Anti-malarial activity of N6-substituted adenosine derivatives. Part I

Article abstract of DOI:10.1016/S0968-0896(01)00331-5

The synthesis and biological evaluation of novel N⁶-substituted adenosine derivatives is reported. The first series of compounds was obtained using an established procedure for the nucleophilic substitution of a 1-(6-chloro-purin-9-yl)-β-D-1-deoxy-ribofuranose with various amines. In addition, attachment of two different amino-functionalised spacer arms at the N⁶-position of adenosine enabled derivatisation by an innovative polymer-assisted protocol. Thus, we were able to prepare three series of substituted derivatives that displayed activity versus the multiresistant Plasmodium falciparum strain Dd2 in cell culture experiments.

Full text of DOI:10.1016/S0968-0896(01)00331-5

Bioorganic & Medicinal Chemistry 10 (2002) 769–777
Anti-Malarial Activity of N6-Substituted Adenosine Derivatives.
Part I
Abolfasl Golisade,a Jochen Wiesner,b Claudia Herforth,a
Hassan Jomaab and Andreas Linka,*
aUniversitat Hamburg, Institut fur Pharmazie, Bundesstraße 45, D-20146Hamburg, Germany
¨
¨
bJomaa Pharmaka GmbH, Frankfurter Straße 50, D-35392 Gießen, Germany
Received 19 June 2001; accepted 18 September 2001
Abstract—The synthesis and biological evaluation of novel N6-substituted adenosine derivatives is reported. The first series of
compounds was obtained using an established procedure for the nucleophilic substitution of a 1-(6-chloro-purin-9-yl)-b-d-1-deoxy-
ribofuranose with various amines. In addition, attachment of two different amino-functionalised spacer arms at the N6-position of
adenosine enabled derivatisation by an innovative polymer-assisted protocol. Thus, we were able to prepare three series of sub-
stituted derivatives that displayed activity versus the multiresistant Plasmodium falciparum strain Dd2 in cell culture experiments.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
or massive parallel synthesis of arrays of adenosine
analogues is therefore highly demanded.
Safe and cost-effective drugs for the treatment of
malaria caused by multidrug-resistant Plasmodium fal-
ciparum strains are urgently needed. Because P. falci-
parum is incapable of de novo purine synthesis, purine
acquisition from the host is an indispensable nutritional
requirement. Unlike the mammalian nucleoside transpor-
ters, those of the parasite exhibit broad substrate specificity
for purine nucleosides.1 Substituted adenosine derivatives
are therefore prone to selective uptake by the parasite.
The adenosine scaffold itself is relatively small and
hydrophilic. Therefore, it may be regarded as a ‘‘lead-
like lead structure’’, according to Teague et al.2 Conse-
quently, the synthetic attachment of lipophilic substituents
to the adenosine scaffold will result in drug-like com-
pounds with balanced physico-chemical properties.
Suitable primary aliphatic amines were selected for the
synthesis of 24 novel and two known N6-substituted
adenosine derivatives. The 26 compounds prepared
were evaluated for their inhibitory activity on a multi-
drug-resistant P. falciparum strain in vitro. Some of the
compounds showed promising activity justifying future
investigation of additional derivatives.
Chemistry
The novel amine 5 containing an ethylene glycol bridge
with three ethylene units was synthesized as outlined
below. Triethyleneglycol ditosylate (1) was thus refluxed
with an equimolar amount of the sodium salt of 1-
naphthol resulting in a mixture of the known compound
2-[2-(2-naphth-1-yloxy-ethoxy)-ethoxy]-ethyl-naphth-1-
yl ether (2), unchanged triethylene glycol ditosylate (1)
and 3. The latter compound was transformed to the
phthalimido derivative 4 and subsequently deprotected
to target amine 5. Because we were not able to obtain
sufficient combustion analysis of the amine 5 or its cor-
responding hydrochloric acid salt, the amide 6 was pre-
pared by treatment of 5 with succinic anhydride as a
derivative for analytical purposes. Succinamic acid 6
Owing to putative interactions with various adenosine
binding motifs and the special importance of the purine
transport systems to parasite survival, the biological
evaluation of substituted adenosine derivatives as
potential anti-malarial drugs seems promising. The
development of novel techniques for the combinatorial
*Corresponding author. Tel.:+49-40-428-38-3467; fax:+49-40-42838-
6573; e-mail: link@uni-hamburg.de
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00331-5

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A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
ily available starting material. The synthesis of 4-
phenyl-benzyl amine (10) was thus performed via Mit-
sunobu reaction starting from 4-phenyl-benzyl alcohol
(7) yielding N-(4-phenyl)benzylphthalimide (9). A rela-
ted approach to access intermediate 9 from 4-phenyl-
benzyl chloride and phthalimide potassium was repor-
ted by Cho et al. in a preliminary paper, recently, but no
analytical data for the obtained compound 9 was made
available.3 The hydrazinolysis of the intermediate 9 to
compound 10 proceeded smoothly under standard con-
ditions (Scheme 2).
In order to access the bifunctional spacer 13, 1,8-
dichloro-3,6-dioxa-octane (11) was converted to the
corresponding azide under phase-transfer catalysis as
described by Reeves and Bahr.4 Subsequent hydro-
genolysis in the presence of Pd on charcoal yielded the
desired compound 13 (Scheme 3).5
This procedure furnished better results than the use of
tosyl leaving groups as described for the synthesis of
intermediate 3.
The synthesis of the desired N6-substituted adenosine
derivatives 16a–g was performed by aminolysis of
chloro-substituted adenosine derivative 14 with amines
5, 10, 13, and 15a,c,d and f at slightly elevated tem-
perature (Scheme 4).
The N6-substituted adenosine derivatives 16a–g served
as test compounds for biological evaluation purposes.
In addition, 16a and b were used as scaffolds for a
polymer-assisted derivatisation protocol, as well.
Scheme 1. Synthesis of 2-[2-(2-Naphth-1-yloxy-ethoxy)-ethoxy]-ethyl-
amine (5) and succinamic acid derivative 6: (i): 1-naphthol, NaH,
THF, reflux; (ii) phthalimide potassium, DMF, 90 ꢀC; (iii) hydrazine
hydrate, EtOH, reflux; (iv) succinic anhydride, Et3N, Na2CO3,
CH2Cl2.
For the introduction of different acid residues in paral-
lel, a fast and simple workup procedure and avoidance
of protecting group operations for the hydroxyl func-
tions of the ribose moiety was regarded as crucial.
Unintentional acylation of the 50-OH of the ribose ring
is a common side reaction in the preparation of adeno-
sine-derived amides. The resulting formed 50-esters can
easily be cleaved but would necessitate a purification
step to remove the hydrolysed acid. The use of OH-
protecting groups easily circumvents this problem, but
would require that the protecting group would have to
be removed at the end of the sequence. Therefore one
individual purification operation on every single test
candidate would be necessary nevertheless. Only a
quantitative and chemoselective reaction of the primary
amino groups of unprotected 16a and b would enable a
rapid parallel derivatisation of theses scaffolds.
