Synthesis of 4-hydroxy-3-[(E)-2-(6-substituted-9H-purin-9-yl)vinyl] coumarins as lipoxygenase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2013.11.102

The synthesis of 4-hydroxy-3-[(E)-2-(6-substituted-9H-purin-9-yl)vinyl] coumarins has been achieved from the reactions of 4-hydroxycoumarin with 2-(6-substituted-9H-purin-9-yl)acetaldehydes in DMF under heating. The new compounds showed significant lipoxy

Full text of DOI:10.1016/j.tetlet.2013.11.102

Tetrahedron Letters 55 (2014) 650–653
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 4-hydroxy-3-[(E)-2-(6-substituted-9H-purin-9-yl)vinyl]-
coumarins as lipoxygenase inhibitors
a
b,
⇑
b
a,
⇑
Michael G. Kallitsakis , Dimitra J. Hadjipavlou-Litina , Aikaterini Peperidou , Konstantinos E. Litinas
a
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 4-hydroxy-3-[(E)-2-(6-substituted-9H-purin-9-yl)vinyl] coumarins has been achieved
from the reactions of 4-hydroxycoumarin with 2-(6-substituted-9H-purin-9-yl)acetaldehydes in DMF
under heating. The new compounds showed significant lipoxygenase inhibitory activity (e.g., 6a:
Received 24 October 2013
Revised 15 November 2013
Accepted 26 November 2013
Available online 1 December 2013
IC50 = 6.25 lM).
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
4
-Hydroxycoumarin
Modified nucleosides
Purines
Lipoxygenase inhibitors
The 3-substituted derivatives of 4-hydroxycoumarin possess a
the coupling of aryl lead compounds with 4-hydroxycoumarins,37
while 3-benzyl-4-hydroxy coumarins have been prepared by the
reduction of the intermediate 3-benzylidene-chroman-2,4-dion
1–7
wide range of biological activities,
including anticoagulant, anti-
cancer, HIV enzyme inhibition, and antibacterial. Warfarin (I)
Fig. 1) has been prescribed as an anticoagulant drug for more than
3
8
(
5
es. Another route to 3-alkylated-4-hydroxycoumarins is via cycli-
8
–10
11
30,39,40
0 years.
The natural substance dicoumarol (II) and the syn-
zation starting from o-hydroxyarylcarbonyl compounds
salicylates.
or
9,10
22
thetic phenprocoumon (III)
(Fig. 1) are also anticoagulants.
Compounds I and II also show anticancer activity.3 Brodifacoum
,6
Modified nucleosides present interesting biological activities, in
1
2
41–46
(
IV) and its parent compound, difenacoum, are rodenticide drugs.
PD099560 (V) is an HIV-1 protease inhibitor, while ferulenol (VI)
Fig. 1), isolated from nature, exhibits antimycobacterial activity.
The 3-substituted 4-hydroxycoumarin derivatives such as war-
farin (I) are prepared, mainly by Michael addition of 4-hydroxy-
particular antiviral, anticancer, and antimetabolic.
Through ra-
13
tional drug design approaches, hybrid molecules with dual func-
1
4
47
(
tionality and/or targets have been developed. Some of these
hybrid drugs have been demonstrated to be potent agents, possess-
ing no or minimum toxicity. In continuation of our previous stud-
1
5–20
48–50
coumarin (5) to
a
,b-unsaturated carbonyl compounds,
as
or
ies
on modified nucleosides bearing two biologically active
1
6a,18,19
racemic products in the presence of different catalysts
moieties, we decided to combine 4-hydroxycoumarin and the
purine moieties in a new entity, a hybrid molecule, in an attempt
to derive potent lipoxygenase inhibitors with possible anti-inflam-
matory activity. The new compounds are synthesized from the
reactions of 4-hydroxycoumarin with (purin-9-yl)-acetaldehyde
derivatives. The reactions studied and the products obtained are
depicted in Scheme 1.
