O (0.1 equiv.) were added and the reaction mixture was stirred at r.t. After 18 h distilled water (10 mL/mmol), CH2Cl2 (10 mL/mmol), the corresponding alkyne (1 or 3, 0.3 equiv.) and L-ascorbic acid (0.5 equiv.) was added and the mixture was stirred at 50 °C (oil bath temp.). When TLC showed complete disappearance of the alkyne (eluent: hexane-EtOAc 4:1 for O-benzylated compounds, 1:1 for O-acetylated compounds) the mixture was diluted with CH2Cl2 and water. After separation of the phases the aqueous layer was washed with CH2Cl2. The combined organic phases were dried, concentrated under reduced pressure and chromatographed to yield the pure 1,2,3-triazole.

3.1.3. General Procedure 3 for Removal of the O-Acetyl Protecting Groups

An O-acyl protected compound (100 mg) was dissolved in anhydr. MeOH (5 mL), a few drops of ~1 M solution of NaOMe/MeOH was added and the mixture was left to stand at r.t. After complete conversion (TLC monitoring, CHCl3-MeOH 7:3) the reaction mixture was neutralized with Amberlyst 15 (hydrogen form). After removal of the resin by filtration, the solvent was evaporated in vacuo and the crude product was purified by column chromatography (CHCl3-MeOH 9:1).

3.1.4. General Procedure 4 for the Synthesis of O-Peracetylated N-(β-d-Glucopyranosyl)tetrazoles

Freshly flame dried K2CO3 (10 equiv., 1.68 g, 12.2 mmol), 4 Å powdered molecular sieves (500 mg), 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (6, 500 mg, 1.22 mmol) and a 5-substituted tetrazole (2 equiv., 2.44 mmol) were mixed in a round bottom flask, anhydr. acetone (15 mL) was added and the mixture was stirred and refluxed for 8 h. After removal of the solids by filtration the filtrate was concentrated under reduced pressure and chromatographed to give N-(β-d-glucopyranosyl)tetrazoles.

