Synthesis and screening of bicyclic carbohydrate-based compounds: A novel type of antivirals

Article abstract of DOI:10.1016/j.bmcl.2005.12.048

A small library of bicyclic carbohydrate derivatives was synthesized and screened. A strong and selective activity against cytomegalovirus was found. Structure-activity relationship for this new type of antivirals is discussed.

Full text of DOI:10.1016/j.bmcl.2005.12.048

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1495–1498
Synthesis and screening of bicyclic carbohydrate-based
compounds: A novel type of antivirals
Steven Van Hoof,a Bart Ruttens,a Idzi Hubrecht,a Gert Smans,a Petra Blom,a
Benedikt Sas,b Johan Van hemel,b Jan Vandenkerckhoveb and Johan Van der Eyckena,*
aLaboratory for Organic and Bioorganic Synthesis, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S.4),
B-9000 Ghent, Belgium
bKemin Pharma Europe, Atealaan 4H, B-2200 Herentals, Belgium
Received 7 October 2005; revised 12 December 2005; accepted 12 December 2005
Available online 5 January 2006
Abstract—A small library of bicyclic carbohydrate derivatives was synthesized and screened. A strong and selective activity against
cytomegalovirus was found. Structure–activity relationship for this new type of antivirals is discussed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
OMe
Activity:
Carbohydrates play a significant role in many biological
processes. For example, they provide signals for protein
targeting and serve as cell-receptors for adhesion of bac-
teria, viruses, and parasites.1 As a result, this class of
compounds has significant diagnostic and therapeutic
potential and promises to be a major source of drug
discovery leads.2
MeO
Ph
O
Ph
CMV- Davis: IC50: 2.4 µg/ml
CMV- AD-169: IC50: 2.0 µg/ml
O
O
1
Figure 1. Parent CMV inhibitor and inhibitory activity.
shows higher toxicity. Foscarnet (4),7 a simple phospho-
nate-containing compound, inhibits viral growth by
blocking the enzymatic phosphate binding pocket. Com-
pounds 2, 3, and 4 are administered intravenously. Fom-
virsen8 is a 21-nucleotide antisense product, used for
treatment of CMV retinitis. It is more potent than ganci-
clovir, but has to be administered by intraocular injection.
All therapies only help to control the infection but fail to
clear the virus. Toxicity and administration present a
problem, and prolonged use may result in the emergence
of resistance.9 More efficaceous and patient-friendly
therapeutic agents are therefore desirable.
High-throughput screening (HTS) of a large number of
diverse carbohydrate derivatives revealed that product
1, a bicyclic C-glycoside (Fig. 1), shows very good and
selective inhibitory activity against human cytomegalo-
virus (CMV).3 This member of the herpes virus family
is widespread: 50–90% of the population worldwide is
infected. Initial infection is followed by persistent,
long-term latency, but does not represent a threat for
persons with a functional immune system. In immuno-
compromised persons however, such as newborns,
patients involved in organ transplant therapy and
AIDS-patients, a CMV-infection can cause severe
clinical manifestations which can be life-threatening.4
Identification of product 1 as a strong CMV inhibitor
was remarkable, as no known antiviral product possess-
Typical therapies for pathological CMV infections in-
clude treatment with ganciclovir (2)5 and cidofovir (3)6
(Fig. 2), two nucleoside analogues that inhibit the viral
DNA polymerase. Cidofovir is more potent, but also
O
N
NH2
N
N
N
HN
H2N
N
O
P
O
P
O
O
O
O
O
3 Na+
O
HO
O
HO
HO
OH
HO
Keywords: Carbohydrates; Antiviral; Anti-CMV; Cytomegalovirus.
*
4
3
2
Corresponding author. Tel: +3292644480; fax: +3292644998; e-mail:
Johan.VanderEycken@UGent.be
Figure 2. Current drugs for treatment of CMV infection.
