Structure-activity relationships of 2,N6,5′-substituted adenosine derivatives with potent activity at the A2B adenosine receptor

Article abstract of DOI:10.1021/jm061278q

2, N⁶, and 5′-substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides leading to 2-arylalkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was examined in both binding and cAMP assays and found to be a potent agonist of the human A_2BAR. Simplification, altered connectivity, and mimicking of the indole ring of 17 failed to maintain A_2BAR potency. Introduction of N⁶-ethyl or N⁶-guanidino substitution, shown to favor A_2BAR potency, failed to enhance potency in the 2-(3-(indolyl)- ethyloxy)adenosine series. Indole 5″- or 6″-halo substitution was favored at the A_2BAR, but a 5′-N-ethylcarboxyamide did not further enhance potency. 2-(3″-(6″-Bromoindolyl)ethyloxy)adenosine 28 displayed an A_2BAR EC₅₀ value of 128 nM, that is, more potent than the parent 17 (299 nM) and similar to 5′-N- ethylcarboxamidoadenosine (140 nM). Compound 28 was a full agonist at A _2B and A_2AARs and a low efficacy partial agonist at A ₁ and A₃ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties in AR agonists that enhance A_2BAR potency and selectivity.

Full text of DOI:10.1021/jm061278q

1810
J. Med. Chem. 2007, 50, 1810-1827
Structure-Activity Relationships of 2,N6,5′-Substituted Adenosine Derivatives with Potent
Activity at the A2B Adenosine Receptor
Hayamitsu Adachi, Krishnan K. Palaniappan, Andrei A. Ivanov, Nathaniel Bergman, Zhan-Guo Gao, and Kenneth A. Jacobson*
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and DigestiVe and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland 20892
ReceiVed NoVember 2, 2006
2, N6, and 5′-substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides
leading to 2-arylalkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was examined in both binding
and cAMP assays and found to be a potent agonist of the human A2BAR. Simplification, altered connectivity,
and mimicking of the indole ring of 17 failed to maintain A2BAR potency. Introduction of N6-ethyl or
N6-guanidino substitution, shown to favor A2BAR potency, failed to enhance potency in the 2-(3-(indolyl)-
ethyloxy)adenosine series. Indole 5′′- or 6′′-halo substitution was favored at the A2BAR, but a 5′-N-
ethylcarboxyamide did not further enhance potency. 2-(3′′-(6′′-Bromoindolyl)ethyloxy)adenosine 28 displayed
an A2BAR EC50 value of 128 nM, that is, more potent than the parent 17 (299 nM) and similar to 5′-N-
ethylcarboxamidoadenosine (140 nM). Compound 28 was a full agonist at A2B and A2AARs and a low
efficacy partial agonist at A1 and A3ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties
in AR agonists that enhance A2BAR potency and selectivity.
Introduction
For several decades, NECA (5′-N-ethylcarboxamidoadenos-
ine) 2 was considered to be the most potent known agonist at
the A2BAR, with an EC50 of 140 nM.25-27 A survey of
structurally diverse adenosine derivatives as agonists of the
human A2BAR failed to identify a lead that surpassed the
potency of 2.28 Cristalli and co-workers have explored the SAR
(structure-activity relationship) of 2-substituted 5′-uronamide
adenosine derivatives such as (S)-PHP-NECA 4 (EC50 ) 220
nM) as potent but relatively nonselective agonists of the
A2BAR.29-31
Recent reports provided new insights into the SAR of agonists
of the A2BAR. A 3-fold enhancement in potency at the A2BAR
was achieved by combining 2 with the N6-guanidino modifica-
tion in 3.32 This structural change produced a 3-fold gain in
potency at the A3AR, a 300-fold loss of potency at the A2AAR,
and no change at the A1AR. Also, while 2-ether derivatives of
adenosine were characterized as potent A2AAR agonists, specific
2-(2-arylethyloxy) ethers were also noted to be particularly
potent at the A2BAR.26 In the present study we characterized
the SAR of potent A2BAR agonists based on compound 17. In
particular, 5′′ or 6′′-functionalization on the indole moiety of
17 led to the achievement of new AR agonists with enhanced
potency at the A2BAR and reduced potency at other AR
subtypes. Moreover, we have used molecular modeling of the
human A2BAR to propose a mode of docking of the potent
2-substituted derivatives.
There are four subtypes of adenosine receptors (ARs): A1,
A2A, A2B, and A3.1 Three of these subtypes already possess
selective and potent agonists and antagonists.2 Only the A2B-
AR remains without a selective agonist. It should be noted,
however, that highly potent and selective antagonists have been
reported for this subtype.3-8 A2BAR antagonists are directed
toward clinical use for treating asthma and diabetes. Conversely,
a selective A2BAR agonist would provide a useful pharmaco-
logical probe for exploring the role of receptor activation.
Activation of the A2BAR is known to induce angiogenesis,9
reduce vascular permeabilization,10 increase production of the
anti-inflammatory cytokine IL-10,11 increase chloride secretion
in epithelial cells,12-14 and increase release of inflammatory
mediators from human and canine mast cells.15,16 A2BAR
agonists have been proposed for the treatment of septic shock17
and cystic fibrosis,18 and cardiac,19 pulmonary,20 and kidney19
diseases associated with remodeling and hyperplasia. Thus, such
an agonist may be useful in preventing restenosis. The A2BAR
mediates vasodilation in the corpus cavernosum of rabbit and
agonists, therefore, may be useful in treating erectile dysfunc-
tion.21 Recently, Yang et al. described a proinflammatory
phenotype resulting from deletion of the gene encoding the A2B-
AR in the mouse, suggesting that activation of the A2BAR can
have anti-inflammatory effects.22 Activation of the A2BAR also
promotes postconditioning salvage of ischemic myocardium.23
Modulation of A2BAR potency has been achieved through
structural changes at several sites on the adenosine molecule.
R-PIA (R-N6-(phenylisopropyl)adenosine) 1 was one of the
earliest potent agonists to be extensively investigated at ARs
and was one of the nucleosides used initially to distinguish the
low affinity A2B and high affinity A2AARs.24 It was found to
activate the A2BAR with a micromolar potency and later was
noted to bind to the A3AR with nearly the same affinity as at
the A2AAR.
Results
Chemical Synthesis. The structures of the target adenosine
2-ether derivatives 5-40 appear in Chart 1 and Table 1.
Compounds 5-7 and 9-16 were studied previously at the
human A2BAR.26 Routes to the synthetic intermediates for the
2-ether component are shown in Schemes 1 and 2. The novel
2-alkoxyadenosines 8 and 17-36, N6-guanidino-2-(3-indolyl)-
ethyloxy)adenosine derivatives 37 and 38, N6-ethyl-2-(3-in-
dolyl)ethyloxy)adenosine 39 and 5′-N-ethylcarboxamido-2-(3-
indolyl)ethyloxy-adenosines 40 were prepared via alkylation of
2-oxypurine nucleosides using arylalkyl/alkyl iodides as shown
in Schemes 3-5.
* To whom correspondence should be addressed. Dr. K. A. Jacobson,
Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH,
NIDDK, LBC, Bethesda, MD 20892-0810. Tel.: 301-496-9024. Fax: 301-
480-8422. E-mail: kajacobs@helix.nih.gov.
10.1021/jm061278q This article not subject to U.S. Copyright. Published 2007 by the American Chemical Society
Published on Web 03/23/2007

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Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1811
Chart 1. Chemical Structures of Selected Adenosine Derivatives 1-4 Previously Used as Pharmacological Reference Compounds for
Characterization of the A2BAR and Novel Adenosine Derivatives 8, and 17-40a
a The remaining adenosine derivatives in the series, 5-7 and 9-16 (structures in Table 1), were reported previously.26
The various arylalkyl iodides used in this study, when not
commercially available, were synthesized by the routes shown
in Schemes 1 and 2. Tryptophol (3-(2-hydroxyethyl)indole) 41,
5-methoxytryptophol 42, and 5-hydroxy-tryptophol 43 were
converted to the corresponding tosylates 44-46, respectively,
followed by iodination with NaI to give the iodides 47-49.
Indole-3-acetic acid analogues 50-52 having a functional group
at the 2- and/or 5-position were transformed to the corresponding
esters, which were reduced with lithium aluminum hydride to
give the alcohols 53-55. Tosylation of the alcohols 53-55
followed by iodination with sodium iodide gave the correspond-
ing iodides 59-61. Furthermore, other 5- or 6-substituted
tryptophols 67-70 were prepared by refluxing the corresponding
phenylhydrazine hydrochloride salts 63-66 and 2-ethoxytet-
rahydrofuran 62 to effect a Fischer indole ring cyclization.34
Compounds 67-70 were converted to the corresponding iodides
74-77, respectively, by using the conventional method men-
tioned above. Compounds 78 and 79 were transformed to the
ethyl glyoxylate derivatives 80 and 81, which were reduced with
lithium aluminum hydride to give the corresponding tryptophol

1812 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
Table 1. Potency of Various Adenosine Derivatives in Activation of the Human A2BAR Expressed in CHO Cellsa
a Values are expressed either as the EC50 (nM) or the percent stimulation at 10 µM (in parentheses). For comparison, binding affinities of the adenosine
derivatives at human A1, A2A, and A3ARs expressed in CHO cells (expressed as Ki value or percent displacement at 10 µM) and maximal agonist effects
at 10 µM at the A3AR. Values for compounds 5-7 and 9-16 are from ref 26. b All experiments were performed using adherent CHO cells stably transfected
with cDNA encoding a human AR. Percent activation of the human A2B or A3AR was determined at 10 µM. Binding at A1, A2A, and A3ARs was carried
out as described in Experimental Procedures. The A3 receptor activation results were from three separate experiments. The Ki and EC50 values from the
present study are expressed as mean ( s.e.m., N ) 3-5. c Compounds 3, MRS3218; 17, MRS3534; 24, MRS3854; and 28, MRS3997. d Data from refs 29
and 31. e Data from ref 26.
derivatives 82 and 83, respectively. Compounds 82 and 83 were
converted to the corresponding iodides 85 and 86 by using
conventional methods.
A tosylated 2-tryptophol 88 was prepared by the palladium-
mediated heteroannulation of 2-iodoaniline with 3-butyn-1-ol
(Scheme 2). The amino group of 2-iodoaniline 87 was activated

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1813
Scheme 1a
a Reagents and conditions: (a) TsCl, NaH, THF, 0 °C-rt; (b) NaI, DMF, 60 °C; (c) (i) TsOH-H2O, MeOH, 60 °C; (ii) LAH, THF, 4 °C-rt; (d) EtOH,
reflux; (e) oxalyl chloride, Et2O, EtOH; (f) LAH, THF, reflux; (g) I2, PPh3, imidazole, benzene.
by the strong electron-withdrawing sulfonyl group, and the
indole cyclization occurred in one pot to give the tosylated
2-tryptophol 88.35 Compound 88 was converted to the corre-
sponding iodide 89 with iodine, triphenylphosphine, and imi-
dazole.
Reduction of benzoimidazol-1-yl-acetic acid 90 and benzo-
triazol-1-yl-acetic acid 91 with lithium aluminum hydride
followed by iodination gave the corresponding iodides 94 and
95, respectively.
N-Tosyl-3-pyrrolylacetic acid methyl ester 97 was synthesized
from pyrrole by the known method36 involving Friedel-Crafts
acylation followed by a Willgerodt-Kindler reaction. Reduction
of 97 with lithium aluminum hydride produced the alcohol 98,
which was converted to the corresponding iodide 99 by using
iodine, triphenylphosphine, and imidazole.
Reaction of the hydroxyl group at the 2-position of 101 with
various iodides 47-49, 59-61, 74-77, 85, 86, 1-iodo-3-
phenylpropane, 89, 94, 95, and 99, respectively, was carried
out in the presence of cesium carbonate to give compounds
102-118. Simultaneous removal of the acetyl group and
amination at the 6-position of 102-118 by using saturated
ammonia in ethanol solution afforded compounds 18, 119-121,
26, 32, 122-126, 30, 8, 21, 35, 36, and 127, respectively.
Deprotection of the N-tosyl group of the indole or pyrrole ring
of 18, 119-121, 26, 32, 122-126, 21, and 127 was conducted
using potassium hydroxide in methanol to give compounds 17,
33, 34, 22, 24, 31, 27, 28, 23, 25, 29, 20, and 19, respectively.
Synthesis of N6-guanidino derivatives 37 and 38 began with
compound 102 (Scheme 4). The guanidinolysis of 102 in the
presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) afforded
37 and the tosylate 38. Treatment of 102 with ethyl amine and
N,N-diisopropylethylamine in DMF at 140 °C followed by
removal of the tosyl group with potassium hydroxide gave the
N6-ethyl derivative 39.
The synthesis of the 5′-CH2OH analogues (Scheme 3) started
from 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-â-D-ribofurano-
syl)purine 100, which was converted to 6-chloro-2-hydroxy-9-
(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)purine 101, as reported.33

