Antiproliferative and antiviral activity of three libraries of adamantane derivatives

Article abstract of DOI:10.1002/ardp.201300345

Three libraries of adamantane derivatives were synthesized and evaluated for antiviral and antiproliferative activities against a broad variety of DNA and RNA viruses. Whereas none of the compounds exhibit antiviral activity at subtoxic concentrations, antiproliferative activity was found against murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and cervix carcinoma cells (HeLa) for 4, 8, and 10.

Full text of DOI:10.1002/ardp.201300345

334
Arch. Pharm. Chem. Life Sci. 2014, 347, 334–340
Full Paper
Antiproliferative and Antiviral Activity of Three Libraries of
Adamantane Derivatives
1
1
1
2
ꢀ1
ꢀ
Nikola Basaric , Margareta Sohora , Nikola Cindro , Kata Mlinaric-Majerski , Erik De Clercq *, and
Jan Balzarini2*
1
ꢀ
Department of Organic Chemistry and Biochemistry, Ruđer Boškovic Institute, Zagreb, Croatia
2
Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, Leuven, Belgium
Three libraries of adamantane derivatives were synthesized and evaluated for antiviral and
antiproliferative activities against a broad variety of DNA and RNA viruses. Whereas none of the
compounds exhibit antiviral activity at subtoxic concentrations, antiproliferative activity was found
against murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and cervix carcinoma cells
(HeLa) for 4, 8, and 10.
Keywords: Adamantanes / Antiproliferative activity / Antiviral activity / Phthalimides / Polycyclic compounds /
Unnatural amino acids
Received: September 11, 2013; Revised: November 15, 2013; Accepted: November 15, 2013
DOI 10.1002/ardp.201300345
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
Introduction
new structure–activity relationships (SAR). Herein, we report
an investigation of the antiviral activity in vitro of three
libraries of adamantane derivatives. In addition, the same
libraries of compounds were also tested for antiproliferative
activity. Recently, we have reported an investigation of
antiproliferative activity of a series of adamantylphthal-
imides, where all investigated compounds exhibited higher
activity than the clinically used drug thalidomide [6].
A number of different antiviral drugs exist nowadays in the
market. However, combating viral diseases and finding
appropriate drugs with minimal side effects remain a
challenge in chemistry, pharmacy, and medicine. A major
problem in antiviral therapy is the rapid mutations of viruses
leading to development of drug resistance. Amantadine
(1-aminoadamantane hydrochloride) and rimantadine [1-(2-
aminoethyl)adamantane hydrochloride] are widely used as Materials and methods
anti-influenza agents that block M2 protein ion channel,
which prevents fusion of the virus with the host-cell
membrane and release of viral RNA into the cytoplasm [1].
The same compounds have been shown to exhibit inhibitory
activity – although rather modest – against some other viruses
such as HIV [2], hepatitis [3], and herpes simplex virus [4].
However, inappropriate use of these drugs in many countries
contributed to an increasing number of resistant influenza
viruses [5]. In the search of new drugs and novel mechanisms
of action based on yet unknown intracellular targets, it is
important to screen new libraries of molecules and develop
Structure design
The first library of compounds (Fig. 1) is composed of
adamantylphthalimides since adamantylphthalimides were
previously reported to be endowed with anti-HIV activity [7].
Structural design of the phthalimide compounds is in
connection with a pharmacophore phenytoin (PHT) that
exhibits anticonvulsant activity. This membrane-reactive
drug has been reported to inhibit HIV binding to CD4
positive lymphocytes [8], and reduced the CD4 receptor
availability for ligand interaction [9]. It was also proposed that
ꢀ
Correspondence: Dr. Nikola Basaric, Department of Organic Chemistry
and Biochemistry, Ruđer Boškovic Institute, Bijenicka Cesta 54, 10 000
Zagreb, Croatia.