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.12.048

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S. V. Hoof et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1495–1498
OR
O
2
OBn
OR
O
B
C
3
OPG
O
OH
O
R O
RO
O
Ph
BnO
HO
OBn
OBn
RO
OR
OR
2
PGO
PGO
OPG
OPG
HO
OH
OH
a
c
R O
O
R
O
Bn
d
O
Bn
b
1
O
1
R
R
O
A
D
14 : R= Bn
15 : R= H
16 : R= H
17 : R= Me
13
Scheme 1. Synthetic strategy and modifications.
Scheme 3. Reagents and conditions: (a) i—oxalylbromide, CH2Cl2, rt,
1 h; ii—benzylmagnesium-chloride, Et2O, rt, 18 h, 50%; (b) 3–4 atm
H2/Pd-C, EtOH, rt, 5 h, 100%; (c) PhCH(OMe)2, CSA, CH3CN, rt,
24 h, 70%; (d) i—NaH, DME, 0 ꢁC, 30 min; ii—MeI, rt, overnight,
91%.
es a similar structure.10 Synthesis of a large number of
analogues was initiated to further explore the scope of
this new type of antiviral compound. Structural modifi-
cations were made in four different regions (Scheme 1):
the anomeric substituent R1 (A), the O-alkyl residues
R2 (B), the acetal substituent R3 (C), and the configura-
tion of the sugar (D). The synthetic strategy (Scheme 1)
includes introduction of the C-glycosyl group by the
Grignard reaction, followed by acetal formation and
alkylation.
R3 = a: 2-furyl, b: 2-thienyl,
c: c-hexyl, d: Bn, e: 4-CH3-Ph,
f: 4-MeO-Ph, g: 4-NO2-Ph,
h: 4-Cl-Ph, i: 3-Cl-Ph,
j: 2-Cl-Ph, k: 4-CF3-Ph,
l: 4-F-Ph, m: 4-biphenyl,
n: 2-naphthyl
OR2
OH
R2O
O
R3
HO
Ph
OH
OH
a
O
Ph
b
O
O
18a-n : R2= H
19a-n : R2= Me
7
Scheme 4. Reagents and conditions: (a) R3CHO, CSA, CuSO4.anh,
CH3CN, reflux, 33–90%; (b) i—NaH, DMF, 0 ꢁC, 30 min; ii—MeI, rt,
overnight, 35–96%.
Analogues with varying substituents at the anomeric po-
sition (R1), including the parent compound 1, were syn-
thesized by Grignard substitution of an anomeric
bromide11 (Scheme 2). b-D-Glucose penta-acetate (5)
was converted into 1-phenyl- (7) or 1-allyl-1-deoxy-
b-D-glucose (9) by bromination at the anomeric
position, followed by nucleophilic substitution with phe-
nylmagnesium bromide or allylmagnesium bromide,
respectively, and subsequent acetylation–deacetylation
to facilitate purification.
OR2
OH
R2O
R1
O
Ph
R2= a: ethyl, b: n-propyl,
c: n-butyl, d: n-pentyl, e: allyl,
f: 4-pentenyl, g: benzyl,
h: iso-butyl, i: propargyl
HO
R1
O
Ph
a
O
O
O
O
20a-i: R1= Ph (β)
1-epi-20a-i: R1= Ph (α)
21a-i: R1= Bn (β)
10: R1= Ph (β)
1-epi-10: R1= Ph (α)
16: R1= Bn (β)
Scheme 5. Reagents and conditions: (a) for a–g: i—NaH, DMF, 0 ꢁC,
30 min; (ii) R2X; for h: i—NaH, DMF, 0 ꢁC, 30 min; ii—i-BuOTs,
50 ꢁC; for i: i—NaH, THF, 0 ꢁC to reflux, 15 h; ii—propargyl bromide,
TBAI, rt (a–i: 45–96%).