3.2. Characterization of the Comounds

1-Phenyl-4-(2′,3′,4′,6′-tetra-O-benzyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (2a). Prepared according to general procedure 1 from alkyne 1 (153 mg, 0.28 mmol), azidobenzene (33 mg, 0.28 mmol) and CuO(CO)C3H7(PPh3)2 (2 mg, 0.003 mmol). Reaction time: 20 min. Purified by column chromatography (eluent: hexane-EtOAc = 4:1 → 2:1 gradient) to yield 145 mg (78%) white crystals. Rf = 0.56 (hexane-EtOAc = 2:1); Mp: 160–162 °C; [α]D = −16 (c 0.53, CHCl3); 1H-NMR (CDCl3, 360 MHz) δ (ppm): 7.81 (1H, s, triazole H-5), 7.66–6.99 (25H, m, Ar), 4.98, 4.93 (2 × 1H, 2 d, J = 11.1 Hz, PhCH2), 4.88, 4.60 (2 × 1H, 2 d, J = 10.7 Hz, PhCH2), 4.69, 4.40 (2 × 1H, 2d, J = 10.9 Hz, PhCH2), 4.57, 4.52 (2 × 1H, 2d, J = 12.1 Hz, PhCH2), 4.61 (1H, d, J = 9.6 Hz, H-1’), 3.98, 3.86 (2H, 2 pseudo t, J = 9.4, 8.8 Hz, H-2’ and/or H-3’ and/or H-4’), 3.79–3.70 (3H, m, H-2’ or H-3’ or H-4’, H-6’a, H-6’b), 3.66 (1H, ddd, J = 9.4, 3.5, 2.4 Hz, H-5’); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 146.4 (C-4), 138.5–136.9 (Ar), 129.6–127.5 (Ar), 120.9 (triazole C-5), 120.4 (Ar), 86.9, 81.5, 79.4, 78.1, 74.0 (C-1’–C-5’), 75.5, 75.0, 74.7, 73.4 (4 × PhCH2), 69.0 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C42H42N3O5+ ([M + H]+): 668.3119. Found: 668.3116.
1-(Naphthalen-2-yl)-4-(2′,3′,4′,6′-tetra-O-benzyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (2b). Prepared according to general procedure 2 from 2-naphthylboronic acid (52 mg, 0.30 mmol), CuSO4·5H2O (8 mg, 0.03 mmol), NaN3 (24 mg, 0.36 mmol), L-ascorbic acid (27 mg, 0.15 mmol) and alkyne 2 (50 mg, 0.09 mmol). Reaction time: 1.5 h. Purified by column chromaography (EtOAc-hexane 1:7 → 1:6 gradient) to yield 52 mg (79%) white crystalline product. Rf = 0.23 (hexane-EtOAc = 4:1); Op: 140–141 °C; [α]D = −19 (c 0.52, CHCl3); 1H-NMR (CDCl3, 360 MHz) δ (ppm): 8.07–7.81 (5H, m, Ar), 7.92 (1H, s, triazole H-5), 7.59–7.53 (2H, m, Ar), 7.38–7.01 (20H, m, Ar), 4.99, 4.95 (2 × 1H, 2 d, J = 11.1 Hz, PhCH2), 4.88, 4.61 (2 × 1H, 2 d, J = 10.7 Hz, PhCH2), 4.71, 4.44 (2 × 1H, 2 d, J = 10.9 Hz, PhCH2), 4.59, 4.53 (2 × 1H, 2 d, J = 12.2 Hz, PhCH2), 4.65 (1H, d, J = 9.7 Hz, H-1’), 3.99, 3.88 (2H, 2 pseudo t, J = 9.4, 8.8 Hz, H-2’ and/or H-3’ and/or H-4’), 3.81–3.72 (3H, m, H-2’ or H-3’ or H-4’, H-6’a, H-6’b), 3.68 (1H, ddd, J = 9.4, 3.5, 1.3 Hz, H-5’); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 146.4 (triazole C-4), 138.5–132.8 (Ar), 129.9–126.9 (Ar), 121.1 (triazole C-5), 118.9, 118.4 (Ar), 87.0, 81.4, 79.5, 78.2, 74.1 (C-1’–C-5’), 75.6, 75.1, 74.7, 73.4 (4 × PhCH2), 69.1 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C46H44N3O5+ ([M + H]+): 718.3275. Found: 718.3273.
1-(Naphthalen-1-yl)-4-(2’,3’,4’,6’-tetra-O-benzyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (2c). Prepared according to General procedure 1 from alkyne 2 (150 mg, 0.27 mmol), 1-azidonaphthalene (46 mg, 0.27 mmol) and CuO(CO)C3H7(PPh3)2 (2 mg, 0.003 mmol). Reaction time: 4 h. Purified by column chromatography (eluent: hexane-EtOAc = 4:1) to yield 167 mg (85%) brown amorphous solid. Rf = 0.13 (EtOAc-hexane = 1:4); [α]D = −2 (c 0.53, CHCl3); 1H-NMR (CDCl3, 360 MHz) δ (ppm): 7.92–7.89 (2H, m, Ar), 7.86 (1H, s, triazole H-5), 7.55-7.07 (25H, m, Ar), 4.99, 4.95 (2 × 1H, 2 d, J = 11.1 Hz, PhCH2), 4.89, 4.61 (2 × 1H, 2 d, J = 10.7 Hz, PhCH2), 4.79, 4.49 (2 × 1H, 2 d, J = 10.7 Hz, PhCH2), 4.59, 4.54 (2 × 1H, 2 d, J = 12.2 Hz, PhCH2), 4.70 (1H, d, J = 9.8 Hz, H-1’), 4.16, 3.90 (2H, 2 pseudo t, J = 9.4, 8.9 Hz, H-2’ and/or H-3’ and/or H-4’), 3.83–3.70 (4H, m, H-2’ or H-3’ or H-4’, H-5’, H-6’a, H-6’b); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 145.2 (triazole C-4), 138.4–122.1 (Ar), 125.7 (triazole C-5), 86.4, 81.6, 79.4, 78.1, 73.8 (C-1’–C-5’), 75.5, 75.0, 74.9, 73.3 (4 × PhCH2), 69.0 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C46H44N3O5+ ([M + H]+): 718.3275. Found: 718.3270.
1-(Naphthalen-2-yl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (4b). Method A: To the solution of 2b (106 mg, 0.15 mmol) in anhydr. CH2Cl2 (4 mL) and acetic anhydride (4 mL) trimethylsilyl trifluoromethanesulfonate (214 μL, 1.18 mmol) was added at −40 °C. The mixture was slowly allowed to warm up and stirred at r.t. for 24 h, then at 50 °C for 24 h. Saturated aqueous NaHCO3 (2 mL) was added to the reaction mixture at 0 °C and the mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic phases were dried, concentrated and purified by column chromatography (hexane-EtOAc 2:1) to yield 53 mg (68%) product.
Method B: Prepared according to general procedure 2 from 2-naphthylboronic acid (80 mg, 0.47 mmol), CuSO4·5H2O (12 mg, 0.05 mmol), NaN3 (36 mg, 0.56 mmol), L-ascorbic acid (41 mg, 0.23 mmol) and 3 (50 mg, 0.14 mmol). Reaction time: 1.5 h. Purified by column chromatography (eluent: hexane-CH2Cl2-EtOAc 5:4:1) to yield 59 mg (80%) product.
White crystals. Rf = 0.31 (hexane-EtOAc 1:1); Mp: 225–227 °C; [α]D = −71 (c 0.54, CHCl3); 1H-NMR (CDCl3, 360 MHz) δ (ppm): 8.19 (1H, s, triazole H-5), 8.16 (1H, s, Ar), 8.01–7.85 (4H, m, Ar), 7.59–7.57 (2H, m, Ar), 5.45–5.38 (2H, m, H-2’ and/or H-3’ and/or H-4’), 5.23 (1H, pseudo t, J = 9.7, 9.5 Hz, H-2’ or H-3’ or H-4’), 4.90 (1H, d, J = 9.6 Hz, H-1’), 4.33 (1H, dd, J = 12.4, 4.9 Hz, H-6’a), 4.17 (1H, dd, J = 12.4, 1.4 Hz, H-6’b), 3.94 (1H, ddd, J = 9.9, 4.7, 1.6 Hz, H-5’), 2.09, 2.08, 2.04, 1.96 (4 × 3H, 4 s, CH3CO); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 170.6, 170.1, 169.6, 169.5 (CH3CO), 144.9 (C-4), 134.1, 133.1, 132.9, 129.9, 128.2, 127.9, 127.5, 127.0, 118.8 (Ar), 120.6 (C-5), 76.3, 73.9, 73.2, 71.2, 68.4 (C-1’–C-5’), 62.1 (C-6’), 20.7 (CH3CO), 20.6 (3 × CH3CO). ESI-HRMS positive mode (m/z): calcd. for C26H27N3NaO9+ ([M + Na]+ ): 548.1640. Found: 548.1636.
1-(Naphthalen-1-yl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (4c) and 1-(5,6,7,8-tetrahydronaphthalen-1-yl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (4d)
