Synthesis of functionalized 5-(3-R-1-adamantyl)uracils and related compounds

Article abstract of DOI:10.1016/j.tet.2010.02.043

Efficient synthetic approaches to functionalized 5-(3-R-1-adamantyl)uracils and related compounds (R=OH, COOH, NH₂, etc.) are described. The selective hydroxylation of the adamantane tertiary C-H bonds in 5-(1-adamantyl)uracils with H₂

Full text of DOI:10.1016/j.tet.2010.02.043

Tetrahedron 66 (2010) 3058–3064
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of functionalized 5-(3-R-1-adamantyl)uracils and related compounds
Alexander Shmailov a, Ludmila Alimbarova b, Elvira Shokova a, Viktor Tafeenko a, Ivan Vatsouro a,
,
Vladimir Kovalev a
*
a Department of Chemistry, Moscow State University, Lenin’s Hills, Moscow, 119991, Russia
b Ivanovsky Institute of Virology, Gamalei 16, Moscow, 123098, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthetic approaches to functionalized 5-(3-R-1-adamantyl)uracils and related compounds
(R¼OH, COOH, NH2, etc.) are described. The selective hydroxylation of the adamantane tertiary C–H
bonds in 5-(1-adamantyl)uracils with H2SO4 in trifluoroacetic anhydride is used as the key step. Sub-
sequent electrophilic reactions of 5-(3-hydroxy-1-adamantyl)uracils with N- and C-nucleophiles in
CF3COOH, H2SO4 or H2SO4/AcOH media yielded derivatives with amide, amino, aryl, carboxy and thio-
urea groups in the adamantane core. The preliminary evaluation of the antiviral activity revealed that
some of the synthesized species display moderate antiviral activity against HSV-1 (SI~20) in Vero cells.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 November 2009
Received in revised form 12 January 2010
Accepted 8 February 2010
Available online 17 February 2010
Keywords:
Adamantylated pyrimidines
Synthesis
Hydroxylation of adamantane derivatives
Trifluoroacetic anhydride
Trifluoroacetic acid
Antiviral activity
1. Introduction
unit have been reported to date. Meanwhile, these compounds
have potential for special pharmacological activity. Moreover, they
Functionalized uracil derivatives are essential units of many
biological compounds and active components of many pharma-
ceuticals. Thus, new and improved synthetic routes to them
continue to be important in modern organic chemistry. Among
these compounds, the adamantane-containing ones are of special
interest due to their known and versatile biological activity
provided by adamantane unit itself. The combination of pyrimi-
dine nucleic bases and adamantane units in one molecule has
led to compounds with notable antiviral,1 anticancer2 and anti-
seem to be useful in developing of novel conjugates of ada-
mantanes and biogenic molecules. Here we report the synthesis of
a number of 5-(3-R-1-adamantyl)uracils and related compounds I
with functional groups in adamantane core and the preliminary
evaluation of their anti-HSV activity.
bacterial3 activities. In most cases,
a ring-closure procedure
has been employed allowing to obtain C-2-,4 C-4-,5 C-5-2a–c,6,7
and C-6-1a,2f,8 adamantylated pyrimidines. We have introduced
a simple and efficient route to C-5-adamantylated hydroxy- and
aminopyrimidines by reaction of the corresponding pyrimidines
with 1-adamantanol in a trifluoroacetic acid (TFA) medium.1b,9
Later on, this was extended to C-5-adamantylated uridine and
2-thiobarbituric acid.10 N-1-Adamantylation can be performed by
the Friedel–Crafts alkylation of, for instance, silylated uracil or
thiouracil with 1-chloroadamantane.11
2. Results and discussion
We supposed that the C-5-adamantane-functionalized pyrimi-
dines I can be obtained either bya direct adamantylation of uracil and
its congeners with pre-functionalized adamantanols inTFA, given the
efficiency and operational simplicity of this reaction for 1-ada-
mantanol,1b,9b or through a direct functionalization of the tertiary
adamantane C–H bond in 5-(1-adamantyl)pyrimidines. Both
At the same time, to the best of our knowledge, no adamanty-
lated pyrimidines bearing any functional group in the adamantane
* Corresponding author. Tel.: þ7 495 939 1302; fax: þ7 495 932 8846.
E-mail address: kovalev@petrol.chem.msu.ru (V. Kovalev).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.043

A. Shmailov et al. / Tetrahedron 66 (2010) 3058–3064
3059
approaches have been explored in the present study. In course of the
research we were interested mainly in the introduction of hydroxy,
carboxy and amino groups into the tertiary position of the ada-
mantane fragments of these molecules since these groups are well
known in adamantane chemistry to possess high synthetic value.12
In the first place, we investigated the interaction of hydroxy- and
aminopyrimidines 1 with the carboxylated adamantanols 2 in a TFA
medium (Scheme 1). It was found that the addition of a catalytic
amount of triflic acid into TFA had a dramatic effect on the reaction
efficiency. Thus, uracil 1a was selectively converted into the corre-
sponding carboxy (3a) and carboxymethyl (3b) derivatives in 69 and
61% yields; whereas in the absence of catalyst, the yield of 3b fell
down to 41%, and the reaction between 1a and 2a didn’t take place
at all. Most probably, the electron withdrawing carboxylic group,
when it is directly attached to the adamantane nucleus as in 2a,
suppresses the generation of the required carbocationic in-
termediate in neat TFA.
bounded to an odd number of protons (13C NMR with APT) at 61–
62 ppm also support the structure suggested for 4a,b.
It should be noted that 2-amino and 2-thiopyrimidines with H,
Me or Cl at C-4-position as well as cytosine undergo the TFA-
mediated adamantylation of the exocyclic NH2 or SH-groups in-
stead of the pyrimidine ring.2d,e,10 It is reasonable to assume that
the additional OH-groups at C-4 and C-6-positions of pyrimidines 2
facilitate the C-5-adamantylation of the heterocycle.