A similar procedure for the synthesis of the 1-benzyl
analogue starting from 5 leads to excessive formation
of the 1-ortho-tolyl derivative in the Grignard substitu-
tion.12 This side reaction could be avoided by starting
from 2,3,4,6-tetra-O-benzyl-D-glucose (Scheme 3). Ano-
meric bromination followed by Grignard reaction yield-
ed protected C-glycoside 14, which after deprotection
afforded tetrol 15. Selective transformation of 7, 9, and
15 into the corresponding 4,6-O-benzylidene acetals
and methylation of the remaining hydroxyl groups fur-
nished 1, 12, and 17, respectively.
focussing mostly on aromatic aldehydes. The resulting
diols were subsequently O-methylated using standard
alkylation procedures.
A series of 2,3-O-dialkyl analogues was synthesized
from 10 by alkylation with the appropriate alkyl bro-
mide (Scheme 5). In this way, 2,3-di-O-ethyl, -propyl,
-butyl, -pentyl, -allyl, -4-pentenyl, and -benzyl ethers
were obtained. The iso-butyl group was introduced by
treatment with iso-butyl tosylate at elevated tempera-
tures.13 The introduction of the propargyl group re-
quired in situ conversion of propargyl bromide to the
more reactive iodide by addition of a catalytic amount
of tetra-n-butylammonium iodide. The same alkylation
procedures were used to prepare a series of compounds
derived from 16 and 1-epi-10, obtained as above via ace-
talyzation of 1-epi-7 (a byproduct of the synthesis of 7).
Analogues with different acetal substituents (R3) were
prepared from 1-phenyl-1-deoxy-b-D-glucose 7 by acid-
catalyzed condensation with an aldehyde, with removal
of water (Scheme 4). A variety of aldehydes were used,
OR2
OAc
OR2
R2O
R1
O
Ph
AcO
AcO
OAc
OAc
R2O
R1
OR2
OR2
a
c
O
O
O
O
6 : R1= Ph; R2= Ac
7 : R1= Ph; R2= H
8 : R1= allyl; R2= Ac
9 : R1= allyl; R2= H
10 : R1= Ph; R2= H
1 : R1= Ph; R2= Me
11 : R1= allyl; R2= H
12 : R1= allyl; R2= Me
5
b
d
D-Galactose (C-4 epimer) and D-mannose (C-2 epimer)
stereoisomers of lead compound 1 were also prepared.
D-Galactose derivative 24 (Scheme 6) was obtained from
b-D-galactose penta-acetate 22, following the same syn-
thetic strategy as described above for the preparation of
1. For the synthesis of analogues with the D-mannose
configuration (Scheme 7), the axial orientation of the
C-2 substituent influenced the stereoselectivity of the
Grignard substitution: both a and b anomers were ob-
tained in a 1:1 ratio. Moreover, subsequent formation
b
d
Scheme 2. Reagents and conditions: (a) i—HBr, HOAc, rt, 30 min;
ii—R1MgBr, Et2O, 0 ꢁC to rt, R1 = Ph: 72 h, R1 = allyl: 23 h; iii—
Ac2O, pyridine, rt, R1 = Ph: 63 h, R1 = allyl: 24 h; iv—column
chromatography, R1 = Ph: 56%, R1 = allyl: 69%; (b) K2CO3, THF,
MeOH, rt, 21 h, R1 = Ph: 90%, R1 = allyl: 100%; (c) PhCH(OMe)2,
CSA, CH3CN, rt, 22 h, R1 = Ph: 97%, R1 = allyl: 92%; (d) i—NaH,
DMF, 0 ꢁC, 30 min; ii—MeI, rt, overnight, R1 = Ph: 93%, R1 = allyl:
98%.

S. V. Hoof et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1495–1498
1497
OAc
OH
OMe
The required selectivity was obtained by treatment of te-
trol 26 with 1,3-dichloro-1,1,3,3-tetraisopropyldisilox-
ane14 to selectively protect the C-4 and C-6 hydroxyl
functions. Methylation of the remaining hydroxyl
groups under mild conditions using silver(I)oxide,14 fol-
lowed by deprotection and acetal-formation, yielded
mannose-based analogue 29. The same procedure was
used for the synthesis of the a-epimer 1-epi-29.