E-mail: nbasaric@irb.hr
Fax: þ385 1 4680 195
ꢀ
ꢁ
*Additional correspondence: Prof. Erik De Clercq,
E-mail: erik.declercq@rega.kuleuven.be;
Prof. Jan Balzarini,
E-mail: jan.balzarini@rega.kuleuven.be
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2014, 347, 334–340
Antiproliferative and Antiviral Activity of Adamantanes
335
Figure 1. Library 1: adamantylphthalimides.
PHT suppresses the influx of Ca2þ ions that occurs shortly
after HIV infection [10]. Later, it was discovered that some of
the HIV proteins may organize as sodium channel entities in
planar lipid bilayers [11]. Screening indicated that the
4-aminophthalimide pharmacophore and N-(l-adamantyl)
substitutions are required for their anti-HIV properties [7].
The structures in library 1 are 1- or 2-adamantyl derivatives
wherein adamantane and phthalimide are connected or
separated by an alkyl spacer of different length (compounds
1–8). Furthermore, structures were modified by substitution
of the phthalimide by an amino or a nitro group (compounds
9–12), or by additional substitution of the adamantane moiety
(compounds 13–15, 19, and 20), and a change of the polycyclic
skeleton (compounds 16–18).
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Arch. Pharm. Chem. Life Sci. 2014, 347, 334–340
The third library of compounds (Fig. 3) is composed of
adamantane amino acids. Anticancer activity of cage amino
acids and the corresponding peptides has recently been
reported [13]. Moreover, it has been demonstrated that
dipeptides with incorporated cage amino acids exhibit HIV
protease inhibition [14].
Synthesis
Compounds in library 1 were prepared according to the
described procedures [6, 15]. Adamantylphthalimides 1–8 were
prepared in a condensation reaction of phthalic anhydride
and the corresponding 1- or 2-aminoalkyladamantane [15a].
Aminophthalimide derivatives 10 and 12 were obtained from
the nitro derivatives 9 and 11, respectively, by reduction with
Zn. Homo-, 16, and protoadamantanes, exo-17 and endo-18, were
made by applying a Mitzunobu protocol, from phthalimide
and the corresponding polycyclic alcohols [15b]. Compounds
19 and 20 were obtained in a photochemical reaction from
carboxylic acid 13 in the presence of acrylonitrile or cyclo-
hexenone, respectively [15c], whereas 15 was obtained as one of
the products in the photochemical reaction of 2 [16].
Compounds in library 2 were obtained in photochemical
reactions from the compounds in library 1 (21 from 6, 22 from
1, 23 from 3, 24 from 2, and 25 and 26 from 5) [16]. Amino acid
27, from library 3 was obtained by a base-hydrolysis of 22 [16a].
Amino acid derivatives 14, and 29 were synthesized from ester
30 in the condensation reaction with phthalic anhydride
(Scheme 1). Base hydrolysis of ester 14 furnished diacid 28
(Scheme 2). Phthalimido acid 13 was also obtained in the
condensation reaction of phthalic anhydride and 3-amino-
adamantane-1-carboxylic acid [15c].
Figure 2. Library 2: adamantyl aza-heterocyclic derivatives.
The second library (Fig. 2) is composed of different aza-
heterocyclic derivatives of adamantane. The design of
compounds is based on reports of antiviral activity of a
series of polycyclic amines and aza-heterocycles [12]. It was
found that the size of the heterocyclic ring influences the
activity against influenza A virus, with a higher activity with
five- than with four- and three-membered rings [12]. On the
other hand, substitution of the heterocylic nitrogen increases
the anti-HIV activity [12]. Compounds in library 2 are
derivatives of azepine (21–23) or pyrrolidine (24–26), that
are also characterized by a different connectivity to the
adamantane skeleton.
All chiral compounds were synthesized as racemates.