Adamantanols are widely used as starting compounds in ada-
mantane chemistry, and hence selective hydroxylation of the ada-
mantane tertiary C–H bond in 5-(1-adamantyl)pyrimidines seems
rather promising for the synthesis of broad spectrum of novel
functionalized adamantylpyrimidines. Previously, we have de-
veloped a simple and efficient protocol of direct adamantane ter-
tiary C–H bond hydroxylation using 1.2–2 equiv of H2SO4 as an
oxidant in trifluoroacetic acid anhydride (TFAA).13 We decided to
apply such conditions for selective oxidation of 5-(1-ada-
mantyl)uracil 5a, supposing also that the uracil unit in 5a would
tolerate them better than those severe conditions, which are
commonly used for the functionalization of adamantanes.12,14
However, we have found that the oxidation of 5a performed with
the simultaneous mixing of components, as described earlier for
adamantane,13 leads to a mixture of compounds, which is hard to
analyze. As the case may be, the presence of free sulfuric acid in the
reaction mixture allows the formation of multiple side products. It is
known that the interaction of sulfuric acid with the excess of TFAA
results in formation of bis(trifluoroacetyl) sulfate,15 which, evidently,
could serve as an oxidizer in this process. Following the proposal, the
mixture of sulfuric acid and TFAA was heated to reflux until a homo-
geneous solution was formed (approximately 2 h), then uracil 5a was
added, and the resultant mixture was heated for additional 4 h. After
removal of the solvent and basic hydrolysis, the desired 5-(3-hydroxy-
1-adamantyl)uracil 6 was isolated in 86% yield. Reaction conditions
and possible mechanism are shown in Scheme 2. Under the same
Scheme 1. Direct C-5-adamantylation of pyrimidines 1a–c with pre-functionalized
1-adamantanols 2a,b: (i) cat.¼CF3SO3H for 3 and 4a or LiClO4 for 4b.
Under the similar conditions, barbituric acid 1b and 2-amino-
4,6-dihydroxypyrimidine 1c were transformed into carboxy-
methylated adamantylpyrimidines 4a,b. However, to obtain 4b we
used lithium perchlorate rather than triflic acid as a catalyst in order
to avoid a possible pyrimidine base 1c deactivation in the electro-
philic substitution reaction due to protonation of the amino group.
Pyrimidines 1 possess nucleophilic sites of different types and,
generally, could be alkylated at C-5, O- and N-atoms, so the sub-
stitution pattern in the heterocycles thus formed cannot be easily
predicted. In our case, the C-5-location of the adamantane unit in 3
and 4 was unambiguously proved by 1H and 13C NMR experiments.
In the 1H NMR spectra of 3a,b single aromatic and both NH signals
appear, while the intensity of singlets at ~2.8 ppm (H-5) in the
spectra of 4a,b corresponds to only one proton in both cases. In the
13C NMR spectra of 3 and 4 the chemical shifts of adamantane
quaternary carbons (
d
C1Ad 34–39 ppm) are typical for C–C bond
Scheme 2. Direct hydroxylation of adamantyluracils 5a and 7 in H2SO4–TFAA medium:
(compare to 51–53 ppm for C1Ad–N9b). The signals of C-5-carbons
(i) ꢀ
D
, 2 h; (ii) ꢀ , 4 h; (iii) ꢀ1 N NaOH; (iv) ꢀ1 N HCl.
D

3060
A. Shmailov et al. / Tetrahedron 66 (2010) 3058–3064
conditions, 5-(1-adamantyl)barbituric acid 5b or 5-(1-adamantyl)-2-
amino-4,6-dihydroxypyrimidine 5c do not undergo the oxidation,
probably due to their low solubility in TFAA. At the same time, the
direct C–Hbond hydroxylationwith bis(trifluoroacetyl)sulfate inTFAA
was successfully applied to 5-(1-adamantyl)-1-carboxymethyluracil
7, which can be easily prepared from 1-carboxymethyluracil and 1-
adamantanol in TFA. The desired 1-carboxymethyl-5-(3-hydroxy-1-
adamantyl)uracil 8 was obtained in 65% yield.
All the novel compounds were characterized by their 1H, 13C
NMR- and ESI mass-spectra. The additivity of 13C substituents
chemical shifts (SCS) was applied for the unambiguous assign-
ment of signals of adamantane carbons in 1,3-disubstituted
adamantanes 3,4,6,8–14 and as a verification of the selectivity of
C-5-adamantylation of uracil and related compounds
1 (the
adamantane carbon atoms numeration is showed in Scheme 3).
To calculate these 13C chemical shifts we employed ada-
mantylpyrimidines 5a–c and 7 as model compounds and SCS of
HO, COOH, CH2COOH, NH2, NHC(S)NH2, NHC(O)CH2Cl, p-tolyl and
p-hydroxyphenyl groups (Table 1). The SCS values reported in
Table 1 were calculated by subtracting the chemical shifts of
identical carbons in adamantane from that of corresponding
monosubstituted adamantane.
As we stated earlier,9b,16 TFA represents an excellent medium for
the alkylation of C-, N- and P-nucleophiles with 1-adamantanols
and other tertiary alcohols. We utilized this method for the ada-
mantylation of different N- and C-nucleophiles (nitriles, urea,
thiourea, arenes) with alcohols 6 and 8 (Scheme 3). Heating of 6
with phenol and 8 with toluene gave arenes 9 and 10 corre-
spondingly; the Ritter reaction of 6 with chloroacetonitrile in TFA
under reflux led to chloroacetamide 11 in good yield; while the
adamantylated nicotinamide 12 was obtained in just a moderate
yield even in the presence of LiClO4 as a catalyst. The interaction of
6 with thiourea yielded the N-adamantylated thiourea 13; the same
synthesis performed with urea as a nucleophile gave a complex
mixture of compounds. However, carrying out the latter reaction in
presence of catalytic amount of CF3SO3H led exclusively to amine
14. For the electrophilic reactions of hydroxylated adamantyluracil
6, other acidic media were applied as well. Thus, under the Koch
reaction conditions (H2SO4þHCOOH), alcohol 6 was converted into
carboxylic acid 3a, while conducting the Ritter reaction of 6 with
chloroacetonitrile in the mixture of acetic and sulfuric acids gave
chloroacetamide 11. Scheme 3 summarizes the above mentioned
derivatizations of adamantyl core in 6 and 8 by the electrophilic
reactions in acidic medium.
Table 1
13C Chemical shifts ( CAd) of adamantylpyrimidines 5a–c, 7 and 13C substituents
d
chemical shifts (SCS) in monosubstituted adamantanes (ppm; DMSO-d6, 20 ꢁC)
Compound
d
CAd
Ca
Cb
Cg
Cd
5a
5b
5c
7
35.3
37.8
38.7
34.7
39. 7
39.9
39.6
40.0
28.3
28.2
29.0
28.3
36.4
35.9
35.8
36.7
R
SCSAd
, Dd
HO
NH2
37.3
24.4
3.2
22.6
10.9
24.6
6.3
7.2
3.4
3.8
2.7
0.5
5.1
4.9
5.1
1.5
1.8
-0.6
0.2
-0.7
1.1
-0.2
0.3
-2.1
-1.6
-1.7
-2.1
-2.0
-3.0
-1.8
-1.3
CH2COOH
NHC(O)CH2Cl
COOH
NHC(S)NH2
p-C6H4(OH)
p-Tola
7.1
a
in CDCl3.