AcO
AcO
OAc
OAc
HO
Ph
OH
OH
MeO
Ph
O
Ph
b,c
a
O
O
O
O
22
24
23
Scheme 6. Reagents and conditions: (a) i—HBr, HOAc, rt, 30 min;
ii—PhMgBr, Et2O, 0 ꢁC to rt, 34 h; iii—Ac2O, pyridine, rt, 6 h;
iv—column chromatography, 43%; v—K2CO3, THF, MeOH, rt,
overnight, 96%; (b) PhCH(OMe)2, CSA, CH3CN, rt, 1.5 h, 95%; (c)
i—NaH, DMF, 0 ꢁC, 30 min; ii—MeI, rt, overnight, 94%.
All analogues of 1, as well as their synthetic intermedi-
ates, were evaluated for their activity against the
CMV-strains Davis and AD-169.15 The most interesting
results are shown in Table 1. All active compounds pos-
sess the D-glucose configuration: changing stereochemis-
try at C-2 (24) or C-4 (29) annihilates activity.
OAc
OH
O
OH
O
Si
O
AcO
AcO
OAc
OAc
HO
Ph
OH
OH
HO
Ph
O
O
Si
a
b
O
25
26: R1: β
27: R1: β
Interestingly, the intermediate diols 18g, 18h, 18k, and
18n also show activity. The compounds with R3 = 4-bi-
phenyl (19m) or R3 = 2-naphthyl (19n) are the most
potent analogues bearing an anomeric phenyl group,
displaying good inhibitory activity for doses below
1 lg/ml.
1−epi-26: R1: α
1−epi-27: R1: α
c
OMe
OMe
OH
MeO
Ph
O
Ph
MeO
Ph
d
O
OH
O
O
29: R1: β
epi-29: R1: α
28: R1: β
1−
1−epi-28: R1: α
Analogues with an anomeric benzyl group also show
potent activity, giving the best results for the
compounds with allyl- (21e) and propargyl ether substit-
uents (21i). The latter compound was the most active
one found. The only active compound with a-configura-
tion at the anomeric center is 1-epi-20h. Absolute
requirements for activity seem to be the presence of an
aromatic functionality at the anomeric position (R1),
and a correct orientation of the substituents imposed
by the sugar scaffold. It is not unlikely that the alkyl
substituents at C-2 and C-3 also influence the orienta-
tion of the anomeric substituent and in this way affect
the inhibitory activity.
Scheme 7. Reagents and conditions: (a) i—HBr, HOAc, rt, 30 min; (ii)
PhMgBr, Et2O, 0 ꢁC to rt, over weekend; iii—Ac2O, pyridine, rt;
iv—column chromatography, 73% (a:b 1:1); v—K2CO3, THF, MeOH,
rt, 16 h, b: 93%, a: 94%; (b) dichloro-tetra-iso-propyl-disiloxane,
pyridine, ꢀ15 ꢁC to rt, 24 h, b: 74%, a: 84%; (c) i—Ag2O, MeI, reflux,
22–72 h, b: 98%, a: 93%; ii—TBAF, THF, rt, 15 h, b: 92%, a: 86%; (d)
PhCH(OMe)2, CSA, CH3CN, rt, 20 h, b: 91%, a: 91%.
of the benzylidene acetal function did not proceed selec-
tively: due to the syn orientation of the hydroxyl groups
at C-2 and C-3, competitive 2,3-O-acetal formation
occurred.