1814 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
Scheme 2a
a Reagents and conditions: (a) (i) TsCl, pyridine, CH2Cl2; (ii) 3-butyn-1-ol, Pd(PPh3)2Cl2, CuI, Et3N, DMF, 70 °C; (b) I2, PPh3, imidazole, Et2O-MeCN,
rt; (c) LAH, THF, 0 °C-rt.
Scheme 3a
a Reagents and conditions: (a) R1CH2CH2-I (47-49, 59-61, 74-77, 85, 86, 1-iodo-3-phenylpropane, 89, 94, 95, and 99, respectively), Cs2CO3, DMF,
rt; (b) saturated NH3 in EtOH, 120 °C; (c) deprotection of tosyl group of 18, 119-121, 26, 32, 122-126, 21, and 127; KOH, MeOH 70-90 °C.
Synthesis of the 5′-N-ethylcarboxamido derivative 40 began
with 100 (Scheme 5). Protection of the 1,2-diol of 100 afforded
the acetonide 128. Oxidation of 128 with potassium perman-
ganate gave the corresponding carboxylic acid derivative 129,
which was converted to the 5′-N-ethylcarboxamide derivative
130 using benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP). Diazotization of 130 with t-butyl
nitrite followed by hydrolysis gave the 2-hydroxy derivative
131 in 47% yield. Coupling of 131 with the iodide 47 in the
presence of cesium carbonate in DMF gave the 2-O-alkylated
derivative 132, which was followed by displacement of the
6-chloro moiety with ammonia to give 133. Removal of the
2′,3′-O-isopropylidene group of 133 with 80% acetic acid
aqueous solution afforded compound 134. Treatment of 134 with
potassium hydroxide in methanol resulted in the desired 5′-N-
ethyluronamide derivative 40.
Biological Evaluation. The AR binding affinities of novel
compounds 8 and 17-40 were investigated in comparison to
known (1-4, 5-7, and 9-16) nucleosides (Table 1). The SAR
proceeded from known agonists with high potency at the A2B-
AR, that is, 1-4. A previous difficulty has been targeting the
A2BAR potency distinctly from the usually more potent activity

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1815
Scheme 4a
a Reagents and conditions: (a) guanidine solution,32 DABCO, EtOH, 110 °C; (b) (i) EtNH2‚HCl, DIPEA, DMF, 140 °C; (ii) KOH, MeOH, 80 °C.
Scheme 5a
a Reagents and conditions: (a) 2,2-dimethoxypropane, p-TsOH-H2O, DMF; (b) KMnO4, KOH, H2O; (c) PyBop, DIPEA, EtNH2 HCl, DMF; (d) t-butyl
nitrite, 2-PrOH/H2O (1:1); (e) iodide 47, Cs2CO3, DMF, rt; (f) saturated NH3, EtOH, 120 °C; (g) 80% AcOH, 80 °C; (h) KOH, MeOH, 70 °C.
at the A2AAR. Compound 4 was reported as a potent A2BAR
agonist; nevertheless, it remained two orders of magnitude
selective for the A2AAR in comparison to the A2BAR.31 Among
2-substituted derivatives, 2-ethers were more potent than the
corresponding amines or thioethers.26 A 2-phenylethyl ether 7
was only 2-fold less potent than R-PIA 1 at the A2BAR.
Nevertheless, the affinity in binding to the A2AAR was nearly
400-fold greater than the A2BAR functional potency. Therefore,
great improvement was necessary to approach A2BAR selectiv-
ity.
Elongation of the spacer alkyl chain beyond ethyl weakened
the affinity against all ARs, as shown in 7-9. Compound 10 is
a variation of 8 in which a methyl group is branched in the
alkyl chain and its affinity was reduced in comparison to 8.

1816 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
The effect of fluoro substitution of the phenyl ring was also
probed. The 2-F 11, 3-F 12, and 4-F 13 analogues were invariant
in affinity at A1, A2A, and A3 ARs, with Ki values at these
subtypes ranging from 60 to 500 nM. These three analogues
were also nearly inactive at the A2BAR.
Three other aromatic moieties in 2-(2-arylethyloxy) ethers
14-16 were reported in a previous study.26 2-Naphthyl and
2-thienyl moieties were tolerated at the A2BAR, while a 3-thienyl
group resulted in inactivity at that subtype. Those modifications
produced relatively minor changes at A1, A2A, and A3ARs in
comparison to the phenyl analogue 7.
Interestingly, the 3-indolyl analogue 17 (a tryptophol ether)
was 12-fold more potent than 7 at the A2BAR and 4-5-fold
less potent than 7 in binding to the A2A and A3ARs. Also, 17
was only 2-fold less potent than 2 at the A2BAR. This consid-
erable enhancement was exploited in subsequent SAR explora-
tion. The corresponding N-tosyl derivative 18, as for similar
N-tosyl derivatives, was considerably less potent at all ARs.
The 3-pyrrolyl derivative 19 was the simplest analogue in
this study, whose pyrrole ring moiety is a critical component
of an indole ring. Compound 19 was tolerated at the A2BAR,
with a potency close to that of the 2-thienyl derivative 15,
leading to 1.4-fold and 8-fold decreased potency at the A1 and
34 was more potent than the 5′′-methoxy analogue 33 at all
ARs. Bulkiness of the substituent at the 5′′-position might be
related to the reduced affinity.
The effect on the 5′′-halo-substitution of the indole moiety
was also investigated. The corresponding 5′′-halo analogues 22-
25 were well tolerated by the A2BAR. Of these analogues, the
5′′-bromo analogue 24 was equipotent to 17 at the A2BAR, but
was 11-fold less potent than 17 in binding to the A2AAR.
Compound 24 was roughly equipotent at all four ARs, however,
its selectivity was improved compared to the parent compound
17. This series of 5′′-halo derivatives showed a tendency toward
increased Ki values at A1 and A2AARs, depending on the
bulkiness of halogen atom.
The importance of bromo-substitution of 26 for A2BAR
potency prompted us to design the positional isomers of bromo-
substituted indole, leading to the 4′′-, 6′′-, or 7′′-bromo
derivatives 28-30. Of these bromo analogues, surprisingly,
compound 28 surpassed the A2BAR potency of the 5′′-bromo
analogue 24, the parent compound 17, and even 2. Also, 28
displayed improved selectivity compared to 17 and 2. On the
other hand, the 5′′-chloro analogue 27 showed a decreased
potency at A2BAR compared to 28.
Activation curves were determined for 28 in comparison to
2 at the A1, A2A, A2BARs, and A3AR (Figure 1). Compound 28
was a partial agonist at A1 and A3ARs and a full agonist at A2A
and A2BARs.
A2AARs, respectively, and similar potency at A3AR.
On the other hand, the corresponding 2-indolyl derivative 20
decreased markedly A2BAR potency compared to 17. Thus, the
3-position was clearly the favored connection point and was
utilized in subsequent synthesis. Its N-tosyl derivative 21 was
less potent at all ARs, similar to results with 18.
It is known from SAR studies of A2B agonists that substitution
of the 4′-hydroxymethyl group of an adenosine analogue with
a 5′-N-ethylcarboxamido group often yields compounds en-
dowed with higher affinity than the parent compound.31,37 Based
on these findings, we have prepared the 5′-N-ethyluronamido
analogue 40 of 17. Unexpectedly, 40 was 3-fold less potent than
the parent 5′-CH2OH compound 17 at the A2BAR and showed
a 2-fold increased potency at only the A3AR.
Cristalli and colleagues have established that the N6-ethyl
analogue of (S)-PHP-adenosine was more potent than the N6-
methyl and N6-isopropyl derivatives at the A2B subtype.31 These
findings were applied to 3-indolyl analogue 17, leading to the
N6-ethyl analogue 39. Compound 39 was somewhat tolerated
at A2BAR and 7-fold more potent than the parent compound 17
at the A3AR.
Molecular Modeling. A recently published rhodopsin-based
molecular model of the human A2BAR38 was adapted to study
the binding mode of compound 28 after docking and energy
optimization using Monte Carlo multiple minimum (MCMM)
calculations.39 The position of the adenosine moiety of 28 in
the A2BAR obtained after MCMM calculations was found to
be similar to its initial position. Furthermore, it was observed
that the 2-(6-bromoindol-3-yl)-ethyloxy substituent fits the
binding site well (Figure 2). In the resulting model, the oxygen
atom of this moiety was found in proximity to the side chain
amino group of Asn254 (6.55) and seemed to be involved in
H-bonding with this residue. The indole ring occupied a pocket
formed by several residues located in TM3 and EL2. In
particular, the NH-group of the indole ring was found near the
OH-group of Ser165 (EL2). Although, a H-bond between the
NH-group of the indole ring and Ser165 was not observed in
the model, a formation of this bond seems to be possible due
to the rotation of the side chain of Ser165.
Another N6-functionalization for 17 was also investigated at
ARs. Recently the N6-guanidino derivative 3 was reported to
display a 3-fold potency enhancement over the parent 5′-N-
ethyluronamide 2 at the A2BAR.32 However, introduction of a
N6-guanidino group to 17 led to derivative 37 and its tosyl
derivative 38 with decreased A2B potency compared to the parent
compounds. Compound 37 showed a 2-fold increased potency
at A1 and A3 ARs. Thus, the effect of N6-guanidinylation to
enhance A2BAR selectivity is not always compatible with other
beneficial structures.
Benzoimidazole and benzotriazole analogues 35 and 36 are
simple congeners of 17, in which the indole ring was substituted
with an imidazole or triazole ring, respectively. Compounds 35
and 36 showed low potency at all AR subtypes.
The effect of substitution of the indole ring moiety was tested.
A 2′′-methyl-5′′-methoxy indolyl derivative 31 showed reduced
potency compared to 17, especially at the A2BAR. Its N-tosyl
derivative 32 lost potency at all ARs. A 5′′-methoxy derivative
Discussion
The goal was to prepare novel A2BAR agonists having high po-
tency and selectivity. Although the most potent agonist 28 is not
truly selective for the A2BAR, it is effectively a mixed A2AAR/
A2BAR agonist, with minimal ability to activate A1 and A3ARs.
Initially, we found a novel lead compound 17 in which
adenosine is substituted with a 3-indolylethyloxy functional
group at the 2-position as an A2BAR agonist having favorable
pharmacological properties. The A2BAR potency (299 nM) of
compound 17 was similar to that of 2 (140 nM). These promis-
ing findings encouraged us to optimize the A2BAR activity and
selectivity of 17 by derivatization at the indole 2-position and
by modification at the ribose 5′-position or the purine 6-position.
Generally, substitution of the 2-position of adenosine is not well
tolerated by the A2BAR; however, (S)-PHP-Ado and (S)-PHP-
NECA 4 were known to show higher A2BAR potencies
compared to 2.31 Distinct from the 2-ethynyl substituent of 4,
exploration of the SAR of a 2-(3-indolylethyloxy) substituent
could provide novel insights to molecular recognition at the A2B-
33 was tolerated at A2BAR, but the affinities against A1, A2A
,
and A3ARs were significantly reduced. 5′′-Hydroxy analogue