Antiviral activity assays
The compounds were evaluated against the following viruses:
herpes simplex virus type 1 (HSV-1) strain KOS, thymidine
kinase-deficient (TKꢀ) HSV-1 KOS strain resistant to ACV
(ACVr), herpes simplex virus type 2 (HSV-2) strains Lyons and
G, varicella-zoster virus (VZV) strain Oka, TKꢀ VZV strain 07–1,
human cytomegalovirus (HCMV) strains AD-169 and Davis,
vaccinia virus Lederle strain, respiratory syncytial virus (RSV)
Figure 3. Library 3: adamantane amino acid
derivatives.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 334–340
Antiproliferative and Antiviral Activity of Adamantanes
337
Scheme 1. Synthesis of 29.
Scheme 2. Synthesis of 28.
strain Long, vesicular stomatitis virus (VSV), Coxsackie B4,
parainfluenza 3, influenza virus A (subtypes H1N1, H3N2),
influenza virus B, Reovirus-1, Sindbis, Reovirus-1, Punta Toro,
human immunodeficiency virus type 1 strain IIIB, and human
immunodeficiency virus type 2 strain ROD. The antiviral,
other than anti-HIV, assays were based on inhibition of virus-
induced cytopathicity or plaque formation in human
embryonic lung (HEL) fibroblasts, African green monkey cells
(Vero), human epithelial cells (HeLa), or Madin-Darby canine
kidney cells (MDCK). Confluent cell cultures in microtiter
for 48 h (murine leukemia L1210 cells) or 72 h (human
lymphocytic CEM and human cervix carcinoma HeLa cells) at
37°C in a humidified CO2-controlled atmosphere. At the end
of the incubation period, the cells were counted in a Coulter
counter. The 50% inhibitory concentration (IC50) was defined
as the concentration of the compound that inhibited cell
proliferation by 50%. Data are derived from two to three
independent experiments (the errors were calculated accord-
ing to a formula given in the Supporting Information).
96-well plates were inoculated with 100 CCID50 of virus Results and discussion
(1 CCID50 being the virus dose to infect 50% of the cell
cultures) or with 20 plaque-forming units (PFU) (VZV) in the
presence of varying concentrations of the test compounds.
Viral cytopathicity or plaque formation was recorded as soon
as it reached completion in the control virus-infected cell
cultures that were not treated with the test compounds.
Antiviral activity was expressed as the EC50 or compound
concentration required to reduce virus-induced cytopathoge-
nicity or viral plaque formation by 50%.
Inhibition of HIV-1(IIIB)- and HIV-2(ROD)-induced cytopa-
thicity in CEM cell cultures was measured in microtiter
96-well plates containing ꢁ3 ꢂ 105 CEM cells/mL infected with
100 CCID50 of HIV per milliliter and containing appropriate
dilutions of the test compounds. After 4–5 days of incubation
at 37°C in a CO2-controlled humidified atmosphere, CEM
giant (syncytium) cell formation was examined microscopi-
cally. The EC50 (50% effective concentration) was defined as
the compound concentration required to inhibit HIV-induced
giant cell formation by 50%.
All three tested libraries of compounds exert no significant
antiviral activity in cell culture at subtoxic concentrations
(see Supporting Information Tables S1–S4).
Antiproliferative activity was tested against three cancer
cell lines (Table 1). Generally, compounds exhibit moderate
activity in micromolar concentration range and show no
selectivity to a specific cancer cell line. From the compounds
in library 1, the highest activity was observed for 4 and 8,
containing the longest alkyl linker between the adamantyl
and the phthalimide moiety (CC50 range between 7.2 and
12 mg/mL). Also, antiproliferative activity can be achieved by
incorporation of an amino substituent at the phthalimide
3-position, but only for the 1-adamantyl derivative 10 but not
the adamantyl derivative 12. Contrary to our previous
report [6] a change of the substitution on the adamantane,
1- versus 2-, virtually does not affect the antiproliferative
activity. However, replacement of the adamantane with a
homoadamantane skeleton (5 vs. 16) enhanced the cytostatic
effect. A minor additional activity enhancement was also
observed by substitution of the adamantane skeleton at the
position 3 with a cyclohexanone ring (compound 20), whereas
other groups (COOH, COOCH3, and CH2CH2CN) had no effect.