The structure of 8 has been confirmed by X-ray analysis (Fig. 1).
Suitable crystal of this compound was grown at room temperature
from a solution of ethanol/H2O (2:1).
Figure 1. The asymmetric unit of 8, showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown
as small spheres of arbitrary radii.
The X-ray study revealed that in the crystal molecules of 8 form
complicated system of hydrogen bonds, geometric parameters of
which are presented in the Table 2. Each molecule is involved in one
centrosymmetric dimer via N1–H1/O1iii hydrogen bond and
simultaneously in another dimer via hydrogen bond with partici-
pation of hydroxyl group O5–H5/O2iv, extending into infinite
ribbons along the axis a. Adjacent ribbons are connected by
hydrogen bonds of the acids-groups and solvate water molecules
O3–H3/O6i, O6–H6/O4 thus generating an undulated sheet
almost normally to b axis (Fig. 2). There are no significant direction-
specific interactions between adjacent sheets.
Scheme 3. Electrophilic reactions of 5-(3-hydroxy-1-adamantyl)uracils 6, 8.

A. Shmailov et al. / Tetrahedron 66 (2010) 3058–3064
3061
Table 2
5-(3-Carboxy-1-adamantyl)- and 5-(3-amino-1-adamantyl)uracils
(compounds 3a and 14) displayed the most pronounced antiviral
Geometric parameters of the hydrogen bonds of 8
D-H/A
D-H/Å
H/A/Å D/A/Å
D-H/A/ꢁ Symmetry codes
activity towards HSV-1 and had a selectivity index (SI¼MCC50
/
MIC50) of ca. 20. Nicotinamide 12 and thiourea 13 had the highest
cytotoxicity while not revealing antiviral activity towards HSV-1,
and for the latter, towards HSV-2 at subtoxic concentration in
Vero cell culture.
O6–H6/O4
O3–H3/O6i
0.93(4) 1.98(4)
0.99(3) 1.59(3)
2.851(3) 155(4)
x, y, z
2.574(2) 170(3)
2.763(2) 161(3)
2.824(2) 176(2)
2.832(2) 165(3)
(i) 1ꢀx, ꢀy, 1ꢀz
O6-H61/O5ii 0.89(4) 1.90(4)
(ii) 1þx, y, z
N1–H1/O1iii
O5–H5/O2iv
0.85(2) 1.97(2)
1.01(3) 1.85(3)
(iii) 1ꢀx, ꢀy, 2ꢀz
(iv) ꢀx, ꢀy, 2ꢀz
Figure 2. Part of the crystal structure of 8, showing the formation of undulated sheets almost normal to b axis via strong hydrogen bonds N–H/O and O–H/O. Hydrogen bonds are
shown as dashed lines.
The cytotoxicity and antiviral activity of the novel adamanty-
lated pyrimidines were examined against herpes simplex virus
types 1 and 2 (HSV-1 and HSV-2) in Vero cells according to the
previously reported method.17 From the MIC50 and MCC50 values
presented in Table 3, it appears that most of synthesized substances
possess low cytotoxicity and display moderate antiviral activity,
yet significantly inferior to the reference pharmaceutical Zovirax.
3. Conclusions
In conclusion, we have developed the effective approaches to
adamantylated uracils and related compounds with various func-
tional groups in the adamantane core. These compounds may be
obtained (i) by interaction of hydroxy- and aminopyrimidines with
3-carboxy- or 3-carboxymethyl-1-adamantanols in TFA or (ii) via
selective C–H bond hydroxylation of the bridgehead position of
adamantane nucleus of 5-(1-adamantyl)uracils 5a and 7 with bis-
trifluoroacetylsulfate in TFAA medium. Electrophilic reactions of
5-(3-hydroxy-1-adamantyl)uracils 6, 8 with N- and C-nucleophiles
in acidic media (TFA, H2SO4, H2SO4/AcOH) were conducted to
obtain adamantyluracils with amide, amino, aryl, carboxy and
thiourea groups in the adamantane core. The examination of the
antiviral activity demonstrated that most of synthesized com-
pounds possess only moderate antiviral activity against HSV-1 and
HSV-2.
Table 3
Cytotoxicity and anti-HSV activity of adamantylpyrimidines 3a, 6, 8, 11–14 in Vero
a
cells culture (
m )
g/cmꢀ3
b
Compound
MCC50
HSV-1
HSV-2
MIC50
c
MIC50
SI
SI
3a
6
8
11
12
13
14
Zovirax
1000
250
1000
500
250
125
50
20
2
10
5
100
NA
500
50
10
125
100
100
NA
NA
50
2
10
5
50
NA
500
0.2
1000
500
20
1250
5
2500
4. Experimental
4.1. Synthesis
0.4
a
The results represent data from three separate experiments, each of which was
performed in duplicate. The variation of these results under standard operating
procedures is below ꢂ10%.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker Avance 400 spectrometer and referenced to DMSO-d6
(2.50 ppm for 1H and 39.52 ppm for 13C). Signals labelled with an
asterisk * are close to one another and could not be attributed more
b
MCC50dminimum cytotoxic concentration causing 50% growth inhibition of
Vero cells.
c
MIC50dminimum inhibitory concentration reducing the cytopatogenic effect of
virus by 50%.

3062
A. Shmailov et al. / Tetrahedron 66 (2010) 3058–3064
definitely without additional experiments. To assign the chemical
shifts in the 1H and 13C NMR spectra the following symbols were
used: HR and CR for hydrogen and carbon atoms of the pyrimidine
(R¼Pyr), adamantane (R¼Ad), aryl (R¼Ar) and pyridine (R¼Py)
fragments. ESI-MS analyses were performed using Agilent 1100 LC/
MS instrument. Melting points are uncorrected. Analytical thin-layer
chromatography was performed on Kieselgel 60 F254 precoated
aluminium plates (Merck), spots were visualized under UV light
(254 nm). Silica gel column chromatography was performed using
Merck Kieselgel 60 0.040–0.063 mm. Chemicals were commercial
grade and used without further purification. 3-Carboxy-1-ada-
mantanol 2a,18 3-carboxymethyl-1-adamantanol 2b19, 5-(1-ada-
mantyl)pyrimidines 5a–c,1b,9 and 1-carboxymethyluracil20 were
prepared as described.