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1817
Figure 1. Functional effects of compound 28 on adenylate cyclase in CHO cells stably expressing the human ARs. Compound 28 was a full
agonist at the A2A and A2BARs to stimulate cAMP production. In the curves shown, the EC50 values for 2 were 21.9 (A2A) and 110 (A2B) nM, and
for 28, the EC50 values of 39.7 (A2A) and 109 (A2B) nM were obtained. The relative maximal efficacy of 28 at the A1 and A3ARs to inhibit cAMP
production was 31.8% and 20.2 ( 1.0% of the full agonist 2, respectively.
moindole-3-acetic acid, 5-methoxyindole-3-acetic acid, and other
reagents and solvents were purchased from Sigma-Aldrich (St.
Louis, MO), and 5-fluoroindole-3-acetic acid was purchased from
Wako Chemicals U.S.A., Inc. (Richmond, VA). Compound 69 was
prepared as reported.34
1H NMR spectra were obtained with a Varian Gemini 300
spectrometer using CDCl3 and CD3OD as solvents. Chemical shifts
are expressed in δ values (ppm) with tetramethylsilane (δ 0.00)
for CDCl3 and (δ 3.30) for CD3OD.
AR. We can speculate that the lack of an additive effect on
A2B potency of combining the 3-(indolyl)ethyloxy- and 5′-N-
ethyluronamido fragments (i.e., 40 in comparison to 2 and 17)
may be due to an unfavorable change in the conformation or
position of the ribose ring inside the ligand binding site.
First, we focused on the simplification, altered connectivity,
and mimicking of the indole ring of 17, as shown in the case
of compounds 19, 8, 20, 35, and 36. Unfortunately, these
approaches failed to maintain the A2BAR potency. Next, we
tried to transform the 4′-hydroxymethyl moiety to an ethylcar-
boxamide, which was expected to favorably increase A2BAR
potency. However, the 5′-N-ethyluronamide analogue 40 showed
only a 2-fold increased potency at the A3AR compared to 17.
In this respect, 40 has quite different pharmacological charac-
teristics from (S)-PHP-NECA 4. Also, the 6′ modification of
17, as shown in the case of compound 37 and 39, did not
improve potency at the A2BAR. Finally, we focused on
functionalization of the indole moiety. Even minor modifications
were examined because of the lack of a prior pharmacological
precedent for the indole ring moiety at this position.
Eventually, through probing a relatively restrictive SAR, we
achieved the new A2B agonist 28 that gained an advantage over
the parent compounds 17 and 2 for the A2BAR in both potency
and selectivity. In addition, compound 28 produced quite a
different selectivity from (S)-PHP-NECA 4 and 6-guanidino-
NECA 3. Compound 4 showed a high potency/affinity at each
AR (Table 1).31 Compound 3 displayed a selectivity at A1 and
A3ARs.32 Compound 28 showed the improved selectivity
compared to compounds 2-4, providing a novel type of potent
A2BAR agonist. Molecular modeling results with 28 docked in
the human A2BAR demonstrated that, in addition to all interac-
tions proposed for adenosine,38 the 2-(6-bromoindol-3-yl)-
ethyloxy fragment can provide additional favorable interactions
of the ligand with a distal region of the putative agonist binding
site of the receptor.
The purity of the nucleosides submitted for biological testing
was checked using a Hewlett-Packard 1100 HPLC equipped with
a Luna 5µ RP-C18(2) analytical column (250 × 4.6 mm; Agilent
Technologies, Santa Clara, CA). System A: linear gradient solvent
system, CH3CN/H2O from 20/80 to 40/60 in 20 min; the flow rate
was 1 mL/min. System B: linear gradient solvent system, CH3-
CN/H2O from 20/80 to 60/40 in 20 min; the flow rate was 1 mL/
min. System C: linear gradient solvent system, CH3CN/5 mM
TBAP from 20/80 to 60/40 in 20 min; the flow rate was 1 mL/
min. System D: linear gradient solvent system, CH3CN/5 mM
TBAP from 5/95 to 80/20 in 20 min; the flow rate was 1 mL/min.
Peaks were detected by UV absorption with a diode array detector.
All derivatives tested for biological activity showed >98% purity
in the HPLC systems.
TLC analysis was carried out on glass precoated with silica gel
F254 (0.25 mm) from Aldrich. Low-resolution mass spectrometry
was performed with a JEOL SX102 spectrometer with 6-kV Xe
atoms following desorption from a glycerol matrix or on an Agilent
LC/MS 1100 MSD with a Waters (Milford, MA) Atlantis C18
column. High-resolution mass spectroscopic (HRMS) measurements
were performed on a proteomics optimized Q-TOF-2 (Micromass-
Waters) using external calibration using polyalanine. Observed mass
accuracies are those expected based on known performance of the
instrument as well as trends in masses of standard compounds
observed at intervals during the series of measurements. Reported
masses are observed masses uncorrected for this time-dependent
drift in mass accuracy.
General Tosylation Procedure for the Synthesis of 3-Iodo-
ethylindole Derivative 44-46, 56-58, 71-73, and 84. To a
solution of the alcohol in THF (tetrahydrofuran) was added sodium
hydride (60%, 3 equiv) at 0 °C, and the reaction mixture was stirred
at 0 °C for 1 h. To the suspension was added tosyl chloride (3
equiv) at 0 °C, and the reaction mixture was stirred at room
Experimental Procedures
Chemical Synthesis. Materials and Instrumentation. 2-Amino-
6-chloropurine-9-riboside, tryptophol, 1-iodo-3-phenylpropane, 5-bro-

1818 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
J ) 9.1 Hz), 7.71 (2H, d with small coupling, J ) 8.5 Hz), 7.53
(2H, d with small coupling, J ) 8.2 Hz), 7.27 (1H, s), 7.21 (2H,
dd, J ) 0.6 and 8.8 Hz), 7.15 (2H, dd, J ) 0.6 and 8.5 Hz), 6.89
(1H, dd, J ) 2.5 and 9.1 Hz), 6.71 (1H, d, J ) 2.2 Hz), 4.23 (2H,
t, J ) 6.6 Hz), 3.77 (3H, s), 2.97 (2H, dt, J ) 0.8 and 6.6 Hz),
2.39 (3H, s), 2.32 (3H, s); HRMS (ESI-MS m/z) calcd for C25H26-
NO6S2, 500.1202 (M+H)+; found, 500.1207.
1-(p-Toluenesulfonyl)-3-(p-toluenesulfonyloxyethyl)-5-(p-tolu-
1
enesulfonyloxy)indole (46). The yield was 57%: H NMR (CDCl3)
δ 7.80 (1H, d, J ) 9.1 Hz), 7.71 (2H, d with small coupling, J )
8.5 Hz), 7.82 (2H, d with small coupling, J ) 8.5 Hz), 7.58 (2H,
d, with small coupling, J ) 8.2 Hz), 7.36 (1H, s), 7.31 (2H, dd, J
) 0.6 and 8.5 Hz), 7.25 (2H, d, J ) 8.4 Hz), 7.19 (2H, d, J ) 8.2
Hz), 6.97 (1H, d, J ) 2.2 Hz), 6.84 (1H, dd, J ) 2.3 and 8.9 Hz),
4.18 (2H, t, J ) 6.5 Hz), 2.90 (2H, t, J ) 6.5 Hz), 2.46 (3H, s),
2.40 (3H, s), 2.35 (3H, s); HRMS (ESI-MS m/z) calcd for C31H30-
NO8S3 (M+H)+, 640.1134; found, 640.1099.
3-Iodoethyl-1-(p-toluenesufonyl)indole (47). The yield was
70%: 1H NMR (CDCl3) δ 7.98 (1H, d with small coupling, J )
8.2 Hz), 7.76 (2H, dt, J ) 1.9 and 8.5 Hz), 7.45 (2H, m), 7.32
(1H, ddd, J ) 1.3, 7.1, and 8.4 Hz), 7.23 - 7.28 (2H, m), 7.20
(2H, d with small coupling, J ) 8.0 Hz), 3.41 (2H, t with small
coupling, J ) 7.1 Hz), 3.24 (2H, t with small coupling, J ) 7.3
Hz), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for C17H17NO2SI
(M + H)+, 426.0025; found, 426.0016.
3-Iodoethyl-5-methoxy-1-(p-toluenesulfonyl)indole (48). The
yield was 74%: 1H NMR (CDCl3) δ 7.74 (1H, d with small
coupling, J ) 9.1 Hz), 7.73 (2H, d with small coupling, J ) 8.2
Hz), 7.40 (1H, s), 7.20 (2H, dd, J ) 0.7 and 8.7 Hz), 6.92 (1H, dd,
J ) 2.5 and 9.2 Hz), 6.85 (1H, d, J ) 2.5 Hz), 3.82 (3H, s), 3.40
(2H, dt, J ) 0.7 and 7.6 Hz), 3.20 (2H, t, J ) 7.3 Hz), 2.33 (3H,
s); HRMS (ESI-MS m/z) calcd for C18H19NO3SI (M + H)+,
456.0130; found, 456.0135.
3-Iodoethyl-1-(p-toluenesulfonyl)-5-(p-toluenesulfonyloxy)in-
dole (49). The yield was 83%: 1H NMR (CDCl3) δ 7.85 (1H, d,
J ) 9.1 Hz), 7.73 (2H, d with small coupling, J ) 8.5 Hz), 7.68
(2H, d with small coupling, J ) 8.2 Hz), 7.47 (1H, s), 7.30 (2H, d,
J ) 8.3 Hz), 7.23 (2H, d, J ) 8.3 Hz), 7.02 (1H, d, J ) 2.5 Hz),
6.91 (1H, dd, J ) 2.3 and 8.9 Hz), 3.26 (2H, t with small coupling,
J ) 7.4 Hz), 3.12 (2H, t with small coupling, J ) 7.1 Hz), 2.46
(3H, s), 2.36 (3H, s); APCI-MS (m/z) 596.0 (M + H)+.
General Procedure for the Synthesis of 3-Hydroxyethylindole
Derivatives 53-55. Esterification and Reduction: To a solution
of a 2- and/or 5-substituted-indole-3-acetic acid in methanol was
added p-toluenesulfonic acid monohydrate (3 equiv), and the
reaction mixture was stirred at 60 °C overnight. After neutralization
with 1 N aqueous NaOH, the solvent was evaporated leaving an
oily residue, which was dissolved in ethyl acetate. The solution
was washed with water, dried over MgSO4, and filtered. The filtrate
was evaporated leaving an oily residue, which was subjected to
column flush chromatography on silica gel. Elution with a mixture
of toluene and acetone (5:1) gave the corresponding ester.
To a solution of the ester in THF was added lithium aluminum
hydride (2.8 equiv) at 0 °C, and the reaction mixture was stirred at
0 °C for 1 h and at room temperature for 1 h. After addition of
ethyl acetate, the reaction mixture was stirred at room temperature
for 30 min. The reaction mixture was diluted with ethyl acetate
and washed with water, dried over MgSO4, and filtered. The filtrate
was evaporated, leaving an oily residue that was subjected to
column chromatography on silica gel. Elution with a mixture of
toluene and acetone (3:1) gave the pure alcohol.
Figure 2. Docking model of compound 28 in the binding site of the
human A2BAR, showing residues in proximity (A) and the Van der
Waals surface of the receptor (B).
temperature overnight. The reaction mixture was diluted with ethyl
acetate and washed with water, dried over MgSO4, and filtered.
The filtrate was evaporated to give a crude oil, which was subjected
to column chromatography on silica gel. Elution with a mixture of
toluene and acetone (40:1) gave the tosylated derivative.
General Iodination Procedure for the Synthesis of Com-
pounds 47-49, 59-61, 74-77, and 85. A solution of the tosylate
and sodium iodide (3.5 equiv) in N,N-dimethylformamide was
stirred overnight at 60 °C. The reaction mixture was diluted with
ethyl acetate and washed with water, dried over MgSO4, and filtered.
The filtrate was evaporated to give a crude oil, which was subjected
to column chromatography on silica gel. Elution with a mixture of
hexanes and ethyl acetate (4:1) gave the iodide.
5-Fluoro-tryptophol (53). Compound 53 was identical to the
known compound reported by Mewshaw et al.40
3-(p-Toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)indole (44).
The yield was 62%: 1H NMR (CDCl3) δ 7.93 (1H, d with small
coupling, J ) 8.0 Hz), 7.74 (2H, d, J ) 8.2 Hz), 7.56 (2H, d, J )
8.5 Hz), 7.12-7.34 (7H, m), 4.24 (2H, t, J ) 6.6 Hz), 3.01 (2H, t,
J ) 6.6 Hz), 2.38 (3H, s), 2.32 (3H, s); HRMS (ESI-MS m/z) calcd
for C24H23NO5S2Na (M+Na)+, 492.0915; found, 492.0914.
5-Methoxy-3-(p-toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)-
indole (45). The yield was 56%: 1H NMR (CDCl3) δ 7.82 (1H, d,
5-Bromo-tryptophol (54). Compound 54 was identical to the
commercially available compound.
3-Hydroxyethyl-5-methoxy-2-methylindole (55). The yield was
81%: 1H NMR (CDCl3) δ 7.27 (1H, br s), 7.16 (1H, d, J ) 8.8
Hz), 6.97 (1H, d, J ) 2.2 Hz), 6.78 (1H, dd, J ) 2.5 and 8.5 Hz),
3.78-3.88 (2H, m overlapped with OCH3), 3.85 (3H, s), 2.94 (2H,
t, J ) 6.5 Hz), 2.39 (3H, s); HRMS (ESI-MS m/z) calcd for C12H16-
NO2, 206.1181; found, 206.1190.

