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

Article abstract of DOI:10.1007/s00044-016-1539-5

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.

Full text of DOI:10.1007/s00044-016-1539-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2016) 25:932–940
DOI 10.1007/s00044-016-1539-5
ORIGINAL RESEARCH
Synthesis of novel N-acyl-b-D-glucopyranosylamines and ureas
as potential lead cytostatic agents
Vanessa Parmenopoulou1 Stella Manta1 Athina Dimopoulou1
•
•
•
Nikolaos Kollatos1 Dominique Schols2 Dimitri Komiotis1
•
•
Received: 12 January 2015 / Accepted: 16 February 2016 / Published online: 29 February 2016
Ó Springer Science+Business Media New York 2016
Abstract Novel classes of acetylated and fully depro-
tected N-acyl-b-D-glucopyranosylamines and ureas have
been synthesized and biologically evaluated. Acylation of
the per-O-acetylated b-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-b-D-
glucopyranosylureas (6a–f), in acceptable-to-moderate
yields. Subsequent deacetylation of analogues 6a–f under
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).
´
Zemplen conditions afforded the fully deprotected deriva-
tives 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 DMA and
RNA viruses. Derivative 7c exhibited cytostatic activity
against the three evaluated tumor cell lines (IC50 9–24 lL)
and might be the basis for the synthesis of structure-related
derivatives with improved cytostatic potential. Only ana-
logue 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 lM.
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 physi-
ological responses, tumor cell proliferation and cell sur-
vival (Blanc et al., 2013). Among them, sorafenib
(Nevaxar), a diaryl urea analogue, is a small molecular
inhibitor of several tyrosine protein kinases for the treat-
ment 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 ana-
logue dasatinib is used for the treatment of several types of
Keywords N-acyl-b-D-glucopyranosylamines Á
N-acyl-b-D-glucopyranosylureas Á Antitumor agents Á
Cytotoxic activity Á Antiviral activity
& Dimitri Komiotis
dkom@bio.uth.gr
1
Laboratory of Bioorganic Chemistry, Department of
Biochemistry and Biotechnology, University of Thessaly, 26
Ploutonos Str., 41 221 Larissa, Greece
2
Department of Microbiology and Immunology, Rega Institute
for Medical Research, KU Leuven, Louvain, Belgium
¨
leukemia (Janne et al., 2009). Probably, the use of amide,
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Med Chem Res (2016) 25:932–940
933
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).
Results and discussion
Chemistry
For the synthesis of the target N-acyl-N0-2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosylureas (6a–f), the per-O-acety-
lated b-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
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 (Somsak et al.,
2008a, b) via the pharmacophore linkers NHCO and
NHCONHCO would be endowed with pronounced antitu-
mor activity. We hereby report the facile synthesis and
biological properties of novel acetylated as well as fully
deprotected N-acyl-b-D-glucopyranosylamines (3a–f, 4a–
f) and ureas (6a–f, 7a–f), respectively.
´
(Somsak et al., 2008a, b), in our case, the b-anomers 6a–
f were solely obtained. Their 1H NMR spectra showed
Ligands (R)
a
b
c
d
e
f
Scheme 1 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
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Med Chem Res (2016) 25:932–940
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 (lM)
MCCb
(lL)
HEL
L1210
CEM
HeLa
3a
C250
C250
C250
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
–
3b
106
6
8
6
2
1
1
116
9
118 23
C250
3c
139
180 100
99 15
3d
110
124 18
C250
3e
184
118
110
5
5
3f
103
64 16
84 21
[250
4a
134
192 82
[250
4b
[250
[250
[250
[250
[250
4c
[250
[250
4d
[250
[250
4e
[250
[250
4f
[250
[250
6a
91 15
110 29
38 10
[250
100 14
66 12
[250
6b
78
0
6c
[250
24
6d
0
16
1
4
1
44 24
88 17
39 23
[250
6e
71 16
47
41
6f
8
32
7a
206 44
[250
9.0 5.9
141
[250
24
5
7b
[250
19
7c
1
4
3
7d
25
2
22
45 27
[250
7e
[250
[250
[250
[250
18
7f
[250
5-Fluorouracil
0.33 0.17
2.8 1.1
5
0.54 0.12
1.1 0.1
6-Mercaptopurine
2.8 1.3
–
a
50 % inhibitory concentration or compound concentration required to inhibit cell proliferation by 50 %
b
Minimal cytotoxic concentration or compound concentration required to affect and alter microscopically detectable human lung fibroblast HEL
cell morphology
large coupling constants for H-1, H-2, H-3, H-4 and H-5
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).