with enantioselectivity under organocatalysis.2
0,21
Dicoumarol
II) and its methylene substituted derivatives are synthesized by
this method through the initially formed 3-alkylidene-chroman-
(
2
2,23
2
,4-diones from the reaction of 5 with formaldehyde,
aldehydes
other polar solvents,
dride at room temperature,
aromatic
2
3–26
23,24,27
25
22–25,27
or aliphatic aldehydes
in ethanol,
2
5,27
without solvent, or in acetic anhy-
2
6
22,23,25
24,26,27
Treatment of 6-piperidinylpurine (1a)48,51 with 2-bromo ace-
under heating,
or using
2
6
microwave irradiation. The direct alkylation of 5 with alkylha-
taldehyde diethyl acetal (2) and anhydrous K
2 3
CO in dry DMF at
lides presents difficulties.2
8–30
Alcohols as alkylating agents have
90 °C under nitrogen for 8 h resulted in the formation of 9-(2,2-
5
2
been utilized to circumvent this problem leading to C3-alkyl-
diethoxyethyl)-6-piperidin-1-yl-9H-purine (3a)
in 73% yield,
3
1–35
35,36
while 14% of the starting material was recovered. The 1H NMR
ated
or O-alkylated
products under Lewis acid catalysis.
3
-Aryl-4-hydroxycoumarin derivatives have been synthesized by
spectrum of 3a exhibited shifts at 1.05 (t, 6H, J = 7.0 Hz), 3.37
(
dq, 2H,
= 9.3 Hz), 4.15 (d, 2H, J = 5.3 Hz), and 4.61 (t, 1H, J = 5.3 Hz) for
the CH CH O–, CH CH O–, –CH CH(OEt)2, and –CH CH(OEt)
2
J
1
= 7.0 Hz,
J
2
= 9.3 Hz), 3.62 (dq, 2H,
1
J = 7.0 Hz,
J
2
⇑
Corresponding authors. Tel.: +30 2310997864; fax: +30 2310997679.
E-mail address: klitinas@chem.auth.gr (K.E. Litinas).
3
2
3
2
2
2
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.102

M. G. Kallitsakis et al. / Tetrahedron Letters 55 (2014) 650–653
651
O
OH
O
OH
O
OH
O
OH
O
O
O O
O
I
II
III
OH
OH
O
OH
O
O
O
O
O
O
VI
V
Br
IV
Figure 1.
A
N
N
N
OH
O
N
O
OH
6
a-g
A
N
A
N
N
A
O
O
N
N
N
N
(
i)
N
(ii)
5
(iii)
A
N
N
N
N
N
N
H
N
N
1
a-g
O
EtO OEt
OH
OH
O
4
a-g
3
a-g
O
O O
A
N
A
7
a-g
1
,3,4,6,7 a:
e:
MeNH
PhCH NH
b:
c:
O
N
f:
2
g:
NH
N
d:
Cl
2 3 2
Scheme 1. Reagents and conditions: (i) 2-bromoacetaldehyde diethyl acetal (2), anhydrous K CO , dry DMF, 90 °C under N , 8 h; (ii) HCl (1 M), reflux, 2 h [extraction with
EtOAc (ꢀ10)]; (iii) 4-hydroxycoumarin (5), dry DMF, 90 °C, N , 2 h.
2
protons, respectively. Similar reactions52 of 6-substituted purines
b–g gave the acetals 3b–g in moderate to good yields (Table 1,
entries 2–7).
Table 1
Synthesis of the 4-hydroxy-3(9H-purin-9-yl)coumarin derivatives 3, 4, and 6
1
Entry
Substrate
Product (Yield %)
5
2
Heating 1 M HCl solution of acetal 3a under reflux for two
hours led to the aldehyde 4a. Repeated extraction of the reaction
mixture with ethyl acetate gave the pure aldehyde 4a in 6% yield.