It is known that acylated alkylsulfonamides represent
chemoselective acylating species.6 At the same time, the
use of polymer-supported reagents in excess and the
subsequent removal by filtration are well recognized,
too.7 Thus, the use of carboxylic acid equivalents
attached to the Kenner linker (as modified by Ellman
and his group) as tool for quantitative and chemoselec-
tive acylation of 16a and b to the final products 18a–l
and 19a–d, g–i, and m is a quite straightforward
approach.8,9 The isolated yields obtained for
Scheme 2. Synthesis of 4-phenyl-benzyl amine (10) from 4-phenyl-
benzyl alcohol (7).
gave satisfactory analytical results unambiguously
(Scheme 1).
The commercially available inexpensive amines 15a and
15c,d,f were purchased from various suppliers. The
expensive 4-phenyl-benzyl amine 10 as well as the
known bifunctional spacer 13 was prepared from read-

A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
Table 1. Anti-malarial activity of compounds 16a–g, 18a–l and 19a–
771
d, g–i, and m and purity and yield of products from polymer-assisted
synthesis 18a–l and 19a–d, g–i, and m
Yieldb (%)
Purityc (%)
a
Compound
IC50 (mM)
16a
16b
16c
16d
16e
16f
16g
18a
18b
18c
18d
18e
18f
18g
18h
18i
115
34
38
31
19
20
16
37
93
98
96
95
87
95
98
93
85
98
82
93
96
97
95
97
95
92
98
96
96
Scheme 3. Synthesis of 8-amino-3,6-dioxa-octylamine (13) from 1,8-
dichloro-3,6-dioxa-octane (11).
55
3097
13098
11
3092
75
>100
>100
>100
16
91
97
96
87
98
85
95
18k
18l
19a
19b
19c
19d
19g
19h
19i
8
4098
38
95
7095
>100
13088
22
96
96
96
96
19m
aThe P. falciparum strain Dd2 (Indochina) used in this study is resis-
tant to most commonly used anti-malarial drugs. When the resistance
pattern was checked in our laboratory, the Dd2 strain was found to be
highly resistant against chloroquine (IC50=170nM), pyrimethamine
(IC50=2500 nM), and cycloguanile (IC50=2200 nM), and moderately
resistant against quinine (IC50=380nM) and mefloquine
(IC50=57 nM). It was sensitive to halofantrine (IC50=18 nm), lume-
fantrine (IC50=30nm), artemisinin (IC 50=18 nm), and atovaquone
(IC50=1 nm).
bIsolated material.
cLC-100% method, UV detection at 254 nm.
compounds 18 and 19 ranged from 82 to 98%, purity
was at least 85% and up to 97%. Typically, the yields
obtained are higher than 90%, details are given in Table 1.
A polymer-assisted protocol reported recently for 20-
amino-20-deoxyadenosine derivatives was therefore
selected as method of choice and adapted for this pur-
pose.10 Resin aliquots 17a–k, m were prepared from
commercially available acids by amide bond forming
procedures using in situ anhydride formation. Because
the Kenner linker tolerates strongly basic or acidic con-
ditions prior to activation, it is ideally suited for the
construction of polymer-bound carboxylic acid equiva-
lent libraries. Via on-bead modifications of carboxylic
acids attached to the linker prior to activation, the
range of accessible acid residues can be extended sig-
nificantly. Thus, intermediate nucleophilic substitution
of a polymer-bound intermediate as a source for diver-
sity was used for the synthesis of resin 17l. 4-Fluoro-3-
nitro-benzoic acid was initially attached to the sulfa-
moyl linker yielding an intermediate that enabled
synthesis of aniline derivative 17l by treatment with
excess N-ethyl benzyl amine. Because the number of
available amines is exceptionally great, this drug dis-
covery approach might become especially valuable.11
This concept is followed by our group.
Scheme 4. Synthesis of N6-substituted adenosine derivatives 16a–g.
Alkylation with bromoacetonitrile as activation step for
the Kenner linker is reported to give poor results for
aromatic residues adjacent to the sulfamoyl attachment
site.12 For that reason we used prolonged reaction times
for this activation protocol to ensure optimal results.
The transfer of the polymer-bound carboxylic acid
equivalents to the primary amine functions proceeded
by agitation of the beads with the amines in solution at
slightly elevated temperatures. Filtration of the beads
and evaporation of the resulting product solutions

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A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
Scheme 5. Polymer-assisted synthesis of N6-substituted adenosine derivatives 18a–l and 19a–d, g–i, and m.
yielded compounds 18a–l and 19a–d, g–i, and m ready
for biological evaluation (Scheme 5).
compounds acting at the low micromolar range were
obtained. The decrease in lipophilicity from 3,5-dichloro
over 3-fluoro-4-methyl to 3-methoxy substitution in the
series of 18e–g is in association with a declining activity
from 11 mM over 30 mM to 75 mM. The relatively high
activity of the N-benzyl, N-ethyl substituted nitro ani-
line 18l (16 mM) is consistent with this tendency. The
highest activity of 8 mM was obtained for the biphenyl
derivative 19a with a 13-atom spacer distance to the
adenine ring.
Biological testing
Compounds 16a–g, 18a–l and 19a–d, g–i, and m were
evaluated for their inhibitory activity against intraery-
throcytic forms of P. falciparum using a semi-automated
microdilution assay as described.13ꢁ15 The growth of the
parasites was monitored through the incorporation of
tritium-labelled hypoxanthine (Table 1).
Conclusion
With respect to the structural diversity of the com-
pounds, it seems likely that not a single molecular target
is recognised. Potential targets include a variety of
nucleotide dependent enzymes, the parasite’s nucleoside
uptake machinery as well as unrelated cell functions. To
further explore their potential as anti-malarial agents,
additional adenosine derivatives, also comprising com-
pounds modified at the ribose moiety, will be synthesised.
Preliminary results suggest, that novel derivatives obtained
by our group posess improved anti-malarial activity and
will be reported as Part II of this series, soon.