Table 1. Activity against human cytomegalovirus (CMV), strains Davis and AD-169, in human embryonic lung (HEL) cells15
Compound
R1
R2
R3
Sugar
CMV Davis
a
IC50 (lg/ml)
CMV AD-169
a
IC50 (lg/ml)
Cell morphology
(MCC) (lg/ml)
Cell growth
(CC50) (lg/ml)
1
12
Ph (b)
All (b)
Bn (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Ph (b)
Bn (b)
Ph (a)
Bn (b)
Bn (b)
Ph (b)
Ph (b)
Me
Me
Ph
Ph
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Glc
D-Gal
D-Man
2.4
>50
5.0
9.3
10.0
1.6
1.8
3.5
4.0
3.2
3.1
0.6
0.8
2.4
3.0
3.0
3.2
1.0
0.5
>50
>50
2.0
n.d.
n.d.
20
n.d.
n.d.
>50
>50
>50
35
>50
20.0
10.0
14.0
1.6
17
Me
H
Ph
18g
18h
18k
18n
19c
19h
19i
4-NO2-Ph
4-Cl-Ph
4-CF3-Ph
2-Naphthyl
c-Hexyl
4-Cl-Ph
3-Cl-Ph
4-CF3-Ph
4-Biphenyl
2-Naphthyl
Ph
50
H
P100
400
P400
20
H
H
Me
1.3
3.2
21
28
Me
Me
5.0
5.0
P100
P40
P16
P16
P16
16
>50
n.d.
>50
>50
>50
182
n.d.
>50
n.d.
>50
n.d.
n.d.
n.d.
19k
19m
19n
20d
20i
Me
Me
1.5
0.8
Me
0.47
>3.2
5.0
n-Pentyl
Propargyl
Ethyl
i-Butyl
Allyl
Propargyl
Me
Ph
Ph
40
21a
1-epi-20h
21e
21ib
24
2.6
2.6
>120
40
20
Ph
Ph
1.2
0.5
Ph
Ph
40
>400
400
>50
>50
29
Me
Ph
n.d. = not determined
a Reference compound is cidofovir (3)6: IC50 (Davis) = 0.6 lg/ml; IC50 (AD-169) = 0.7 lg/ml.
b See Ref. 16 for experimental data.

1498
S. V. Hoof et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1495–1498
microtiter plates were infected with 20 PFU virus/well.
After 2 h of incubation at 37 ꢁC, the infected cells were
replenished with 0.1 ml of medium containing serial
dilutions of the test compound. On day 7 the plaques
were counted microscopically after staining the cells with
Giemsa’s solution. The minimum antiviral concentration
was expressed as IC50, the dose required to inhibit virus-
induced plaque formation by 50%. For cytotoxicity
measurements, confluent monolayers of HEL cells, as
well as growing HEL cells in 96-well microtiter plates,
were treated with different concentrations of the exper-
imental drugs. Growing cells were incubated for 3 days.
At that time, the cells were trypsinized, and the cell
number was determined using a Coulter counter. The
50% cytotoxic concentration (CC50) was defined as the
compound concentration required to reduce the cell
growth by 50%. During the antiviral assay, the minimum
cytotoxic concentration (MCC) was evaluated at day 7 as
the lowest compound concentration giving microscopi-
cally visible cytotoxicity on the confluent cells. Neyts, J.;
Andrei, G.; Snoeck, R.; Meerbach, A.; De Clercq, E. In
Cytomegalovirus Protocols; Sinclair, J., Ed.; Humana
Press: Totowa, NJ, 2000; pp 129–152.
Cytotoxicity levels are good, especially for compound
19n, which combines a very good activity with a low tox-
icity. Some products have a smaller therapeutic window,
with the non-alkylated compounds showing higher tox-
icity. Further improvement of the antiviral activity of
the lead structures is currently investigated. Preclinical
tests are pursued for the most active compounds.
In conclusion, a strong and selective activity of bicyclic
carbohydrate derivative 1 against CMV was discovered.