(0.38 g, 3 mmol) 1c and 3-carboxymethyl-1-adamantanol 2b
(0.42 g, 2 mmol) in TFA (4 mL) in presence of a catalytic amount of
lithium perchlorate was heated for 18 h at 95ꢂ5 ꢁC. On comple-
tion of the reaction, solvents were removed at reduced pressure,
residue was treated with water (10 mL) and filtrate left cooled
overnight. The precipitate formed was collected and dried. Yield:
0.40 g (62%); colourless needle-shaped crystals. Rf 0.21 (10% EtOH
in CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH (DMSO-d6): 2.89 (s, 1H,
H
5Pyr), 2.03 (br s, 2H, CHAd), 1.98 (s, 2H, CH2COOH), 1.75–1.40
(m, 12H, CHA2d). 13C NMR dC (DMSO-d6): 172.2 (COOH), 168.4
(CO4,6Pyr), 155.3 (CO2Pyr), 61.8 (C5Pyr), 47.7 (CH2COOH), 44.4 (C2Ad),
40.5 (C4,10Ad), 39.1 (C1Ad), 38.9 (C8,9Ad), 35.0 (C6Ad), 33.0 (C3Ad),
28.4 (C5,7Ad). ESI-MS: m/z¼341.9 [MþNa]þ for C16H21N3O4þNa
(342.36). Anal. Calcd for C16H21N3O4: C, 60.18; H, 6.63; N, 13.16.
Found: C, 60.27; H, 6.51; N, 13.47.
4.1.1. General procedure for the synthesis of 3a,b, 4a. A mixture of
the corresponding pyrimidine 1a,b (1.2 mmol) and the alcohol 2a,b
(1 mmol) in TFA (2 mL) in presence of a catalytic amount of
CF3SO3H (0.02 mL) was kept for 12 h at 105ꢂ5 ꢁC in the case of 2a or
at 95ꢂ5 ꢁC in the case of 2b. On completion of the reaction, the
solvents were removed under reduced pressure. The resulting dark
oil was treated with water (5 mL) and left overnight. The solid
formed was filtered, washed with water (2ꢃ5 mL) and acetone
(2ꢃ5 mL), dissolved in 1 N NaOH (5 mL) and filtered. The pre-
cipitate formed upon addition of concd HCl was collected, washed
with water, Et2O and dried.
4.1.3. 5-(1-Adamantyl)-1-carboxymethyluracil (7). A mixture of 1-
carboxymethyluracil (0.26 g, 1.5 mmol) and 1-adamantanol (0.29 g,
1.9 mmol) in TFA (2 mL) was heated for 12 h at 95ꢂ5 ꢁC. On com-
pletion of the reaction, solvents were removed at reduced pressure,
the residue was dissolved in 1 N NaOH (10 mL) and filtered. The
precipitate formed upon addition of concd HCl to the filtrate was
collected, washed with water and dried. Yield 0.25 g (55%); white
solid. Rf 0.20 (10% EtOH in CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH
(DMSO-d6): 11.12 (1H, s, NHPyr), 7.22 (1H, s, H6Pyr), 4.40 (2H, s,
CH2COOH), 1.93 (3H, br s, CHAd), 1.88–1.54 (12H, m, CH2Ad). 13C NMR
dC (DMSO-d6): 170.0 (COOH), 163.4 (COPyr), 151.0 (COPyr), 141.5
(C6Pyr), 120.9 (C5Pyr), 49.1 (CH2COOH), 40.0 (C2,8,9Ad), 36.7 (C4,6,10Ad),
34.7 (C1Ad), 28.3 (C3,5,7Ad). ESI-MS: m/z¼342.8 [MþK]þ for
C16H20N2O4þK (343.44). Anal. Calcd for C16H20N2O4: C, 63.14; H,
6.62; N, 9.20. Found: C, 62.18; H, 6.52; N, 9.55.
4.1.1.1. 5-(3-Carboxy-1-adamantyl)uracil (3a). Compound 3a
was prepared from uracil 1a and 3-carboxy-1-adamantanol 2a,
yield 0.20 g (69%); white solid. Rf 0.28 (33% EtOH in CHCl3 (v/v)),
mp >300 ꢁC. 1H NMR dH (DMSO-d6): 10.83 (1H, s, NHPyr), 10.55
(1H, m, NHPyr), 6.95 (1H, d, J¼5.89 Hz, H6Pyr), 2.01 (2H, br s, CHAd),
1.95–1.40 (12H, m, CH2Ad). 13C NMR dC (DMSO-d6): 178.4 (COOH),
163.6 (COPyr), 151.1 (COPyr), 136.8 (C6Pyr), 119.0 (C5Pyr), 40.8 (C2Ad),
40.4 (C3Ad), 38.8 (C8,9Ad), 38.0 (C4,10Ad), 35.6 (C1Ad), 34.5 (C6Ad),
27.9 (C5,7Ad). ESI-MS: m/z¼290.9 [MþH]þ for C15H18N2O4þH
(290.32). Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65.
Found: C, 62.11; H, 6.22; N, 9.83.
4.1.4. General procedure for the synthesis of 6, 8. A mixture of TFAA
(3.4 mL, 24 mmol) and 98% sulfuric acid (0.24 mL, 4.4 mmol) was
heated to reflux for 2 h at 60–65 ꢁC. The adamantyluracil (5a or 7,
2 mmol) was added to the formed homogeneous solution and the
resulting mixture was heated for 4 h at 70–75 ꢁC. On completion of
the reaction, solvents were removed at reduced pressure, the res-
idue was dissolved in 1 N NaOH (10 mL), heated for 2 h at 45–50 ꢁC,
the basic solution was cooled to rt and filtered. The precipitate
formed upon addition of concd HCl to the filtrate was collected,
washed with water and dried.
4.1.1.2. 5-(3-Carboxymethyl-1-adamantyl)uracil (3b). Compound
3b was prepared from uracil 1a and 3-carboxymethyl-1-ada-
mantanol 2b, yield 0.19 g (61%); white solid. Rf 0.30 (33% EtOH in
CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH (DMSO-d6): 10.80 (1H, br s,
NHPyr), 10.55 (1H, m, NHPyr), 6.86 (1H, d, J¼5.80 Hz, H6Pyr), 2.02 (2H,
br s, CHAd), 1.97 (2H, s, CH2COOH), 1.85–1.40 (12H, m, CHA2d). 13C
NMR dC (DMSO-d6): 172.4 (COOH), 163.4 (COPyr), 150.9 (COPyr),
136.3 (C6Pyr), 119.3 (C5Pyr), 48.2 (CH2COOH), 44.2 (C2Ad), 41.1
(C4,10Ad), 38.8 (C8,9Ad), 35.7 (C6Ad), 34.8 (C1Ad), 32.5 (C3Ad), 28.3
(C5,7Ad). ESI-MS: m/z¼327.0 [MþNa]þ for C16H20N2O4þNa (327.35).