Discussion
Despite of considerable structural diversity most of the
N6-substituted adenosine derivatives displayed moder-
ate but significant anti-malarial activity with IC50 values
in the range between 10and 10 mM. Within series 16
different substituents (16b–g) lead to comparable activ-
ity (16–38 mM) while the ethyl amino derivative 16a
showed reduced activity (115 mM). Within the two het-
erogeneous series 18 and 19 both compounds that lack
activity at the highest concentration tested (100 mM) and

A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
773
Experimental
tical sample was obtained by purification on silica gel
1
using dichloromethane as eluent. H NMR (400 MHz,
The structures of all compounds were assigned by NMR
spectroscopy. NMR spectra were recorded on a Bruker
AMX 400 spectrometer, using tetramethylsilane as
internal standard. Identity and purity of compounds
prepared on larger (g) scale was ascertained by com-
bustion analysis, test samples prepared in mg quantities
were evaluated by high resolution MS. The purity of the
DMSO-d6) d (ppm)=8.11 (d, 1H, 8.1), 7.88–7.79 (m,
5H), 7.77 (d, 2H, 8.2 Hz), 7.55–7.38 (m, 4H), 6.90(d,
1H, 7.1 Hz), 4.18 (t, 2H, 4.6 Hz), 3.75 (t, 2H, 4.6 Hz),
3.69–3.52 (m, 4H); calcd (C24H23NO5) C 71.10, H 5.72,
N 3.45, found: C 71.49, H 5.87, N 3.41.
2-[2-(2-Naphth-1-yloxy-ethoxy)-ethoxy]-ethylamine (5).
A solution of 12 g crude 4 (30mmol) and 4 g hydrazine
hydrate (66 mmol) in 50mL ethanol was stirred for
1
latter compounds was deduced from H NMR data as
well as evaluated by LC. Yields are reported as isolated
material. MS data (FAB) were obtained on a Finnigan
MAT 311A instrument with m-nitrobenzylic alcohol as
matrix. Elemental compositions were calculated on the
basis of microanalysis results obtained on a Heraeus
CHN-O rapid instrument. Preparative column chroma-
tography was performed using glass columns
(4.5ꢂ15 cm) on silica gel 100–200 active, 60 A, from
ICN or DowexTM OHꢁ (1ꢂ2–200). TLC reaction con-
trol was performed on Macherey-Nagel PolygramTM Sil
G/UV254 precoated microplates, spots were visualized
under UV-illumination.
ꢀ
30min at 50 C and successively refluxed for 2 h. After
cooling to room temperature, 15 mL of concentrated
hydrochloric acid was added. After refluxing for 2 h the
mixture was cooled to room temperature, again. The
pH was adjusted to 1 by addition of hydrochloric acid
and the precipitate formed was removed by filtration.
The solvent was evaporated and the residue was treated
with 1 L of water and alkalized by addition of sodium
hydroxide and extracted with dichloromethane. The
organic phase was extracted three times with 500 mL
dilute hydrochloric acid (1%). The combined acidic
phases were alkalized by addition of 6 M NaOH and
again extracted with dichloromethane. Evaporation of
the combined organic phases yielded 2.79 g (34%) of a
brownish oil. 1H NMR (400 MHz, DMSO-d6) d
(ppm)=8.20–8.15 (m, 1H), 7.89–7.84 (m, 1H), 7.55–7.46
(m, 3H), 7.41 (t, 1H, 8.2 Hz), 6.90(d, 1H, 7.1 Hz), 4.28
(t, 2H, 5.1 Hz), 3.90(t, 2H, 4.6 Hz), 3.70–3.65 (m, 2H),
3.60–3.53 (m, 2H), 3.37 (t, 2H, 6.1 Hz), 2.64 (br s, 4H,
2H exchangeable by D2O, NH2); (C16H21NO3) No
microanalysis obtained within reasonable range. There-
fore, for analytical purposes, derivative 6 was prepared
and gave satisfactory results.
Toluene-4-sulfonic acid 2-[2-(2-naphth-1-yloxy-ethoxy)-
ethoxy] - ethyl ester (3). To a solution of 14.42 g
(0.1 mol) 1-naphthol in 135 mL THF was added 3 g
NaH (0.13 mol) and the resulting mixture was refluxed
under nitrogen until the hydrogen formation had
ceased. The hot solution was poured into another flask
containing a solution of 45.8 g (0.1 mol) commercially
available triethyleneglycol ditosylate (1) in 500 mL THF
and refluxed for 2 h. After cooling to room temperature,
the precipitate formed was removed by filtration and the
solvent was evaporated in vacuo. The resulting red oil
was dissolved in dichloromethane and washed with
water, dried over sodium sulfate and concentrated to
yield 43 g of a mixture of 3, reactant 1 and the known
2-[2-(2-Naphth-1-yloxy-ethoxy)-ethoxy]-ethyl succinamic
acid (6). A solution of 1.92 g (7 mmol) 5 in 10mL di-
chloromethane was treated with 3 mL triethylamine and
combined with a suspension of 2.00 g (20 mmol) succinic
anhydride and 5 g (48 mmol) sodium carbonate in
100 mL dichloromethane. After 72 h TLC analysis indi-
cated consumption of reactant 5. The reaction mixture
was extracted with 600 mL 0.5 M NaOH solution in
three portions, acidified by means of dilute hydrochloric
acid (3.7%) and extracted with dichloromethane. After
drying over magnesium sulfate and evaporation of the
solvent 1.31 g (50%) of a pure yellow oil was obtained.
1H NMR (400 MHz, DMSO-d6) d (ppm) 12.05 (br s,
1H, OH, D2O-exchangable), 8.20–8.15 (m, 1H), 7.91 (t,
1H, 5.6 Hz, NH, D2O-exchangable), 7.89–7.84 (m, 1H),
7.55–7.48 (m, 2H), 7.41 (t, 1H, 7.6 Hz), 6.98 (d, 2H,
7.1 Hz), 4.28 (t, 2H, 4.6 Hz), 3.90(t, 2H, 4.6 Hz),
3.70–3.66 (m, 2H), 3.59–3.53 (m, 2H), 3.42 (t, 2H,
6.1 Hz, CH2–CH2–N), 3.19 (‘q’, 2H, 5.6/6.1 Hz, CH2–
N, simplifies upon treatment with D2O to: t, 6.1 Hz),
side-product
ethyl-naphth-1-yl ether (2) in a percentage 52:25:23 as
2-[2-(2-naphth-1-yloxy-ethoxy)-ethoxy]-
1
calculated from the H NMR signal ratio. The com-
pound 3 was obtained in 48% yield (21 g) as yellow oil
after chromatographic separation on silica gel using
dichloromethane as eluent. 1H NMR (400 MHz,
DMSO-d6) d (ppm)=8.16 (d, 1H, 8.1), 7.87 (d, 1H,
7.6 Hz), 7.77 (d, 2H, 8.2 Hz), 7.55–7.38 (m, 6H), 6.97 (d,
1H, 7.1 Hz), 4.26 (t, 2H, 4.6 Hz), 4.10(t, 2H, 4.6 Hz),
3.87 (t, 2H, 4.6 Hz), 3.63–3.58 (m, 4H), 3.53–3.49 (m,
2H), 2.39 (s, 3H, CH3); calcd (C23H26O6S) C, H, S.
C=64.17, H=6.09, S=7.45, found: C=63.64, H=6.10,
S=7.28.
