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. 2016 Feb 29;25(5):932–940. doi: 10.1007/s00044-016-1539-5

Synthesis of novel N-acyl-β-d-glucopyranosylamines and ureas as potential lead cytostatic agents

Vanessa Parmenopoulou 1, Stella Manta 1, Athina Dimopoulou 1, Nikolaos Kollatos 1, Dominique Schols 2, Dimitri Komiotis 1,✉
PMCID: PMC7079967  PMID: 32214768

Abstract

Novel classes of acetylated and fully deprotected N-acyl-β-d-glucopyranosylamines and ureas have been synthesized and biologically evaluated. Acylation of the per-O-acetylated β-d-glucopyranosylurea (5), easily prepared via its corresponding phosphinimine derivative, by zinc chloride catalyzed reaction of the corresponding acyl chlorides RCOCl (a–f) gave the protected N-acyl-β-d-glucopyranosylureas (6a–f), in acceptable-to-moderate yields. Subsequent deacetylation of analogues 6a–f under Zemplén conditions afforded the fully deprotected derivatives 7a,b,d,e,f, while the desired urea 7c was formed after treatment of 6c with dibutyltin oxide. All protected and unprotected compounds were examined for their cytotoxic activity in different L1210, CEM and HeLa tumor cell lines and were also evaluated against a broad panel of DΝΑ and RNA viruses. Derivative 7c exhibited cytostatic activity against the three evaluated tumor cell lines (IC50 9–24 μΜ) and might be the basis for the synthesis of structure-related derivatives with improved cytostatic potential. Only analogue 6f weakly but significantly inhibited the replication of parainfluenza-3 virus, Sindbis virus and Coxsackie virus B4 in cell cultures at concentrations of 45–58 μM.

Keywords: N-acyl-β-d-glucopyranosylamines, N-acyl-β-d-glucopyranosylureas, Antitumor agents, Cytotoxic activity, Antiviral activity

Introduction

Cancer figures among the major concerns of modern healthcare due to its rapidly increasing rates and associated mortality. In light of the growing prevalence of malignant carcinomas and their implications, equal impetus is being paid by the scientific community to research on the disease (Ferlay et al., 2015). Although significant effort has been made to improve the current preventive and/or therapeutic strategies against carcinogenesis, the development of new selective agents capable of suppressing tumor growth and metastasis would contribute greatly to a better prognosis and current therapy (Sethi and Kang, 2011).

In the beginning of 1990s (Lu et al., 2013), small molecule kinase inhibitors have shown great potential as novel therapeutics for the treatment of cancer (Sausville, 2000) because of their intimate involvement in oncogenic signal transduction pathways that present multiple physiological responses, tumor cell proliferation and cell survival (Blanc et al., 2013). Among them, sorafenib (Nevaxar), a diaryl urea analogue, is a small molecular inhibitor of several tyrosine protein kinases for the treatment of advanced renal cell carcinoma (RCC) and advanced hepatocellular carcinoma (HCC) (Wilhelm et al., 2006; Montagut and Settleman, 2009). In the same manner, PAC-1 bearing the N-acylhydrazone pharmacophore is promising as a new antitumor drug that can directly influence the apoptotic machinery or suicide of cells and has shown good results in mouse models (Zhang et al., 2012; Peterson et al., 2009; Putt et al., 2006). Finally, carboxamide analogue sunitinib (Sutent) has proven to be successful in the treatment of renal cancer and pancreatic neuroendocrine tumors, while thiazole carboxamide analogue dasatinib is used for the treatment of several types of leukemia (Jänne et al., 2009). Probably, the use of amide, urea or heteroatom linkers such as nitrogen or oxygen in the structure of the aforementioned inhibitors are important features for their selectivity that allow the formation of one or two hydrogen bonds with residues of the specific kinase (Davis et al., 2011).

In view of the above observations and as a continuation of our long-term interest in glucopyranosyl analogues as antitumor/antiviral agents and potent enzyme inhibitors (Parmenopoulou et al., 2014; Dimopoulou et al., 2013; Manta et al., 2012; Kantsadi et al., 2012), it was envisaged that compounds bearing a glucopyranosyl moiety linked with various aralkyl and aralkenyl groups (Somsák et al., 2008a, b) via the pharmacophore linkers NHCO and NHCONHCO would be endowed with pronounced antitumor activity. We hereby report the facile synthesis and biological properties of novel acetylated as well as fully deprotected N-acyl-β-d-glucopyranosylamines (3a–f, 4a–f) and ureas (6a–f, 7a–f), respectively.

Results and discussion

Chemistry

For the synthesis of the target N-acyl-N′-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylureas (6a–f), the per-O-acetylated β-d-glucopyranosylurea (5), easily prepared via its corresponding phosphinimine derivative (Pinter et al., 1995), seemed a suitable precursor. Therefore, acylation of compound 5 (Pinter et al., 1995) by zinc chloride (ZnCl2) catalyzed reaction of the corresponding acyl chlorides RCOCl (a–f) gave derivatives 6a–f, in acceptable-to-moderate yields (35–67 %). Although the Lewis acidic zinc chloride not only activates acid chlorides but also catalyze iminium ion formation (Paulsen and Pflufhaupt, 1980; Isbell and Frush, 1958) and, thereby, anomerization (Somsák et al., 2008a, b), in our case, the β-anomers 6a–f were solely obtained. Their 1H NMR spectra showed large coupling constants for H-1, H-2, H-3, H-4 and H-5 (J 1,2 ≥ 9.4 Hz, J 2,3 ≥ 8.5 Hz, J 3,4 ≥ 8.9 Hz and J 4,5 ≥ 9.4 Hz) arising from the trans-diaxial orientation of these consecutive protons, indicating the β-configuration of the sugar moiety and equatorially oriented acetyl groups.