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1819
5-Fluoro-1-(p-toluenesulfonyl)-3-(p-toluenesulfonyloxyethyl)-
indole (56). The yield was 58%: 1H NMR (CDCl3) δ 7.87 (1H,
dd, J ) 4.1 and 9.1 Hz), 7.72 (2H, d with small couplings, J ) 8.5
Hz), 7.55 (2H, d with small coupling, J ) 8.2 Hz), 7.36 (1H, S),
7.24 (2H, d with small coupling, J ) 8.0 Hz), 7.16 (2H, dd, J )
0.7 and 8.7 Hz), 7.00 (1H, dt, J ) 2.4 and 9.0 Hz), 6.89 (1H, dd,
J ) 2.2 and 8.5 Hz), 4.22 (2H, t, J ) 6.5 Hz), 2.95 (2H, t, J ) 6.5
Hz), 2.39 (3H, s), 2.34 (3H, s); HRMS (ESI-MS m/z) calcd for
C24H23NO5S2F (M + H)+, 488.1002; found, 488.0995.
5-Bromo-3-(p-toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)-
indole (57). The yield was 63%: 1H NMR (CDCl3) δ 7.80 (1H, d
with small coupling, J ) 9.6 Hz), 7.73 (2H, d with small coupling,
J ) 8.2 Hz), 7.52 (2H, d with small coupling, J ) 8.5 Hz), 7.32-
7.39 (3H, m), 7.25 (2H, d, J ) 8.0 Hz), 7.13 (2H, d, J ) 8.0 Hz),
4.23 (2H, t, J ) 6.3 Hz), 2.95 (2H, dt, J ) 0.8 and 6.5 Hz), 2.39
(3H, s), 2.34 (3H, s); HRMS (ESI-MS m/z) calcd for C24H22NO5S2-
BrLi (M + Li)+, 554.0283; found, 554.0292.
J ) 6.3 Hz), 2.97 (2H, t, J ) 6.3 Hz), 2.40 (3H, s), 2.35 (3H, s);
APCI-MS (m/z) 504.1 (M + H)+.
6-Bromo-3-(p-toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)-
indole (72). The yield was 30%: 1H NMR (CDCl3) δ 8.10 (1H, d,
J ) 1.4 Hz), 7.74 (2H, d with small coupling, J ) 8.2 Hz), 7.51
(2H, d with small coupling, J ) 8.2 Hz), 7.23-7.30 (5H, m), 7.13
(2H, dd, J ) 1.7 and 8.2 Hz), 4.23 (2H, t, J ) 6.3 Hz), 2.97 (2H,
t, J ) 6.3 Hz), 2.40 (3H, s), 2.35 (3H, s); APCI-MS (m/z) found
548.0 (M + H)+.
5-Chloro-3-(p-toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)-
indole (73). The yield was 30%: 1H NMR (CDCl3) δ 7.85 (1H,
dd, J ) 0.6 and 8.8 Hz), 7.73 (2H, dt, J ) 2.1 and 8.7 Hz), 7.53
(2H, dt, J ) 1.8 and 8.5 Hz), 7.36 (1H, s), 7.21-7.26 (3H, m),
7.19 (1H, dd, J ) 0.6 and 1.9 Hz), 7.14 (2H, dd, J ) 0.5 and 8.5
Hz), 4.23 (2H, t, J ) 6.5 Hz), 2.95 (2H, dt, J ) 0.8 and 6.5 Hz),
2.39 (3H, s), 2.34 (3H, s); HRMS (ESI-MS m/z) calcd for C24H22-
NO5NaS2Cl (M + Na)+, 526.0526; found, 526.0535.
6-Chloro-3-iodoethyl-1-(p-toluenesulfonyl)indole (74). The
yield was 67%: 1H NMR (CDCl3) δ 8.00 (1H, d, J ) 1.7 Hz),
7.76 (2H, d with small coupling, J ) 8.5 Hz), 7.43 (1H, s), 7.36
(1H, d, J ) 8.5 Hz), 7.25∼7.28 (2H overlapped with CHCl3), 7.22
(1H, dd, J ) 1.8 and 8.4 Hz), 3.39 (2H, t with small coupling, J )
7.3 Hz), 3.21 (2H, t, J with small coupling, J ) 7.3 Hz), 2.38 (3H,
s); APCI-MS (m/z) 460.0 (M + H)+.
5-Methoxy-2-methyl-3-(p-toluenesulfonyloxyethyl)-1-(p-tolu-
enesulfonyl)indole (58). The yield was 30%: 1H NMR (CDCl3) δ
8.02 (1H, d, J ) 9.1 Hz), 7.58 (2H, d with small coupling, J ) 8.2
Hz), 7.48 (2H, d with small coupling, J ) 8.2 Hz), 7.18 (2H, dd,
J ) 0.7 and 8.7 Hz), 7.13 (2H, dd, J ) 0.6 and 8.5 Hz), 6.84 (1H,
dd, J ) 2.8 and 9.1 Hz), 6.64 (1H, d, J ) 2.5 Hz), 4.11 (2H, t, J
) 6.7 Hz), 3.79 (3H, s), 2.90 (2H, t, J ) 6.7 Hz), 2.43 (3H, s),
2.39 (3H, s), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for C26H27-
NO6S2Na (M + Na)+, 536.1178; found, 536.1186.
3-Iodoethyl-5-fluoro-1-(p-toluenesulfonyl)indole (59). Yield
70%: 1H NMR (CDCl3) δ 7.92 (1H, ddd, J ) 0.6, 4.3 and 9.1
Hz), 7.74 (2H, dt, J ) 1.9 and 8.5 Hz), 7.48 (1H, s), 7.22 (2H, d,
J ) 8.0 Hz), 7.09 (1H, dd, J ) 2.5 and 8.5 Hz), 7.04 (1H, dt, J )
2.5 and 9.1 Hz), 3.39 (2H, dt, J ) 0.7 and 6.8 Hz), 3.19 (2H, t, J
) 7.3 Hz), 2.35 (3H, s); HRMS (ESI-MS m/z) calcd for C17H15-
NO2FS (M - I)+, 316.0808; found, 316.0810.
5-Bromo-3-Iodoethyl-1-(p-toluenesufonyl)indole (60). The yield
was 65%: 1H NMR (CDCl3) δ 7.85 (1H, d, J ) 8.8 Hz), 7.74
(2H, d with small coupling, J ) 8.2 Hz), 7.57 (1H, d, J ) 1.9 Hz),
7.45 (1H, s), 7.41 (1H, dd, J ) 1.9 and 8.8 Hz), 7.22 (2H, d, J )
8.2 Hz), 3.88 (2H, t, J ) 7.0 Hz), 3.19 (2H, t, J ) 7.3 Hz), 2.35
(3H, s); HRMS (ESI-MS m/z) calcd for C17H15NO2SBrI (M + H)+,
502.9025; found, 502.9036.
3-Iodoethyl-5-methoxy-2-methyl-1-(p-toluenesufonyl)indole (61).
The yield was 85%: 1H NMR (CDCl3) δ 8.07 (1H, d, J ) 9.1
Hz), 7.58 (2H, dt, J ) 1.8 and 8.5 Hz), 7.17 (2H, d, J ) 8.2 Hz),
6.87 (1H, dd, J ) 2.5 and 9.1 Hz), 6.79 (1H, d, J ) 2.5 Hz), 3.84
(3H, s), 3.26 (2H, m), 3.14 (2H, m), 2.52 (3H, s), 2.33 (3H, s);
HRMS (ESI-MS m/z) calcd for C19H21NO3IS (M + H)+, 470.0287;
found, 470.0294.
General Synthetic Procedure for 3-Hydroxyethylindole De-
rivatives 67-70 via Fischer Indole Ring Preparation. A solution
of substituted phenylhydrazine hydrochloride and ethoxytetrahy-
drofuran (1.5 equiv) in 95% ethanol was refluxed overnight. The
reaction mixture was filtered through celite. The filtrate was
evaporated to give a crude solid. The solid was dissolved in ethyl
acetate, and the solution was washed with water, dried over MgSO4,
and filtered. The filtrate was evaporated to give a crude oil, which
was subjected to column chromatography on silica gel. Elution with
a mixture of toluene and acetone (2:1) gave the alcohol.
6-Chloro-tryptophol (67),41 6-Bromo-tryptophol (68),42 and
5-Chloro-tryptophol (69).34 Compounds 67-69 are identical to
the known compounds.
5-Iodo-tryptophol (70). The yield was 32%: 1H NMR (CDCl3)
δ 8.07 (1H, br s), 7.95 (1H, m), 7.45 (1H, dd, J ) 1.7 and 8.5 Hz),
7.16 (1H, d, J ) 8.5 Hz), 7.06 (1H, d, J ) 2.2 Hz), 3.89 (2H, br
s), 2.98 (2H, dt, J ) 0.8 and 6.3 Hz), 1.45 (1H, br s); APCI-MS
(m/z) 288.0 (M + H)+.
6-Bromo-3-iodoethyl-1-(p-toluenesulfonyl)indole (75). The
yield was 67%: 1H NMR (CDCl3) δ 8.16 (1H, d, J ) 1.7 Hz),
7.76 (2H, dd, J ) 1.9 and 8.5 Hz), 7.42 (1H, br s), 7.36 (1H, dd,
J ) 1.7 and 8.5 Hz), 7.30 (1H, d, J ) 8.2 Hz), 7.25 (2H, d, J )
8.5 Hz), 3.38 (2H, t with small coupling, J ) 7.4 Hz), 3.21 (2H, t
with small coupling, J ) 7.3 Hz), 2.36 (3H, s); HRMS (ESI-MS
m/z) calcd for C17H15BrINO2S (M)+, 502.9052; found, 502.9066.
5-Chloro-3-iodoethyl-1-(p-toluenesulfonyl)indole (76). The
yield was 60%: 1H NMR (CDCl3) δ 7.90 (1H, dd, J ) 0.6 and 8.8
Hz), 7.74 (2H, d with small coupling, J ) 8.2 Hz), 7.47 (1H, s),
7.41 (1H, dd, J ) 0.6 and 1.9 Hz), 7.24-7.29 (1H overlaped with
CHCl3), 7.22 (2H, d, J ) 8.3 Hz), 3.39 (2H, dt, J ) 0.8 and 7.3
Hz), 3.20 (2H, t, J ) 7.3 Hz), 2.35 (3H, s); HRMS (ESI-MS m/z)
calcd for C17H16NO2IClS (M + H)+, 459.9635; found, 459.9625.
5-Iodo-3-iodoethyl-1-(p-toluenesulfonyl)indole (77). The yield
was 68%: 1H NMR (CDCl3) δ 7.77 (1H, d, J ) 1.6 Hz), 7.74
(1H, d, J ) 8.8 Hz), 7.73 (2H, d with small coupling, J ) 8.5 Hz),
7.58 (1H, dd, J ) 1.7 and 8.5 Hz), 7.41 (1H, s), 7.22 (2H, d, J )
8.2 Hz), 3.83 (2H, t, J ) 7.2 Hz), 3.19 (2H, t, J ) 7.3 Hz), 2.35
(3H, s); APCI-MS (m/z) 551.9 (M + H)+.
Ethyl 4-Bromo-3-indolylglyoxylate (80). To a solution of 78
(2.94 g, 15.0 mmol) in diethyl ether (60 mL) was added oxalyl
chloride (3.01 mL, 34.5 mmol) at 0 °C, and the reaction mixture
was stirred at room temperature for 10 h. After evaporation, ethanol
(30 mL) was added to the solids, and the solution was stirred at
room temperarure overnight. The solvent was evaporated to give a
solid. This residue was dissolved in ethyl acetate, washed with
water, dried over MgSO4, and filtered. The filtrate was evaporated
to give a crude solid, which was subjected to column chromatog-
raphy on silica gel. Elution with a mixture of hexanes and ethyl
acetate (1:1) gave 80 (2.3 g, 52%). 1H NMR (CDCl3) δ 9.55 (1H,
br s), 8.24 (1H, d, J ) 3.3 Hz), 7.50 (1H, dd, J ) 0.8 and 7.7 Hz),
7.42 (1H, dd, J ) 0.8 and 8.3 Hz), 7.13 (1H, t, J ) 8.0 Hz), 4.41
(2H, q, J ) 7.1 Hz), 1.40 (3H, t, J ) 7.1 Hz); APCI-MS (m/z)
296.0 (M + H)+.
Ethyl 7-Bromo-3-indolylglyoxylate (81). Compound 81 was
obtained from 79 by the similar procedure for the preparation of
1
80 (yield 70%). H NMR (CDCl3) δ 8.96 (1H, br s), 8.55 (1H, d,
J ) 3.3 Hz), 8.39 (1H, dd, J ) 0.6 and 8.0 Hz), 7.48 (1H, dd, J )
0.8 and 8.0 Hz), 7.23 (1H, t, J ) 7.8 Hz), 4.43 (2H, q, J ) 7.1
Hz), 1.44 (3H, t, J ) 7.1 Hz); APCI-MS (m/z) 296.0 (M + H)+.
4-Bromo-tryptophol (82). To a solution of 80 (20 mg, 0.0675
mmol) in THF (1.4 mL) was added lithium aluminum hydride (17.4
mg, 0.459 mmol), and the reaction mixture was refluxed for 2 h.
The mixture was diluted with ethyl acetate and washed with water,
dried over MgSO4, and filtered. The filtrate was evaporated to give
a crude oil, which was subjected to preparative TLC developed
6-Chloro-3-(p-toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)-
indole (71). Yield 32%: 1H NMR (CDCl3) δ 7.94 (1H, d, J ) 1.7
Hz), 7.74 (2H, d with small coupling, J ) 8.5 Hz), 7.51 (2H, d
with small coupling, J ) 8.2 Hz), 7.29 (2H, d, J ) 8.5 Hz), 7.25
(1H, s), 7.19 (1H, d, J ) 8.2 Hz), 7.10-7.16 (3H, m), 4.27 (2H, t,