N-2-[2-(2-Naphth-1-yloxy-ethoxy)-ethoxy]-ethyl phthali-
mide (4). A mixture of 860mg (2.0mmol) 3 and 410mg
(2.2 mmol) phthalimide potassium salt was stirred in
DMF at 90 ꢀC for 17 h and successively at room tem-
perature for 72 h. After adding 50mL each of dichloro-
methane and water, the aqeous phase was extracted
twice with 25 mL dichloromethane. The organic phases
were combined and dried over magnesium sulfate. Fil-
tration over a plug of silica gel and evaporation of the
solvent yielded 367 mg (45%) of a yellow oil. An analy-
2.40(t, 2H, 6.1 Hz, CH –CH2 succinamic acid), 2.31 (t,
2
2H, 6.1 Hz, CH2–CH2 succinamic acid); calcd
(C20H25NO6) C 63.99, H 6.71, N 3.73, found: C 63.74,
H 6.82, N 3.68.
1
N-(4-Phenyl)benzylphthalimid (9). H NMR (400 MHz,
DMSO-d6) d (ppm)=7.93–7.85 (m, 4H), 7.63 (d, 4H,
J=8.14 Hz), 7.47–7.33 (m, 5H), 4.82 (s, 2H). 13C NMR

774
A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
(100 MHz, DMSO-d6) d (ppm)=168.10, 140.10, 139.75,
136.23, 134.96, 131.93, 129.28, 128.40, 127.83, 127.29,
127.00, 123.61, 40.93. calcd (C21H15NO2) C=80.49,
H=4.82, N=4.47, found: C=80.11, H=4.76, N=4.20.
4H), 7.34 (t, 1H, J=7.63 Hz), 5.91 (d, 1H, J=6.10Hz),
5.47 (d, 1H, J=6.10Hz), 5.42–5.37 (m, 1H), 5.20 (d,
1H, 4.58 Hz), 4.75 (bs, 2H), 4.63 (dd, 1H, J=6.10,
5.09 Hz), 4.19–4.14 (m, 1H), 4.00–3.95 (m, 1H), 3.70–
3.65 (m, 1H), 3.58–3.53 (m, 1H). 13C NMR (100 MHz,
DMSO-d6) d (ppm) 154.85, 152.73, 140.38, 140.34,
138.94, 129.24, 128.06, 127.61, 126.92, 88.29, 86.25,
73.82, 71.00, 62.10, 42.95. HRFAB-MS [M+H]+ calcd
434.1829, found 434.1848.
General procedure for the synthesis of compounds 16a–g
A solution of 1-(6-chloro-purin-9-yl)-b-d-1-deoxy-ribo-
furanose (14) in n-propanol was treated with 1.1
equivalents of the appropriate amine and 1 equivalent
of Hunig’s base at 60 ꢀC. The reaction was monitored
by TLC and terminated when the starting material had
disappeared (12–24 h). The volatile components were
removed by evaporation. The residue of the primary
amines 16a and b was purified over Dowex1 OHꢁ
(1ꢂ2–200) with MeOH as eluent. Compounds 16c–g
were crystallized from MeOH without resort to chro-
matographic purification.
1
N6-[3,6-Dioxa-8-(1-naphthoxy)octyl]adenosine (16g). H
NMR (400 MHz, DMSO-d6) d (ppm) 8.37 (s, 1H), 8.23
(bs, 1H), 8.18 (d, 1H, J=7.57 Hz), 7.77 (bs, 1H), 7.52–
7.46 (m, 3H), 7.40(t, 1H, J=7.89 Hz), 6.96 (d, 1H,
J=7.57 Hz), 5.92 (d, 1H, J=5.99 Hz), 5.45 (d, 1H,
J= 6.30Hz), 5.41 (dd, 1H, J= 4.73, 2.52 Hz), 5.19 (d,
1H, J=4.73 Hz), 4.63 ( dd, 1H, J=5.99, 5.04 Hz), 4.26
(t, 2H, J=4.41, 4.73 Hz), 4.18–4.16 (m, 1H), 3.99 (dd,
1H, J=3.47, 3.15 Hz), 3.89 (t, 2H, J=4.41, 4.73 Hz),
+
3.71–3.55 (m, 10H), HRFAB-MS [M+H]
526.2302, found 526.2346.
calcd
N6-(3,6-Dioxa-8-aminooctyl)adenosine (16b)
1H NMR (400 MHz, DMSO-d6) d (ppm) 8.37 (s, 1H),
8.23 (s, 1H), 7.79 (bs, 1H), 5.90(d, 1H, J=6.11 Hz),
5.45 (bs, 1H), 5.41 (bs, 1H), 5.20(bs, 1H), 4.65–4.56 (m,
1H), 4.20–4.12 (m, 1H), 4.00–3.94 (m, 1H), 3.66–3.55
(m, 12 H). 13C NMR (100 MHz, DMSO-d6) d (ppm)
154.52, 152.22, 148.26, 139.73, 87.82, 85.77, 73.40,
70.53, 69.44, 69.39, 69.33, 66.54, 66.46, 61.54, 48.48;
calcd (C16H27ClN6O6 as hydrochloride) C 44.19, H
6.26, Cl 8.15, N 19.32, found: C 44.55, H 6.38, Cl 8.32,
N 19.22. HRFAB-MS [M+H]+ calcd 399.1992, found
399.2015.
Synthesis of polymer-bound acids 17
To a flask containing 2.0g of dry 4-sulfamylbenzoyl-
aminomethyl polystyrene with an initial loading level of
1.24 mmol/g as determined by elemental analysis (pre-
pared from very high load aminomethylated poly-
styrene, purchased from Novabiochem, Switzerland)
was added 20mL of THF. The resin was allowed to
swell at room temperature for 2 h. In another flask,
10mmol of the appropriate acid was dissolved in 10–20
mL dry THF and preactivated via in situ anhydride
formation by adding 780 mL (5 mmol) N,N-diisopro-
pylcarbodiimide. After addition of 580 mL Hunig’s base
(3.4 mmol) and 15 mg (0.12 mmol) 4-(dimethylamino)-
pyridine as catalyst, to the swollen resin, the coupling
mixture was added. The resulting reaction mixture was
agitated at room temperature for 24 h. The resin beads
were filtered off and washed exhaustively with THF
(two times 5 mL), methanol (two times 5 mL), and THF
(two times 5 mL). After careful drying the increase in
weight was determined. The success of the reaction
could be followed by IR spectroscopy, too: the acyla-
tion of the sulfonamide linker leads to a decrease of the
intensity of the sulfonamide absorption at 3340cm ꢁ1
while a new carbonyl stretch at 1718 cmꢁ1 is formed.
Activation: the sulfonamide linker of 400 mg (approxi-
mately 0.4 mmol) of the resins obtained was activated
for cleavage by alkylation with 640 mL (9 mmol) bro-
moacetonitrile, and 340 mL (2 mmol) Hunig’s base in
4 mL 1-methylpyrrolidone overnight and washed with
dry dimethylsulfoxide (five times 3 mL) and THF (five
times 5 mL). Resin 17l was obtained by aminolysis of 4-
fluoro-3-nitro-benzoic acid attached to the linker with
excess N-ethyl benzyl amine.