Subsequent deacetylation of analogues 6a–f under Zemplén conditions (Agoston et al., 2001) at 0 °C for 20 min afforded the fully deprotected derivatives 7a,b,d,e,f after flash chromatography, in good yields (72–82 %). Deprotection of acyl urea 6c either with basic or acidic transesterification conditions (sodium methoxide, methanolic ammonia, methanolic hydrogen chloride) was unsuccessful, due to faster cleavage of the N-acyl moiety than removal of the O-protecting groups. In order to overcome this difficulty and to successfully synthesize compound 7c, we sought to couple the free glucosyl urea (McKay and Nguyen, 2014; Helm and Kakhesy, 1989) with the desired acyl chloride RCOCl (c) in the presence of ZnCl2, but unfortunately only the starting materials were recovered. To our delight, when the acyl urea 6c was stirred in methanol in the presence of 0.5 eq dibutyltin oxide (Bu2SnO) at reflux (Liu et al., 2002), the acetyl groups were smoothly deprotected and derivative 7c was isolated after flash chromatography, in 83 % yield (Scheme 1).

Scheme 1.

Scheme 1

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Reagents and conditions: (i) H2, 10 % Pd/C, EtOAc, 20 °C, 24 h; (ii) DMF, RCOCl, Et3N, room temperature, 1 h; (iii) ammonia/MeOH or MeOH, methanolic NaOMe (1 M), Amberlyst 15 (H+ form), room temperature; (iv) NH3, CO2, THF, Ph3P, 24 h; (v) CHCl3, RCOCl, ZnCl2, reflux; (vi) MeOH, methanolic NaOMe (1 M), Amberlyst 15 (H+ form), 0 °C, 20 min or MeOH, Bu2SnO, reflux, 2 h

All compounds were well characterized by 1H and 13C NMR, mass spectrometry and elemental analysis and gave satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structure. During the spectroscopic characterization, compound 6f appeared to consist of two rotamers, judged from their 1H NMR spectra, which is probably due to hindered rotation of the amide bond.

Anticancer activity

The cytostatic activity of 3a–f, 4a–f, 6a–f and 7a–f was determined against murine leukemia (L1210), human lymphocyte (CEM) and human cervix carcinoma (HeLa) cell cultures, and the results are summarized in Table 1.

Table 1.

Cytostatic activity of compounds 3a–f, 4a–f, 6a–f and 7a–f against murine leukemia (L1210), human lymphocyte (CEM) and human cervix carcinoma (HeLa) cell cultures and primary fibroblasts

Compound ICa50 (μM) MCCb (μΜ)
L1210 CEM HeLa HEL
3a ≥250 ≥250 ≥250 >100
3b 106 ± 6 116 ± 9 118 ± 23 >100
3c 139 ± 8 180 ± 100 ≥250 >100
3d 110 ± 6 99 ± 15 124 ± 18 >100
3e 184 ± 2 118 ± 5 ≥250 >100
3f 103 ± 1 110 ± 5 64 ± 16 >100
4a 134 ± 1 192 ± 82 84 ± 21 >100
4b >250 >250 >250 >100
4c >250 >250 >250 >100
4d >250 >250 >250 >100
4e >250 >250 >250 >100
4f >250 >250 >250 >100
6a 91 ± 15 110 ± 29 100 ± 14 >100
6b 78 ± 0 38 ± 10 66 ± 12 >100
6c >250 >250 >250 >100
6d 24 ± 0 16 ± 1 44 ± 24 >100
6e 71 ± 16 41 ± 4 88 ± 17 >100
6f 47 ± 8 32 ± 1 39 ± 23 >100
7a 206 ± 44 141 ± 5 >250 >100
7b >250 >250 >250 >100
7c 9.0 ± 5.9 24 ± 1 19 ± 3 >100
7d 25 ± 2 22 ± 4 45 ± 27 >100
7e >250 >250 >250 >100
7f >250 >250 >250 >100
5-Fluorouracil 0.33 ± 0.17 18 ± 5 0.54 ± 0.12 –
6-Mercaptopurine 2.8 ± 1.1 2.8 ± 1.3 1.1 ± 0.1 –
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a50 % inhibitory concentration or compound concentration required to inhibit cell proliferation by 50 %

bMinimal cytotoxic concentration or compound concentration required to affect and alter microscopically detectable human lung fibroblast HEL cell morphology

From the overall results obtained, it was clear that the acetylated N-acyl-β-d-glucopyranosylamines (3b–f) and ureas (6a, b, e, f) showed a better cytostatic profile than their corresponding unprotected derivatives 4b–f and 7a, b, e, f, respectively (Table 1). Exceptions were analogues 4a and 7c, which proved to be more cytostatic than their corresponding acetylated congeners 3a and 6c; in particular derivative 7c proved to be the most cytotoxic for all three tumor cell lines (IC50 of 9, 24 and 19 μΜ, respectively). The cytostatic potential of 7c was only 5- to 15-fold lower than the established 6-mercaptopurine anticancer drug. Finally, the acetylated analogue 6d and the unprotected 7d exhibited a comparable degree of cellular cytotoxicity (IC50 of 16–45 μΜ). Also, the tested compounds were not cytotoxic in normal (primary) confluent human lung fibroblast (HEL) cell cultures (MCC50 > 100 μΜ).