A small library of analogues of lead compound 1 was syn-
thesized and screened. Several more potent CMV growth
inhibitors were identified. Specific conclusions toward
SAR are difficult to make. The mechanism of activity is
yet unknown and is the subject of further investigation.
Acknowledgments
The authors thank Prof. Dr. J. Balzarini (Rega Institute,
K. U. Leuven, Belgium) for the screening, and the
Flemish Government and the IWT (IWT990252) for
funding.
16. Synthesis of compound 21i: To a solution of compound 15
(1.0 g, 3.93 mmol) in DMF (38.6 ml) were added benz-
aldehyde dimethylacetal (708 ll, 1.2 eq) and camphor-
sulfonic acid (274 mg, 0.3 eq). After 2 h, ethyl acetate
(150 ml) was added and the mixture was washed with 1 N
NaOH solution (2· 150 ml), saturated NaHCO3 solution
(2· 100 ml), and brine (2· 100 ml), dried over MgSO4,
filtered, and concentrated. The residue was purified by
column chromatography (eluent CH2Cl2: MeOH 99:1),
affording acetal 16 (940 mg; 70% yield). To a solution of
16 (80 mg, 0.234 mmol) in THF (410 ll) was added
sodium hydride (23 mg, 60% dispersion in mineral oil,
2.2 eq) at 0 ꢁC, and the mixture was subsequently heated
to reflux temperature. After 1.5 h, the mixture was cooled
to room temperature and tetra-n-butylammonium iodide
(1.8 mg, 0.02 eq) and propargyl bromide (57 ll, 2.2 eq)
were added. After stirring overnight at room tempera-
ture, extra sodium hydride (1.1 eq), tetra-n-butylammo-
nium iodide (0.02 eq), and propargyl bromide (1 eq) were
added. After stirring for another 2.5 h, the reaction
mixture was poured into H2O (50 ml) and extracted with
ether (3· 40 ml). The combined organic layers were
washed with brine (50 ml), dried over MgSO4, filtered,
and concentrated. The residue was purified by column
chromatography (eluent pentane:Et2O 85:15), to yield
compound 21i (83 mg; 86% yield). Spectral data of
compound 21i: 1H NMR (500 MHz, CDCl3): d (ppm)
7.47–7.45 (2H, m), 7.39–7.35 (3H, m), 7.31–7.21 (5H, m),
5.51 (1H, s), 4.62 (1H, dd, J = 15.7, 2.4 Hz), 4.52 (1H,
dd, J = 15.7, 2.4 Hz), 4.50 (1H, dd, J = 15.7, 2.4 Hz), 4.43
(1H, dd, J = 15.7, 2.4 Hz), 4.25 (1H, dd, J = 10.5,
5.0 Hz), 3.83 (1H, dd, J = 9.1, 8.6 Hz), 3.67 (1H, dd
[app. t], J = 10.3, 10.3 Hz), 3.58 (1H, dd [app. t], J = 9.4,
9.4 Hz), 3.55 (1H, ddd [app. dt], J = 9.0, 9.0, 2.2 Hz),
3.36–3.27 (3H, m), 2.73 (1H, dd, J = 14.5, 8.7 Hz), 2.50
(1H, t, J = 2.4 Hz), 2.48 (1H, t, J = 2.4 Hz); APT-NMR
(125 MHz, CDCl3) : d (ppm) 138.4 (C), 137.2 (C), 129.7
(CH), 129.0 (CH), 128.3 (CH), 128.1 (CH), 126.3 (CH),
126.0 (CH), 101.1 (CH), 82.6 (CH), 82.2 (CH), 80.1
(CH), 79.5 (CH), 74.7 (C), 74.5 (C), 69.8 (CH), 68.8
(CH2), 60.2 (CH2), 59.7 (CH2), 38.1 (CH2); mp = 81–
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15. For determination of antiviral activity against CMV,
human embryonic lung fibroblast cells grown in 96-well
20
83 ꢁC; ½aꢁD ꢀ45.0 (c 1.02, CHCl3).