N6 - (3,5 - Difluorobenzyl)adenosine (16c). 1H NMR
(400 MHz, DMSO-d6) d (ppm) 8.54 (bs, 1H), 8.42 (s,
1H), 8.23 (s, 1H), 7.10–7.03 (m, 3H), 5.92 (d, 1H,
J=6.10Hz), 5.46 (d, 1H, J=6.11 Hz), 5.37–5.34 (m,
1H), 5.20(d, 1H, J=4.58 Hz), 4.72 (bs, 2H), 4.63 (dd,
1H, J=6.10, 5.60 Hz), 4.16 (dd, 1H, J=4.58, 3.05 Hz),
3.98 (dd, 1H, J=3.56, 3.06 Hz), 3.71–3.66 (m, 1H),
3.59–3.53 (m, 1H). 13C NMR (100 MHz, DMSO-d6) d
(ppm) 162.22 (dd, 2C, JCF=246, 12 Hz), 154.24, 152.22,
144.92, 140.08, 110.03, 109.78, 101.97, 87.82, 85.77,
73.42, 70.50, 61.51, 42.31; calcd (C17H17F2N5O4) C
51.91, H 4.36, N 17.80, found: C 51.59, H 4.50, N 17.48.
N6 - (2,4 - Dimethoxybenzyl)adenosine (16d). 1H NMR
(400 MHz, DMSO-d6) d (ppm) 8.37 (bs, 1H), 8.11 (s,
1H), 8.08 (bs, 1H), 7.63 (d, 1H, J=7.63 Hz), 6.55 (d,
1H, J=2.55 Hz), 6.43 (dd, 1H, J=6.10, 2.55 Hz), 5.90
(d, 1H, J=6.11 Hz), 5.45 (d, 1H, J=6.11 Hz), 5.42–5.39
(m, 1H), 5.19 (d, 1H, J=4.58 Hz), 4.67–4.54 (m, 3H,
benzyl CH2 and 20H are overlapping), 4.16–413 (m,
1H), 3.99–3.93 (m, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.69–
3.65 (m, 1H), 3.58–3.52 (m, 1H), 13C NMR (100 MHz,
DMSO-d6) d (ppm) 159.36, 157.43, 152.23, 139.75,
127.57, 104.07, 98.08, 87.85, 85.80, 73.34, 70.55, 61.57,
55.28, 55.04; calcd (C19H23N5O6) C 54.67, H 5.55, N
16.78, found: C 54.45, H 5.65, N 16.50.
General procedure for the synthesis of compounds 18a–l
and 19a–d, g–i, and m
N6 - [(4 - Phenyl)benzyl]adenosine (16e). 1H NMR
(400 MHz, DMSO-d6) d (ppm) 8.54 (bs, 1H), 8.40(s,
1H), 8.22 (bs, 1H), 7.63–7.58 (m, 4H), 7.46–7.41 (m,
The activated polymer-supported acids 17 resulting
from the alkylation of 400 mg (approximately 0.4 mmol)
described above were transferred to the amino group of

A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
775
10 mmol the appropriate amine dissolved in 0.5 mL
NMP, by shaking at 55 ꢀC in 5 mL THF. The reaction
was monitored by TLC and terminated when the start-
ing material was quenched (6–96 h). Polymer beads and
particulates were removed by filtration, the beads where
extracted exhaustively with dry THF and the combined
THF fractions were evaporated to furnish the target
compounds.
5.45 (d, 1H, J=6.10Hz), 5.43–5.40 (m, 1H), 5.20 (d,
1H, J=5.09 Hz), 4.62 (dd, 1H, J=5.60, 6.11 Hz), 4.15
(dd, 1H, J=4.58, 3.05 Hz), 3.97 (dd, 1H, J=3.56,
3.06 Hz), 3.70–3.65 (m, 1H), 3.58–3.53 (m, 3H), 3.32–
3.28 (m, 2H), 2.91 (t, 2H, J=8.14, 7.12 Hz), 2.43 (t, 2H,
J=8.14, 7.63 Hz). HRFAB-MS [M+H]+ calcd
482.2153, found 482.2134.
N6 - [2- (3,5 - Dichlorobenzamido)ethyl]adenosine (18e).
From resin 17e and amine 16a. Yield: 87%, purity:
91%. 1H NMR (400 MHz, DMSO-d6) d (ppm)=8.80(t,
1H, J=5.09, 5.59 Hz), 8.37 (s, 1H), 8.22 (bs, 1H), 8.03
(bs, 1H), 7.84 (d, 2H, J=7.84 Hz), 7.82–7.79 (m, 1H),
5.90(d, 1H, J=6.11 Hz), 5.45 (d, 1H, J=6.10Hz), 5.40
(dd, 1H, J=4.58, 2.55 Hz), 5.20(d, 1H, J=4.58 Hz),
4.61 (dd, 1H, J=5.59, 5.60Hz), 4.16–4.13 (m, 1H), 3.97
(dd, 1H, J=3.05, 3.56 Hz), 3.70–3.65 (m, 3H, 50H and
CH2 overlapped), 3.58–3.50(m, 3H, 5 0H and CH2
overlapped). HRFAB-MS [M+H]+ calcd 483.0951,
found 483.0912.
N6-(2-{4-Oxo-4-[(4-phenyl)-phenyl]butanamido}ethyl)-
adenosine (18a). From resin 17a and amine 16a. Yield:
1
93%, purity: 96%. H NMR (400 MHz, DMSO-d6) d
(ppm) 8.37 (s, 1H), 8.23 (bs, 1H), 8.06 (d, 2H,
J=8.14 Hz), 7.89 (bs, 1H), 7.84 (d, 2H, J=8.14 Hz),
7.77 (d, 2H, J=7.63 Hz), 7.66 (d, 1H, J=7.63 Hz), 7.54–
7.43 (m, 3H), 5.90(d, 1H, J=6.10Hz), 5.45 (d, 1H,
J=6.10Hz), 5.41 (dd, 1H, J=4.58, 2.54 Hz), 5.20(d,
1H, J=4.58 Hz), 4.62 (dd, 1H, J=4.60Hz), 4.17–4.12
(m, 1H), 3.99–3.95 (m, 1H), 3.70–3.65 (m, 1H), 3.58–
3.52 (m, 3H, 50H and CH2 overlapped), 3.29–3.25
(m, 2H), 2.50–2.45 (m, 2H, overlapped by DMSO
signal). HRFAB-MS [M+H]+ calcd 547.2306, found
547.2326.