Method A: To the solution of 1-(naphthalen-1-yl)-4-(2’,3’,4’,6’-tetra-O-benzyl-β-d-glucopyranosyl)-1H-1,2,3-triazole (2c, 159 mg, 0.22 mmol) in anhydr. EtOAc (5 mL) Pd(C) (10 wt. %, 16 mg) was added and the mixture was stirred in H2 atmosphere (1 bar) at 40 °C for 5 h. The catalyst was removed by filtration and the filtrate was concentrated and the residue was dissolved in pyridine (2.5 mL) and acetic anhydride (1 mL) and kept at 90 °C for 3 h. After evaporation the products were separated by column chromatography (hexane-EtOAc 2:1) to yield 4c (34 mg, 29%) and 4d (3 mg, 3%).
Method B: Compound 4c was prepared according to general procedure 1 from alkyne 3 (50 mg, 0.14 mmol), 1-azidonaphthalene (15 mg, 0.14 mmol) and CuO(CO)C3H7(PPh3)2 (0.6 mg, 0.001 mmol). Reaction time: 5 h. Isolation by column chromatography (hexane-EtOAc 2:1 → 1:1 gradient) yielded 4c (67 mg, 91%).
4c: white crystals. Rf = 0.30 (hexane-EtOAc = 1:1); Mp: 195–197 °C; [α]D = −29 (c 0.5, CHCl3); 1H-NMR (CDCl3, 360 MHz) δ (ppm): 8.00 (1H, s, triazole H-5), 8.04–7.97 (2H, m, Ar), 7.60–7.55 (5H, m, Ar), 5.47–5.38 (2H, m, H-2’ and/or H-3’ and/or H-4’), 5.23 (1H, pseudo t, J = 9.7, 9.3 Hz, H-2’ or H-3’ or H-4’), 4.94 (1H, d, J = 9.4 Hz, H-1’), 4.32 (1H, dd, J = 12.5, 4.8 Hz, H-6’a), 4.18 (1H, dd, J = 12.5, 1.8 Hz, H-6’b), 3.95 (1H, ddd, J = 9.9, 4.7, 1.8 Hz, H-5’), 2.09, 2.07, 2.04, 1.99 (4 × 3H, 4 s, CH3CO); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 170.6, 170.1, 169.6, 169.5 (CH3CO), 144.1 (triazole C-4), 134.1, 133.4, 130.5, 128.4, 128.2, 127.9, 127.0, 124.9, 123.6, 122.1 (Ar), 125.0 (triazole C-5), 76.3, 73.9, 73.4, 71.4, 68.4 (C-1’–C-5’), 62.1 (C-6’), 20.7 (CH3CO), 20.6 (3 × CH3CO). ESI-HRMS positive mode (m/z): calcd. for C26H27N3NaO9+ ([M + Na]+): 548.1640. Found: 548.1639.
4d: colouress syrup. Rf = 0.40 (hexane-EtOAc 1:1); [α]D = −49 (c 0.15, CHCl3); 1H-NMR (CDCl3, 360 MHz) δ (ppm): 7.75 (1H, s, H-5), 7.26–7.22 (2H, m, Ar), 7.12 (1H, m, Ar), 5.42–5.33 (2H, m, H-2’ and/or H-3’ and/or H-4’), 5.21 (1H, pseudo t, J = 9.6, 9.4 Hz, H-2’ or H-3’ or H-4’), 4.86 (1H, d, J = 9.4 Hz, H-1’), 4.30 (1H, dd, J = 12.4, 4.8 Hz, H-6’a), 4.16 (1H, dd, J = 12.5, <1 Hz, H-6’b), 3.92 (1H, ddd, J = 10.0, 4.6, 1.9 Hz, H-5’), 2.86 (2H, pseudo t, J = 5.8, 6.2 Hz, tetralin H-5’’), 2.40 (2H, pseudo t, J = 5.6, 6.2 Hz, tetralin H-8’’), 2.08, 2.07, 2.02, 1.93 (4 × 3H, 4 × s, CH3CO), 1.82–1.70 (4H, m, tetralin H-6’’, H-7’’). ESI-HRMS positive mode (m/z): calcd. for C26H31N3NaO9+ ([M + Na]+): 552.1953. Found: 552.1953.
1-Phenyl-4-(β-d-glucopyranosyl)-1H-1,2,3-triazole (5a). Triazole 2a (137 mg, 0.21 mmol) was dissolved in a 1:1 mixture of anhydr. EtOH and EtOAc (4 mL), Pd(C) (10 wt. %, 13 mg) was added and the mixture was stirred in H2 atmosphere (1 bar) at rt for 72 h. The catalyst was removed by filtration and the filtrate was purified by column chromatography (eluent: CHCl3-MeOH 7:3) to yield 58 mg (92%) colorless syrup. Rf = 0.46 (CHCl3-MeOH 7:3); [α]D = +15 (c 1.14, MeOH); 1H-NMR (D2O, 360 MHz) δ (ppm): 8.30 (1H, s, triazole H-5), 7.50–7.48 (2H, m, Ar), 7.40–7.36 (3H, m, Ar), 4.55 (1H, d, J = 9.7 Hz, H-1’), 3.91 (1H, dd, J = 12.1, <1 Hz, H-6’a), 3.78–3.71 (2H, m, H-2’ or H-3’ or H-4’, H-6’b), 3.64 (1H, pseudo t, J = 8.8, 8.2 Hz, H-2’ or H-3’ or H-4’), 3.58–3.55 (2H, m, H-2’ or H-3’ or H-4’, H-5’); 13C-NMR (D2O, 90 MHz) δ (ppm): 145.6 (triazole C-4), 136.0, 129.9, 129.6, 120.8 (Ar), 123.1 (triazole C-5), 80.3, 77.4, 73.7, 73.2, 69.8 (C-1’–C-5’), 61.1 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C14H17N3NaO5+ ([M + Na]+): 330.1060. Found: 330.1058.
1-(Naphthalen-2-yl)-4-(β-d-glucopyranosyl)-1H-1,2,3-triazole (5b). Prepared from compound 4b (72 mg, 0.14 mmol) according to General procedure 3. Yield: 47 mg (96%) white crystals. Rf = 0.35 (CHCl3-MeOH 8:2); Mp: 224–225 °C; [α]D = +12 (c 0.65, MeOH); 1H-NMR (DMSO-d6, 360 MHz) δ (ppm): 8.92 (1H, s, Ar), 8.45 (1H, s, triazole H-5), 8.17–8.01 (4H, m, Ar), 7.62 (2H, m, Ar), 4.36 (1H, d, J = 9.7 Hz, H-1’), 3.70 (1H, dd, J = 11.6, <1 Hz, H-6’a), 3.59 (1H, dd, J = 11.2, <1 Hz, H-6’b), 3.44 (1H, m, H-5’), 3.36–3.31 (2H, m, H-2’ and/or H-3’ and/or H-4’), 3.20 (1H, pseudo t, J = 9.0, 8.9 Hz; H-2’ or H-3’ or H-4’); 13C-NMR (DMSO-d6, 90 MHz) δ (ppm): 147.3 (triazole C-4), 134.3, 133.0, 132.4, 130.2, 128.4, 128.0, 127.7, 127.2, 122.3, 118.7, 117.8 (Ar), 81.4, 78.0, 74.3, 73.1, 70.3 (C-1’–C-5’), 61.3 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C18H19N3NaO5+ ([M + Na]+): 380.1217. Found: 380.1216.
1-(Naphthalen-1-yl)-4-(β-d-glucopyranosyl)-1H-1,2,3-triazole (5c). Prepared from compound 4c (79 mg, 0.15 mmol) according to General procedure 3. Yield: 51 mg (94%) pale brown syrup. Rf = 0.37 (CHCl3-MeOH 4:1); [α]D = +7 (c 0.42, MeOH); 1H-NMR (CD3OD, 360 MHz) δ (ppm): 8.37 (1H, s, triazole H-5), 8.10–8.08 (1H, m, Ar), 8.02–8.00 (1H, m, Ar), 7.62–7.54 (1H, m, Ar), 4.59 (1H, d, J = 9.7 Hz, H-1’), 3.93 (1H, dd, J = 11.8, <1 Hz, H-6’a), 3.77–3.72 (2H, m, H-2’ and/or H-3’ and/or H-4’ and/or H-5’ and/or H-6’b), 3.62–3.50 (3H, m, H-2’ and/or H-3’ and/or H-4’ and/or H-5’ and/or H-6’b); 13C-NMR (CD3OD, 90 MHz) δ (ppm): 147.6 (triazole C-4), 135.6, 134.8, 131.8, 129.8, 129.5, 129.0, 128.3, 126.2, 124.9, 123.2 (Ar), 127.5 (triazole C-5), 82.4, 79.6, 75.7, 75.1, 71.6 (C-1’–C-5’), 63.0 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C18H19N3NaO5+ ([M + Na]+): 380.1217. Found: 380.1216.
1-(2’,3’,4’,6’-Tetra-O-acetyl-β-d-glucopyranosyl)-4-phenyl-1H-imidazole (7). To a solution of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl-bromide (6, 0.20 g, 0.49 mmol) and 4-phenylimidazole (0.14 g, 0.97 mmol) in anhydr. CH3CN (5 mL) mercury(II) cyanide (0.12 g, 0.49 mmol) and activated 4 Å molecular sieves (powder, 200 mg) were added. The reaction mixture was heated at 60 °C until the TLC (hexane-EtOAc 2:3) showed disappearance of 6. After cooling the reaction mixture to rt the insoluble inorganic salts and molecular sieves were filtered off, and the solution was evaporated under diminished pressure. The residue was dissolved in CHCl3 (30 mL) and extracted with 1M aq. KBr solution (2 × 20 mL) and water (20 mL), respectively. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (hexane-EtOAc 2:3) to yield 140 mg (61%) white solid. Mp = 179–181 °C; Rf = 0.29 (hexane-EtOAc 1:2); [α]D = −54 (c 0.22, CHCl3); 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.77 (2H, dd, J = 7.2, 1.3 Hz, Ph), 7.67 (1H, d, J = 1.1 Hz, imidazole CH), 7.40–7.36 (3H, m, Ph, imidazole CH), 7.26 (1H, dt, J = 7.2, 1.4 Hz, Ph), 5.42, 5.37 (2 × 1H, 2 pseudo t, J = 9.2, 9.1 Hz in each, H-2’, H-3’), 5.34 (1H, d, J = 9.1 Hz, H-1’), 5.26 (1H, pseudo t, J = 9.9, 9.1 Hz, H-4’), 4.30 (1H, dd, J = 12.6, 5.0 Hz, H-6’a), 4.15 (1H, dd, J = 12.6, 2.1 Hz, H-6’b), 3.95 (1H, ddd, J = 9.9, 5.0, 2.1 Hz, H-5’), 2.09, 2.07, 2.03, 1.88 (4 × 3H, 4 s, 4 × CH3CO); 13C-NMR (100 MHz, CDCl3) δ (ppm): 170.6, 170.1, 169.4, 168.8 (4 × CH3CO), 143.2 (imidazole C-4), 136.9 (imidazole C-2), 133.5, 128.7 (2), 127.3, 125.1 (2) (Ph), 112.3 (imidazole C-5), 83.8 (C-1’), 75.0 (C-5’), 73.0, 70.6 (C-2’, C-3’), 67.9 (C-4’), 61.8 (C-6’), 20.8, 20.6 (2), 20.3 (4 × CH3CO). ESI-HRMS positive mode (m/z): calcd. for C23H27N2O9+ ([M + H]+): 475.1711. Found: 475.1711.