Cytostatic activity assays
All assays were performed in 96-well microtiter plates. To each
well (5–7.5) ꢂ 104 tumor cells and a given amount of the test
compound were added. The cells were allowed to proliferate
All compounds in library
2
exhibited similar modest
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Arch. Pharm. Chem. Life Sci. 2014, 347, 334–340
Table 1. Antiproliferative activities against L1210, CEM, and Conclusion
HeLa tumor cells.
Three libraries of adamantane derivatives were synthesized
and screened for antiviral and antiproliferative activity.
Whereas none of the compounds exhibited pronounced
activity against virus infection, antiproliferative activity was
found against L1210, CEM, and HeLa for 4, 8, and 10.
IC50 (mmol/L)a)
Comp.
L1210
CEM
HeLa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
>300
200 ꢃ 100
>300
>300
70 ꢃ 10
>300
>300
90 ꢃ 20
ꢄ300
30 ꢃ 7
34 ꢃ 6
22 ꢃ 1
Experimental
30 ! >300b)
220 ꢃ 10
>300
7 ! ꢄ300b)
190 ꢃ 10
ꢄ300
ꢄ300
230 ꢃ 30
ꢄ300
General
1H and 13C NMR spectra were recorded on a Bruker spectrometer
at 300 or 600 MHz, respectively. All NMR spectra were measured
in CDCl3 or DMSO-d6 using tetramethylsilane as a reference.
Melting points were obtained using an Original Kofler Mikro-
heitztisch apparatus (Reichert, Wien) and were uncorrected. IR
spectra were recorded on an ABB Bomem M-102 spectrophoto-
meter. Elemental analyses were carried out on a Perkin-Elmer
31 ꢃ 0
37 ꢃ 6
26 ꢃ 3
>300
>300
>300
29 ꢃ 3
30 ꢃ 3
33 ꢃ 3
>300
>300
200 ꢃ 100
ꢄ300
>300
>300
>300
>300
>300
60 ! 300b)
138 ꢃ 3
16 ꢃ 10
300 ꢃ 80
>300
150 ꢃ 120
120 ꢃ 30
30 ꢃ 10
210 ꢃ 160
>300
30 ! 300b)
150 ꢃ 60
80 ꢃ 30
120 ꢃ 80
320 ꢃ 50
>300
ꢀ
2400 Series II CHNS Analyzer at the Ruđer Boškovic Institute.
Silica gel (Merck 0.05–0.2 mm) was used for chromatographic
purifications. Solvents were purified by distillation. The
chemicals for synthesis were obtained from usual commercial
sources.
>300
>300
50 ꢃ 30
280 ꢃ 80
170 ꢃ 0
113 ꢃ 3
210 ꢃ 10
270 ꢃ 3
128 ꢃ 7
>300
100 ꢃ 0
110 ꢃ 60
190 ꢃ 10
103 ꢃ 3
280 ꢃ 100
300 ꢃ 50
100 ꢃ 60
>300
70 ꢃ 10
180 ꢃ 130
180 ꢃ 0
64 ꢃ 6
290 ꢃ 40
220 ꢃ 50
90 ꢃ 10
>300
3-(N-Phthalimido)adamantane-1-carboxylic acid methyl
ester (14)
In a round bottom flask (50 mL) equipped with a stopper,
phthalic anhydride (889 mg, 6 mmol) was melted. To the melt,
ester 30 (1.14 g, 3 mmol) was added as a CH2Cl2 solution in
several portions. After the addition was completed, the
reaction mixture was stirred over 10 min with the stopper,
after which stopper was removed and stirring continued for
another 10 min to remove water. To the cooled reaction
mixture, CH2Cl2 (100 mL) was added, and the solution washed
with 10% acetic acid (3 ꢂ 30 mL) and 10% solution of NaHCO3
(3 ꢂ 30 mL). Washed organic layer was dried over anhydrous
MgSO4, filtered, and the solvent was removed on a rotary
evaporator. The crude reaction mixture was purified by
column chromatography on SiO2 using CH2Cl2 as an eluent.