N6 - [2- (3 - Fluoro - 4 - methylbenzamido)ethyl]adenosine
(18f). From resin 17f and amine 16a. Yield: 92%, pur-
1
ity: 95%. H NMR (400 MHz, CDCl3) d (ppm) 8.61 (t,
N6 -{2-[4-(3-Thienyl)butanamido]ethyl}adenosine (18b).
From resin 17b and amine 16a. Yield: 98%, purity:
1H, J=4.58 Hz), 8.37 (s, 1H), 8.23 (s, 1H), 8.02 (bs,
1H), 7.60–7.57 (m, 2H), 7.38 (dd, 1H, J=8.13, 7.63 Hz),
5.90(d, 1H, J=5.60Hz), 5.46 (d, 1H, J=6.61 Hz), 5.41
(dd, 1H, J=4.58, 2.55 Hz), 5.20(d, 1H, J=4.58 Hz),
4.62 (dd, 1H, J=5.60, 6.11 Hz), 4.15 (t, 1H, J=4.58,
3.56 Hz), 3.97 (dd, 1H, J=3.56, 3.06 Hz), 3.70–3.66 (m,
3H, 50H and CH2 overlapped), 3.58–3.49 (m, 3H, 50H
and CH2 overlapped), 2.28 (s, 3H). HRFAB-MS
[M+H]+ calcd 447.1793, found 447.1802.
1
96%. H NMR (400 MHz, DMSO-d6) d (ppm) 8.36 (s,
1H), 8.21 (bs, 1H), 7.95 (t, 1H, J=5.59 Hz), 7.87 (bs,
1H), 7.30(dd, 1H, J=4.07, 1.01 Hz), 6.92 (dd, J= 3.57,
1.52 Hz), 6.82 (d, 1H, J=3.57 Hz), 5.89 (d, 1H,
J=6.10Hz), 5.45 (d, 1H, J=6.10Hz), 5.41 (dd, 1H,
J=4.58, 3.05, 4.07 Hz), 5.20 (d, 1H, J=5.20Hz), 4.61
(dd, 1H, J=6.11, 5.08 Hz), 4.15 (dd, 1H, J=5.08, 4.57,
3.06 Hz), 3.97 (dd, 1H, J=3.57, 3.05 Hz), 3.70–3.65 (m,
1H), 3.58–3.52 (m, 3H, 50H and CH2 overlapped), 3.30–
3.28 (m, 2H), 2.75 (t, 1H, J=7.63 Hz), 2.12 (t, 2H,
J=7.12, 7.63 Hz), 2.10(t, 2H, J=7.63 Hz), 1.85–1.77
(m, 2H). HRFAB-MS [M+H]+ calcd 463.1764, found
463.1736.
N6 - [2- (3 - Methoxybenzamido)ethyl]adenosine (18g).
From resin 17g and amine 16a. Yield: 98%, purity:
1
97%. H NMR (400 MHz, DMSO-d6) d (ppm) 8.58 (t,
1H, J=5.09, 4.57 Hz), 8.36 (s, 1H), 8.23 (bs, 1H), 8.01
(bs, 1H), 7.42–7.34 (m, 3H), 7.09 (dd, 1H, J=5.09, 2.03,
1.52, Hz), 5.90(d, 1H, J=6.11 Hz), 5.45 (d, 1H,
J=6.11 Hz), 5.40(dd, 1H, J=4.57, 2.55 Hz), 5.20(d.
1H, J=4.58 Hz), 4.61 (dd, 1H, J=6.10, 5.60 Hz), 4.14
(dd, 1H, J=4.58, 3.05 Hz), 3.97 (dd, 1H, J=3.56,
3.05 Hz), 3.79 (s, 3H), 3.70–3.65 (m, 3H, 50H and CH2
overlapped), 3.58–3.51 (m, 3H, 50H and CH2 over-
lapped), HRFAB-MS [M+H]+ calcd 445.1836, found
445.1812.
N6 - {2- [(3 - Indolyl)butanamido]ethyl}adenosine (18c).
From resin 17c and amine 16a. Yield: 97%, purity:
1
96%. H NMR (400 MHz, DMSO-d6) d (ppm)=10.74
(s, 1H), 8.36 (s, 1H), 8.21 (bs, 1H), 7.94 (t, 1H,
J=5.60Hz), 7.88 (bs, 1H), 7.49 (d, 1H, J=7.62 Hz),
7.33 (d, 1H, J=7.63 Hz), 7.09 (s, 1H), 7.05 (t, 1H,
J=7.63, 7.12 Hz), 6.95 (t, 1H, J=7.63, 7.12 Hz), 5.89 (d,
1H, J=6.10Hz), 5.45 (d, 1H, J=6.62 Hz), 5.41 (dd, 1H,
J=4.58, 2.54 Hz), 5.19 (d, 1H, J=4.57 Hz), 4.61 (dd,
1H, J=6.11, 5.08 Hz), 4.15 (dd, 1H, J=4.58, 3.56 Hz),
3.97 (dd, 1H, J=3.56, 3.05 Hz), 3.70–3.65 (m, 1H),
3.58–3.52 (m, 3H, 50H and CH2 overlapped), 3.30–3.28
(m, 2H), 2.65 (t, 2H, J=7.63, 7.12 Hz), 2.13 (t, 2H,
J=7.63, 7.12 Hz), 1.85 (t, 2H, J=7.63, 7.12 Hz).
HRFAB-MS [M+H]+ calcd 496.2309, found 496.2270.
N6 - {2- [(3 - Thienyl)acetamido]ethyl}adenosine (18h).
From resin 17h and amine 16a. Yield: 93%, purity:
1
96%. H NMR (400 MHz, DMSO-d6) d (ppm) 8.36 (s,
1H), 8.21 (bs, 1H), 8.10(t, 1H, J=5.60, Hz), 7.41–7.39
(m, 1H), 7.23–7.20(m, 1H), 6.98 (dd, 1H, J=3.56,
1.27 Hz), 5.90(d, 1H, J=6.11 Hz), 5.46 (bs, 1H), 5.38
(bs, 1H), 5.18 (bs, 1H), 4.62–4.60(m, 1H), 4.16–4.14 (m,
1H), 3.98–3.96 (m, 1H), 3.70–3.66 (m, 1H), 3.62–3.48
(m, 3H, 50H and CH2 overlapped), 3.41 (s, 2H), 3.41 (d,
2H, J=5.60Hz), 3.33–3.28 (m, 2H, by H 2O signal
overlapped). HRFAB-MS [M+H]+ calcd 435.1451,
found 435.1400.
N6 - {2- [(3 - Indolyl)propanamido]ethyl}adenosine (18d).
From resin 17d and amine 16a. Yield: 98%, purity:
95%. 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.73 (s,
1H), 8.37 (s, 1H), 8.23 (bs, 1H), 8.01 (t, 1H, J=5.60Hz),
7.89 (bs, 1H), 7.52 (d, 1H, J=7.63 Hz), 7.33 (d, 1H,
J=8.14 Hz), 7.09 (s, 1H), 7.05 (t, 1H, J=7.63, 7.12 Hz),
6.96 (t, 1H, J=7.63, 7.12 Hz), 5.90(d, 1H, J=6.10Hz),
N6 - [2- (3,3 - Dimethylacrylamido)ethyl]adenosine (18i).