1820 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
with a mixture of hexanes and ethyl acetate (1:1) to give 82 (10
mg, 63% yield). 1H NMR (CDCl3) δ 8.12 (1H, br s), 7.32 (1H, dd,
J ) 0.8 and 7.7 Hz), 7.28 (1H, dd, J ) 0.8 and 7.7 Hz), 7.14 (1H,
d, J ) 2.5 Hz), 7.02 (1H, t, J ) 7.8 Hz), 3.97 (2H, q, J ) 6.1 Hz),
3.29 (2H, dt, J ) 0.6 and 6.5 Hz), 1.46 (1H, t, J ) 5.6 Hz); HRMS
(ESI-MS m/z) calcd for C10H11BrNO (M + H)+, 240.0024; found,
240.0028.
7-Bromo-tryptophol (83). Compound 83 was obtained from 81
by the similar procedure for the preparation of 82 (yield 52%). 1H
NMR (CDCl3) δ 8.82 (1H, br s), 7.57 (1H, d, J ) 8.0 Hz), 7.36
(1H, d, J ) 8.0 Hz), 7.16 (1H, d, J ) 2.2 Hz), 7.02 (1H, t, J ) 7.8
Hz), 3.91 (2H, q, J ) 6.2 Hz), 3.02 (2H, dt, J ) 0.5 and 6.3 Hz),
1.46 (1H, t, J ) 6.0 Hz); HRMS (ESI-MS m/z) calcd for C10H11-
NOBr (M + H)+, 240.0024; found, 240.0031.
4-Bromo-3-(p-toluenesulfonyloxyethyl)-1-(p-toluenesulfonyl)-
indole (84). The yield was 41%: 1H NMR (CDCl3) δ 7.91 (1H,
dd, J ) 0.8 and 8.2 Hz), 7.75 (2H, d with small coupling, J ) 8.5
Hz), 7.55 (2H, d with small coupling, J ) 8.2 Hz), 7.41 (1H, s),
7.28 (1H, dd, J ) 1.0 and 7.8 Hz), 7.25 (2H, d, J ) 8.2 Hz), 7.11
(2H, d, J ) 8.0 Hz), 7.09 (1H, t, J ) 8.0 Hz), 4.32 (2H, t, J ) 6.5
Hz), 3.25 (2H, t, J ) 6.3 Hz), 2.34 (6H, s); APCI-MS (m/z) 548.0
(M + H)+.
4-Bromo-3-iodoethyl-1-(p-toluenesulfonyl)-indole (85). The
yield was 67%: 1H NMR (CDCl3) δ 7.96 (1H, dd, J ) 0.8 and 8.2
Hz), 7.76 (2H, d with small coupling, J ) 8.5 Hz), 7.52 (1H, s),
7.38 (1H, dd, J ) 0.8 and 8.0 Hz), 7.23 (2H, dd, J ) 0.6 and 8.5
Hz), 7.13 (1H, t, J ) 8.1 Hz), 3.45 (4H, s), 2.35 (3H, s); HRMS
(ESI-MS m/z) calcd for C17H16NO2IBrS (M + H)+, 509.9130;
found, 509.9114.
d with small coupling, J ) 8.0 Hz), 6.50 (1H, s), 3.46-3.60 (4H,
m), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for C17H17NO2IS (M
+ H)+, 426.0025; found, 426.0035.
Benzoimidazol-1-yl-ethanol (92). To a solution of benzoimi-
dazol-1-yl-acetic acid (893 mg, 5.06 mmol) in THF (20 mL) was
added lithium aluminum hydride (672 mg, 17.7 mmol) at 0 °C,
and the reaction mixture was stirred at room temperature for 5 h.
After dilution with ethyl acetate, the solution was washed with
water, dried over MgSO4, and filtered. The filtrate was evaporated
to give a crude oil, which was subjected to column chromatography
on silica gel. Elution was with a mixture of chloroform and
1
methanol (8:1) to give 92 (620 mg, 76%). H NMR (CDCl3) δ
7.63 (1H, s), 7.38 (1H, dt, J ) 1.0 and 8.2 Hz), 7.31 (1H, dt, J )
1.0 and 8.0 Hz), 7.17 (1H, ddd, J ) 1.0, 7.1, and 8.1 Hz), 7.06
(1H, ddd, J ) 1.1, 7.1, and 8.1 Hz), 4.22 (2H, t, J ) 4.9 Hz), 3.99
(2H, t, J ) 4.8 Hz); HRMS (ESI-MS m/z) calcd for C9H11N2O (M
+ H)+, 163.0871; found, 163.0880.
Benzotriazol-1-yl-ethanol (93). The procedure used for the
preparation of 93 from 91 was similar to those used for the
preparation of 92 from 90; amorphous solid, the yield was 59%.
1H NMR (CDCl3) δ (1H, d with small coupling, J ) 8.5 Hz), 7.61
(1H, d with small coupling, J ) 8.2 Hz), 7.50 (1H, ddd, J ) 1.1,
7.0 and 8.1 Hz), 7.36 (1H, ddd, J ) 1.2, 6.9 and 8.1 Hz), 4.75
(2H, t, J ) 5.1 Hz), 4.25 (2H, dd, J ) 5.9 and 10.3 Hz), 2.55 (1H,
t, J ) 6.0 Hz); HRMS (ESI-MS m/z) calcd for C8H10N3O (M +
H)+, 164.0824; found, 164.0812.
Benzoimidazol-1-yl-ethyliodide (94). To a solution of 92 (22
mg, 0.134 mmol) in a mixture of acetonitrile (0.3 mL) and
diethylether (0.9 mL) were added triphenylphosphine (105 mg,
0.402 mmol), imidazole (29 mg, 0.428 mmol), and iodine (108 mg,
0.428 mmol) at 0 °C, and the reaction mixture was stirred for 2 h.
The mixture was diluted with ethyl acetate, washed with water,
dried over MgSO4, and filtered. The filtrate was evaporated to give
a crude oil, which was subjected to preparative TLC developed
with a mixture of toluene and acetone (2:1) to give 94 (32.3 mg,
88%). 1H NMR (CDCl3) δ 7.97 (1H, s), 7.80-7.87 (1H, m), 7.28-
7.42 (3H, m), 4.58 (2H, t, J ) 7.0 Hz), 3.51 (2H, t, J ) 7.1 Hz);
APCI-MS (m/z) 273.0 (M + H)+.
Benzotriazol-1-yl-ethyliodide (95). The procedure used for the
preparation of 95 from 93 was similar to those used for the
preparation of 94 from 92; amorphous solid, the yield was 88%.
1H NMR (CDCl3) δ 8.09 (1H, dt, J ) 1.0 and 8.3 Hz), 7.50 -
7.60 (2H, m), 7.40 (1H, ddd, J ) 1.8, 6.3, and 8.1 Hz), 5.02 (2H,
t, J ) 7.3 Hz), 3.67 (2H, t, J ) 7.3 Hz); HRMS (ESI- MS m/z)
calcd for C8H9N3I (M + H)+, 273.9841; found, 273.9833.
3-Hydroxyethyl-1-(p-toluenesulfonyl)pyrrole (98). To a solu-
tion of 97 (1.24 g, 4.21 mmol) in THF (20 mL) was added lithium
aluminum hydride (340 mg, 6.32 mmol) at 0 °C. The reaction mix-
ture was stirred for 2 h. After addition of ethyl acetate, the mixture
was stirred for 30 min. The mixture was diluted with ethyl acetate,
washed with water, dried over MgSO4, and filtered. The filtrate
was evaporated to give a crude oil, which was subjected to column
chromatography on silica gel. Elution with a mixture of chloroform
and methanol (20:1) gave 98 (692 mg, 62%). 1H NMR δ 7.74 (2H,
d, J ) 8.4 Hz), 7.28 (2H, d, J ) 8.7 Hz), 7.10 (1H, t, J ) 2.7 Hz),
6.99 (1H, m), 6.19 (1H, dd, J ) 1.5 and 3.3 Hz), 3.74 (2H, t, J )
6.5 Hz), 2.64 (2H, t, J ) 6.5 Hz), 2.40 (3H, s); HRMS (ESI-MS
m/z) calcd for C13H16NO3S (M + H)+, 266.0851; found, 266.0837.
3-Iodoethyl-1-(p-toluenesulfonyl)pyrrole (99). The procedure
used for the preparation of 99 from 98 is similar to those used for
the preparation of 89 from 88; the yield was 62%. 1H NMR (CDCl3)
δ 7.73 (2H, d, J ) 8.2 Hz), 7.29 (2H, d, J ) 8.5 Hz), 7.08 (1H, t,
J ) 2.8 Hz), 6.99 (1H, m), 6.16 (1H, dd, J ) 1.6 and 3.3 Hz), 3.24
(2H, t, J ) 7.3 Hz), 2.96 (2H, t, J ) 7.6 Hz), 2.40 (3H, s); HRMS
(ESI-MS m/z) calcd for C13H15NO2SI (M + H)+, 375.9868; found,
375.9857.
7-Bromo-3-iodoethylindole (86). The yield was 88%: 1H NMR
(CDCl3) δ 8.21 (1H, br s), 7.52 (1H, dd, J ) 0.8 and 8.0 Hz), 7.36
(1H, d, J ) 7.7 Hz), 7.16 (1H, d, J ) 2.2 Hz), 7.02 (1H, t, J ) 7.7
Hz), 3.39-3.46 (2H, m), 3.29-3.37 (2H, m); HRMS (ESI-MS m/z)
calcd for C10H10NBrI (M + H)+, 349.9041; found, 349.9036.
2-Hydroxyethyl-1-(p-toluenesulfonyl)-indole (88). To a solution
of 2-iodoaniline (1.0616 g, 4.84 mmol) in dichloromethane (20 mL)
were added pyridine (1.17 mL, 14.5 mmol) and tosyl chloride (1.10
g, 5.81 mmol), and the reaction mixture was stirred overnight. The
mixture was diluted with chloroform, washed with water, dried over
MgSO4 and filtered. The filtrate was evaporated to give crude solids
which were subjected to column chromatography on silica gel.
Elution with a mixture of hexane and ethyl acetate (5:1) gave
N-tosyl-2-iodoaniline (1.40 g, 77%). To a solution of N-tosyl-2-
iodoanilide (1.172 g, 3.14 mmol) in DMF were added 3-butyn-1-
ol (1.42 mL, 18.8 mmol), copper iodide (119 mg, 0.628 mmol),
triethyl amine (13.56 mL, 97.3 mmol), and Pd(PPh3)2Cl2 (220.3
mg, 0.314 mmol), and the reaction mixture was stirred at 70 °C
overnight. The reaction mixture was diluted with ethyl acetate. The
solution was washed with water, dried over MgSO4, and filtered.
The filtrate was evaporated to give an oil, which was subjected to
column chromatography on silica gel. Elution with a mixture of
hexanes and ethyl acetate (1:1) gave 88 (820 mg, 83%). 1H NMR
(CDCl3) δ 8.16 (1H, d, J ) 8.2 Hz), 7.61 (2H, d with small
coupling, J ) 8.2 Hz), 7.42 (1H, dd, J ) 1.7 and 7.4 Hz), 7.28
(1H, dt, J ) 2.2 and 7.6 Hz), 7.23 (1H overlapped with Ph), 7.18
(2H, d, J ) 8.5 Hz), 6.50 (1H, s), 4.01 (2H, t, J ) 6.1 Hz), 3.29
(2H, t, J ) 6.2 Hz), 2.33 (3H, s); APCI-MS (m/z) 316.0 (M +
H)+.
2-Iodoethyl-1-(p-toluenesulfonyl)-indole (89). To a solution of
88 (638 mg, 2.02 mmol) in a mixture of diethylether (24 mL) and
acetnitrile (8 mL) were added triphenylphosphine (1.589 g, 6.06
mmol), imidazole (439 mg, 6.46 mmol), and iodine (1.639 g, 6.46
mmol), and the reaction mixture was stirred at 0 °C for 1 h. The
reaction mixture was diluted with ethyl acetate. The solution was
washed with water, dried over MgSO4, and filtered. The filtrate
was evaporated to give an oil, which was subjected to column
chromatography on silica gel. Elution with a mixture of hexanes
and ethyl acetate (4:1) gave 89 (847 mg, 98%). 1H NMR (CDCl3)
δ 8.14 (1H, d with small coupling, J ) 8.2 Hz), 7.60 (2H, dt, J )
2.0 and 8.6 Hz), 7.45 (1H, dd, J ) 1.0 and 6.7 Hz), 7.30 (1H, dt,
J ) 1.5 and 8.0 Hz), 7.23 (1H, dd, J ) 1.2 and 7.6 Hz), 7.18 (2H,
General Synthetic Procedure for 2-Substituted Adenosine
Derivatives. To a solution of 6-chloro-2-hydroxy-9-(2,3,5-tri-O-
acetyl-â-D-ribofuranosyl) purine in N,N-dimethylformamide were
added iodide (1.8 equiv) and Cs2CO3 (2.7 equiv) at room temper-
ature, and the reaction mixture was stirred overnight. After dilution