Broad-spectrum evaluation for potential antiviral activity

Compounds 3a–f, 4a–f, 6a–f and 7a–f have been evaluated against a broad panel of DΝΑ and RNA viruses, including herpes simplex virus type 1 [HSV-1(KOS)], HSV-2 (G), vaccinia virus and vesicular stomatitis virus (VSV) in HEL cultures; VSV, Coxsackie virus B4 and respiratory syncytial virus (RSV) in HeLa cell cultures; parainfluenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4 and Punta Toro virus in Vero cell cultures; influenza virus A (H1N1, H3N2) and influenza virus B in MDCK cell cultures, feline corona virus (FIPV) and feline herpes virus in CRFK cell cultures and human inmmunodeficiency virus (HIV-1IIIB and HIV-2ROD) in CEM T cell cultures.

Only the acetylated glucopyranosyl urea 6f was found to inhibit the proliferation of parainfluenza-3 virus, Sindbis virus and Coxsackie virus B4 in Vero cells at the concentration of 45 and 58 μM (vide IC50), respectively, whereas the well-described antiviral drug ribavirin showed no activity at all (≥250 μM). The polyanionic compound dextran sulfate (DS) (mw 10,000) was also included as a control compound (Table 2).

Table 2.

Cytotoxicity and antiviral activity of 6f in Vero cell cultures

Compound ICb50 (µM)
Minimum cytotoxic concentrationa (µM) Parainfluenza-3 virus Reovirus-1 Sindbis virus Coxsackie virus B4 Punta Toro virus
6f >100 45 >100 58 58 100
DS-10.000 (µg/mL) >100 >100 >100 20 100 100
Ribavirin >250 250 >250 >250 >250 146
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aRequired to cause a microscopically detectable alteration of normal cell morphology

bRequired to reduce virus-induced cytopathicity by 50 %

Conclusion

In this study, we report the synthesis of novel acetylated as well as fully deprotected N-acyl-β-d-glucopyranosylamines and ureas as potential cytotoxic agents. Since the N-acyl-β-d-glucopyranosylureas proved to be more cytostatic than the corresponding amines and the final analogues were less potent than their acetylated congeners, it seems that the cytostatic activity of compounds is associated with the type of the linker, while the acetyl moiety may also contribute to the antitumor effect. Derivative 7c exhibited the most enhanced cytostatic activity (IC50 of 9, 24 and 19 μΜ, respectively) and might be the basis for preparing structure-related derivatives with improved cytostatic potential, while analogue 6f inhibited the proliferation of parainfluenza-3 virus, Sindbis virus and Coxsackie virus B4 in Vero cell cultures at the concentration of 45, 58 and 58 μM (vide IC50), respectively, as compared to ribavirin (>250 μM).

Experimental

Chemistry

Thin layer chromatography (TLC) was performed on Merck precoated 60F254 plates. Reactions were monitored by TLC on silica gel, with detection by UV light (254 nm) or by charring with sulfuric acid. Flash chromatography was performed using silica gel (240–400 mesh, Merck). 1H NMR and 13C NMR spectra were obtained at room temperature with a Bruker 300 spectrometer at 300 and 75.5 MHz, respectively, using chloroform-d (CDCl3) and methanol-d 4 (CD3OD) with internal tetramethylsilane (TMS). The 1H assignments of compounds 6 were based on 1H–1H COSY experiments executed using standard Varian software. Chemical shifts (δ) were given in ppm measured downfield from TMS, and spin–spin coupling constants are in Hz. Mass spectra were obtained on a ThermoQuest Finnigan AQA Mass Spectrometer (electrospray ionization). Optical rotations were measured using an Autopol I polarimeter.

All reactions sensitive to oxygen or moisture were carried out under nitrogen atmosphere using oven-dried glassware. Chloroform (CHCl3) was distilled from phosphorus pentoxide and stored over 4E molecular sieves. Methanol (MeOH) was stored over 3E molecular sieves. 2,3,4,6-Tetra-O-acetyl-β-d-glucopyranosyl azide (1) (Tropper et al., 1992), 2,3,4,6-tetra-O-acetyl-β-d-glycopyranosylamine (2), N-acyl-β-d-glucopyranosylamines 3a–f and 4a–f (Parmenopoulou et al., 2014) and 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylurea (5) (Pinter et al., 1995) were prepared according to the procedures described in literature, and their chemical and physical properties were in agreement with previous data.