The solid residue, after evaporation of the water layer, was a 1:1
mixture of 4a (43% yield, totally 49% yield) and its hydrate (40%
48,51
1
2
3
4
5
6
7
8
9
1a
3a (73)
3b (80)
3c (73)
3d (41)
3e (75)
3f (80)
3g (74)
4a (49), 4a hydrate (40)
4b (51), 4b hydrate (43)
4c (47), 4c hydrate (41)
4d (59), 4d hydrate (28)
4e (57), 4e hydrate (33)
4f (55), 4f hydrate (32)
4g (51), 4g hydrate (38)
6a (81)
6b (89)
6c (72)
6d (65)
6e (80)
4
8,51
1b
52,53
1c
1d
1e
5
4
51
1f
1
yield). In the H NMR spectrum of 4a, there were shifts at 5.09
55
1g
3a
(
s, 2H) and 9.78 (s, 1H) for the CH
2
and CH protons of the acetalde-
1
3b
hyde moiety, respectively. In the H NMR spectrum of hydrate 4a
there were shifts at 4.19 (d, 2H, J = 4.8 Hz) and 5.12 (t, 1H,
5
6
10
11
12
3c
3d
3e
3f
5
7
J = 4.8 Hz) for the CH
2
and CH protons of the hydrate unit.
Analogous treatment of acetals 3b–g gave aldehydes 4b–g in good
yields (Table 1, entries 9–14).
13
14
1
1
1
1
19
2
2
3g
4a
4b
4c
4d
4e
4f
5
6
7
8
4
-Hydroxycoumarin (5) was added to a solution of the crude
mixture of aldehyde 4a and its hydrate in dry DMF and the mixture
was heated at 90 °C under nitrogen for two hours to give 4-hydro-
xy-3-[(E)-2-(6-piperidin-1-yl-9H-purin-9-yl)vinyl]-2H-chromen-2
5
2
0
1
6f (76)
6g (80)
-
one (6a) in 81% yield (12% of the aldehyde 4a and its hydrate
4g
were recovered). In the MS spectrum of compound 6a there was

6
52
M. G. Kallitsakis et al. / Tetrahedron Letters 55 (2014) 650–653
Although lipophilicity is referred58 to as an important physico-
chemical property for LOX inhibitors, all the above tested deriva-
tives do not follow this concept. In contrast, the stereochemistry
of the 6-substituent might influence the activity. In the future,
compound 6a will be used as a lead for the design and the synthe-
sis of more potent LOX inhibitors and multifunctional agents
(Table 2).
In conclusion, we have developed an efficient method for the synthe-
sis of 4-hydroxy-3-[(E)-2-(9H-purin-9-yl)vinyl] -2H-chromen-2-ones in
good to excellent yields from the reactions of 4-hydroxycoumarin with
N
N
N
OH
O
N
N
N
N
N
N
+
O
O
(
i)
H
(ii)
O
N
5
OH
O
O
4
a
A
N
N
N
6-substituted (9H-purin-9-yl) acetaldehydes. Preliminary biological eval-
N
N
N
N
N
uation of these new compounds showed that they act as very good
lipoxygenase inhibitors.
O
O
OH
O
H
N
(iii)
N
O
O
Acknowledgements
B
6a
We would like to thank Dr. A. Leo as well as Biobyte Corp.59 for
free access to the C-QSAR program.
Scheme 2. Conditions: (i) ‘Aldol’ type reaction; (ii)
2
H O elimination; (iii)
tautomerization.
Supplementary data
an expected molecular ion at 390 [M+H] , while in the 1H NMR
spectrum there were two doublets at 7.73 (d, 1H, J = 14.8 Hz) and
+
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.11
8
.46 (d, 1H, J = 14.8 Hz), which revealed that the product was the
trans-isomer. Similar reactions of the crude mixtures of aldehydes
b–g (with their hydrates) with 4-hydroxycoumarin (5) resulted in
.
102.
4
References and notes
the 3-substituted 4-hydroxycoumarin derivatives 6b–g in good to
excellent yields (Table 1, entries 16–21).
1.
Murray, D. H.; Mendez, J.; Brown, S. A. In: The Natural Coumarins: Occurrence,
Chemistry and Biochemistry; John Wiley & Sons: New York, 1982, p. 1.