Anal. Calcd for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20. Found: C,
63.23; H, 6.55; N, 9.38.
4.1.4.1. 5-(3-Hydroxy-1-adamantyl)uracil (6). Compound 6 was
prepared from 5a, yield 0.45 g (86%); white solid. Rf 0.70 (33% EtOH
in CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH (DMSO-d6): 10.87 (1H, s,
NHPyr), 10.59 (1H, m, NHPyr), 6.87 (1H, d, J¼5.89 Hz, H6Pyr), 4.41 (1H,
br s, OH), 2.11 (2H, br s, CHAd), 1.90–1.40 (12H, m, CH2Ad). 13C NMR dC
(DMSO-d6): 163.5 (COPyr), 150.9 (COPyr), 136.3 (C6Pyr), 118.8 (C5Pyr),
66.7 (C3Ad), 47.5 (C2Ad), 44.6 (C4,10Ad), 38.5 (C8,9Ad), 37.3 (C1Ad), 35.3
(C6Ad), 30.0 (C5,7Ad). ESI-MS: m/z¼284.6 [MþNa]þ for
C14H18N2O3þNa (285.31). Anal. Calcd for C14H18N2O3: C, 64.11; H,
6.92; N, 10.68. Found: C, 64.25; H, 6.98; N, 10.31.
4.1.1.3. 5-(3-Carboxymethyl-1-adamantyl)barbituric acid (4a).
Compound 4a was prepared from barbituric acid 1b and 3-car-
boxymethyl-1-adamantanol 2b, yield 0.17 g (53%); white solid. Rf
0.28 (10% EtOH in CHCl3 (v/v)), mp¼257–259 ꢁC. 1H NMR dH
(DMSO-d6): 11.11 (2H, s, NHPyr), 2.72 (1H, s, H5Pyr), 2.02 (2H, br s,
CHAd), 1.97 (2H, s, CH2COOH), 1.70–1.35 (12H, m, CH2Ad). 13C NMR dC
(DMSO-d6): 172.3 (COOH), 168.7 (CO4,6Pyr), 151.5 (CO2Pyr), 61.1
(C5Pyr), 47.9 (CH2COOH), 44.5 (C2Ad), 40.7 (C4,10Ad), 39.2 (C8,9Ad), 38.5
(C1Ad), 35.2 (C6Ad), 33.1 (C3Ad), 28.5 (C5,7Ad). ESI-MS m/z¼358.9
[MþK]þ for C16H20N2O5þK (359.44). Anal. Calcd for C16H20N2O5: C,
59.99; H, 6.29; N, 8.74. Found: C, 59.87; H, 6.23; N, 8.46.
4.1.4.2. 5-(3-Hydroxy-1-adamantyl)-1-carboxymethyuracil
(8). Compound 8 was prepared from 7, yield 0.42 g (65%); colourless
crystals. Rf 0.26 (33% EtOH in CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH
(DMSO-d6): 11.16 (1H, s, NHPyr), 7.27 (1H, s, H6Pyr), 4.42 (3H, br s,
CH2COOHþOH), 2.13 (2H, br s, CHAd), 2.10–1.40 (12H, m, CH2Ad). 13
C
NMR dC (DMSO-d6): 169.7 (COOH), 163.0 (COPyr), 150.5 (COPyr), 141.1
(C6Pyr), 119.5 (C5Pyr), 66.7 (C3Ad), 48.7 (CH2COOH), 47.7 (C2Ad), 44.6
(C4,10Ad), 38.7 (C8,9Ad), 37.6 (C1Ad), 35.2 (C6Ad), 30.0 (C5,7Ad). ESI-MS: m/
z¼343.0 [MþNa]þ for C16H20N2O5þNa (343.35). Anal. Calcd for
C16H20N2O5: C, 59.99; H, 6.29; N, 8.74. Found: C, 60.08; H, 6.36; N, 8.68.
Crystal data. C16H20N2O5$H2O, M¼320.35ꢃ18.02, monoclinic,
4.1.2. 2-Amino-5-(3-carboxymethyl-1-adamantyl)-4,6-dihydrox-
ypyrimidine (4b). A mixture of 2-amino-4,6-dihydroxypyrimidine
a¼11.7625(11), b¼11.4654(18), c¼12.320(2),
b
¼108.009(11)ꢁ,

A. Shmailov et al. / Tetrahedron 66 (2010) 3058–3064
3063
V¼1580.1(4) Å3, space group P21/c, Z¼4, Dc¼1.422 g cmꢀ3
,
m
(Mo
39.0 (C8,9Ad), 36.3* (C1Ad), 35.6 (C6Ad), 35.6* (C3Ad), 28.8 (C5,7Ad), 20.7
(CH3). ESI-MS: m/z¼395.2 [MþH]þ for C23H26N2O4þH (395.47).
Anal. Calcd for C23H26N2O4: C, 70.03; H, 6.64; N, 7.10. Found: C,
70.20; H, 6.69; N, 7.29.
Ka
)¼0.917.
Data collection. X-ray diffraction data were collected from
a colourless crystal (size 0.1ꢃ0.1ꢃ0.4 mm) on an Enraf Nonius
CAD4 diffractometer using graphite monochromated Cu
(1.54179 Å) radiation at room temperature [293(2) K], -scan
mode at 295 K. R¼0.038 for 2442 independent observed
K
a
u
4.1.5.3. 5-(3-Chloromethylcarbamoyl-1-adamantyl)uracil
(11). Compound 11 was prepared from 6 and chloroacetonitrile
(0.21 g, 2 mmol) for 15 h at 105ꢂ5 ꢁC. The solid formed on com-
pletion of the reaction was collected, dissolved in 1 N NaOH (5 mL)
at rt and filtered off immediately. The basic water solution was
made acidic with concd HCl, the resulting precipitate was collected,
washed with water and dried. Yield 0.25 g (74%); white solid. Rf
0.38 (10% EtOH in CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH (DMSO-d6):
10.89 (1H, s, NHPyr), 10.61 (1H, m, NHPyr), 7.70 (1H, s, AdNH), 6.88
(1H, d, J¼5.89 Hz, H6Pyr), 3.94 (2H, s, CH2Cl), 2.11 (2H, br s, CHAd),
2.08–1.50 (12H, m, CH2Ad). 13C NMR dC (DMSO-d6): 164.9 (CONH),
163.4 (COPyr), 150.9 (COPyr), 136.5 (C6Pyr), 118.6 (C5Pyr), 51.9 (C3Ad),
43.5 (CH2Cl), 43.0 (C2Ad), 40.0 (C4,10Ad), 38.5 (C8,9Ad), 35.9 (C6Ad),
35.3 (C1Ad), 28.8 (C5,7Ad). ESI-MS: m/z¼338.2 [MþH]þ for
C16H20ClN3O3þH (338.81). Anal. Calcd for C16H20ClN3O3: C, 56.89;
H, 5.97; N, 12.44. Found: C, 56.97; H, 6.08; N, 12.13.
reflections with [I>2s(I)]. The WinGX standard procedure was
applied for data reduction.21 Two standard reflections were mea-
sured every 120 min as intensity control. No absorption correction
was applied.