General procedure for preparation of the N-acyl-N′-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylureas (6a–f)

To a solution of an acyl chloride (18 mmol) in 20 mL of dry CHCl3, anhydrous ZnCl2 (0.59 mmol) and 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylurea (5) (2.56 mmol) were added with stirring. The reaction mixture was refluxed until TLC showed the complete transformation of the urea. Then, the reaction mixture was poured into ice water and was extracted with chloroform (2×). The organic phases were collected and washed with sat. aq. NaHCO3 solution and water. After drying, the solvent was evaporated under vacuo and the residue was purified by flash chromatography (n-hexane/EtOAc 1:1).

N-(E)-3-(Biphenyl-4-yl)acryloyl-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-urea (6a)

White foam, yield 44 %; Rf = 0.28 (n-hexane/EtOAc 1:1); [α]22D = +4 (c = 0.20, CHCl3); 1H NMR (300 MHz, CDCl3): δ 9.37 (d, 1H, J = 9.0 Hz, NH), 9.10 (s, 1H, NH), 7.86 (d, 1H, J = 15.6 Hz, CH=CH), 7.68–7.38 (m, 9H, ArH), 6.51 (d, 1H, CH=CH), 6.39–5.29 (2pseudo t, 2H, J = 9.6, 9.4 Hz, H-1, H-3), 5.17–5.08 (2pseudo t, 2H, J = 9.4, 9.5 Hz, H-4, H-2), 4.25 (dd, 1H, J = 4.3, 12.5 Hz, H-6a), 4.10 (dd, 1H, J = 1.9, 12.5 Hz, H-6b), 3.83 (ddd, 1H, J = 2.1, 4.1, 10.0 Hz, H-5), 2.06, 2.05, 2.03, 2.01 (4s, 12H, 4OAc); 13C NMR (75.5 MHz, CDCl3) δ 170.6, 170.1, 169.8, 169.4, 166.4, 154.8 (CO), 145.4, 143.7, 139.9, 132.8, 128.9, 128.8, 128.0, 127.7, 127.0, 118.3 (CH=CH and Ar–C), 79.0, 73.6, 73.0, 70.0, 68.2, 61.6 (C-1–C-6), 20.7, 20.6, 20.5 (OCOCH3); ESI–MS: m/z, 597.24 [M + H]+. Anal. calcd for C30H32N2O11: C, 60.40; H, 5.41; N, 4.70; Found: C, 60.17; H, 5.59; N, 4.83.

N-4-(5,6,7,8-Tetrahydronaphthalen-2-yl)butanoyl-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-urea (6b)

Yellow foam, Yield 38 %; Rf = 0.38 (n-hexane/EtOAc 1:1); [α]22D = +2 (c = 0.20, CHCl3); 1H NMR (300 MHz, CDCl3): δ 6.99–6.86 (m, 4H, ArH, NH), 6.13 (d, 1H, J = 9.2 Hz, NH), 5.34–5.25 (2pseudo t, 2H, J = 9.4, 8.9 Hz, H-1, H-3), 5.06 (t, 1H, J = 9.9 Hz, H-4), 4.90 (t, 1H, J = 9.6 Hz, H-2), 4.30 (dd, 1H, J = 3.8, 12.5 Hz, H-6a), 4.08 (dd, 1H, J = 1.1, 12.5 Hz, H-6b), 3.82 (ddd, 1H, J = 1.8, 3.8, 10.3 Hz, H-5), 2.73 (m, 4H, tetrahydronaphthalene moiety), 2.60 (t, 2H, J = 7.4 Hz, CH2), 2.38 (t, 2H, J = 7.4 Hz, CH2), 2.07, 2.03, 2.02, 2.01 (4s, 12H, 4OAc), 1.95–1.88 (m, 2H, CH2), 1.79 (m, 4H, tetrahydronaphthalene moiety); 13C NMR (75.5 MHz, CDCl3) δ 173.8, 170.5, 169.9, 169.7, 169.4, 152.9 (CO), 137.7, 137.3, 135.2, 129.3, 129.1, 125.6 (Ar–C), 79.1, 73.7, 73.2, 70.4, 68.4, 61.8 (C-1–C-6), 36.4, 34.4, 29.4, 29.1, 26.0, 23.3, 23.2 (3CH2 and 4CH2 of tetrahydronaphthalene moiety), 20.7, 20.5, 20.4 (OCOCH3); ESI–MS: m/z, 591.21 [M + H]+. Anal. calcd for C29H38N2O11: C, 58.97; H, 6.49; N, 4.74; Found: C, 59.31; H, 6.67; N, 4.53.

N-2-(Biphenyl-4-yloxy)acetyl-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-urea (6c)