(J1,2 C 9.4 Hz,
J2,3 C 8.5 Hz,
J3,4 C 8.9 Hz
and
J4,5 C 9.4 Hz) arising from the trans-diaxial orientation of
these consecutive protons, indicating the b-configuration of
the sugar moiety and equatorially oriented acetyl groups.
Subsequent deacetylation of analogues 6a–f under
´
Zemplen 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
1
transesterification
conditions
(sodium
methoxide,
All compounds were well characterized by H and 13C
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
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
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Med Chem Res (2016) 25:932–940
935
Table 2 Cytotoxicity and antiviral activity of 6f in Vero cell cultures
Compound
ICb50 (lM)
Minimum cytotoxic
concentrationa (lM)
Parainfluenza-3
virus
Reovirus-1
Sindbis
virus
Coxsackie
virus B4
Punta
Toro virus
6f
[100
[100
[250
45
[100
[100
[250
58
58
100
100
146
DS-10.000 (lg/mL)
[100
250
20
100
Ribavirin
[250
[250
a
Required to cause a microscopically detectable alteration of normal cell morphology
Required to reduce virus-induced cytopathicity by 50 %
b
consist of two rotamers, judged from their 1H NMR
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 con-
centration of 45 and 58 lM (vide IC50), respectively,
whereas the well-described antiviral drug ribavirin showed
no activity at all (C250 lM). The polyanionic compound
dextran sulfate (DS) (mw 10,000) was also included as a
control compound (Table 2).
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.
From the overall results obtained, it was clear that the
acetylated N-acyl-b-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 cor-
responding 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 lL, 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 lL). Also, the tested compounds were not cyto-
toxic in normal (primary) confluent human lung fibroblast
(HEL) cell cultures (MCC50 [ 100 lL).
Conclusion
In this study, we report the synthesis of novel acetylated
as well as fully deprotected N-acyl-b-D-glucopyranosy-
lamines and ureas as potential cytotoxic agents. Since the
N-acyl-b-D-glucopyranosylureas proved to be more
cytostatic than the corresponding amines and the final
analogues were less potent than their acetylated con-
geners, 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 lL, 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 lM (vide
IC50), respectively, as compared to ribavirin ([250 lM).
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 DMA 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 syncy-
tial 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
Experimental
Chemistry
Thin layer chromatography (TLC) was performed on Merck
precoated 60F254 plates. Reactions were monitored by TLC
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Med Chem Res (2016) 25:932–940
on silica gel, with detection by UV light (254 nm) or by
charring with sulfuric acid. Flash chromatography was per-
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)
d 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.
1
formed using silica gel (240–400 mesh, Merck). H 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-d4
1
(CD3OD) with internal tetramethylsilane (TMS). The H
1
assignments of compounds 6 were based on H–1H COSY
experiments executed using standard Varian software.
Chemical shifts (d) 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-b-D-glucopyranosyl azide
(1) (Tropper et al., 1992), 2,3,4,6-tetra-O-acetyl-b-D-
glycopyranosylamine (2), N-acyl-b-D-glucopyranosylami-
nes 3a–f and 4a–f (Parmenopoulou et al., 2014) and
2,3,4,6-tetra-O-acetyl-b-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.
N-4-(5,6,7,8-Tetrahydronaphthalen-2-yl)butanoyl-N0-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-urea (6b)
Yellow foam, Yield 38 %; Rf = 0.38 (n-hexane/EtOAc
1
1:1); [a]2D2 = ?2 (c = 0.20, CHCl3); H NMR (300 MHz,
CDCl3): d 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, tetrahy-
dronaphthalene 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) d 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.
General procedure for preparation of the N-acyl-N0-
2,3,4,6-tetra-O-acetyl-b-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-te-
tra-O-acetyl-b-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 (29). 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 chromatogra-
phy (n-hexane/EtOAc 1:1).
N-2-(Biphenyl-4-yloxy)acetyl-N0-(2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl)-urea (6c)
Yellow foam, Yield 62 %; Rf = 0.32 (n-hexane/EtOAc
1:1); [a]2D2 = ? 16 (c = 0.20, CHCl3); 1H NMR
(300 MHz, CDCl3): d 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) d 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-(Biphenyl-4-yl)acryloyl-N0-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-urea (6a)
White foam, yield 44 %; Rf = 0.28 (n-hexane/EtOAc 1:1);
[a]2D2 = ?4 (c = 0.20, CHCl3); 1H NMR (300 MHz,
CDCl3): d 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,
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Med Chem Res (2016) 25:932–940
937
N-(E)-3-(4-Isopropylphenyl)acryloyl-N0-(2,3,4,6-tetra-O-
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) d 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.
acetyl-b-D-glucopyranosyl)-urea (6d)
White foam, Yield 67 %; Rf = 0.36 (n-hexane/EtOAc 1:1);
[a]2D2 = -4 (c = 0.20, CHCl3); 1H NMR (300 MHz,
CDCl3): d 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)
d 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.