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1821
with ethyl acetate, the solution was washed with water twice, dried
over MgSO4, and filtered. The filtrate was evaporated to give a
crude oil that was purified by column chromatography or prepara-
tive TLC on silica gel. Elution or developing with a mixture of
toluene and acetone (4:1) gave the 2-substituted 2′,3′,5′-triacetyl-
6-chloroadenosine derivative.
A solution of 2-substituted 2′,3′,5′-triacetyl-6-chloroadenosine
derivative in saturated ammonia ethanol solution was stirred in
sealed tube overnight at 110-120 °C. The solvent was evaporated
to give an oil, which was subjected to preparative TLC developed
with a mixture of chloroform and methanol (8:1) to give the
2-substituted adenosine derivative.
2.09 (3H, s), 2.03 (3H, s); HRMS (ESI-MS m/z) calcd for
C33H32N5O10SClBr (M + H)+, 804.0742; found, 804.0752.
6-Chloro-2-(3′′-(5′′-methoxy-2′′-methyl-1′′-(p-toluenesulfonyl)-
indolyl)ethyloxy)-3′,4′,5′-triacetyladenosine (107). The yield was
72%: 1H NMR (CDCl3) δ 8.08 (1H, s), 8.07 (1H, d, J ) 9.6 Hz),
7.60 (2H, d with small coupling, J ) 8.5 Hz), 7.17 (2H, d, J ) 8.0
Hz), 6.98 (1H, d, J ) 2.5 Hz), 6.87 (1H, dd, J ) 2.8 and 9.1 Hz),
6.12 (1H, d, J ) 5.0 Hz), 5.83 (1H, t, J ) 5.2 Hz), 4.36 - 4.54
(5H, m), 4.31 (1H, dd, J ) 4.1 and 12.4 Hz), 3.86 (3H, s), 3.13
(2H, t, J ) 7.8 Hz), 2.61 (3H, s), 2.32 (3H, s), 2.13 (3H, s), 2.06
(3H, s), 2.05 (3H, s); HRMS (ESI-MS m/z) calcd for C35H37N5O11-
SCl (M + H)+, 770.1899; found, 770.1895.
6-Chloro-2-(3′′-(6′′-chloro-1′′-(p-toluenesulfonyl)indolyl)ethyl-
oxy)-3′,4′,5′-triacetyladenosine (108). The yield was 70%: 1H
NMR (CDCl3) d 8.09 (1H, s), 7.99 (1H, d, J ) 1.9 Hz), 7.76 (2H,
d with small coupling, J ) 8.5 Hz), 7.53 (1H, d, J ) 8.5 Hz), 7.52
(1H, s), 7.20-7.28 (3H, m), 6.11 (1H, d, J ) 4.7 Hz), 5.95 (1H, t,
J ) 4.9 Hz), 5.66 (1H, t, J ) 5.5 Hz), 4.68 (2H, m), 4.38-4.50
(2H, m), 4.31 (1H, dd, J ) 4.5 and 12.2 Hz), 3.20 (2H, t, J ) 6.9
Hz), 2.35 (3H, s), 2.14 (3H, s), 2.09 (3H, s), 2.06 (3H, s); APCI-
MS (m/z) 760.1 (M + H)+.
2-(3′′-(6′′-Bromo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)-6-
chloro-3′,4′,5′-triacetyladenosine (109). The yield was 45%: 1H
NMR (CDCl3) δ 8.15 (1H, d, J ) 1.6 Hz), 8.09 (1H, s), 7.76 (2H,
d with small coupling, J ) 8.2 Hz), 7.50 (1H, s), 7.49 (1H, d, J )
9.1 Hz), 7.38 (1H, dd, J ) 1.7 and 8.5 Hz), 7.25 (2H, d, J ) 8.2
Hz), 6.11 (1H, d, J ) 4.7 Hz), 5.95 (1H, t, J ) 4.9 Hz), 5.66 (1H,
t, J ) 5.5 Hz), 4.68 (2H, m), 4.18-4.50 (2H, m), 4.31 (1H, dd, J
) 4.5 and 12.5 Hz), 3.20 (2H, t, J ) 7.0 Hz), 2.35 (3H, s), 2.14
(3H, s), 2.09 (3H, s), 2.06 (3H, s); HRMS (ESI-MS m/z) calcd for
C33H32N5O10SCl Br (M + H)+, 804.0742; found, 804.0760.
6-Chloro-2-(3′′-(5′′-chloro-1′′-(p-toluenesulfonyl)indolyl)ethyl-
oxy)-3′,4′,5′-triacetyladenosine (110). The yield was 46%: 1H
NMR (CDCl3) δ 8.09 (1H, s), 7.89 (1H, d, J ) 9.1 Hz), 7.73 (2H,
d with small coupling, J ) 8.2 Hz), 7.59 (1H, d, J ) 2.2 Hz),
7.24-7.30 (2H, m), 7.22 (2H, d, J ) 8.0 Hz), 6.12 (1H, d, J ) 4.4
Hz), 5.94 (1H, t, J ) 5.1 Hz), 5.67 (1H, t, J ) 5.4 Hz), 4.69 (2H,
m), 4.40-4.49 (2H, m), 4.31 (1H, dd, J ) 4.9 and 13.2 Hz), 3.18
(2H, t, J ) 6.7 Hz), 2.33 (3H, s), 2.15 (3H, s), 2.09 (3H, s), 2.04
(3H, s); HRMS (ESI-MS m/z) calcd for C33H31N5O10SCl2Na (M +
Na)+, 782.1066; found, 782.1071.
6-Chloro-2-(3′′-(5′′-iodo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)-
3′,4′,5′-triacetyladenosine (111). The yield was 45%: 1H NMR
(CDCl3) δ 8.09 (1H, s), 7.93 (1H, d, J ) 1.7 Hz), 7.73 (3H, m),
7.57 (1H, dd, J ) 1.8 and 8.7 Hz), 7.50 (1H, s), 7.22 (2H, d, J )
8.0 Hz), 6.13 (1H, d, J ) 4.7 Hz), 5.94 (1H, t, J ) 5.1 Hz), 5.67
(1H, t, J ) 5.4 Hz), 4.68 (2H, t, J ) 7.0 Hz), 4.40-4.48 (2H, m),
4.31 (1H, dd, J ) 5.1 and 13.3 Hz), 3.18 (2H, t, J ) 6.9 Hz), 2.33
(3H, s), 2.15 (3H, s), 2.09 (3H, s), 2.04 (3H, s); HRMS (ESI-MS
m/z) calcd for C33H32N5O10SClI (M + H)+, 852.0603; found,
852.0566.
6-Chloro-2-(3′′-(4′′-bromo-1′′-(p-toluenesulfonyl)indolyl)ethyl-
oxy)-3′,4′,5′-triacetyladenosine (112). The yield was 40%: 1H
NMR (CDCl3) δ 8.09 (1H, s), 7.95 (1H, dd, J ) 0.8 and 8.2 Hz),
7.75 (2H, d with small coupling, J ) 8.5 Hz), 7.59 (1H, s), 7.39
(1H, dd, J ) 0.8 and 8.0 Hz), 7.23 (2H, d, J ) 8.5 Hz), 7.12 (1H,
t, J ) 8.1 Hz), 6.13 (1H, d, J ) 5.0 Hz), 5.92 (1H, t, J ) 5.1 Hz),
5.64 (1H, t, J ) 5.4 Hz), 4.75 (2H, m), 4.38-4.50 (2H, m), 4.33
(1H, dd, J ) 4.7 and 12.9 Hz), 3.53 (2H, t, J ) 7.0 Hz), 2.34 (3H,
s), 2.13 (3H, s), 2.09 (3H, s), 2.05 (3H, s); APCI-MS (m/z) 806.1
(M + H)+.
In case of deprotection of the tosyl group of the 2-substituent,
the tosylated adenosine derivative was treated with KOH (20 equiv)
in methanol overnight at 70 °C in a sealed tube. The reaction
mixture was concentrated to a small amount of solution, which was
subjected to preparative TLC developed with a mixture of
chloroform and methanol (5:1) to give the final product.
6-Chloro-2-(3′′-(1′′-(p-toluenesulfonyl)indolyl)ethyloxy)-3′,4′,5′-
triacetyladenosine (102). The yield was 86%: 1H NMR (CDCl3)
δ 8.09 (1H, s), 7.98 (1H, d with small coupling, J ) 6.6 Hz), 7.76
(2H, d with small coupling, J ) 8.2 Hz), 7.61 (1H, d with small
coupling, J ) 7.1 Hz), 7.53 (1H, s), 7.14 - 7.36 (4H, m), 6.13
(1H, d, J ) 4.7 Hz), 5.93 (1H, t, J ) 5.1 Hz), 5.65 (1H, t, J ) 5.5
Hz), 4.71 (2H, m), 4.39 - 4.49 (2H, m), 4.32 (1H, dd, J ) 4.7 and
12.6 Hz), 3.24 (2H, t, J ) 7.0 Hz), 2.32 (3H, s), 2.14 (3H, s), 2.09
(3H, s), 2.05 (3H, s); HRMS (ESI-MS m/z) calcd for C33H32N5O10-
ClSNa (M + Na)+, 748.1456; found, 748.1455.
6-Chloro-2-(3′′-(5′′-methoxy-1′′-(p-toluenesulfonyl)indolyl)-
ethyloxy)-3′,4′,5′′-triacetyladenosine (103). The yield was 72%:
1H NMR (CDCl3) δ 8.09 (1H, s), 7.86 (1H, dd, J ) 9.1 Hz), 7.73
(2H, d, J ) 8.5 Hz), 7.48 (1H, s), 7.20 (2H, d, J ) 8.2 Hz), 7.03
(1H, d, J ) 2.5 Hz), 6.92 (1H, dd, J ) 2.3 and 8.9 Hz), 6.12 (1H,
d, J ) 4.7 Hz), 5.93 (1H, t, J ) 5.1 Hz), 5.66 (1H, t, J ) 5.6 Hz),
4.69 (2H, ddd, J ) 3.8, 7.4, and 14.3 Hz), 4.40 - 4.49 (2H, m),
4.31 (1H, dd, J ) 4.4 and 12.6 Hz), 3.85 (3H, s), 3.19 (2H, t, J )
6.7 Hz), 2.32 (3H, s), 2.14 (3H, s), 2.09 (3H, s), 2.05 (3H, s); HRMS
(ESI-MS m/z) calcd for C34H35N5O11SCl (M + H)+, 756.1742;
found, 756.1735.
6-Chloro-2-(3′′-(5′′-(p-toluenesulfonyloxy)-1′′-(p-toluenesulfon-
yl)indolyl)ethyloxy)-3′,4′,5′-triacetyladenosine (104). The yield
was 51%: 1H NMR (CDCl3) δ 8.09 (1H, s), 7.83 (1H, d, J ) 8.5
Hz), 7.72 (2H, d with small coupling, J ) 8.5 Hz), 7.68 (2H, d
with small coupling, J ) 8.2 Hz), 7.57 (1H, s), 7.25-7.31 (3H,
m), 7.22 (2H, d, J ) 8.0 Hz), 6.83 (1H, dd, J ) 2.3 and 8.9 Hz),
6.12 (1H, d, J ) 4.4 Hz), 5.94 (1H, dd, J ) 4.7 and 5.5 Hz), 5.67
(1H, t, J ) 5.4 Hz), 4.64 (2H, m), 4.40-4.50 (2H, m), 4.31 (1H,
dd, J ) 5.1 and 12.8 Hz), 3.13 (2H, t, J ) 6.7 Hz), 2.42 (3H, s),
2.34 (3H, s), 2.15 (3H, s), 2.08 (3H, s), 2.03 (3H, s); HRMS (ESI-
MS m/z) calcd for C40H39ClN5O13S2 (M + H)+, 896.1674; found,
896.1638.
6-Chloro-2-(3′′-(5′′-fluoro-1′′-(p-toluenesulfonyl)indolyl)ethyl-
oxy)-3′,4′,5′-triacetyladenosine (105). The yield was 59%: 1H
NMR (CDCl3) δ 8.09 (1H, s), 7.91 (1H, dd, J ) 4.4 and 9.1 Hz),
7.74 (2H, d with small coupling, J ) 8.5 Hz), 7.57 (1H, s), 7.25-
7.31 (1H overlapped with CHCl3), 7.22 (2H, d, J ) 8.0 Hz), 7.04
(1H, dt, J ) 2.6 and 9.0 Hz), 6.11 (1H, d, J ) 4.7 Hz), 5.94 (1H,
t, J ) 4.9 Hz), 5.67 (1H, t, J ) 5.5 Hz), 4.69 (2H, m), 4.40-4.50
(2H, m), 4.31 (1H, dd, J ) 4.9 and 12.9 Hz), 3.18 (2H, t, J ) 6.9
Hz), 2.33 (3H, s), 2.15 (3H, s), 2.09 (3H, s), 2.04 (3H, s); HRMS
(ESI-MS m/z) calcd for C32H23N5O10SFCl (M + H)+, 744.1542;
found, 744.1522.
2-(3′′-(5′′-Bromo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)-6-
chloro-3′,4′,5′-triacetyladenosine (106). The yield was 47%: 1H
NMR (CDCl3) δ 8.09 (1H, s), 7.84 (1H, d, J ) 8.8 Hz), 7.75 (1H,
s), 7.73 (2H, d with small coupling, J ) 6.6 Hz), 7.54 (1H, s),
7.40 (1H, dd, J ) 1.8 and 8.9 Hz), 7.22 (2H, d, J ) 8.5 Hz), 6.13
(1H, d, J ) 4.7 Hz), 5.94 (1H, t, J ) 4.9 Hz), 5.67 (1H, t, J ) 5.4
Hz), 4.69 (2H, t, J ) 6.6 Hz), 4.40-4.50 (2H, m), 4.31 (1H, dd, J
) 5.2 Hz), 3.19 (2H, t, J ) 6.7 Hz), 2.33 (3H, s), 2.15 (3H, s),
6-Chloro-2-(3′′-(7′′-bromoindolyl)ethyloxy)-3′,4′,5′-triacetyl-
adenosine (113). The yield was 10%: 1H NMR (CDCl3) δ 8.06
(1H, s), 7.66 (1H, d, J ) 8.0 Hz), 7.35 (1H, d, J ) 7.7 Hz), 7.27
(1H overlapped with CHCl3), 7.03 (1H, t, J ) 7.7 Hz), 6.11 (1H,
d, J ) 5.0 Hz), 5.91 (1H, t, J ) 5.2 Hz), 5.64 (1H, t, J ) 5.2 Hz),
4.70 (2H, m), 4.37-4.46 (2H, m), 4.32 (1H, dd, J ) 5.4 and 13.1
Hz), 3.30 (2H, t, J ) 7.1 Hz), 2.13 (3H, s), 2.07 (3H, s), 2.07 (3H,
s); APCI-MS (m/z) 672.1 (M + Na)+.
6-Chloro-2-phenypropoxy-3′,4′,5′-triacetyladenosine (114). The
yield was 63%: 1H NMR (CDCl3) δ 8.08 (1H, s), 7.16-7.34 (5H,