Yellow foam, Yield 62 %; Rf = 0.32 (n-hexane/EtOAc 1:1); [α]22D = + 16 (c = 0.20, CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.92 (d, 1H, J = 9.0 Hz, NH), 8.51 (s, 1H, NH), 7.58–7.30 (m, 7H, ArH), 7.00 (d, 2H, J = 8.6 Hz, ArH), 7.35–5.25 (2pseudo t, 2H, J = 9.4, 9.2 Hz, H-1, H-3), 5.14–5.06 (2pseudo t, 2H, J = 9.7, 9.5 Hz, H-4, H-2), 4.63, 4.58 (q, AB-system, 2H, J = 16.3 Hz, CH2), 4.28 (dd, 1H, J = 4.4, 12.5 Hz, H-6a), 4.13 (dd, 1H, J = 2.1, 12.5 Hz, H-6b), 3.83 (ddd, 1H, J = 2.2, 4.3, 10.1 Hz, H-5), 2.09, 2.04, 2.03, 2.02 (4s, 12H, 4OAc); 13C NMR (75.5 MHz, CDCl3) δ 170.7, 170.0, 169.8, 169.5, 169.4, 169.3 (CO), 157.4, 140.6, 134.8, 128.8, 128.4, 128.2, 126.8, 114.9 (Ar–C), 77.9, 75.0, 72.9, 70.1, 68.0, 67.5, 61.4 (CH2 and C1–C6), 20.7, 20.6, 20.5 (OCOCH3); ESI–MS: m/z, 601.22 [M + H]+. Anal. calcd for C29H32N2O12: C, 58.00; H, 5.37; N, 4.66; Found: C, 57.88; H, 5.73; N, 5.06.

N-(E)-3-(4-Isopropylphenyl)acryloyl-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-urea (6d)

White foam, Yield 67 %; Rf = 0.36 (n-hexane/EtOAc 1:1); [α]22D = -4 (c = 0.20, CHCl3); 1H NMR (300 MHz, CDCl3): δ 9.32 (d, 1H, J = 9.0 Hz, NH), 8.59 (s, 1H, NH), 7.80 (d, 1H, J = 15.6 Hz, CH=CH), 7.47 (d, 2H, J = 8.1 Hz, ArH cumenyl), 7.28 (d, 2H, J = 10.1 Hz, ArH cumenyl), 6.39 (d, 1H, CH=CH), 5.37–5.27 (2pseudo t, 2H, J = 9.4, 9.8 Hz, H-1, H-3), 5.15–5.08 (2pseudo t, 2H, J = 9.4, 9.6 Hz, H-4, H-2), 4.26 (dd, 1H, J = 4.4, 12.4 Hz, H-6a), 4.15–4.08 (dd, 1H, J = 1.6, 12.4 Hz, H-6b), 3.83 (ddd, 1H, J = 2.1, 4.1, 10.0 Hz, H-5), 2.99–2.90 (m, 1H, CH3–CH–CH3), 2.05, 2.03 (2s, 12H, 4OAc), 1.27 (d, 6H, J = 6.9 Hz, CH3–CH–CH3); 13C NMR (75.5 MHz, CDCl3) δ 170.7, 170.1, 169.9, 169.4, 166.3, 154.4 (CO), 152.5, 146.1, 131.4, 128.5, 127.2, 117.3 (CH=CH and Ar–C), 79.0, 73.6, 73.0, 70.1, 68.1, 61.6 (C-1–C-6), 34.2, 23.7 (CH3–CH–CH3), 20.7, 20.6, 20.5 (OCOCH3); ESI–MS: m/z, 563.21 [M + H]+. Anal. calcd for C27H34N2O11: C, 57.64; H, 6.09; N, 4.98; Found: C, 57.46; H, 6.34; N, 5.29.

N-(R)-3-(4-Ethylphenyl)butanoyl-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-urea (6e)

Yellow foam, Yield 44 %; Rf = 0.28 (n-hexane/EtOAc 1:1); [α]22D = -10 (c = 0.20, CHCl3); 1H NMR (300 MHz, CDCl3): δ 9.05 (d, 1H, J = 8.2 Hz, NH), 8.28 (s, 1H, NH), 7.19–711 (m, 4H, ArH), 5.31–5.16 (2pseudo t, 2H, J = 9.4, 9.2 Hz, H-1, H-3), 5.12–5.02 (2pseudo t, 2H, J = 9.5, 10.0 Hz, H-4, H-2), 4.25 (dd, 1H, J = 4.3, 12.4 Hz, H-6a), 4.11 (dd, 1H, J = 2.0, 12.4 Hz, H-6b), 3.80 (ddd, 1H, J = 2.1, 4.0, 10.7 Hz, H-5), 3.35–3.22 (m, 1H, CH), 3.69–3.54 (m, 4H, CH2, CH2CH3), 2.07, 2.02, 2.01, 1.98 (4s, 12H, 4OAc), 1.34 (d, 3H, J = 6.8 Hz, CH3), 1.20 (t, 3H, J = 7.6 Hz, CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 175.9, 172.3, 171.5, 170.1, 169.8, 154.4 (CO), 142.5, 142.4, 128.7, 126.6 (Ar–C), 77.9, 73.3, 72.4, 70.7, 68.2, 61.6 (C-1–C-6), 45.5, 42.3, 36.0 (CH and 2CH2), 27.7, 21.0, 20.8, 20.7, 15.1 (OCOCH3, CHCH3, CH2CH3); ESI–MS: m/z, 565.20 [M + H]+. Anal. calcd for C27H36N2O11: C, 57.44; H, 6.43; N, 4.96; Found: C, 57.34; H, 6.72; N, 4.57.