1-(β-d-Glucopyranosyl)-4-phenyl-1H-imidazole (8). Prepared from compound 7 (250 mg, 0.53 mmol) according to general procedure 3. Purification by recrystallisation from MeOH yielded 120 mg (75%) white solid. Rf = 0.45 (CHCl3-MeOH 7:3); Mp = 273–274 °C; [α]D = +56 (c 0.22, DMSO); 1H-NMR (360 MHz, DMSO-d6 + 1 drop of D2O) δ (ppm): 7.84 (1H, s, imidazole CH), 7.77–7.73 (3H, m, Ph, imidazole CH), 7.35 (2H, t, J = 7.4 Hz, Ph), 7.20 (1H, t, J = 7.4 Hz, Ph), 5.13 (1H, d, J = 9.1 Hz, H-1’), 3.67 (1H, H-6’a), 3.54 (1H, pseudo t, J = 9.8, 9.1 Hz, H-2’ or H-3’ or H-4’), 3.46 (1H, dd, J = 11.6, 5.6 Hz, H-6’b), 3.40–3.31 (2H, m, H-2’ or H-3’ or H-4’, H-5’), 3.23 (1H, pseudo t, J = 9.1, 9.1 Hz, H-2’ or H-3’ or H-4’); -13C-NMR (90 MHz, DMSO-d6) δ (ppm): 140.3 (imidazole C-4), 137.4 (imidazole C-2), 134.4, 128.3 (2), 126.1, 124.1 (2) (Ph), 114.1 (imidazole C-5), 85.4 (C-1’), 79.6, 77.0, 72.4, 69.6 (C-2’–C-5’), 60.8 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C15H21N2O5+ ([M + H]+): 307.1288. Found: 307.1286.
2-Phenyl-5-(2’,3’,4’,6’-tetra-O-benzoyl-β-d-glucopyranosyl)-2H-tetrazole (10a)
Method A: To the solution of tosylhydrazone 12 (100 mg, 0.13 mmol) in anhydr. pyridine benzenediazonium tetrafluoroborate (25 mg, 0.13 mmol) was added at −40 °C. The mixture was allowed to reach −10 °C in 20 min then CH2Cl2 was added and the mixture was washed with 10% aqueous HCl, saturated aqueous NaHCO3 and brine. The organic phase was dried, evaporated and the residue was purified by column chromatography (eluent: hexane-EtOAc 1:4 → 1:3 gradient) to give 57 mg (61%) yellowish syrup.
Method B: To the solution of tetrazole 9 (300 mg, 0.46 mmol) in anhydr. CH2Cl2 (6 mL) phenylboronic acid (1.6 equiv., 90 mg, 0.74 mmol), CuCl2 (0.12 equiv., 7 mg, 0.06 mmol), N,N,N’,N’-tetra-methylethylenediamine (0.12 equiv., 8 µL, 0.06 mmol) and K2CO3 (1.1 equiv., 70 mg, 0.51 mmol) were added and the mixture was stirred at r.t. under air. After 20 h CH2Cl2 was added and the solution was washed with 10% aqueous NH3, water and brine. The organic phase was dried, evaporated and the residue was purified by column chromatography (eluent: hexane-EtOAc 1:4 → 1:3 gradient) to give 319 mg (95%) colorless syrup.
Rf = 0.43 (hexane-EtOAc 3:2); [α]D = −5 (c 0.36, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.03–7.80 (10H, m, Ar), 7.53–7.27 (15H, m, Ar), 6.23 (1H, pseudo t, J = 9.7, 9.8 Hz, H-2’ or H-3’ or H-4’), 6.09 (1H, pseudo t, J = 9.5, 9.5 Hz, H-2’ or H-3’ or H-4’), 5.90 (1H, pseudo t, J = 9.7, 9.8 Hz, H-2’ or H-3’ or H-4’), 5.38 (1H, d, J = 10.0 Hz, H-1’), 4.69 (1H, dd, J = 12.4, 2.9 Hz, H-6’a), 4.56 (1H, dd, J = 12.4, 5.1 Hz, H-6’b), 4.42 (1H, ddd, J = 9.9, 5.1, 2.9 Hz, H-5’); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 166.1, 165.8, 165.1, 164.6 (PhCO), 162.2 (tetrazole C-5), 136.6 (phenyl C-1”), 133.4-128.2 (Ar), 120.0 (phenyl C-2”), 77.0, 74.3, 72.5, 71.1, 69.4 (C-1’–C-5’), 63.2 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C41H32N4NaO9 + ([M + Na]+): 747.2061. Found: 747.2060.
2-Methyl-5-(2’,3’,4’,6’-tetra-O-benzoyl-β-d-glucopyranosyl)-2H-tetrazole (10e) and 1-methyl-5-(2’,3’,4’,6’-tetra-O-benzoyl-β-d-glucopyranosyl)-1H-tetrazole (11e). A solution of diazomethane was prepared by a portionwise addition of N-nitroso-N-methylurea (400 mg, 3.88 mmol) to a stirred mixture of diethyl ether (5 mL) and 40% w/w aqueous solution of KOH (5 mL) at 0 °C. Ethereal phase was added dropwise to the solution of tetrazole 9 (500 mg, 0.77 mmol) in anhydr. CH2Cl2 (22 mL) at r.t. After disappearance of the tetrazole (TLC, PhMe-EtOAc 4:1) the solvent was removed in vacuo, and the residue was purified by column chromatography (eluent: PhMe-EtOAc 20:1 → 10:1 gradient) to give 10e (192 mg, 38%) and 11e (194 mg, 38%).
10e: white amorphous solid. Rf = 0.46 (PhMe-EtOAc 4:1); [α]D = +36 (c 0.45, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.01–7.79 (8H, m, Ar), 7.50–7.21 (12H, m, Ar), 6.17–6.08 (2H, m, H-2’, H-3’), 5.90 (1H, pseudo t, J = 9.5, 9.4 Hz, H-4’), 5.35 (1H, d, J = 9.3 Hz, H-1’), 4.68 (1H, dd, J = 12.4, 2.9 Hz, H-6’a), 4.56 (1H, dd, J = 12.4, 5.1 Hz, H-6’b), 4.42 (1H, ddd, J = 9.6, 5.0, 2.8 Hz, H-5’), 4.19 (3H, s, CH3); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 166.0, 165.7, 165.0, 164.4 (PhCO), 162.1 (tetrazole C-5), 133.3–128.2 (Ar), 76.8, 74.2, 72.4, 71.1, 69.3 (C-1’–C-5’), 63.1 (C-6’), 39.4 (CH3). ESI-HRMS positive mode (m/z): calcd. for C36H30N4NaO9+ ([M + Na]+): 685.1905. Found: 685.1900.
11e: white amorphous solid. Rf = 0.34 (PhMe-EtOAc 4:1); [α]D = −7 (c 0.53, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.05–7.77 (8H, m, Ar), 7.58–7.23 (12H, m, Ar), 6.19 (1H, pseudo t, J = 9.6, 9.6 Hz, H-3’), 5.90 (1H, pseudo t, J = 9.8, 9.9 Hz, H-4’), 5.83 (1H, pseudo t, J = 9.9, 9.9 Hz, H-2’), 5.49 (1H, d, J = 10.2 Hz, H-1’), 4.74 (1H, dd, J = 12.5, 2.6 Hz, H-6’a), 4.54 (1H, dd, J = 12.5, 4.9 Hz, H-6’b), 4.42 (1H, ddd, J = 9.3, 4.7, 2.6 Hz, H-5’), 4.24 (3H, s, CH3); 13C-NMR (CDCl3, 90 MHz) δ (ppm): 165.8, 165.5, 165.1 (2) (PhCO), 149.9 (tetrazole C-5), 133.6–127.9 (Ar), 77.2, 73.1, 71.8, 69.8, 68.8 (C-1’–C-5’), 62.3 (C-6’), 34.7 (CH3). ESI-HRMS positive mode (m/z): calcd. for C36H30N4NaO9+ ([M + Na]+): 685.1905. Found: 685.1902.