1822 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
m), 6.14 (1H, d, J ) 4.9 Hz), 5.91 (1H, t, J ) 5.4 Hz), 5.63 (1H,
t, J ) 5.2 Hz), 4.38-4.52 (5H, m), 4.31 (1H, dd, J ) 3.8 and 11.8
Hz), 2.85 (2H, dd, J ) 7.4 and 8.0 Hz), 2.12-2.24 (2H, m), 2.15
(3H, s), 2.10 (3H, s), 2.09 (3H, s); HRMS (ESI-MS m/z) calcd for
C25H27N4O8ClLi (M + Li)+, 553.1677; found, 553.1661.
6-Chloro-2-(2′′-(1′′-(p-toluenesulfonyl)indolyl)ethyloxy)-3′,4′,5′-
triacetyladenosine (115). The yield was 40%: 1H NMR (CDCl3)
δ 8.16 (1H, d, J ) 8.2 Hz), 8.09 (1H, s), 7.63 (2H, d, J ) 8.5 Hz),
7.42 (2H, d, J ) 7.1 Hz), 7.15-7.32 (3H, m), 6.59 (1H, s), 6.16
(1H, d, J ) 5.0 Hz), 5.87 (1H, t, J ) 5.2 Hz), 5.61 (1H, t, J ) 5.2
Hz), 4.83 (2H, m), 4.40-4.48 (2H, m), 4.34 (1H, dd, J ) 4.9 and
13.2 Hz), 3.58 (2H, t, J ) 6.6 Hz), 2.33 (3H, s), 2.12 (3H, s), 2.08
(3H,s), 2.07 (3H,s); HRMS (ESI-MS m/z) calcd for C33H33N5O10-
ClS (M + H)+, 726.1637; found, 726.1640.
6-Chloro-2-(3′′-(benzoimidazol-1′′-yl)ethyloxy)-3′,4′,5′-tri-
acetyladenosine (116). The yield was 51%: 1H NMR (CD3OD) δ
8.09 (2H, d, J ) 8.0 Hz), 7.79 (1H, dd, J ) 1.4 and 7.1 Hz), 7.55
(1H, dd, J ) 1.1 and 7.1 Hz), 7.34 (1H, dt, J ) 1.4 and 7.4 Hz),
7.28 (1H, dt, J ) 1.4 and 7.5 Hz), 6.05 (1H, d, J ) 4.7 Hz), 5.92
(1H, t, J ) 4.9 Hz), 5.67 (1H, t, J ) 5.4 Hz), 4.82 (2H, m), 4.66
(2H, t, J ) 5.4 Hz), 4.39-4.48 (2H, m), 4.27 (1H, dd, J ) 5.2 and
13.2 Hz), 2.16 (3H, s), 2.09 (3H, s), 2.02 (3H, s); HRMS (ESI-MS
m/z) calcd for C25H26N6O8Cl (M + H)+, 573.1501; found, 573.1503.
6-Chloro-2-(3′′-(benzotriazol-1′′-yl)ethyloxy)-3′,4′,5′-triacetyl-
adenosine (117). The yield was 53%: 1H NMR (CDCl3) δ 8.08
(1H, s), 8.03 (1H, dt, J ) 0.8 and 8.5 Hz), 7.72 (1H, dt, J ) 0.8
and 8.5 Hz), 7.52 (1H, ddd, J ) 1.0, 7.1 and 8.1 Hz), 7.36 (1H,
ddd, J ) 1.1, 7.1 and 8.2 Hz), 6.07 (1H, d, J ) 4.4 Hz), 5.89 (1H,
dd, J ) 4.7 and 5.5 Hz), 5.62 (1H, t, J ) 5.4 Hz), 5.11 (2H, m),
5.00 (2H, m), 4.40-4.48 (2H, m), 4.26-4.34 (1H, m), 2.15, 2.10
and 2.05 (each 3H, s); HRMS (ESI-MS m/z) calcd for C24H25N7O8-
Cl (M + H)+, 574.1453; found, 574.1456.
6-Chloro-2-(3′′-(1′′-p-toluenesulfonyl)pyrrolyl)ethyloxy)-3′,4′,5′-
triacetyladenosine (118). The yield was 61%: 1H NMR (CDCl3)
δ 8.08 (1H, s), 7.73 (1H, d, J ) 8.5 Hz), 7.27 (2H, d overlapped
with CHCl3), 7.08 (2H, m), 6.28 (1H, dd, J ) 1.9 and 3.0 Hz),
6.13 (1H, d, J ) 5.0 Hz), 5.91 (1H, t, J ) 5.1 Hz), 5.63 (1H, t, J
) 5.4 Hz), 4.57 (1H, dd, J ) 2.8 and 7.4 Hz), 4.53 (1H, dd, J )
3.0 and 7.7 Hz), 4.38-4.45 (2H, m), 4.32 (1H, dd, J ) 4.3 and
12.2 Hz), 2.95 (2H, t, J ) 7.0 Hz), 2.40 (3H, s), 2.15 (3H, s), 2.09
(3H, s), 2.07 (3H, s); HRMS (ESI-MS m/z) calcd for C29H31N5O10-
SCl (M + H)+, 676.1480; found, 676.1450.
2-(3′′-(5′′-Methoxy-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)-
adenosine (119). The yield was 56%: 1H NMR (CD3OD) δ 8.14
(1H, s), 7.81 (1H, d, J ) 9.3 Hz), 7.67 (2H, dt, J ) 1.9 and 8.5
Hz), 7.52 (1H, s), 7.15 (2H, dd, J ) 0.6 and 8.5 Hz), 7.02 (1H, d,
J ) 2.5 Hz), 6.89 (1H, dd, J ) 2.8 and 8.8 Hz), 5.89 (1H, d, J )
6.0 Hz), 4.72 (1H, t, J ) 5.6 Hz), 4.55 (2H, dt, J ) 1.1 and 6.3
Hz), 4.33 (1H, dd, J ) 3.3 and 5.0 Hz), 4.12 (1H, q, J ) 3.0 Hz),
3.88 (1H, dd, J ) 2.7 and 12.4 Hz), 3.78 (3H, s), 3.74 (1H, dd, J
) 3.2 and 12.5 Hz), 3.11 (2H, t, J ) 6.3 Hz), 2.25 (3H, s); HRMS
(ESI-MS m/z) calcd for C28H31N6O8S (M + H)+, 611.1924; found,
611.1899.
2-(3′′-(5′′-(p-Toluenesulfonyloxy)-1′′-(p-toluenesulfonyl)indolyl)-
ethyloxy)adenosine (120). The yield was 63%: 1H NMR (CD3-
OD) δ 8.15 (1H, s), 7.86 (1H, d, J ) 8.8 Hz), 7.71 (2H, d with
small coupling, J ) 8.5 Hz), 7.64 (1H, s), 7.60 (2H, d with small
coupling, J ) 8.2 Hz), 7.28 (2H, d, J ) 8.5 Hz), 7.21 (2H, d, J )
8.0 Hz), 7.08 (1H, d, J ) 2.5 Hz), 6.93 (1H, dd, J ) 2.2 and 9.1
Hz), 5.90 (1H, d, J ) 6.1 Hz), 4.71 (1H, t, J ) 5.6 Hz), 4.42 (2H,
t, J ) 6.6 Hz), 4.33 (2H, t, J ) 6.6 Hz), 4.33 (1H, dd, J ) 3.2 and
5.1 Hz), 4.14 (1H, q, J ) 3.0 Hz), 3.90 (1H, dd, J ) 2.8 and 12.6
Hz), 3.74 (1H, dd, J ) 3.2 and 12.5 Hz), 3.00 (2H, t, J ) 6.6 Hz),
2.34 (3H, s), 2.29 (3H, s); HRMS (ESI-MS m/z) calcd for
C34H35N6O10S2 (M + H)+, 751.1856; found, 751.1819.
) 6.2 Hz), 4.33 (1H, dd, J ) 3.3 and 5.2 Hz), 4.12 (1H, q, J ) 3.0
Hz), 3.89 (1H, dd, J ) 2.7 and 12.4 Hz), 3.74 (1H, dd, J ) 3.2
and 12.5 Hz), 3.10 (2H, t, J ) 6.3 Hz), 2.26 (3H, s); HRMS (ESI-
MS m/z) calcd for C27H28N6O7SF (M + H)+, 599.1724; found,
599.1714.
2-(3′′-(6′′-Chloro-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (122). The yield was 51%: 1H NMR (CD3OD) δ 8.13 (1H,
s), 7.92 (1H, d, J ) 1.7 Hz), 7.72 (2H, d with small coupling, J )
8.2 Hz), 7.61 (1H, s), 7.58 (1H, d, J ) 8.5 Hz), 7.25 (1H, dd, J )
1.9 and 8.5 Hz), 7.21 (2H, dd, J ) 0.7 and 8.7 Hz), 5.89 (1H, d,
J ) 6.1 Hz), 4.72 (1H, t, J ) 5.5 Hz), 4.55 (2H, m), 4.33 (1H, dd,
J ) 3.3 and 5.2 Hz), 4.12 (1H, q, J ) 2.9 Hz), 3.88 (1H, dd, J )
2.8 and 12.4 Hz), 3.74 (1H, dd, J ) 3.3 and 12.4 Hz), 3.12 (2H, t,
J ) 6.5 Hz), 2.28 (3H, s); HRMS (ESI-MS m/z) calcd for
C27H28N6O7SCl (M + H)+, 615.1429; found, 615.1413.
2-(3′′-(6′′-Bromo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (123). The yield was 50%: 1H NMR (CD3OD) δ 8.13 (1H,
s), 8.08 (1H, d, J ) 1.7 Hz), 7.71 (2H, dt, J ) 2.1 and 8.5 Hz),
7.60 (1H, s), 7.53 (1H, d, J ) 8.2 Hz), 7.38 (1H, dd, J ) 1.7 and
8.2 Hz), 7.21 (2H, d with small coupling, J ) 8.2 Hz), 5.89 (1H,
d, J ) 6.1 Hz), 4.72 (1H, t, J ) 5.5 Hz), 4.54 (2H, m), 4.33 (1H,
dd, J ) 3.3 and 5.2 Hz), 4.12 (1H, q, J ) 3.0 Hz), 3.88 (1H, dd,
J ) 2.7 and 12.4 Hz), 3.74 (1H, dd, J ) 3.3 and 12.4 Hz), 3.12
(2H, t, J ) 6.5 Hz), 2.28 (3H, s); HRMS (ESI-MS m/z) calcd for
C27H28N6O7BrS (M + H)+, 659.0924; found, 659.0910.
2-(3′′-(5′′-Chloro-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (124). The yield was 62%: 1H NMR (CD3OD) δ 8.13 (1H,
s), 7.90 (1H, d, J ) 8.8), 7.71 (2H, d with small coupling, J ) 8.8
Hz), 7.64 (1H, s), 7.57 (1H, d, J ) 1.9 Hz), 7.27 (1H, dd, J ) 1.9
and 8.8 Hz), 7.18 (2H, d, J ) 8.2 Hz), 5.89 (1H, d, J ) 5.8 Hz),
4.73 (1H, t, J ) 5.6 Hz), 4.55 (2H, t, J ) 6.5 Hz), 4.33 (1H, dd,
J ) 3.3 and 5.2 Hz), 4.12 (1H, q, J ) 3.1 Hz), 3.89 (1H, dd, J )
2.7 and 12.6 Hz), 3.74 (1H, dd, J ) 3.2 and 12.5 Hz), 3.11 (2H, t,
J ) 6.3 Hz), 2.27 (3H, s); HRMS (ESI-MS m/z) calcd for
C27H28N6O7SCl (M + H)+, 615.1429; found, 615.1401.
2-(3′′-(5′′-Iodo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (125). The yield was 71%: 1H NMR (CD3OD) δ 8.14 (1H,
s), 7.89 (1H, d, J ) 1.7 Hz), 7.73 (1H, d, J ) 9.1 Hz), 7.71 (2H,
d with small coupling, J ) 8.5 Hz), 7.58 (1H, s), 7.57 (1H, dd, J
) 1.8 and 8.7 Hz), 7.18 (2H, d, J ) 8.2 Hz), 5.89 (1H, d, J ) 5.8
Hz), 4.73 (1H, t, J ) 5.5 Hz), 4.54 (2H, t, J ) 6.3 Hz), 4.34 (1H,
dd, J ) 3.3 and 5.2 Hz), 4.12 (1H, q, J ) 3.0 Hz), 3.89 (1H, dd,
J ) 2.9 and 12.5 Hz), 3.75 (1H, dd, J ) 3.3 and 12.4 Hz), 3.10
(2H, t, J ) 6.3 Hz), 2.27 (3H, s); APCI-MS (m/z) 707.0 (M +
H)+.
2-(3′′-(4′′-Bromo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (126). The yield was 43%: 1H NMR (CD3OD) δ 8.13 (1H,
s), 7.95 (1H, dd, J ) 0.7 and 8.4 Hz), 7.73 (2H, d with small
coupling, J ) 8.5 Hz), 7.69 (1H, s), 7.39 (1H, dd, J ) 0.8 and 7.7
Hz), 7.19 (2H, dd, J ) 0.6 and 8.5 Hz), 7.15 (1H, t, J ) 8.1 Hz),
5.89 (1H, d, J ) 6.1 Hz), 4.74 (1H, t, J ) 5.5 Hz), 4.61 (2H, m),
4.33 (1H, dd, J ) 3.3 and 5.2 Hz), 4.12 (1H, q, J ) 3.1 Hz), 3.89
(1H, dd, J ) 2.8 and 12.4 Hz), 3.75 (1H, dd, J ) 3.3 and 12.4
Hz), 3.44 (2H, m), 2.27 (3H, s); APCI-MS (m/z) 659.1 (M + H)+.
2-(3′′-(1′′-(p-Toluenesulfonyl)pyrrolyl)ethyloxy)-adenosine (127).
The yield was 69%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.72 (2H,
d with small coupling, J ) 8.5 H), 7.29 (2H, d, J ) 8.5 Hz), 7.08-
7.14 (2H, m), 6.30 (1H, dd, J ) 1.7 and 3.2 Hz), 5.88 (1H, d, J )
6.0 Hz), 4.71 (1H, t, J ) 5.5 Hz), 4.41 (2H, t, J ) 6.7 Hz), 4.32
(1H, dd, J ) 3.4 and 5.1 Hz), 4.11 (1H, q, J ) 3.2 Hz), 3.86 (1H,
dd, J ) 2.6 and 12.5 Hz), 3.73 (1H, dd, J ) 3.3 and 12.7 Hz), 2.85
(2H, t, J ) 6.5 Hz), 2.36 (3H, s); HRMS (ESI-MS m/z) calcd for
C23H27N6O7S (M + H)+, 531.1662; found, 531.1667.
(2R,3S,4S,5R)-2-(2′-Amino-6′-chloropurin-9′-yl)-5-hydroxy-
methyl-3, 4-O-isopropylidene-tetrahydrofuran (128). To a solu-
tion of 2-amino-6-chloropurine-9-riboside (100 mg, 0.331 mmol)
in N,N-dimethylformamide (2 mL) were added 2,2-dimethoxypro-
pane (0.242 mL, 1.97 mmol) and p-toluenesulfonic acid monohy-
drate (188 mg, 0.993 mmol), and the reaction mixture was stirred
overnight at room temperature. The reaction was diluted with ethyl
acetate, washed with water, dried over MgSO4, and filtered. The
2-(3′′-(5′′-Fluoro-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (121). The yield was 55%: 1H NMR (CD3OD) δ 8.13 (1H,
s), 7.91 (1H, dd, J ) 4.4 and 9.1 Hz), 7.70 (2H, d with small
coupling, J ) 8.5 Hz), 7.64 (1H, s), 7.29 (1H, dd, J ) 2.5 and 8.8
Hz), 7.16 (2H, d, J ) 8.0 Hz), 7.05 (1H, dt, J ) 2.5 and 9.1 Hz),
5.89 (1H, d, J ) 6.0 Hz), 4.73 (1H, t, J ) 5.5 Hz), 4.54 (2H, t, J