From resin 17i and amine 16a. Yield: 85%, purity:

776
A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
87%. 1H NMR (400 MHz, DMSO-d6) d (ppm) 8.36
(s, 1H), 8.22 (bs, 1H), 7.88 (bs, 1H N6-H and t, 1H
NH amid J=5.60Hz overlapped), 5.89 (d, 1H, J=6.10
Hz), 5.61 (s, 1H), 5.45 (d, 1H, J=6.62 Hz), 5.41 (dd,
1H, J=4.57, 2.55 Hz), 5.20(d, 1H, J=4.57 Hz), 4.61
(dd, 1H, J=6.10, 5.09 Hz), 4.16–4.13 (m, 1H), 3.97
(dd, 1H, J=3.56, 3.05 Hz), 3.70–3.65 (m, 1H), 3.58–3.52
(m, 3H, 50H and CH2 overlapped), 2.06 (s, 3H), 1.77
(s, 3H). HRFAB-MS [M+H]+ calcd 393.1887, found
393.1857.
3.49 (m, 14 H), 2.75 (t, 2H, J=7.63 Hz), 2.12 (t, 2H,
J=7.63, 7.12 Hz), 1.84–1.77 (m, 2H). HRFAB-MS
[M+H]+ calcd 551.2289, found 551.2247.
N6-{3,6-Dioxa-8-[4-(3-indolyl)butanamido)octyl]adeno-
sine (19c). From resin 17c and amine 16b. Yield: 97%,
1
purity: 96%. H NMR (400 MHz, DMSO-d6) d (ppm)
10.74 (s, 1H), 8.37 (s, 1H), 8.23 (bs, 1H); 7.86 (t, 1H,
J=5.60, 5.09 Hz), 7.78 (bs, 1H), 7.50 (d, 1H,
J=7.63 Hz), 7.33 (d, 1H, J=8.14 Hz), 7.09 (s, 1H), 7.05
(t, 1H, J=7.63, 7,13 Hz), 6.95 (t, 1H, J=7.63, 7.13 Hz),
5.91 (d, 1H, J=6.10Hz), 5.52 (bs, 1H), 5.43 (bs, 1H),
5.22 (bs, 1H), 4.62 (t, 1H, J=5.60Hz), 4.17–4.15 (m,
1H), 3.99–3.97 (m, 1H), 3.70–3.50 (m, 10H), 3.22–3.17
(m, 2H), 2.65 (t, 2H, J=7.63, 7.12 Hz), 2.14 (t, 2H,
J=7.63 Hz), 1.93–1.82 (m, 2H). HRFAB-MS [M+H]+
calcd 584.2833, found=584.2849.
N6-[(2-Biotinylamido)ethyl]adenosine (18k). From resin
1
17k and amine 16a. Yield: 98%, purity: 98%. H NMR
(400 MHz, DMSO-d6) d (ppm)=8.36 (s, 1H), 8.22 (s,
1H ), 7.94 (t, 1H, J=5.60Hz), 7.85 (bs, 1H), 6.41(s, 1H),
6.35 (s, 1H), 5.89 (d, 1H, J=6.10Hz), 5.45 (d, 1H,
J=6.10Hz), 5.42 (dd, 1H, J=4.58, 2.55 Hz), 5.20(d,
1H), 4.61 (dd, 1H), 4.31–4.28 (m, 1H), 4.16–4.09 (m,
2H), 3.98–3.95 (m, 1H), 3.70–3.65 (m, 1H), 3.58–3.52
(m, 3H, 50H and CH2 overlapped), 3.08–3.03 (m, 1H),
2.82(dd, 1H, J=5.09, 7.63 Hz), 2.58(d, 1H,
J=12.21 Hz), 2.05 (t, 2H, J=7.12, 7.63 Hz), 1.64–
1.20(m, 6H). HRFAB-MS [M+H]+ calcd 537.2245,
found 537.2249.
N6-{3,6-Dioxa-8-[3-(3-indolyl)propanamido)octyl]adeno-
sine (19d). From resin 17d and amine 16b. Yield: 95%,
1
purity: 96%. H NMR (400 MHz, DMSO-d6) d (ppm)
10.74 (s, 1H), 8.37 (s, 1H), 8.23 (bs, 1H), 7.92 (t, 1H,
J=5.60Hz), 7.78 (bs, 1H), 7.52 (d, 1H, J=7.63 Hz),
7.33 (d, 1H, J=8.14 Hz), 7.08 (s, 1H), 7.05 (t, 1H,
J=7.63, 7.12 Hz), 6.96 (t, 1H, J=7.63, 7.12 Hz), 5.91
(d, 1H, J=6.61 Hz), 5.46 (bs, 1H), 5.42 (bs, 1H), 5.21
(bs, 1H), 4.63–4.61 (m, 1H), 4.17–4.15 (m, 1H), 4.00–
3.96 (m, 1H), 3.70–3.47 (m, 10 H), 3.21–3.17 (m, 2H),
2.91 (t, 2H, J=8.14, 7.12 Hz), 2.44 (t, 2H, J=8.14,
7.12 Hz). HRFAB-MS [M+H]+ calcd 570.2677, found
570.2692.
N6-{2-[4-(N-ethyl-N-benzylamino)-3-nitrobenzamido]e-
thyl}adenosine (18l). From resin 17l and amine 16a.
1
Yield: 82%, purity: 85%. H NMR (400 MHz, DMSO-
d6) d (ppm)=8.61 (t, 1H, J=5.60, 5.08 Hz), 8.36 (s, 1H),
8.22 and 8.21 (2s, 2H overlapped), 8.01 (bs, 1H), 7.90
(dd, 1H, J=6.61, 2.04 Hz), 7.33–7.21 (m, 6H), 5.89 (d,
1H, J=6.10Hz), 5.46 (d, 1H, J=5.60Hz), 5.39 (dd, 1H,
J=4.58, 2.54 Hz), 5.20(d, 1H, J=4.57 Hz), 4.61 (dd,
1H, J=5.60, 5.08 Hz), 4.44 (s, 2H), 4.14 (dd, 1H,
J=4.58, 3.05 Hz), 3.96 (dd, 1H, J=3.56, 3.05 Hz), 3.70–
3.63 (m, 3H, 50H and CH2 overlapped), 3.58–3.48 (m,
3H, 50H and CH2 overlapped), 3.18 (q, 2H, J=7.12,
7.13 Hz), 1.07 (t, 3H, J=7.13, 7.12 Hz). HRFAB-MS
[M+H]+ calcd 593.2473, found 593.2448.