2-Phenyl-5-(β-d-glucopyranosyl)-2H-tetrazole (13a). Prepared from compound 10a (200 mg, 0.28 mmol) according to general procedure 3. Yield: 80 mg (94%) white amorphous solid. Rf = 0.41 (CHCl3-MeOH 4:1); [α]D = +12 (c 0.27, MeOH); 1H-NMR (DMSO-d6, 360 MHz) δ (ppm): 8.10–8.07 (2H, m, Ar), 7.70–7.59 (3H, m, Ar), 4.58 (1H, d, J = 9.8 Hz, H-1’), 3.77–3.69 (2H, m, H-2’ and/or H-3’ and/or H-4’ and/or H-5’ and/or H-6’), 3.48–3.34 (3H, m, H-2’ and/or H-3’ and/or H-4’ and/or H-5’ and/or H-6’), 3.23 (1H, pseudo t, J = 9.1, 9.0 Hz, H-2’ or H-3’ or H-4’); 13C-NMR (DMSO-d6, 90 MHz) δ (ppm): 164.8 (tetrazole C-5), 136.2, 130.3, 130.2, 119.9 (Ar), 81.7, 77.6, 73.4, 72.5, 70.1 (C-1’–C-5’), 61.1 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C13H16N4NaO5+ ([M + Na]+): 331.1013. Found: 331.1013.
2-Methyl-5-(β-d-glucopyranosyl)-2H-tetrazole (13e). Prepared from compound 10e (150 mg, 0.23 mmol) according to general procedure 3. Yield: 40 mg (72%) colourless syrup. Rf = 0.41 (CHCl3-MeOH 7:3); [α]D = +1 (c 0.63, MeOH); 1H-NMR (D2O, 400 MHz) δ (ppm): 4.76 (1H, d, J = 10.0 Hz, H-1’), 4.41 (3H, s, CH3), 3.92 (1H, dd, J = 12.4, 1.8 Hz, H-6’a), 3.81 (1H, pseudo t, J = 9.3, 9.7 Hz, H-2’ or H-3’ or H-4’), 3.75 (1H, dd, J = 12.4, 5.7 Hz, H-6’b), 3.68-3.58 (2H, m, H-2’ or H-3’ or H-4’, H-5’), 3.56 (1H, pseudo t, J = 9.2, 9.4 Hz, H-2’ or H-3’ or H-4’); 13C-NMR (D2O, 100 MHz) δ (ppm): 163.9 (tetrazole C-5), 81.0, 77.5, 73.6, 73.1, 70.1 (C-1’–C-5’), 61.4 (C-6’), 40.4 (CH3). ESI-HRMS positive mode (m/z): calcd. for C8H14N4NaO5+ ([M + Na]+): 269.0856. Found: 269.0855.
1-Methyl-5-(β-d-glucopyranosyl)-1H-tetrazole (14e). Prepared from compound 11e (150 mg, 0.23 mmol) according to general procedure 3. Yield: 54 mg (97%) pale yellow syrup. Rf = 0.33 (CHCl3-MeOH 7:3); [α]D = +7 (c 0.83, MeOH); 1H-NMR (D2O, 360 MHz) δ (ppm): 4.91 (1H, d, J = 9.7 Hz, H-1’), 4.17 (3H, s, CH3), 3.92 (1H, dd, J = 12.4, <1 Hz, H-6’a), 3.83–3.66 (4H, m, H-2’ and/or H-3’ and/or H-4’ and/or H-5’ and/or H-6’b), 3.57 (1H, pseudo t, J = 9.4, 9.1 Hz, H-2’ or H-3’ or H-4’); 13C-NMR (D2O, 90 MHz) δ (ppm): 153.9 (tetrazole C-5), 81.1, 77.3, 73.0, 71.5, 69.9 (C-1’–C-5’), 61.4 (C-6’), 35.1 (CH3). ESI-HRMS positive mode (m/z): calcd. for C8H14N4NaO5+ ([M + Na]+): 269.0856. Found: 269.0857.
5-Phenyl-2-(2’,3’,4’,6’-tetra-O-acetyl-β-d-glucopyranosyl)-2H-tetrazole (15a) and 5-phenyl-1-(2’,3’,4’,6’-tetra-O-acetyl-β-d-glucopyranosyl)-1H-tetrazole (16a). Prepared according to general procedure 4 from bromide 6 (500 mg, 1.22 mmol) and 5-phenyltetrazole (355 mg, 2.43 mmol). Products were separated by column chromatography (eluent: hexane-acetone 3:1) to give 15a (460 mg, 79%) and 16a (96 mg, 17%). 1H and 13C-NMR spectra of the isolated compounds are in agreement with those reported earlier [61].
5-Methyl-2-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-2H-tetrazole (15e). Prepared according to general procedure 4 from bromide 6 (500 mg, 1.22 mmol) and 5-methyltetrazole (204 mg, 2.43 mmol). Products were separated by column chromatography (eluent: hexane-acetone 9:1 → 4:1 gradient) to give 15e (131 mg, 26%) and glycal 17 [67] (181 mg, 45%).
15e: White amorphous solid. Rf = 0.48 (hexane-acetone 1:1); [α]D = +7 (c 0.46, CHCl3); 1H-NMR (CDCl3, 400 MHz) δ (ppm): 6.06 (1H, d, J = 9.4 Hz, H-1’), 5.83 (1H, pseudo t, J = 9.4, 9.4 Hz, H-2’ or H-3’ or H-4’), 5.42 (1H, pseudo t, J = 9.5, 9.5 Hz, H-2’ or H-3’ or H-4’), 5.30 (1H, pseudo t, J = 9.9, 9.7 Hz, H-2’ or H-3’ or H-4’), 4.30 (1H, dd, J = 12.7, 5.0 Hz, H-6’a), 4.17 (1H, dd, J = 12.7, 2.0 Hz, H-6’b), 4.03 (1H, ddd, J = 10.0, 5.0, 2.0 Hz, H-5’), 2.58 (3H, s, CH3), 2.08, 2.08, 2.04, 1.85 (4 × 3H, s, 4 × CH3CO); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 170.6, 170.2, 169.2, 168.4 (CH3CO), 163.9 (tetrazole C-5), 86.5 (C-1’), 75.1, 73.0, 69.8, 67.4 (C-2’–C-5’), 61.5 (C-6’), 20.7, 20.6 (2), 20.2 (CH3CO), 11.1 (CH3). ESI-HRMS positive mode (m/z): calcd. for C16H22N4NaO9+ ([M + Na]+): 437.1279. Found: 437.1281.
5-Phenyl-2-(β-d-glucopyranosyl)-2H-tetrazole (18a). Prepared from compound 15a (155 mg, 0.33 mmol) according to General procedure 3. Yield: 85 mg (85%) white amorphous solid. Rf = 0.29 (CHCl3-MeOH 4:1); [α]D = −4 (c 1.31, MeOH); 1H-NMR (D2O, 400 MHz) δ (ppm): 8.01-7.98 (2H, m, Ar), 7.54–7.50 (3H, m, Ar), 6.08 (1H, d, J = 9.2 Hz, H-1’), 4.20 (1H, pseudo t, J = 9.3, 9.3 Hz, H-2’ or H-3’ or H-4’), 3.97–3.93 (1H, m, H-2’ or H-3’ or H-4’ or H-5’ or H-6’), 3.82–3.76 (3H, m, H-2’ and/or H-3’ and/or H-4’ and/or H-5’ and/or H-6’), 3.67 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2’ or H-3’ or H-4’); 13C-NMR (D2O, 100 MHz) δ (ppm): 165.9 (tetrazole C-5), 131.9, 129.9, 127.5, 126.3 (Ar), 89.9 (C-1’), 79.7, 76.4, 72.5, 69.5 (C-2’–C-5’), 61.1 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C13H16N4NaO5+ ([M + Na]+): 331.1013. Found: 331.1014.
5-Methyl-2-(β-d-glucopyranosyl)-2H-tetrazole (18e). Prepared from compound 15e (136 mg, 0.33 mmol) according to general procedure 3. Yield: 68 mg (84%) white amorphous solid. Rf = 0.29 (CHCl3-MeOH 4:1); [α]D = −14 (c 0.66, CHCl3); 1H-NMR (D2O, 400 MHz) δ (ppm): 6.03 (1H, d, J = 9.2 Hz, H-1’), 4.13 (1H, pseudo t, J = 9.2, 9.3 Hz, H-2’ or H-3’ or H-4’), 3.93 (1H, dd, J = 10.7, <1 Hz, H-6’a), 3.82–3.73 (2H, m, H-5’ and H-6’b), 3.75 (1H, pseudo t, J = 9.2, 9.3 Hz, H-2’ or H-3’ or H-4’), 3.64 (1H, pseudo t, J = 9.3, 9.3 Hz, H-2’ or H-3’ or H-4’), 2.58 (3H, s, CH3); 13C-NMR (D2O, 100 MHz) δ (ppm): 164.7 (tetrazole C-5), 89.5 (C-1’), 79.6, 76.4, 72.4, 69.5 (C-2’–C-5’), 61.0 (C-6’), 10.5 (CH3). ESI-HRMS positive mode (m/z): calcd. for C8H14N4NaO5+ ([M + Na]+): 269.0856. Found: 269.0858.
5-Phenyl-1-(β-d-glucopyranosyl)-1H-tetrazole (19a). Prepared from compound 16a (86 mg, 0.18 mmol) according to general procedure 3. Yield: 48 mg (86%) colourless syrup. Rf = 0.29 (CHCl3-MeOH 4:1); [α]D = +17 (c 0.68, MeOH); 1H-NMR (D2O, 400 MHz) δ (ppm): 7.74–7.67 (3H, m, Ar), 7.64–7.60 (2H, m, Ar), 5.60 (1H, d, J = 9.1 Hz, H-1’), 4.31 (1H, pseudo t, J = 9.1, 9.1 Hz, H-2’ or H-3’ or H-4’), 3.95 (1H, dd, J = 12.4, 1.7 Hz, H-6’a), 3.78 (1H, dd, J = 12.4, .6 Hz, H-6’b), 3.71, (1H, ddd, J = 9.4, 5.8, 1.4 Hz, H-5’), 3.66–3.62 (2H, m, H-2’ and/or H-3’ and/or H-4’); 13C-NMR (D2O, 100 MHz) δ (ppm): 157.3 (tetrazole C-5), 133.0, 130.1, 129.8, 122.3 (Ar), 85.5, 79.5, 76.5, 72.0, 69.6 (C-1’–C-5’), 61.1 (C-6’). ESI-HRMS positive mode (m/z): calcd. for C13H16N4NaO5+ ([M + Na]+): 331.1013. Found: 331.1012.