General procedure for the preparation of the N-acyl-N0-b-
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 trans-
formation (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-(R)-3-(4-Ethylphenyl)butanoyl-N0-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-urea (6e)
Yellow foam, Yield 44 %; Rf = 0.28 (n-hexane/EtOAc
1
1:1); [a]2D2 = -10 (c = 0.20, CHCl3); H NMR (300 MHz,
CDCl3): d 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) d
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-(E)-3-(Biphenyl-4-yl)acryloyl-N0-(b-D-glucopyranosyl)-
urea (7a)
White syrup, Yield 72 %; Rf = 0.22 (EtOAc/MeOH 4:1);
[a]2D2 = ? 2 (c = 0.20, MeOH); 1H NMR (300 MHz,
CD3OD): d 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–H-5); 13C NMR (75.5 MHz,
CD3OD) d 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-(S)-3-(4-Isopropylphenyl)-2-methylpropanoyl-N0-
(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-urea (6f)
N-4-(5,6,7,8-Tetrahydronaphthalen-2-yl)butanoyl-N0-(b-D-
glucopyranosyl)-urea (7b)
Yellow foam, Yield 35 %; Rf = 0.33 (n-hexane/EtOAc
1:1); [a]2D2 = ? 4 (c = 0.20, CHCl3); The H NMR spec-
1
1
trum showed hindered rotation around the amide bond. H
Yellow syrup, Yield 82 %; Rf = 0.25 (EtOAc/MeOH 4:1);
[a]2D2 = ? 22 (c = 0.20, MeOH); 1H NMR (300 MHz,
CD3OD): d 6.94–6.85 (m, 3H, ArH), 4.90 (d, 1H,
NMR (300 MHz, CDCl3): d 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,
123

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Med Chem Res (2016) 25:932–940
N-(R)-3-(4-Ethylphenyl)butanoyl-N0-(b-D-glucopyranosyl)-
urea (7e)
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–H-5), 2.71 (m, 4H, tetrahydron-
aphthalene 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) d 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.
Yellow syrup, Yield 74 %; Rf = 0.37 (EtOAc/MeOH 4:1);
[a]2D2 = ?20 (c = 0.20, MeOH); 1H NMR (300 MHz,
CD3OD): d 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) d 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-2-(Biphenyl-4-yloxy)acetyl-N0-(b-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); [a]2D2 = -8 (c = 0.20,
N-(S)-3-(4-Isopropylphenyl)-2-methylpropanoyl-N0-
(b-D-glucopyranosyl)-urea (7f)
Yellow syrup, Yield 72 %; Rf = 0.35 (EtOAc/MeOH 4:1);
[a]2D2 = ?36 (c = 0.20, MeOH); 1H NMR (300 MHz,
CD3OD): d 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) d
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.
1
MeOH); H NMR (300 MHz, CD3OD): d 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, H-2–H-5); 13C NMR
(75.5 MHz, CD3OD) d 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-N0-(b-D-
glucopyranosyl)-urea (7d)
Antiviral activity assays (Kokosza et al., 2013;
Novikov et al., 2013)
White syrup, Yield 76 %; Rf = 0.29 (EtOAc/MeOH 4:1);
[a]2D2 = ? 20 (c = 0.20, MeOH); 1H NMR (300 MHz,
CD3OD): d 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) d 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.
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, reo-
virus-1, Sindbis virus, and Coxsackie B4), HeLa (vesicular
stomatitis virus, Coxsackie virus B4, and respiratory syn-
cytial 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
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Med Chem Res (2016) 25:932–940
939
presence of varying concentrations (100, 20, etc., lM) of
the test compounds. The viral cytopathicity was recorded
as soon as it reached completion in the control virus-in-
fected 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 con-
centration (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 9 103 cells/well into 96-well micro-
titer 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 (*39105 cells/cm3)
cells were infected with 100 CCID50 of HIV-1IIIB or
HIV-2ROD and seeded in 200-lL wells of a microtiter
plate containing appropriate dilutions of the test com-
pounds. After 4 days of incubation at 37 °C, the HIV-
induced CEM giant cell formation was examined light
microscopically.
compounds (i.e., 100, 20, 4, 0.8 lL). 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 Post-
graduate Programmes ‘‘Biotechnology-Quality assessment in Nutri-
tion and the Environment,’’ ‘‘Application of Molecular Biology-
Molecular Genetics-Molecular Markers,’’ Department of Biochem-
istry 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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