Structure analysis and refinement. The structure was solved
and refined with SHELX program.22 The non-hydrogen atoms
were refined using the anisotropic full matrix least squares
procedure. The molecular graphics were prepared using
DIAMOND.23 The H atoms attached to carbons were placed in the
calculated positions and allowed to ride on their parent atoms
(C–H 0.97–0.98; Uiso¼1.2Ueq(parent atom)). H atoms attached to
nitrogen and oxygen were determined from a difference Fourier
synthesis and refined freely. The isotropic displacement param-
eters for freely refined hydrogen atoms are 0.05–0.14(1) Å2.
Refinement was made against all reflection. The threshold ex-
pression of F2>2
s
(F2) is used for calculation R-factor, the final
4.1.5.4. 5-(3-Nicotinamido-1-adamantyl)uracil (12). Compound
12 was prepared from 6 and nicotinic acid nitrile (0.21 g, 2 mmol)
for 22 h at 115ꢂ5 ꢁC. The solid formed on completion of the re-
action was filtered off and dissolved in 1 N NaOH (5 mL) at rt. The
basic water solution was neutralized to pH 7–8 with diluted HCl,
the resulting precipitate was collected, washed with water and
dried. Yield 0.10 g (27%); white solid. Mp decomposes >210 ꢁC. 1H
NMR dH (DMSO-d6): 10.84 (1H, br s, NHPyr), 8.91 (1H, br s, HPy),
8.67 (1H, m, HPy), 8.12 (1H, m, HPy), 7.95 (1H, br s, AdNH), 7.44
value of which is 0.038.
Crystallographic data (excluding structure factors) for the
structure 8 have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication nos. CCDC
732269. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC,12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.1.5. General procedure for the synthesis of 9–14 in TFA medium. The
corresponding adamantanol (6 or 8, 1 mmol) and a nucleophilic
reagent were heated in TFA (2 mL) (in the case of adamantylation of
nicotinic acid nitrile and urea LiClO4 or CF3SO3H were added as
a catalyst, correspondingly). On completion of the reaction, solvents
were removed at reduced pressure, the residue was treated with
water (5 mL) and left overnight. Further workup procedure for
individual uracils was as follows.
(1H, m, H
Py), 6.92 (1H, s, H6Pyr), 2.30–1.40 (14H, m, CHAd
þCH2Ad). 13C NMR dC (DMSO-d6): 164.6 (COPyr), 163.5 (NHCO), 151.4
(COPyr), 150.9 (CHPy), 148.5 (CHPy), 136.6 (C6Pyr), 135.1 (CHPy), 131.2
(CHPy), 123.2 (CPy), 118.7 (C5Pyr), 52.5 (C3Ad), 43.3 (C2Ad), 40.1
(C4,10Ad), 38.6 (C8,9Ad), 36.0 (C6Ad), 35.3 (C1Ad), 29.0 (C5,7Ad). ESI-
MS: m/z¼366.7 [MþH]þ for C20H22N4O3þH (367.42). Anal. Calcd
for C20H22N4O3: C, 65.56; H, 6.05; N, 15.29. Found: C, 65.43; H,
6.11; N, 15.41.
4.1.5.1. 5-(3-p-Hydroxyphenyl-1-adamantyl)uracil (9). Compound
9 was prepared from 6 and phenol (0.12 g, 1.2 mmol) for 15 h at
95ꢂ5 ꢁC. The precipitate formed on completion of the reaction
was filtered off, washed with warm water and dried. Yield 0.26 g
(77%); white solid. Rf 0.21 (10% EtOH in CHCl3 (v/v)), mp >300 ꢁC.
1H NMR dH (DMSO-d6): 10.88 (1H, s, NHPyr), 10.61 (1H, m, NHPyr),
7.12 (2H, d, J¼8.71 Hz, HAr), 6.94 (1H, d, J¼5.89 Hz, H6Pyr), 6.67 (2H,
d, J¼8.70 Hz, HAr), 2.13 (2H, br s, CHAd), 2.00–1.60 (12H, m, CHA2d).
13C NMR dC (DMSO-d6): 163.5 (COPyr), 155.1 (CAr), 151.0 (COPyr),
140.9 (CAr), 136.5 (C6Pyr), 125.6 (CHAr), 119.4 (C5Pyr), 114.8 (CHAr),
45.3 (C2Ad), 42.2 (C4,10Ad), 38.8 (C8,9Ad), 35.7* (C3Ad), 35.6* (C1Ad),
35.2 (C6Ad), 28.7 (C5,7Ad). ESI-MS: m/z¼339.3 [MþH]þ for
C20H22N2O3þH (339.41). Anal. Calcd for C20H22N2O3: C, 70.99; H,
6.55; N, 8.28. Found: C, 71.15; H, 6.51; N, 8.44.
4.1.5.5. 5-(3-Thioureido-1-adamantyl)uracil (13). Compound 13
was prepared from 6 and thiourea (0.19 g, 2.5 mmol) for 15 h at
95ꢂ5 ꢁC. The solid formed on completion of the reaction was fil-
tered off, washed with water, dried. Yield 0.29 g (91%); white solid.
Rf 0.55 (33% EtOH in CHCl3 (v/v)), mp >300 ꢁC. 1H NMR dH (DMSO-
d6): 10.91 (1H, s, NHPyr), 10.75 (1H, m, NHPyr), 9.66 (1H, s, NH), 9.20
(2H, s, NH2), 6.99 (1H, d, J¼5.97 Hz, H6Pyr), 2.27–1.52 (14H, m,
CHAdþCHA2d). 13C NMR dC (DMSO-d6): 163.9 (CS), 163.3 (COPyr),150.8
(COPyr), 137.0 (C6Pyr), 117.9 (C5Pyr), 53.5 (C3Ad), 45.4 (C2Ad), 42.4
(C4,10Ad), 37.7 (C9,10Ad), 36.8 (C1Ad), 34.4 (C6Ad), 29.7 (C5,7Ad). ESI-MS:
m/z¼321.1 [MþH]þ for C15H20N4O2SþH (321.42). Anal. Calcd for
C15H20N4O2S: C, 56.23; H, 6.29; N, 17.49. Found: C, 56.09; H, 6.33; N,
17.27.