Colorless crystals (832 mg, 45%); m.p. 98–99°C; IR (KBr)
nmax/cmꢀ1 3343, 2957, 2925, 2890, 2852, 1767, 1724, 1463,
>300
>200
>77
>300
>200
>42
>300
>200
>77
29
Thalidomide
a)
Fifty percent inhibitory concentration.
No dose response between these concentrations.
b)
cytostatic activity, so that no SAR could be established. On the
contrary, the amino acid derivatives from library 3 exhibit no
antiproliferative activity at all. Thus, the presence of a
heterocyclic ring (phthalimide or other aza-heterocycle) is
essential for the antiproliferative effect.
It was shown that the activity of thalidomide, a clinically
used anticancer drug with the phthalimide pharmacophore,
is related to the modulation of tumor necrosis factor
TNF-a, especially in multiple myeloma. Namely, TNF-a is a
multifunctional cytokine playing a key role in both apoptosis
and cell survival, as well as in inflammation and immunity
[17]. TNF-a also shows the capacity to form a voltage-
dependent cationic channel in lipid bilayers [11, 18].
Thalidomide was proposed to elicit its anti-HIV by accelerat-
ing the decay of the TNF-a mRNA [19]. Consequently, the
antiproliferative activity of the compounds presented herein
may be perhaps related to TNF-a inhibition. This concept is to
be further tested, and if shown to be correct, it is anticipated
to have impact in further development of anticancer agents.
1
1436, 1371, 1346, 1320, 1079, 876, 714, 642; H NMR (DMSO-d6,
600 MHz) d/ppm 7.75 (m, 2H), 7.67 (m, 2H), 3.67 (s, 3H, OCH3), 2.64
(s, 2H), 2.57 (dd, 2H, J¼ 12.2 Hz, J¼ 1.3 Hz), 2.45 (d, 2H, J¼ 11.7 Hz),
2.29 (br s, 2H), 1.96 (dd, 2H, J¼ 12.6 Hz, J¼ 1.3 Hz), 1.87 (d, 2H,
J¼ 12.3 Hz), 1.78 (ddd, 1H, J¼ 12.6 Hz, J¼ 1.9 Hz, J¼ 1.6 Hz), 1.67
(ddd, 1H, J¼ 12.6 Hz, J¼ 1.9 Hz, J¼ 1.6 Hz); 13C NMR (DMSO-d6,
150 MHz) d/ppm 176.7 (s), 169.5 (s), 133.6 (d, 2C), 131.8 (s, 2C),
122.5 (d, 2C), 60.0 (s), 51.7 (q), 42.7 (s), 40.8 (t), 39.2 (t, 2C), 37.6
(t, 2C), 35.1 (t), 28.2 (d, 2-C); Elemental analysis calcd. for
C20H21NO4 (Mr 339.38) C 70.78, H 6.24, N 4.13%; found: C 70.78,
H 6.30, N 4.12%.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 334–340
Antiproliferative and Antiviral Activity of Adamantanes
339
N1,N2-{bis[3-(Methyloxocarbonyl)adamantan-1-yl]}-
phthalamide (29)
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42, 993–1003.