2
3,24,27
The expected
2:1 adducts 7a–g, analogous to dicoumarol
(
II), were not isolated in the above experiments. In the proposed
2. O’Kennedy, R.; Thornes, R. D. In: Coumarins: Biology, Applications and Mode of
Action; John Wiley & Sons: Chichester, 1997, p. 1.
mechanism for this reaction (Scheme 2) the intermediate alcohol
3
4
.
.
Kostova, I. Curr. Med. Chem.-Anti-Cancer Agents 2005, 5, 29.
Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887.
A is formed from the ‘aldol’ type24 reaction of 4-hydroxycoumarin
(5) and aldehyde 4a. Elimination of H
2
O from A gives the enamine
5
6
7
.
.
.
Kostova, I.; Raleva, S.; Genova, P.; Argirova, R. Bioinorg. Chem. Appl. 2006, 1.
Lacy, A.; O’Kennedy, R. Curr. Pharm. Des. 2004, 10, 3797.
Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr.
Pharm. Des. 2004, 10, 3813.
B, which upon tautomerization leads to the final product 6a. The
formation of the intermediate enamine B, with the p-orbital over-
lapping with the heteroaromatic system,56 and the subsequent
tautomerization to give compound 6a, with extended conjugation,
is probably the driving force for the formation of products 6a–g
and not of the possible dicoumarol (II) derivatives 7a–g.
8.
Holbrook, A. M.; Pereira, J. A.; Labiris, R.; Douketis, J. D.; Crowther, M.; Wells, P.
S. Arch. Interm. Med. 2005, 165, 1095.
9.
Ufer, M. Clin. Pharmacokinet. 2005, 44, 1227.
10. Beinema, M.; Brouwers, J. R.; Schalekamp, T.; Wilffert, B. Thromb. Haemost.
008, 100, 1052.
2
The products 6 were tested as possible lipoxygenase inhibitors
and antioxidant agents. Compounds 6b–c showed significantly
high reducing ability compared to the reference compound nord-
ihydrogualaretic acid [4,4 -(2,3-dimethylbutane-1,4-diyl)diben-
zene-1,2-diol] (NDGA), whereas 6a and 6d showed similar
results. All compounds 6 caused significant inhibition of lipid per-
1
1
1. Kresge, N.; Simoni, R. D.; Hill, R. L. J. Biol. Chem. 2005, 280, e5.
2. van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron 1997, 53,
6045.
0
13. Lunney, E. A.; Hagen, S. E.; Domagala, J. M.; Humblet, C.; Kosinski, J.; Tait, B. D.;
Warmus, J. S.; Wilson, M.; Ferguson, D.; Hupe, D.; Tummino, P. J.; Baldwin, E.
T.; Bhat, T. N.; Liu, B.; Erickson, J. W. J. Med. Chem. 1994, 37, 2664.
14. Appendino, G.; Mercalli, E.; Fuzzati, N.; Arnoldi, L.; Stavri, M.; Gibbons, S.;
oxidation (LPO). Compound 6a (IC50 = 6.25 lM), which has a pipe-
ridinyl ring attached at C-6, is a very potent inhibitor compared to
the standard reference compound NDGA. The next significant
derivative is compound 6f (IC50 = 20 lM). The antioxidant biologi-
cal activities are correlated with their common structural charac-
teristics, example the 4-OH coumarin and the purine ring.
Ballero, M.; Maxia, A. J. Nat. Prod. 2004, 67, 2108.
1
1
5. Hutchinson, D. W.; Tomlinson, J. A. Tetrahedron Lett. 1968, 5027.
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30, 531.
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L.-Q. Org. Lett. 2004, 6, 4853.