4.1.5.6. 5-(3-Amino-1-adamantyl)uracil (14). Compound 14 was
prepared from 6 and urea (0.12 g, 2 mmol) for 10 h at 115ꢂ5 ꢁC. The
solid formed on completion of the reaction was neutralized to pH
7–8 with 20% aq NaOH solution. The resulting precipitate was
collected on a filter, washed with water (2 mL) and dried. Yield
0.23 g (88%); white solid. Rf 0.22 (33% EtOH in CHCl3 (v/v)), mp
>300 ꢁC. 1H NMR dH (DMSO-d6): 10.97 (1H, s, NHPyr),10.78 (1H, br s,
NHPyr), 7.95 (2H, br s, NH2), 6.96 (1H, d, J¼5.97 Hz, H6Pyr), 2.19 (2H,
br s, CHAd), 2.10–1.50 (12H, m, CH2Ad). 13C NMR dC (DMSO-d6): 163.5
(COPyr), 150.8 (COPyr), 136.9 (C6Pyr), 117.6 (C5Pyr), 51.6 (C3Ad), 42.1
(C2Ad), 39.9 (C4,10Ad), 38.0 (C8,9Ad), 35.8 (C1Ad), 34.6 (C6Ad), 28.5
(C5,7Ad). ESI-MS: m/z¼261.6 [MþH]þ for C14H19N3O2þH (262.33).
4.1.5.2. 5-(3-p-Tolyl-1-adamantyl)-1-carboxymethyluracil
(10). Compound 10 was prepared from 8 and toluene (0.14 mL,
1.2 mmol) for 15 h at 95ꢂ5 ꢁC. The precipitate formed on comple-
tion of the reaction was filtered off, washed with water and dried.
Yield 0.18 g (91%); white solid. Rf 0.23 (33% EtOH in CHCl3 (v/v)),
mp¼290 ꢁC. 1H NMR dH (DMSO-d6): 11.19 (1H, s, NHPyr), 7.32 (1H, s,
H
6Pyr), 7.23 (2H, d, J¼8.11 Hz, HAr), 7.09 (2H, d, J¼8.02 Hz, HAr), 4.42
(2H, br s, CH2COOH), 2.30–1.60 (17H, m, CHAdþCH2AdþCH3). 13C
NMR dC (DMSO-d6): 169.9 (COOH),163.3 (COPyr),150.7 (COPyr), 147.6
(AdCAr), 141.4 (C6Pyr), 134.7 (CH3CAr), 128.9 (CH3CCHAr), 124.8
(AdCCHAr), 120.2 (C5Ar), 49.0 (CH2COOH), 45.5 (C2Ad), 42.2 (C4,10Ad),

3064
A. Shmailov et al. / Tetrahedron 66 (2010) 3058–3064
Anal. Calcd for C14H19N3O2: C, 64.35; H, 7.33; N, 16.08. Found: C,
64.25; H, 7.18; N, 16.22.
References and notes
1. (a) Kuchar, M.; Strof, J.; Vachek, J. Collect. Czech. Chem. Commun. 1969, 34, 2278;
(b) Shokova, E. A.; Alimbarova, L. M.; Kovalev, V. V. Pharm. Chem. J. 1999, 33,
372; (c) Skorobogatyi, M. V.; Ustinov, A. V.; Stepanova, I. A.; Pchelintseva, A. A.;
Petrunina, A. L.; Andronova, V. L.; Galegov, G. A.; Malakhov, A. D.; Korshun, V. A.
Org. Biomol. Chem. 2006, 4, 1091.
4.1.6. Synthesis of 3a and 11 under Koch and Ritter reaction
conditions.
2. (a) Jonak, J. P.; Zakrzewski, S. F.; Mead, L. H. J. Med. Chem. 1972, 15, 662; (b)
Jonak, J. P.; Mead, L. H.; Ho, Y. K.; Zakrzewski, S. F. J. Med. Chem. 1973, 16, 724; (c)
Creaven, P. J.; Zakrewski, S. F.; Greco, W. R.; Madajevicz, S.; Mittelman, A.;
Pontes, J. E.; Karakousis, C.; Takita, H.; Proefrock, A. Cancer Chemother. Phar-
macol. 1988, 21, 122; (d) Kazimierczuk, Z.; Gorska, A.; Switaj, T.; Lasek, W.
Bioorg. Med. Chem. Lett. 2001, 11, 1197; (e) Maurin, J. K.; Lasek, W.; Go´rska, A.;
Switaj, T.; Jakubowska, A. B.; Kazimierczuk, Z. Chem. Biodiver. 2004, 1, 1498; (f)
Orzeszko, B.; Kazimierczuk, Z.; Maurin, J. K.; Laudy, A. E.; Starosciak, B. J.; Vilpo,
J.; Vilpo, L.; Balzarini, J.; Orzeszko, A. Farmaco 2004, 59, 929; (g) Orzeszko, B.;
Sc´witaj, T.; Jakubowska-Muc´ka, A. B.; Lasek, W.; Orzeszko, A.; Kazimierczuk, Z.
Z. Naturforsch., B: Chem. Sci. 2005, 60, 471; (h) Novakov, I. A.; Orlinson, B. S.;
Brunilin, R. V.; Nawrozkij, M. B.; Savel’ev, E. N.; Novikova, G. A. Chem. Heterocycl.
Comp. 2006, 42, 1331.
4.1.6.1. 5-(3-Carboxy-1-adamantyl)uracil (3a). A suspension of
6 (1.05 g, 4 mmol) in 98% sulfuric acid (10 mL) was cooled to 0 ꢁC.
Formic acid (98%, 1 mL, 26.5 mmol) was added dropwise over 1 h
and reaction mixture was stirred for 24 h at rt. On completion of
the reaction the solution was poured on ice, formed precipitate
was filtered off, washed with water and dried. Yield 0.97 g (84%).