N-(S)-3-(4-Isopropylphenyl)-2-methylpropanoyl-N′-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-urea (6f)

Yellow foam, Yield 35 %; Rf = 0.33 (n-hexane/EtOAc 1:1); [α]22D = + 4 (c = 0.20, CHCl3); The 1H NMR spectrum showed hindered rotation around the amide bond. 1H NMR (300 MHz, CDCl3): δ 9.11 (t, 1H, J = 10.1 Hz, NH), 8.10 (2br s, 1H, NH), 7.17–7.05 (m, 4H, ArH cumenyl), 5.32–5.18 (2pseudo t, 2H, J = 9.4, 9.1 Hz, H-1, H-3), 5.12–5.03 (2pseudo t, 2H, J = 9.4, 8.5 Hz, H-4, H-2), 4.26 (dd, 1H, J = 4.3, 12.5 Hz, H-6a), 4.09 (dd, 1H, J = 1.6, 12.5 Hz, H-6b), 3.77 (ddd, 1H, J = 2.0, 4.0, 10.1 Hz, H-5), 3.05–2.83 (m, 2H, CH2), 2.69–2.58 (m, 2H, CH, CH3-CH–CH3), 2.08, 2.07, 2.02, 2.01 (4s, 12H, 4OAc), 1.24, 1.23 (2d, 6H, J = 6.9 Hz, CH3–CH–CH3), 1.19 (2d, 3H, J = 6.5 Hz, CH3); 13C NMR (75.5 MHz, CDCl3) δ 177.2, 170.5, 170.0, 169.5, 169.3, 153.8 (CO), 147.4, 135.8, 128.8, 126.7 (Ar–C), 79.1, 73.8, 73.2, 70.4, 68.4, 61.8 (C-1–C-6), 43.9, 39.1, 33.7 (2CH and CH2), 23.9, 20.6, 20.5, 20.4, 16.8 (CH3–CH–CH3, OCOCH3, CHCH3); ESI–MS: m/z, 579.25 [M + H]+. Anal. calcd for C28H38N2O11: C, 58.12; H, 6.62; N, 4.84; Found: C, 58.26; H, 6.35; N, 4.72.

General procedure for the preparation of the N-acyl-N′-β-d-glucopyranosylureas 7a,b,d,e,f

The protected ureas 6a,b,d,e,f (0.18 mmol) were dissolved in dry MeOH (1 mL), 1–2 drops of 1 M methanolic sodium methoxide (NaOMe) solution were added and the reaction mixture was kept at 0 °C until completion of the transformation (20 min, TLC, EtOAc/MeOH 4:1). Amberlyst 15 (H+ form) was then added to remove sodium ions, the resin was filtered off, the solvent was removed and the residue was purified by flash chromatography (EtOAc/MeOH 4:1) to afford pure 7a,b,d,e,f.

N-(E)-3-(Biphenyl-4-yl)acryloyl-N′-(β-d-glucopyranosyl)-urea (7a)

White syrup, Yield 72 %; Rf = 0.22 (EtOAc/MeOH 4:1); [α]22D = + 2 (c = 0.20, MeOH); 1H NMR (300 MHz, CD3OD): δ 7.83 (d, 1H, J = 15.7 Hz, CH=CH), 7.71–7.65 (m, 6H, ArH), 7.51–7.36 (m, 3H, ArH), 6.76 (d, 1H, CH=CH), 4.98 (d, 1H, J = 8.9 Hz, H-1), 3.88 (dd, 1H, J = 1.5, 11.8 Hz, H-6b), 3.71 (dd, 1H, J = 4.4, 11.8 Hz, H-6a), 3.50–3.37 (m, 4H, H-2–Η-5); 13C NMR (75.5 MHz, CD3OD) δ 168.8, 156.3 (CO), 145.6, 144.9, 141.4, 134.7, 130.0, 129.9, 129.0, 128.6, 128.0, 120.2 (CH=CH and Ar–C), 82.2, 79.8, 79.1, 74.6, 71.6, 62.9 (C-1–C-6); ESI–MS: m/z, 429.17 [M + H]+. Anal. calcd for C22H24N2O7: C, 61.67; H, 5.65; N, 6.54; Found: C, 61.39; H, 5.48; N, 6.65.

N-4-(5,6,7,8-Tetrahydronaphthalen-2-yl)butanoyl-N′-(β-d-glucopyranosyl)-urea (7b)

Yellow syrup, Yield 82 %; Rf = 0.25 (EtOAc/MeOH 4:1); [α]22D = + 22 (c = 0.20, MeOH); 1H NMR (300 MHz, CD3OD): δ 6.94–6.85 (m, 3H, ArH), 4.90 (d, 1H, J = 9.0 Hz, H-1), 3.83 (dd, 1H, J = 1.3, 11.8 Hz, H-6b), 3.66 (dd, 1H, J = 4.4, 11.8 Hz, H-6a), 3.44–3.35 and 3.28–3.22 (2 m, 4H, H-2–Η-5), 2.71 (m, 4H, tetrahydronaphthalene moiety), 2.56 (t, 2H, J = 7.5 Hz, CH2), 2.33 (t, 2H, J = 7.3 Hz, CH2), 1.95–1.85 (m, 2H, CH2), 1.78 (m, 4H, tetrahydronaphthalene moiety); 13C NMR (75.5 MHz, CD3OD) δ 177.2, 156.0 (CO), 139.7, 138.1, 135.8, 130.1, 126.7 (Ar–C), 82.1, 79.8, 79.1, 74.5, 71.6, 62.9 (C-1–C-6), 36.8, 35.6, 30.4, 30.1, 27.7, 24.6, 24.5 (3CH2 and 4CH2 of tetrahydronaphthalene moiety); ESI–MS: m/z, 423.18 [M + H]+. Anal. calcd for C21H30N2O7: C, 59.70; H, 7.16; N, 6.63; Found: C, 59.85; H, 7.01; N, 6.49.