1
1
8. Liu, Y.; Zhu, J.; Qian, J.; Jiang, B.; Xu, Z. J. Org. Chem. 2011, 76, 9096.
Table 2
Reducing activity % DPPH (RA%); % inhibition of lipid peroxidation (AAPH%); in vitro inhibition of soybean lipoxygenase (%LOX)/(IC50
lM)
Compound
ClogP59
RA% @ 100
l
M 20 min (±SD)a
AAPH% @ 100
l
M (±SD)a
IC50
lM or % LOX Inh. @ 100
l
M (±SD)a
6
6
6
6
6
6
6
a
b
c
d
e
f
3.81
2.43
3.25
2.91
3.09
4.54
4.56
—
66 ± 2
93 ± 4
73 ± 2
68 ± 1
52 ± 3
44 ± 1
45 ± 1
83 ± 3
—
99 ± 4
99 ± 3
99 ± 2
97 ± 2
100 ± 5
92 ± 4
98 ± 3
—
6.25
l
M (±0.2)
45% (±2)
100 M (±3)
l
24% (±1)
37% (±2)
20
NA
28
—
l
M (±1)
M (±1)
g
NDGA
Trolox
l
—
63 ± 1
NA: no activity under the reported experimental conditions.
a
Values are the mean ± SD of three or four different determinations.

M. G. Kallitsakis et al. / Tetrahedron Letters 55 (2014) 650–653
653
1
2
9. Kischel, J.; Michalik, D.; Zapf, A.; Beller, M. Chem. Asian J. 2007, 2, 909.
0. Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Org. Lett. 2011, 13, 4382. and
references cited therein.
(b) General procedure for the synthesis of the acetals 3a–g. To a solution of 6-
piperidinopurine (1a) (0.88 g, 3.88 mmol) in dry DMF (20 ml), anhydrous
K
2
CO
diethyl acetal (2) (0.764 g, 0.58 ml, 3.88 mmol). The mixture was heated at
90 °C under an N atmosphere for 8 h, filtered under vacuum while hot, and
washed with CH Cl . The filtrate was evaporated and the residue separated by
3
(0.539 g, 3.88 mmol) was added followed by 2-bromo acetal dehyde
2
1. Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem. 2009,
5
185.
2
2
2
2. Stahmann, M. A.; Wolff, I.; Link, K. P. J. Am. Chem. Soc. 1943, 65, 2285.
3. Appendino, G.; Cravotto, G.; Tagliapietra, S.; Ferraro, S.; Nano, G. M.; Palmisano,
G. Helv. Chim. Acta 1991, 74, 1451.
2
2
column chromatography [silica gel No 60, hexane/EtOAc (4:1)] to give 9-(2,2-
diethoxyethyl)-6-piperidin-1-yl-9H-purine (3a) (0.908 g, 73% yield), white solid,
ꢁ
1 1
2
4. Sullivan, W. R.; Huebner, C. F.; Stahmann, M. A.; Link, K. P. J. Am. Chem. Soc.
mp 42–44 °C (CH
1.05 (t, 6H, J = 7.0 Hz); 1.54-1.67 (m, 6H); 3.37 (dq, 2H, J
3.62 (dq, 2H, J = 7.0 Hz, J
4.61 (t, 1H, J = 5.3 Hz); 7.71 (s, 1H); 8.21 (s, 1H); C NMR (CDCl
15.2; 24.9; 26.1; 46.2; 46.4; 63.8; 100.5; 119.5; 139.1; 151.0; 152.5; 154.0; MS
2
Cl
2
), IR (Nujol): 3060, 1570, 1540 cm
;
H-NMR (CDCl
3
) d
1
943, 65, 2288.
1
= 7.0 Hz, J = 9.3 Hz);
2
2
2
2
5. Kumar, A.; Gupta, M. K.; Kumar, M. Tetrahedron Lett. 2011, 52, 4521.
6. Gasparova, R.; Kotlebova, K.; Lacova, M. Nova Biotechnol. 2009, 9, 349.
7. Appendino, G.; Cravotto, G.; Nano, G. M.; Palmisano, G.; Annunziata, R. Helv.
Chim. Acta 1993, 76, 1194.
1
2
= 9.3 Hz); 4.07–4.19 (m, 4H); 4.15 (d, 2H, J = 5.3 Hz);
13
3
, 75 MHz) d
+
+
(ESI): 320 [M+H] , 342 [M+Na] . Anal. Calcd for C16
N, 21.93. Found: C, 60.32; H, 7.64; N, 22.09.