4.1.6.2. 5-(3-Chloromethylcarbamoyl-1-adamantyl)uracil
(11). To the mixture of 6 (0.93 g, 3.55 mmol) and ClCH2CN (0.9 ml,
14.2 mmol) glacial acetic acid (1.15 mL) was added, and the
resulting mixture was cooled to 0–3 ꢁC. H2SO4 (1.15 mL, 22 mmol)
was added dropwise keeping the temperature below 10 ꢁC. The
resulting solution was stirred for 24 h at rt and poured into ice
water (15 mL), the formed precipitate was filtered off, washed with
water and dried. Yield 0.83 g (69%).
ꢀ
´
3. Orzeszko, B.; Fedorynski, M.; Laudy, A. E.; Starosciak, B. J.; Orzeszko, A. Acta Pol.
Pharm. 2006, 63, 374.
4. Aigami, K.; Inamoto, Y.; Takaishi, N.; Hattori, K.; Takatsuki, A.; Tamura, G. J. Med.
Chem. 1975, 18, 713.
5. (a) Litvinov, V. P.; Dermugin, V. S.; Shvedov, V. I.; Shklover, V. E.; Struchkov, Y. T.
Rus. Chem. Bull. 1986, 1708; (b) Makarova, N. V.; Boreko, E. I.; Moiseev, I. K.;
Pavlova, N. I.; Nikolaeva, S. N.; Zemtsova, M. N.; Vladyko, G. V. Pharm. Chem. J.
2002, 36, 3; (c) Makarova, N. V.; Zemtsova, M. N.; Moiseev, I. K. Chem. Het.
Comp. 2003, 39, 613.
6. Landa, S.; Burkhard, J.; Vais, J. Collect. Czech. Chem. Commun. 1973, 38, 2947.
7. Basnak, I.; Balkan, A.; Coe, P. L.; Walker, R. T. Nucleosides Nucleotides 1994, 13,
177.
8. Draminski, M.; Turski, K.; Tateoka, Y.; Kimura, T.; Watanabe, K.; Kondo, S.; Ho, I.
K.; Yamamoto, I. Chem. Pharm. Bull. 1998, 43, 177.
9. (a) RF Patent 2,064,930, 1996. (b) Shokova, E.; Mousoulou, T.; Lyzikov, Y.;
Kovalev, V. Synthesis 1997, 1034.
4.2. Pharmacology
Cells. Vero cells culture (green monkey kidney cells) was grown
in Eagle’s medium (Institute of Poliomyelitis and Viral Encephalit-
ides, Moscow, Russia) supplemented with 10% foetal calf serum
(‘PanEco’, Moscow).
10. Kazimierczuk, Z.; Orzeszko, A. Helv. Chim. Acta 1999, 82, 2020.
11. Sasaki, T.; Usuki, A.; Ohno, M. J. Org. Chem. 1980, 45, 3559.
Viruses. Herpes simplex virus type 1 (strain KL 1, HSV-1) and
type 2 (strain VN, HSV-2) were from the Laboratory of Virus Mu-
seum (Ivanovsky Institute of Virology, Moscow, Russia).
Cytotoxicity assays. Vero cells in 96-well microtiter plates were
treated with different concentrations of the experimental drugs
12. (a) Fort, R. C.; Schleyer, P. v.
R Chem. Rev. 1964, 64, 277; (b) Fort, R. C.
Adamantane. The Chemistry of Diamond Molecules; Marcel Dekker: New York.
NY, 1976; p 385.
13. Kovalev, V. V.; Fedorova, O. A.; Shokova, E. A. Zh. Org. Khim. 1987, 23, 1882.
14. (a) Wanka, L.; Cabrele, C.; Vanejews, M.; Schreiner, P. R. Eur. J. Org. Chem.
2007, 1474; (b) Maison, W.; Frangioni, J. V.; Pannier, N. Org. Lett. 2004, 6,
4567; (c) Fokin, A. A.; Shubina, T. E.; Gunchenko, P. A.; Isaev, S. D.; Yurch-
enko, A. G.; Schreiner, P. R. J. Am. Chem. Soc. 2002, 124, 10718; (d) Moiseev, I.
K.; Makarova, N. V.; Zemtsova, M. N. Russ. Chem. Rev. 1999, 68, 1001 and
references therein.
15. (a) Tyobeka, T. E.; Hancock, R. A.; Weigel, H. Tetrahedron 1988, 44, 1971;
(b) Tyobeka, T. E.; Hancock, R. A.; Weigel, H. J. Chem. Soc., Chem. Commun.
1980, 114.
16. (a) Kovalev, V. V.; Khomich, A. N.; Shokova, E. A.; Luzikov, Y. N. New J. Chem.
1996, 20, 483; (b) Kovalev, V.; Shokova, E.; Rozov, A. Tetrahedron 1996, 52, 3983;
(c) Erochina, E.; Shokova, E.; Lyzikov, Y.; Kovalev, V. Synthesis 1995, 851.
17. (a) De Clercq, E.; Descamps, J.; Verheist, G.; Walker, R. T.; Jones, A. S.; Torrence,
P. F.; Shugar, D. J. Infect. Des. 1980, 141, 563; (b) Motornaya, A. E.; Alimbarova, L.
M.; Shokova, E. A.; Kovalev, V. V. Pharm. Chem. J. 2006, 40, 68.
18. Baklan, V. F.; Hil’chevskii, A. N.; Sologub, P. S.; Kuchar’, V. P. Zh. Org. Khim. 1992,
28, 2098.
(1.4ꢃ105 cells in 185
mL of the medium per well). Cell cultures were
incubated for 72 h. At the indicated time, the cells were coloured with
Trypan Blue, and the cell number was determined. The 50% minimum
cytotoxic concentration (MCC50) was defined as the compound
concentration required reducing the cell number by 50%.
Antiviral assays. Vero cells were inoculated with HSV-1 or HSV-2
at an input of 0.1 PFU (plaque formation units) per cell and then
incubated with a medium containing various concentrations of
adamantylated pyrimidines for 48 h (95–100% virus-inducted
cytopathicity in the untreated control). Antiviral activity was
expressed as the compound concentration required to reduce virus-
inducted cytopathicity by 50% (MIC50) compared to untreated
control.
19. Bott, K. Chem. Ber. 1968, 101, 564.
20. Jones, A. S.; Lewis, P.; Withers, S. F. Tetrahedron 1973, 29, 2293.
21. Harms, K.; Wocadlo, S. XCAD-4: Program for Processing CAD4 Diffractometer
Data; University of Marburg: Germany, 1995.
Acknowledgements
22. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, A64, 112.
23. Brandenburg, K. 2000; DIAMOND. Release 2.1d Crystal Impact GbR, Bonn,
Germany.
The research was supported by grant from the Russian Foun-
dation for Basic Research, projects # 09-03-00971.