N-2-(Biphenyl-4-yloxy)acetyl-N′-(β-d-glucopyranosyl)-urea (7c)

The protected derivative 6c (1 mmol) was heated under reflux in dry MeOH (4 mL) containing Bu2SnO (0.5 mmol) for 2 h and the fully deprotected compound 7c was obtained as a yellow syrup after flash chromatography using EtOAc/MeOH 4:1 as eluting solvents. Yield 83 %; Rf = 0.18 (EtOAc/MeOH 4:1); [α]22D = −8 (c = 0.20, MeOH); 1H NMR (300 MHz, CD3OD): δ 7.59–7.56 (m, 4H, ArH), 7.40, 7.28 (2t, 3H, J = 7.6 Hz, ArH), 7.10 (d, 2H, J = 8.7 Hz, ArH), 5.04 (d, 1H, J = 8.6 Hz, H-1), 4.63, 4.60 (q, AB-system, 2H, J = 15.0 Hz, CH2), 3.84 (dd, 1H, J = 1.3, 11.8 Hz, H-6b), 3.68 (dd, 1H, J = 4.4, 11.8 Hz, H-6a), 3.46–3.36 (m, 4H, Η-2–Η-5); 13C NMR (75.5 MHz, CD3OD) δ 172.1, 158.7 (CO), 141.9, 136.2, 129.8, 129.2, 127.9, 127.6, 116.3 (Ar–C), 80.9, 79.5, 79.0, 73.9, 71.3, 68.4, 62.6 (C1–C6, CH2); ESI–MS: m/z, 433.18 [M + H]+. Anal. calcd for C21H24N2O8: C, 58.33; H, 5.59; N, 6.48; Found: C, 58.67; H, 5.32; N, 6.23.

N-(E)-3-(4-Isopropylphenyl)acryloyl-N′-(β-d-glucopyranosyl)-urea (7d)

White syrup, Yield 76 %; Rf = 0.29 (EtOAc/MeOH 4:1); [α]22D = + 20 (c = 0.20, MeOH); 1H NMR (300 MHz, CD3OD): δ 7.74 (d, 1H, J = 15.7 Hz, CH=CH), 7.53, 7.29 (2d, 4H, J = 8.2 Hz ArH cumenyl), 6.64 (d, 1H, CH=CH), 4.94 (d, 1H, J = 9.0 Hz, H-1), 3.85 (dd, 1H, J = 1.8, 11.6 Hz, H-6b), 3.67 (dd, 1H, J = 4.4, 11.6 Hz, H-6a), 3.46–3.34 (m, 4H, H-2–H-5), 2.97–2.88 (m, 1H, CH), 1.25 (d, 6H, J = 6.9 Hz, CH3–CH–CH3); 13C NMR (75.5 MHz, CD3OD) δ 168.9, 156.4 (CO), 153.5, 146.2, 133.4, 129.6, 128.2, 119.3 (CH=CH and Ar–C), 82.2, 79.8, 79.1, 74.6, 71.6, 62.9 (C-1–C-6), 35.4, 24.1 (CH3–CH–CH3); ESI–MS: m/z, 395.20 [M + H]+. Anal. calcd for C19H26N2O7: C, 57.86; H, 6.64; N, 7.10; Found: C, 57.69; H, 6.29; N, 7.23.

N-(R)-3-(4-Ethylphenyl)butanoyl-N′-(β-d-glucopyranosyl)-urea (7e)

Yellow syrup, Yield 74 %; Rf = 0.37 (EtOAc/MeOH 4:1); [α]22D = +20 (c = 0.20, MeOH); 1H NMR (300 MHz, CD3OD): δ 7.13–7.09 (m, 4H, ArH), 4.88 (d, 1H, J = 9.0 Hz, H-1), 3.83 (dd, 1H, J = 4.5, 11.8 Hz, H-6a), 3.70–3.62 (m, 1H, H-6b), 3.42–3.34 and 3.26–3.19 (2 m, 4H, H-2–H-5), 2.64–2.53 (m, 5H, CH, CH2, CH2CH3), 1.29–1.24 (m, 6H, CHCH3, CH2CH3); 13C NMR (75.5 MHz, CD3OD) δ 176.0, 155.9 (CO), 145.7, 143.7, 129.0, 127.8 (Ar–C), 82.1, 79.8, 79.0, 74.5, 71.5, 62.8 (C-1–C-6), 45.9, 37.2, 29.4 (CH and 2CH2), 22.3, 16.1 (CHCH3, CH2CH3); ESI–MS: m/z, 397.16 [M + H]+. Anal. calcd for C19H28N2O7: C, 57.56; H, 7.12; N, 7.07; Found: C, 57.73; H, 6.86; N, 6.70.