4. Conclusions

In this study, initiated by the objective of extending the structure-activity relationships of C- and N-β-d-glucopyranosyl derivatives of a wide range of azole type heterocycles as glycogen phosphorylase inhibitors, new methyl and aryl substituted 1,2,3-triazoles, imidazoles and tetrazoles have been synthesized. Enzyme kinetic investigation of the new compounds showed most of them to have no significant inhibitory activity against RMGPb. These and previous [44] experiences with β-d-Glcp-azole-Ar type compounds indicate that the inhibitory effect of these is highly sensible to the structure of the azole moieties and the range of efficacy expands from inactives to the best known glucose derived inhibitors. The understanding of such an enormous variability seems to be beyond simple or intuitive discretion, therefore, computational studies are underway to get a deeper insight in these phenomena.

Acknowledgments

The work received financial support from the National Research, Innovation and Development Office of Hungary (PD 121406 to SK), as well as from the EU co-financed by the European Regional Development Fund under the projects GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004. A. Gáspár is thanked for running the HRMS measurements.

Author Contributions

Sándor Kun and Éva Bokor designed the experiments, performed the synthetic work and wrote the paper, Ádám Sipos and Tibor Docsa carried out the enzyme kinetic measurements, László Somsák conceived the research and wrote the paper.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Praly, J.P.; Vidal, S. Inhibition of Glycogen Phosphorylase in the Context of Type 2 Diabetes, with Focus on Recent Inhibitors Bound at the Active Site. Mini-Rev. Med. Chem. 2010, 10, 1102–1126. [Google Scholar] [CrossRef]
  2. Somsák, L. Glucose derived inhibitors of glycogen phosphorylase. Comptes Rendus Chim. 2011, 14, 211–223. [Google Scholar] [CrossRef]
  3. Hayes, J.M.; Kantsadi, A.L.; Leonidas, D.D. Natural products and their derivatives as inhibitors of glycogen phosphorylase: Potential treatment for type 2 diabetes. Phytochem. Rev. 2014, 13, 471–498. [Google Scholar] [CrossRef]
  4. Henke, B.R. Inhibition of glycogen phosphorylase as a strategy for the treatment of type 2 diabetes. RSC Drug Discov. Ser. 2012, 27, 324–365. [Google Scholar] [CrossRef]
  5. Gaboriaud-Kolar, N.; Skaltsounis, A.L. Glycogen phosphorylase inhibitors: a patent review (2008–2012). Expert Opin. Ther. Patents 2013, 23, 1017–1032. [Google Scholar] [CrossRef] [PubMed]
  6. Donnier-Maréchal, M.; Vidal, S. Glycogen phosphorylase inhibitors: A patent review (2013–2015). Expert Opin. Ther. Patents 2016, 26, 199–212. [Google Scholar] [CrossRef] [PubMed]
  7. Tracey, W.; Treadway, J.; Magee, W.; McPherson, R.; Levy, C.; Wilder, D.; Li, Y.; Yue, C.; Zavadoski, W.; Gibbs, E.; et al. A novel glycogen phosphorylase inhibitor, CP-368296, reduces myocardial ischemic injury. Diabetes 2003, 52, A135. [Google Scholar]
  8. Tracey, W.R.; Treadway, J.L.; Magee, W.P.; Sutt, J.C.; McPherson, R.K.; Levy, C.B.; Wilder, D.E.; Yu, L.J.; Chen, Y.; Shanker, R.M.; et al. Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor. Am. J. Physiol.-Heart Circul. Physiol. 2004, 286, H1177–H1184. [Google Scholar] [CrossRef] [PubMed]
  9. Xu, L.; Sun, H. Pharmacological manipulation of brain glycogenolysis as a therapeutic approach to cerebral ischemia. Mini-Rev. Med. Chem. 2010, 10, 1188–1193. [Google Scholar] [CrossRef] [PubMed]
  10. Guan, T.; Qian, Y.S.; Tang, X.Z.; Huang, M.H.; Huang, L.F.; Li, Y.M.; Sun, H.B. Maslinic Acid, a Natural Inhibitor of Glycogen Phosphorylase, Reduces Cerebral Ischemic Injury in Hyperglycemic Rats by GLT-1 Up-Regulation. J. Neurosci. Res. 2011, 89, 1829–1839. [Google Scholar] [CrossRef] [PubMed]
  11. Schnier, J.B.; Nishi, K.; Monks, A.; Gorin, F.A.; Bradbury, E.M. Inhibition of glycogen phosphorylase (GP) by CP-91,149 induces growth inhibition correlating with brain GP expression. Biochem. Biophys. Res. Commun. 2003, 309, 126–134. [Google Scholar] [CrossRef]
  12. Geschwind, J.F.; Georgiades, C.S.; Ko, Y.H.; Pedersen, P.L. Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev. Anticancer Ther. 2004, 4, 449–457. [Google Scholar] [CrossRef] [PubMed]
  13. Boros, L.G.; Go, V.L.W.; Lee, W.N.P. Glycogen phosphorylase inhibitor CP-320626 inhibits pancreatic cancer cell proliferation via inhibiting pentose cycle metabolism and glycolysis. Pancreas 2003, 27, 368–420. [Google Scholar]
  14. Favaro, E.; Bensaad, K.; Chong, M.G.; Tennant, D.A.; Ferguson, D.J.P.; Snell, C.; Steers, G.; Turley, H.; Li, J.L.; Günther, U.L.; et al. Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells. Cell Metab. 2012, 16, 751–764. [Google Scholar] [CrossRef] [PubMed]
  15. Zois, C.E.; Favaro, E.; Harris, A.L. Glycogen metabolism in cancer. Biochem. Pharmacol. 2014, 92, 3–11. [Google Scholar] [CrossRef] [PubMed]
  16. Zois, C.E.; Harris, A.L. Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy. J. Mol. Med. 2016, 94, 137–154. [Google Scholar] [CrossRef] [PubMed]
  17. Martin, W.H.; Hoover, D.J.; Armento, S.J.; Stock, I.A.; McPherson, R.K.; Danley, D.E.; Stevenson, R.W.; Barrett, E.J.; Treadway, J.L. Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. Proc. Natl. Acad. Sci. USA 1998, 95, 1776–1781. [Google Scholar] [CrossRef] [PubMed]
  18. Furukawa, S.; Murakami, K.; Nishikawa, M.; Nakayama, O.; Hino, M. FR258900, a novel glycogen phosphorylase inhibitor isolated from Fungus No. 138354 - II. Anti-hyperglycemic effects in diabetic animal models. J. Antibiot. 2005, 58, 503–506. [Google Scholar] [CrossRef] [PubMed]
  19. Docsa, T.; Czifrák, K.; Hüse, C.; Somsák, L.; Gergely, P. The effect of glucopyranosylidene-spiro-thiohydantoin on the glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats. Mol. Med. Rep. 2011, 4, 477–481. [Google Scholar] [CrossRef] [PubMed]
  20. Docsa, T.; Marics, B.; Németh, J.; Hüse, C.; Somsák, L.; Gergely, P.; Peitl, B. Insulin sensitivity is modified by a glycogen phosphorylase inhibitor: glucopyranosylidene-spiro-thiohydantoin in streptozotocin-induced diabetic rats. Curr. Top. Med. Chem. 2015, 15, 2390–2394. [Google Scholar] [CrossRef] [PubMed]
  21. Goyard, D.; Kónya, B.; Chajistamatiou, A.S.; Chrysina, E.D.; Leroy, J.; Balzarin, S.; Tournier, M.; Tousch, D.; Petit, P.; Duret, C.; et al. Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition. Eur. J. Med. Chem. 2016, 108, 444–454. [Google Scholar] [CrossRef] [PubMed]
  22. Nagy, L.; Docsa, T.; Brunyánszki, A.; Szántó, M.; Hegedűs, C.; Márton, J.; Kónya, B.; Virág, L.; Somsák, L.; Gergely, P.; et al. Glycogen phosphorylase inhibitor N-(3,5-dimethyl-benzoyl)-N’-(β-d-glucopyranosyl) urea improves glucose tolerance under normoglycemic and diabetic conditions through rearranging hepatic metabolism. PLoS ONE 2013, 8, e69420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Nagy, L.; Márton, J.; Vida, A.; Kis, G.; Bokor, É.; Kun, S.; Gönczi, M.; Docsa, T.; Tóth, A.; Antal, M.; et al. Glycogen phosphorylase inhibition improves β-cell function. Br. J. Pharmacol. 2018, 175, 301–319. [Google Scholar] [CrossRef] [PubMed]
  24. Somsák, L.; Czifrák, K.; Tóth, M.; Bokor, É.; Chrysina, E.D.; Alexacou, K.M.; Hayes, J.M.; Tiraidis, C.; Lazoura, E.; Leonidas, D.D.; et al. New inhibitors of glycogen phosphorylase as potential antidiabetic agents. Curr. Med. Chem. 2008, 15, 2933–2983. [Google Scholar] [CrossRef] [PubMed]
  25. Stravodimos, G.A.; Chetter, B.A.; Kyriakis, E.; Kantsadi, A.L.; Chatzileontiadou, D.S.M.; Skamnaki, V.T.; Kato, A.; Hayes, J.M.; Leonidas, D.D. Phytogenic Polyphenols as Glycogen Phosphorylase Inhibitors: The Potential of Triterpenes and Flavonoids for Glycaemic Control in Type 2 Diabetes. Curr. Med. Chem. 2017, 24, 384–403. [Google Scholar] [CrossRef]