25 5 2
H N O : C, 60.17; H, 7.89;
2
8. Trkovnik, M.; Djudjic, R.; Tabakovic, I.; Kules, M. Org. Prep. Proced. Int. 1982, 14,
2
1.
(c) General procedure for synthesis of the aldehydes 4a–g. A solution of acetal 3a
(0.45 g, 1.41 mmol) in HCl (1 M) (8 ml) was heated under reflux for 2 h. After
cooling, the mixture was extracted with EtOAc (10 ꢀ 5 ml). The organic layer
2
3
9. Schroeder, C. H.; Titus, E. D.; Link, K. P. J. Am. Chem. Soc. 1957, 79, 3291.
0. Appendino, G.; Cravotto, G.; Nano, G. M.; Palmisano, G. Synth. Commun. 1992,
22, 2205. and references cited therein.
2 4
was dried with anhydrous Na SO , filtered and evaporated to give (6-piperidin-
3
3
3
3
3
3
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garel-Rey, V.; Combes, S.; Finet, J.-P.; Fedorov, A. Y. J. Org. Chem. 2007, 72, 3293.
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0. Clerici, A.; Porta, O. Synthesis 1993, 99.
1. De Clercq, E. J. Med. Chem. 2010, 53, 1438.
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3. De Clercq, E. J. Med. Chem. 2005, 48, 1297.
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Medicine; Wiley-VCH: Weinheim, Germany, 2008.
5. Parker, W. B. Chem. Rev. 2009, 109, 2880.
1-yl-9H-purin-9-yl)acetaldehyde (4a) (20 mg, 6% yield). The aqueous layer was
evaporated to give a crude 1:1 mixture of aldehyde 4a (0.3 g, yield 43%, totally
49%) and its hydrate (0.3 g, 40% yield).
Compound 4a, white solid, mp 100–101 °C (EtOAc), IR (Nujol): 3040, 2750,
ꢁ
1 1
1710, 1610, 1580, 1500 cm
4.19-4.37 (m, 4H), 5.09 (s, 2H), 7.75 (s, 1H), 8.32 (s, 1H), 9.78 (s, 1H); C NMR
(CDCl , 75 MHz) d 24.8, 26.2, 46.7, 52.4, 119.5, 138.1, 150.7, 152.3, 153.7,
; H NMR (CDCl 300 MHz) d 1.64–1.83 (m, 6H),
3
13
3
+
+
3
193.6; MS (ESI): 268 [M+Na] , 300 [M+Na+MeOH] . Anal. Calcd for C12
C, 58.76; H, 6.16; N, 28.55. Found: C, 58.54; H, 6.42; N, 28.83.
15 5
H N O:
3
3
4
4
4
4
4
(d) Genral procedure for the synthesis of 4-hydroxy-3-[(E)-2-(6-substituted-9H-
purin-9-yl)vinyl]coumarins (6a–g). 4-Hydroxycoumarin (5) (64 mg, 0.39 mmol)
was added to a solution of a mixture of aldehyde 4a (50 mg, 0.2 mmol) and its
hydrate (50 mg, 0.19 mmol) in dry DMF (5 ml). The mixture was heated at
90 °C under an N atmosphere for 2 h. After cooling, CH Cl (1 ml) was added
2 2 2
and 4-hydroxy-3-[(E)-2-(6-piperidin-1-yl-9H-purin-9-yl)vinyl]-2H-chromen-2-
one (6a) (0.124 g, 81% yield) precipitated; light yellow solid, mp 210–212 °C,
ꢁ
1
1
IR (Nujol): 3380, 3040, 1661, 1632, 1580, 1515 cm
300 MHz) d 1.60-1.68 (m, 6H), 4.18–4.28 (m, 4H), 7.39–7.44 (m, 2H), 7.66 (dd,
1H, J = 1.7 Hz, J = 7.6 Hz), 7.73 (d, 1H, J = 14.8 Hz), 7.96 (br s, 1H), 8.10 (d, 1H,