Colorless crystals, 240 mg (5.4%); m.p. 215–216°C; IR (KBr)
nmax/cmꢀ1 3283, 2912, 2857, 1729, 1648, 1546, 1534, 1454,
1434, 1366, 1244, 1102; 1H NMR (CDCl3, 600 MHz) d/ppm 7.74
(m, 2H), 7.43 (m, 2H), 6.41 (s, 2H, NH), 3.66 (s, 6H, OCH3), 2.30
(s, 4H), 2.25 (br s, 4H), 2.15 (d, 4H, J ¼ 11.4 Hz), 2.01 (d, 4H,
J ¼ 11.4 Hz), 1.90 (d, 4H, J ¼ 12.0 Hz), 1.86 (d, 4H, J ¼ 12.0 Hz),
1.71 (d, 2H, J ¼ 12.5 Hz), 1.67 (d, 2H, J ¼ 12.5 Hz); 13C NMR
(CDCl3, 75 MHz) d/ppm 176.7 (s, 2C), 168.4 (s, 2C), 134.9 (s, 2C),
129.9 (d, 2C), 128.2 (d, 2C), 51.8 (s, 2C), 51.6 (q, 2C), 42.5 (s, 2C),
42.0 (t, 2C), 40.5 (t, 4C), 37.7 (t, 4C), 35.2 (t, 2C), 28.95 (d, 4C).
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N-(3-Carboxyadamantan-1-yl)-2-carbamoylbenzoic
acid (28)
A round bottom flask (50 mL) was charged with ester 14
(500 mg, 1.47 mmol), CH3OH (10 mL) and an aqueous solution
of Na2CO3 (20 mL, 10%). The mixture was heated at reflux
temperature for 2 days. The cooled reaction mixture was
washed with CH2Cl2 (3 ꢂ 25 mL) and basic aqueous layer
acidified by use of 1 M HCl until pH 2 was reached. The
resulting suspension was extracted with EtOAc (3 ꢂ 45 mL)
and the combined extracts were dried over anhydrous MgSO4.
After filtration and removal of the solvent, the pure product
was obtained (277 mg, 58%) in the form of colorless crystals.
Colorless crystals, m.p. 295–297°C; IR (KBr) nmax/cmꢀ1 3366,
3032, 2917, 1689, 1675, 1532, 1310, 1287; 1H NMR (DMSO-d6,
600 MHz) d/ppm 12.40 (br s, 2H, COOH), 7.79 (s, 1H, NH), 7.74
(dd, 1H, J¼ 1.0 Hz, J¼ 7.7 Hz), 7.53 (ddd, 1H, J¼ 1.3 Hz, J¼ 7.5 Hz,
J¼ 7.7 Hz), 7.45 (ddd, 1H, J¼ 1.3 Hz, J¼ 7.5 Hz, J¼ 7.7 Hz), 7.34
(dd, 1H, J¼ 1.0 Hz, J¼ 7.7 Hz), 2.14 (s, 2H), 2.12 (br s, 2H), 2.03
(d, 2H, J¼ 11.7 Hz), 1.91 (d, 2H, J¼ 11.7 Hz), 1.76–1.71 (m, 4H),
1.60–1.57 (m, 2H); 13C NMR (DMSO, 150 MHz) d/ppm 177.8 (s),
168.2 (s), 167.8 (s), 139.6 (s), 131.1 (d), 129.0 (d), 128.6 (d), 127.7 (d),
51.6 (s), 41.8 (t), 41.5 (s), 40.0 (t, 2C), 37.7 (t, 2C), 35.2 (t), 28.6 (d);
Elemental analysis calcd. for C19H21NO5 (Mr 343.14) C 66.46;
H 6.16; N 4.08%; found: C 65,92; H 6,39; N 4,03%.
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These materials are based on work financed by the Foundation for
Science of the Republic of Croatia (HRZZ grant no. 02.05/25), the
Ministry of Science Education and Sports of the Republic of Croatia
(grant no. 098-0982933-2911). We thank Leentje Persoons, Frieda De
Meyer, Lies Van den Heurck, Steven Carmans, Anita Camps, Lizette van
Berckelaer, and Leen Ingels for excellent technical assistance for the
biological assays. The research of JB was supported by grants of the KU
Leuven (GOA 10/14).
The authors have declared no conflict of interest.
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