  26. Watson, K.A.; Mitchell, E.P.; Johnson, L.N.; Cruciani, G.; Son, J.C.; Bichard, C.J.F.; Fleet, G.W.J.; Oikonomakos, N.G.; Kontou, M.; Zographos, S.E. Glucose Analogue Inhibitors of Glycogen Phosphorylase: from Crystallographic Analysis to Drug Prediction using GRID Force-Field and GOLPE Variable Selection. Acta Cryst. 1995, D51, 458–472. [Google Scholar] [CrossRef] [PubMed]
  27. Somsák, L.; Kovács, L.; Tóth, M.; Ősz, E.; Szilágyi, L.; Györgydeák, Z.; Dinya, Z.; Docsa, T.; Tóth, B.; Gergely, P. Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides. J. Med. Chem. 2001, 44, 2843–2848. [Google Scholar] [CrossRef] [PubMed]
  28. Györgydeák, Z.; Hadady, Z.; Felföldi, N.; Krakomperger, A.; Nagy, V.; Tóth, M.; Brunyánszky, A.; Docsa, T.; Gergely, P.; Somsák, L. Synthesis of N-(β-d-glucopyranosyl)- and N-(2-acetamido-2-deoxy-β-d-glucopyranosyl) amides as inhibitors of glycogen phosphorylase. Bioorg. Med. Chem. 2004, 12, 4861–4870. [Google Scholar] [CrossRef] [PubMed]
  29. Chrysina, E.D.; Bokor, É.; Alexacou, K.-M.; Charavgi, M.-D.; Oikonomakos, G.N.; Zographos, S.E.; Leonidas, D.D.; Oikonomakos, N.G.; Somsák, L. Amide-1,2,3-triazole bioisosterism: The glycogen phosphorylase case. Tetrahedron: Asymmetry 2009, 20, 733–740. [Google Scholar] [CrossRef]
  30. Chrysina, E.D. The Prototype of Glycogen Phosphorylase. Mini-Rev. Med. Chem. 2010, 10, 1093–1101. [Google Scholar] [CrossRef]
  31. Patani, G.A.; LaVoie, E.J. Bioisosterism: A rational approach in drug design. Chem. Rev. 1996, 96, 3147–3176. [Google Scholar] [CrossRef] [PubMed]
  32. Lima, L.M.A.; Barreiro, E.J. Bioisosterism: A useful strategy for molecular modification and drug design. Curr. Med. Chem. 2005, 12, 23–49. [Google Scholar] [CrossRef] [PubMed]
  33. Meanwell, N.A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529–2591. [Google Scholar] [CrossRef] [PubMed]
  34. Bokor, É.; Docsa, T.; Gergely, P.; Somsák, L. Synthesis of 1-(d-glucopyranosyl)-1,2,3-triazoles and their evaluation as glycogen phosphorylase inhibitors. Bioorg. Med. Chem. 2010, 18, 1171–1180. [Google Scholar] [CrossRef] [PubMed]
  35. Hadady, Z.; Tóth, M.; Somsák, L. C-(β-d-glucopyranosyl) heterocycles as potential glycogen phosphorylase inhibitors. Arkivoc 2004, 140–149. [Google Scholar] [CrossRef]
  36. Chrysina, E.D.; Kosmopolou, M.N.; Tiraidis, C.; Kardarakis, R.; Bischler, N.; Leonidas, D.D.; Hadady, Z.; Somsák, L.; Docsa, T.; Gergely, P.; et al. Kinetic and crystallographic studies on 2-(β-d-glucopyranosyl)-5-methyl-1,3,4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site. Protein Sci. 2005, 14, 873–888. [Google Scholar] [CrossRef] [PubMed]
  37. Tóth, M.; Kun, S.; Bokor, É.; Benltifa, M.; Tallec, G.; Vidal, S.; Docsa, T.; Gergely, P.; Somsák, L.; Praly, J.P. Synthesis and structure-activity relationships of C-glycosylated oxadiazoles as inhibitors of glycogen phosphorylase. Bioorg. Med. Chem. 2009, 17, 4773–4785. [Google Scholar] [CrossRef] [PubMed]
  38. Benltifa, M.; Vidal, S.; Fenet, B.; Msaddek, M.; Goekjian, P.G.; Praly, J.P.; Brunyánszki, A.; Docsa, T.; Gergely, P. In the Search of Glycogen Phosphorylase Inhibitors: 5-Substituted 3-C-Glucopyranosyl-1,2,4-Oxadiazoles from β-d-Glucopyranosyl Cyanides upon Cyclization of O-Acyl-amidoxime Intermediates. Eur. J. Org. Chem. 2006, 4242–4256. [Google Scholar] [CrossRef]
  39. Benltifa, M.; Vidal, S.; Gueyrard, D.; Goekjian, P.G.; Msaddek, M.; Praly, J.P. 1,3-Dipolar cycloaddition reactions on carbohydrate-based templates: synthesis of spiro-isoxazolines and 1,2,4-oxadiazoles as glycogen phosphorylase inhibitors. Tetrahedron Lett. 2006, 47, 6143–6147. [Google Scholar] [CrossRef]
  40. Bokor, É.; Docsa, T.; Gergely, P.; Somsák, L. C-Glucopyranosyl-1,2,4-triazoles as new potent inhibitors of glycogen phosphorylase. ACS Med. Chem. Lett. 2013, 4, 612–615. [Google Scholar] [CrossRef] [PubMed]
  41. Kun, S.; Bokor, É.; Varga, G.; Szőcs, B.; Páhi, A.; Czifrák, K.; Tóth, M.; Juhász, L.; Docsa, T.; Gergely, P.; et al. New synthesis of 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase. Eur. J. Med. Chem. 2014, 76, 567–579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Bokor, É.; Kun, S.; Docsa, T.; Gergely, P.; Somsák, L. 4(5)-Aryl-2-C-glucopyranosyl-imidazoles as new nanomolar glucose analog inhibitors of glycogen phosphorylase. ACS Med. Chem. Lett. 2015, 6, 1215–1219. [Google Scholar] [CrossRef] [PubMed]
  43. Kantsadi, A.L.; Bokor, É.; Kun, S.; Stravodimos, G.A.; Chatzileontiadou, D.S.M.; Leonidas, D.D.; Juhász-Tóth, É.; Szakács, A.; Batta, G.; Docsa, T.; et al. 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. Eur. J. Med. Chem. 2016, 123, 737–745. [Google Scholar] [CrossRef] [PubMed]
  44. Bokor, É.; Kun, S.; Goyard, D.; Tóth, M.; Praly, J.P.; Vidal, S.; Somsák, L. C-Glycopyranosyl arenes and hetarenes: Synthetic methods and bioactivity focused on antidiabetic potential. Chem. Rev. 2017, 117, 1687–1764. [Google Scholar] [CrossRef] [PubMed]
  45. Dondoni, A.; Mariotti, G.; Marra, A. Synthesis of α- and β-Glycosyl Asparagine Ethylene Isosteres (C-Glycosyl Asparagines) via Sugar Acetylenes and Garner Aldehyde Coupling. J. Org. Chem. 2002, 67, 4475–4486. [Google Scholar] [CrossRef] [PubMed]
  46. Meldal, M.; Tornoe, C.W. Cu-catalyzed azide-alkyne cycloaddition. Chem. Rev. 2008, 108, 2952–3015. [Google Scholar] [CrossRef] [PubMed]
  47. Bokor, É.; Koppány, C.; Gonda, Z.; Novák, Z.; Somsák, L. Evaluation of bis-triphenylphosphano-copper(I)-butyrate (C3H7COOCu(PPh3)2) as catalyst for the synthesis of 1-(d-glycopyranosyl)-4-substituted-1,2,3-triazoles. Carbohydr. Res. 2012, 351, 42–48. [Google Scholar] [CrossRef] [PubMed]
  48. Tao, C.Z.; Cui, X.; Li, J.; Liu, A.X.; Liu, L.; Guo, Q.X. Copper-catalyzed synthesis of aryl azides and 1-aryl-1,2,3-triazoles from boronic acids. Tetrahedron Lett. 2007, 48, 3525–3529. [Google Scholar] [CrossRef]
  49. Kun, S.; Nagy, G.Z.; Tóth, M.; Czecze, L.; Nguyen van Nhien, A.; Docsa, T.; Gergely, P.; Charavgi, M.D.; Skourti, P.V.; Chrysina, E.D.; et al. Synthesis of variously coupled conjugates of d-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase. Carbohydr. Res. 2011, 346, 1427–1438. [Google Scholar] [CrossRef] [PubMed]
  50. Kantsadi, A.L.; Stravodimos, G.A.; Kyriakis, E.; Chatzileontiadou, D.S.; Solovou, T.G.; Kun, S.; Bokor, É.; Somsák, L.; Leonidas, D.D. van der Waals interactions govern C-β-d-glucopyranosyl triazoles’ nM inhibitory potency in human liver glycogen phosphorylase. J. Struct. Biol. 2017, 199, 57–67. [Google Scholar] [CrossRef] [PubMed]
  51. Alzeer, J.; Vasella, A. Oligosaccharide Analogues of Polysaccharides. Part 2. Regioselective deprotection of monosaccharide-derived monomers and dimers. Helv. Chim. Acta 1995, 78, 177–193. [Google Scholar] [CrossRef]
  52. Patt, M.; Sorger, D.; Scheunemann, M.; Stocklin, G. Adduct of 2-[F18]FDG and 2-nitroimidazole as a putative radiotracer for the detection of hypoxia with PET: Synthesis, in vitro- and in vivo-characterisation. Appl. Radiat. Isot. 2002, 57, 705–712. [Google Scholar] [CrossRef]
  53. Onaka, T.; Umemoto, H.; Miki, Y.; Nakamura, A.; Maegawa, T. [Cu(OH)(TMEDA)]2Cl2-Catalyzed Regioselective 2-Arylation of 5-Substituted Tetrazoles with Boronic Acids under Mild Conditions. J. Org. Chem. 2014, 79, 6703–6707. [Google Scholar] [CrossRef] [PubMed]
  54. Ito, S.; Tanaka, Y.; Kakehi, A.; Kondo, K. Facile synthesis of 2,5-disubstituted tetrazoles by reaction of phenylsulfonylhydrazones with arenediazonium salts. Bull. Chem. Soc. Jpn. 1976, 49, 1920–1923. [Google Scholar] [CrossRef]