J = 7.6 Hz), 8.33 (s, 1H), 8.46 (d, 1H, J = 14.8 Hz), 8.69 (s, 1H); C NMR (DMSO-
, 75 MHz) d 25.9, 34.1, 46.4, 100.2, 111.0, 115.3, 116.1, 119.1, 121.6, 122.8,
123.7, 123.9, 131.0, 132.2, 137.3, 151.7, 152.2, 161.5, 162.6; MS (ESI): 390
6
; H NMR (DMSO-d ,
4
4
4
6. Matsuda, A.; Sasaki, T. Cancer Sci. 2004, 95, 105.
7. Barreiro, E. J.; Fraga, C. A. M.; Miranda, A. L. P.; Rodrigues, C. R. Quim. Nova
1
2
1
3
2
002, 25, 129.
d
6
4
4
5
8. Thalassitis, A.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Miltiadou, P. Bioorg. Med.
Chem. Lett. 2009, 19, 6433.
9. Kallitsakis, M. G.; Hadjipavlou-Litina, D. J.; Litinas, K. E. J. Enz. Inhib. Med. Chem.
+
[M+H] . Anal. Calcd for C21
H, 4.76; N, 17.88.
19 5 3
H N O C, 64.77; H, 4.92; N, 17.98. Found: C, 64.53;
2
013, 28, 765.
53. Villar, J. D. F.; Motta, M. A. Nucleosides, Nucleotides, Nucleic Acids 2000, 19, 1005.
54. Elion, G. B.; Burgi, E.; Hitchins, G. H. J. Am. Chem. Soc. 1952, 74, 411.
55. De Ligt, R. A. F.; Van der Klein, P. A. M.; Von Frijtag Drabbe Kunzel, J. K.;
Lorenzen, A.; El Maate, F. A.; Fujikawa, S.; Van Westhoven, R.; Van den Hoven,
T.; Brussee, J.; Ijzerman, A. P. Bioorg. Med. Chem. 2004, 12, 139.
56. Dolakova, P.; Masojidkova, M.; Holy, A. Nucleosides, Nucleotides, Nucleic Acids
2003, 22, 2145.
57. Lidak, M. Y.; Shluke, Y. Y.; Poritere, S. E. Chem. Heterococycl. Compd. (Engl.
Transl.) 1972, 8, 1411.
58. (a) Pontiki, E.; Hadjipavlou-Litina, D. Mini Rev. Med. Chem. 2003, 3, 487; (b)
Pontiki, E.; Hadjipavlou-Litina, D. Med. Res. Rev. 2008, 28, 39.
59. Biobyte Corp., C-QSAR Database 201 West 4th Str., Suite 204, Claremont CA,
California 91711, USA.
0. Thalassitis, A.; Katsori, A.-M.; Dimas, K.; Hadjipavlou-Litina, D.J.; Pyleris, F.;
Sakellaridis, N.; Litinas, K.E. J. Enz. Inhib. Med. Chem. 2013, accepted for
publication.
1. Huang, L.-K.; Cherng, Y.-C.; Cheng, Y.-R.; Jang, J.-P.; Chao, Y.-L.; Cherng, Y.-J.
Tetrahedron 2007, 63, 5323.
5
5
2. Selected data: (a) General Procedure. Amination of chloropurine under MW
irradiation. In a MW reaction vessel (30 ml) were placed a solution of 6-
chloropurine (1d) (1 g, 6.45 mmol) in H
.78 ml, 12.9 mmol). The mixture was irradiated [Biotage (Initiator 2.0)
scientific MW oven] at 100 °C for 2 min. After cooling, the precipitate was
filtered, washed thoroughly with H
O (5 ꢀ 10 ml) and dried under vacuum to
give 1.11 g (91% yield) of 6-pyrrolidin-1-yl-9H-purine (1c), mp 307–309 °C
dec.) (Lit.53 mp 309–310 °C).
2
O (10 ml) and pyrrolidine (0.916 g,
0
2
(