N-(S)-3-(4-Isopropylphenyl)-2-methylpropanoyl-N′-(β-d-glucopyranosyl)-urea (7f)

Yellow syrup, Yield 72 %; Rf = 0.35 (EtOAc/MeOH 4:1); [α]22D = +36 (c = 0.20, MeOH); 1H NMR (300 MHz, CD3OD): δ 7.15–7.08 (m, 4H, ArH cumenyl), 4.90 (d, 1H, J = 9.0 Hz, H-1), 3.84 (m, 1H, H-6b), 3.68 (dd, 1H, J = 4.3, 12.0 Hz, H-6a), 3.46–3.35 (m, 4H, H-2–H-5), 3.00–2.83 and 2.81–2.57 (2 m, 4H, CH2, CH, CH3–CH–CH3), 1.22 (d, 6H, J = 6.9 Hz, CH3–CH–CH3), 1.14 (d, 3H, J = 6.8 Hz, CH3); 13C NMR (75.5 MHz, CD3OD) δ 180.3, 156.1 (CO), 148.2, 137.8, 130.0, 127.5 (Ar–C), 82.0, 79.8, 79.0, 74.4, 71.3, 62.7 (C-1–C-6), 44.4, 40.0, 35.1 (2CH and CH2), 24.5, 17.8 (CH3–CH–CH3, CHCH3); ESI–MS: m/z, 411.19 [M + H]+. Anal. calcd for C20H30N2O7: C, 58.52; H, 7.37; N, 6.82; Found: C, 58.33; H, 7.63; N, 6.42.

Antiviral activity assays (Kokosza et al., 2013; Novikov et al., 2013)

The antiviral assays, other than the anti-HIV assays, were based on the inhibition of virus-induced cytopathicity or plaque formation in HEL [herpes simplex virus type 1 (HSV-1) (KOS), HSV-2 (G), vaccinia virus, vesicular stomatitis virus, human cytomegalovirus (HCMV), and varicella-zoster virus (VZV)], Vero (parainfluenza-3, reovirus-1, Sindbis virus, and Coxsackie B4), HeLa (vesicular stomatitis virus, Coxsackie virus B4, and respiratory syncytial virus) or MDCK [influenza A (H1N1; H3N2) and influenza B] cell cultures. The confluent cell cultures (or nearly confluent for MDCK cells) in microtiter 96-well plates were inoculated with 100 CCID50 of virus (1 CCID50 being the virus dose to infect 50 % of the cell cultures) or with 20 plaque-forming units (PFU) (for VZV) in the presence of varying concentrations (100, 20, etc., µM) of the test compounds. The viral cytopathicity was recorded as soon as it reached completion in the control virus-infected cell cultures that were not treated with the test compounds. The antiviral activity was expressed as the EC50 or the compound concentration required to reduce virus-induced cytopathogenicity or viral plaque (VZV) plaque formation by 50 %. The minimal cytotoxic concentration (MCC) of the compounds was defined as the compound concentration that caused a microscopically visible alteration of cell morphology. Alternatively, the cytostatic activity of the test compounds was measured based on the inhibition of cell growth. HEL cells were seeded at a rate of 5 × 103 cells/well into 96-well microtiter plates and allowed to proliferate for 24 h. Then, the medium containing different concentrations of the test compounds was added. After three days of incubation at 37 °C, the cell number was determined with a Coulter counter. The cytostatic concentration was calculated as the CC50, or the compound concentration required to reduce cell proliferation by 50 % relative to the number of cells in the untreated controls. The methodology of the anti-HIV assays was as follows: human CEM (~3×105 cells/cm3) cells were infected with 100 CCID50 of HIV-1IIIB or HIV-2ROD and seeded in 200-µL wells of a microtiter plate containing appropriate dilutions of the test compounds. After 4 days of incubation at 37 °C, the HIV-induced CEM giant cell formation was examined light microscopically.

Antiproliferative assays (Kokosza et al., 2013; Novikov et al., 2013)

The cytostatic effects of the test compounds on murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and human cervix carcinoma cells (HeLa) were evaluated as follows: an appropriate number of cells suspended in growth medium were allowed to proliferate in 200-µL-wells of 96-well microtiter plates in the presence of variable amounts of test compounds at 37 °C in a humidified CO2-controlled atmosphere. After 48 h (L1210), 72 h (CEM) or 96 h (HeLa), the number of cells was determined in a Coulter counter. The IC50 value was defined as the compound concentration required to inhibit cell proliferation by 50 %.

Cytotoxic activity assay (Kokosza et al., 2013; Novikov et al., 2013)

Confluent human lung fibroblast (HEL) cultures in 96-well microtiter plate were exposed to serial dilutions of the test compounds (i.e., 100, 20, 4, 0.8 μΜ). After 3 days of incubation at 37 °C, microscopical detectable alterations of cell morphology were examined.

Acknowledgments

This work was supported in part by the Postgraduate Programmes “Biotechnology-Quality assessment in Nutrition and the Environment,” “Application of Molecular Biology-Molecular Genetics-Molecular Markers,” Department of Biochemistry and Biotechnology, University of Thessaly, and the KU Leuven (GOA 10/14). We thank Lizette van Berckelaer, Leen Ingels, Leentje Persoons and Frieda De Meyer for excellent technical assistance in the evaluation of these compounds in the cellular assays.

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