  55. Tóth, M.; Kövér, K.E.; Bényei, A.; Somsák, L. C-Glycosylmethylene carbenes: synthesis of anhydro-aldose tosylhydrazones as precursors; generation and a new synthetic route to exo-glycals. Org. Biomol. Chem. 2003, 1, 4039–4046. [Google Scholar] [CrossRef] [PubMed]
  56. Tóth, M.; Somsák, L.; Goyard, D. Preparation of 2,6-Anhydro-aldose-tosylhydrazones. In Carbohydrate Chemistry: Proven Synthetic Methods; Kováč, P., Ed.; CRC Press: Boca Raton, FL, USA, 2012; Volume 1, pp. 355–365. [Google Scholar]
  57. Roe, A. Preparation of Aromatic Fluorine Compounds from Diazonium Fluoborates. In Organic Reactions; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2011; pp. 193–228. [Google Scholar]
  58. Flood, D.T. Fluorobenzene. Org. Synth. 1933, 13, 46–49. [Google Scholar] [CrossRef]
  59. Kobe, J.; Prhavc, M.; Hohnjec, M.; Townsend, L.B. Preparation and utility of 5-β-d-ribofuranosyl-1H-tetrazole as a key synthon for C-nucleoside synthesis. Nucleosides Nucleotides 1994, 13, 2209–2244. [Google Scholar] [CrossRef]
  60. Ostrovskii, V.A.; Koldobskii, G.I.; Trifonov, R.E. Tetrazoles. In Comprehensive Heterocyclic Chemistry III; Katritzky, A.R., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier: Oxford, UK, 2008; Volume 6, pp. 257–423. [Google Scholar]
  61. Couri, M.R.; Luduvico, I.; Santos, L.; Alves, R.; Prado, M.A.; Gil, R.F. Microwave-assisted efficient preparation of novel carbohydrate tetrazole derivatives. Carbohydr. Res. 2007, 342, 1096–1100. [Google Scholar] [CrossRef] [PubMed]
  62. Wittenberger, S.J.; Donner, B.G. Dialkyltin Oxide-Mediated Addition of Trimethylsilyl Azide to Nitriles—A Novel Preparation of 5-Substituted Tetrazoles. J. Org. Chem. 1993, 58, 4139–4141. [Google Scholar] [CrossRef]
  63. Valverde, I.E.; Mindt, T.L. 1,2,3-Triazoles as Amide-bond Surrogates in Peptidomimetics. Chimia 2013, 67, 262–266. [Google Scholar] [CrossRef] [PubMed]
  64. Bonandi, E.; Fumagalli, G.; Perdicchia, D.; Christodoulou, M.S.; Rastelli, G.; Passarella, D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov. Today 2017, 22, 1572–1581. [Google Scholar] [CrossRef] [PubMed]
  65. Watson, K.A.; Mitchell, E.P.; Johnson, L.N.; Son, J.C.; Bichard, C.J.F.; Orchard, M.G.; Fleet, G.W.J.; Oikonomakos, N.G.; Leonidas, D.D.; Kontou, M.; et al. Design of Inhibitors of Glycogen Phosphorylase: A Study of α- and β-C-Glucosides and 1-Thio-β-d-glucose Compounds. Biochemistry 1994, 33, 5745–5758. [Google Scholar] [CrossRef] [PubMed]
  66. Cheng, Y.C.; Prusoff, W.H. Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22, 3099–3108. [Google Scholar] [CrossRef] [PubMed]
  67. Udodong, U.E.; Fraser-Reid, B. Formal total synthesis of 1-β-methylcarbapenem via a novel route to deoxyamino sugars. J. Org. Chem. 1989, 54, 2103–2112. [Google Scholar] [CrossRef]
Sample Availability: Not available.
Molecules 23 00666 sch001 550
Scheme 1. Synthesis of 1-(β-d-glucopyranosyl)-4-phenyl-imidazole.
Scheme 1. Synthesis of 1-(β-d-glucopyranosyl)-4-phenyl-imidazole.
Molecules 23 00666 sch001
Table
Table 1. Selected glucose derived inhibitors of rabbit muscle glycogen phosphorylase b (Ki [μM]).
Table 1. Selected glucose derived inhibitors of rabbit muscle glycogen phosphorylase b (Ki [μM]).
RCH3 Molecules 23 00666 i001 Molecules 23 00666 i002
abc
I Molecules 23 00666 i00332 [26]81 [26]
144 [27]		10 [28]
13 [29]
II Molecules 23 00666 i004-151 [29]
162 [34]		16 [29]
36 [34]
III Molecules 23 00666 i005212 [35]
145 [36]		10%
at 625 μM [37]		10%
at 625 μM [37]
IV Molecules 23 00666 i006No inh. at 625 μM [38]10%
at 625 μM [38]		38 [38]
V Molecules 23 00666 i007-27 [39]
64 [37]		12 * [37]
VI Molecules 23 00666 i008499 [41]7 [40,41]0.41 [40,41]
VII Molecules 23 00666 i009-0.28 [42,43]0.031 [42,43]
VIII Molecules 23 00666 i010No inh. at 625 μM [35]
* A Ki value of 2.4 μM was measured by N.G. Oikonomakos et al. (unpublished results in ref. [37])
Target compounds in this study: Molecules 23 00666 i011
IX Molecules 23 00666 i012X Molecules 23 00666 i013XI Molecules 23 00666 i014XII Molecules 23 00666 i015
Table
Table 2. Synthesis of 1-aryl-4-(β-d-glucopyranosyl)-1,2,3-triazoles.
Table 2. Synthesis of 1-aryl-4-(β-d-glucopyranosyl)-1,2,3-triazoles.
Molecules 23 00666 i016
Reagents and conditions: (a) ArN3, CuO(CO)C3H7(PPh3)2, dry CH2Cl2, r.t.; (b) і. ArB(OH)2, NaN3, CuSO4·5H2O, MeOH, r.t., іі. 1 or 3, L-ascorbic acid, CH2Cl2-H2O (1:1), 50 °C; (c) H2, Pd(C), dry EtOH, dry EtOAc, r.t.; (d) TMSOTf, Ac2O, −40 °C; (e) і. H2, Pd(C), dry EtOAc, dry MeOH, 40 °C, іі. Ac2O, pyridine, 90 °C; (f) ~1M NaOMe in MeOH, r.t.
ArConditions and Yields (%)
2 4 5
a Molecules 23 00666 i017a78 (from 1)--c92 (from 2a)
b Molecules 23 00666 i018b79 (from 1)d68 (from 2b)f96 (from 4b)
b80 (from 3)
c Molecules 23 00666 i019a85 (from 1)e29 (from 2c)f94 (from 4c)
a91 (from 3)
d Molecules 23 00666 i020--e3 (from 2c)--
Table
Table 3. Synthesis of 5-(β-d-glucopyranosyl)-N-substituted-tetrazoles.
Table 3. Synthesis of 5-(β-d-glucopyranosyl)-N-substituted-tetrazoles.
Molecules 23 00666 i021
Reagents and conditions: (a) R’B(OH)2, CuCl2, TMEDA, K2CO3, dry CH2Cl2, r.t.; (b) CH2N2 in Et2O, dry CH2Cl2, r.t.; (c) PhN2BF4, dry pyridine, −40 °C; (d) ~1M NaOMe in MeOH, r.t.
Conditions, Yields (%) and Chemical Shifts (ppm) for Tetrazole C-5 (Solvent)
R’ 1011 1314
aPhenyla95162.2
(CDCl3)		--d94164.8
(DMSO-d6)		--
c61-
eMethylb38162.1
(CDCl3)		38149.9
(CDCl3)		d72163.9
(D2O)		97153.9
(D2O)
Table
Table 4. Synthesis of N-(β-d-glucopyranosyl)-5-substituted-tetrazoles.
Table 4. Synthesis of N-(β-d-glucopyranosyl)-5-substituted-tetrazoles.
Molecules 23 00666 i022
Reagents and conditions: (a) K2CO3, 4 Å molecular sieves, dry acetone, reflux; (b) ~1 M NaOMe in MeOH, r.t.
R’Conditions, Yields (%) and Chemical Shifts (ppm) for Tetrazole C-5 (Solvent)
151617 1819
aPhenyla79165.8
(CDCl3)		17155.9
(CDCl3)		-b85165.9
(D2O)		86157.3
(D2O)
eMethyla26163.9
(CDCl3)		- 45b84164.7
(D2O)		-
Table
Table 5. Inhibitory effect of the new and some earlier compounds against rabbit muscle glycogen phosphorylase b (RMGPb).
Table 5. Inhibitory effect of the new and some earlier compounds against rabbit muscle glycogen phosphorylase b (RMGPb).
EntryCompoundInhibition * (μM)
1.Ib Molecules 23 00666 i023Ki 81 [26]
Ki 144 [27]
2.IIb Molecules 23 00666 i024Ki 151 [29]
Ki 162 [34]
3.20 Molecules 23 00666 i025Ki 5400 [65]
4.5a Molecules 23 00666 i026N.I.
5.5b Molecules 23 00666 i027N.I.
6.5c Molecules 23 00666 i028N.I.
7.8 Molecules 23 00666 i029N.I.
8.13a Molecules 23 00666 i030N.I.
9.13e Molecules 23 00666 i031N.I.
10.14e Molecules 23 00666 i032N.I.
11.18a Molecules 23 00666 i033IC50 600
(calculated ** Ki 327)
12.18e Molecules 23 00666 i034N.I.
13.19a Molecules 23 00666 i035N.I.
* N.I. no inhibition at 625 μM concentration; ** Calculated by the Cheng-Prusoff equation [66].

Share and Cite

MDPI and ACS Style

Kun, S.; Bokor, É.; Sipos, Á.; Docsa, T.; Somsák, L. Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase. Molecules 2018, 23, 666. https://doi.org/10.3390/molecules23030666

AMA Style

Kun S, Bokor É, Sipos Á, Docsa T, Somsák L. Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase. Molecules. 2018; 23(3):666. https://doi.org/10.3390/molecules23030666

Chicago/Turabian Style

Kun, Sándor, Éva Bokor, Ádám Sipos, Tibor Docsa, and László Somsák. 2018. "Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase" Molecules 23, no. 3: 666. https://doi.org/10.3390/molecules23030666

APA Style

Kun, S., Bokor, É., Sipos, Á., Docsa, T., & Somsák, L. (2018). Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase. Molecules, 23(3), 666. https://doi.org/10.3390/molecules23030666

Article Metrics

Back to TopTop