N6-[3,6-Dioxa-8-(3-methoxybenzamido)octyl]adenosine
(19g). From resin 17g and amine 16b. Yield: 95%, pur-
ity: 97%. 1H NMR (400 MHz, DMSO-d6)
d
(ppm)=8.51 (t, 1H, J=5.59, 5.09 Hz), 8.36 (s, 1H), 8.21
(bs, 1H), 7.78 (bs, 1H), 7.42–7.33 (m, 3H), 7.08–7.06 (m,
1H), 5.89 (d, 1H, J=6.10Hz), 5.45 (d, 1H, J=6.10Hz),
5.40(dd, 1H,
J=4.58, 2,54 Hz), 5.20(d, 1H,
J=4.58 Hz), 4.60(dd, 1H, J=6.10, 5.09 Hz), 4.16–4.13
(m, 1H), 3.96 (dd, 1H, J=3.56, 3.05 Hz), 3.79 (s, 3H),
3.70–3.51 (m, 12H), 3.40–3.38 (m, 2H). HRFAB-MS
[M+H]+ calcd 533.2361, found=533.2331.
N6-(3,6-Dioxa-8-{4-oxo-4-[(4-phenyl)-phenyl]butanam-
ido}octyl)adenosine (19a). From resin 17a and amine
16b. Yield: 93%, purity: 95%. 1H NMR (400 MHz,
DMSO-d6) d (ppm) 8.36 (s, 1H), 8.22 (bs, 1H), 8.06 (d,
2H, J=8.14 Hz), 7.98 (t, 1H, J=5.60Hz), 7.83 (d, 2H,
J=8.14 Hz), 7.76 (d, 2H, J=7.63 Hz), 7.70–7.65 (m,
1H), 7.53–7.41 (m, 3H), 5.89 (d, 1H, J=6.10Hz), 5.45
(d, 1H, J=6.11 Hz), 5.40(dd, 1H, J=4.58, 2.54 Hz),
N6 - [3,6 - Dioxa - 8 - (3 - thienyl)acetamido)octyl]adenosine
(19h). From resin 17h and amine 16b. Yield: 95%, pur-
1
ity: 96%. H NMR (400 MHz, DMSO-d6) d (ppm) 8.37
(s, 1H), 8.23 (bs, 1H), 8.06 (t, 1H, J=5.60, 5.06 Hz),
7.44–7.42 (m, 1H), 7.23–7.21 (m, 1H), 7.02–6.99 (m,
1H), 5.90(d, 1H, J=6.11 Hz), 5.46 (bs, 1H), 5.42 (bs,
1H), 5.21 (bs, 1H), 4.64–4.57 (m, 1H), 4.18–4.13 (m,
1H), 3.70–3.46 (m, 10H), 3.42 (s, 2H), 3.41 (d, 2H,
5.20(d, 1H,
J=4.58 Hz), 4.61 (dd, 1H, J=6.11,
5.08 Hz), 4.15 (dd, 1H, J=4.58, 3.05 Hz), 3.97 (dd, 1H,
J=3.56, 3.05 Hz), 3.70–3.51 (m, 10H), 3.42–3.37 (m,
2H), 3.25 (t, 2H, J=6.61 Hz), 3.22–3.17 (m, 2H), 2.50–
2.47 (m, 2H, overlapped by DMSO signal). HRFAB-
MS [M+H]+ calcd 635.2830, found 635.2838.
+
J=5.60Hz), 3.22–3.18 (m, 2H). HRFAB-MS [M+H]
calcd 523.1976, found 523.2018.
N6-{3,6-Dioxa-8-[4-(3-thienyl)butyramido)octyl]adeno-
sine (19b). From resin 17b and amine 16b. Yield: 98%,
N6-[3,6-Dioxa-8-(3,3-dimethylacrylamido)octyl]adenosine
(19i). From resin 17i and amine 16b. Yield: 88%, pur-
ity: 92%. H NMR (400 MHz, DMSO-d6) d (ppm) 8.36
1
purity: 96%. 1H NMR (400 MHz, DMSO-d6)
d
(ppm)=8.39 (s, 1H), 8.24 (s, 1H), 7.92 (bs,1H), 7.86 (t,
1H, J=5.60Hz), 7.29 (dd, 1H, J=4.07, 1.02 Hz), 6.92
(dd, 1H, J=3.56, 1.52 Hz), 6.83 (d, 1H, J=3.58 Hz),
5.90(d, 1H, J=6.10Hz), 4.59 (t, 1H, J=5.60, 5.08 Hz),
4.16–4.14 (m, 1H), 3.97 (t, 1H, J=3.56, 3.06 Hz), 3.69–
(s, 1H), 8.22 (bs, 1H), 7.78 (t, 1H, J=5.09 Hz, and bs
1H overlapped), 5.89 (d, 1H, J=6.10Hz), 5.64 (s, 1H),
5.45 (d, 1H, J=6.10Hz), 5.41 (dd, 1H, J=4.58,
2.54 Hz), 5.20(d, 1H, J=4.57 Hz), 4.61 (dd, 1H,
J=6.11, 5.08 Hz), 4.15 (dd, 1H, J=4.58, 3.56 Hz), 3.96

A. Golisade et al. / Bioorg. Med. Chem. 10 (2002) 769–777
777
(dd, 1H, J=3.56, 3.05 Hz), 3.70–3.49 (m, 10H), 3.41–
Acknowledgements
3.38 (m, 2H), 3.22–3.18 (m, 2H), 2.06 (s, 3H), 1.75 (s,
3H). HRFAB-MS [M+H]+ calcd 481.2411, found
481.2462.
This work was supported by the Fonds der Chemischen
Industrie FCI, and the Deutsche For-
schungsgemeinschaft DFG. Helpful discussion and
encouragement by Prof. Dr. D. Geffken is gratefully
acknowledged.
N6 - [3,6 - Dioxa - 8 - (diphenylacetamido)octyl]adenosine
(19m). From resin 17m and amine 16b. Yield: 98%,
purity: 96%. H NMR (400 MHz, DMSO-d6) d (ppm)
1
8.36 (s, 1H), 8.31 (t, 1H, J=5.60, 5.34 Hz), 8.22 (bs,
1H), 7.73 (bs 1H), 7.29 (s, 4H), 7.28 (s, 4H), 7.23–7.18
(m, 2H), 5.90(d, 1H, J=6.11 Hz), 5.44 (bs, 1H), 5.38
(bs, 1H), 5.19 (bs, 1H), 4.96 (s, 1H), 4.64–4.58 (m, 1H),
4.17–4.14 (m, 1H), 3.98–3.96 (m, 1H), 3.70–3.47 (m,
10H), 3.42 (t, 2H, J=5.85, 5.60Hz), 3.26–3.21 (m, 2H).
HRFAB-MS [M+H]+ calcd 593.2724, found 593.2698.
References and Notes
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