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1823
filtrate was evaporated to give an oil, which was subjected to
preparative TLC developed with a mixture of toluene and acetone
(1:1) to give 128 (56 mg, 50%). 1H NMR (CDCl3) δ 7.81 (1H, s),
5.79 (1H, d, J ) 4.9 Hz), 5.68 (1H, dd, J ) 1.4 and 11.3 Hz),
5.14-5.24 (3H, m), 5.08 (1H, dd, J ) 1.4 and 6.0 Hz), 4.51 (1H,
d, J ) 1.7 Hz), 3.97 (1H, d with small coupling, J ) 12.6 Hz),
3.78 (1H, ddd, J ) 1.9, 11.3 and 13.2 Hz), 1.64 (3H, s), 1.38 (3H,
s); HRMS (ESI-MS m/z) calcd for C13H17N5O4Cl (M + H)+,
342.0969; found, 342.0979.
(2R,3S,4S,5R)-2-(2′-Amino-6′-chloropurin-9′-yl)-5-carboxy-
3,4-O-isopropylidene-tetrahydrofuran (129). To a solution of 128
(16.9 mg, 0.0494 mmol) in water (4.5 mL) were added potassium
permanganate (70.3 mg, 0.445 mmol) and potassium hydroxide (25
mg, 0.444 mmol), and the reaction mixture was stirred for 1 h.
After addition of isopropanol, the reaction mixture was filtered.
The filtrate was neutralized with 0.1 N hydrochloric acid aqueous
solution and evaporated to give a crude solid, which was subjected
to preparative TLC developed with a mixture of chloroform,
methanol, and saturated aqueous ammonia (2: 1: 0.3) to give 129
(9 mg, 51%). 1H NMR (CD3OD) δ 8.29 (1H, s), 6.18 (1H, d, J )
1.2 Hz), 5.52 (1H, dd, J ) 1.7 and 6.2 Hz), 5.37 (1H, d, J ) 6.0
Hz), 4.59 (1H, d, J ) 1.7 Hz), 1.55 (3H, s), 1.39 (3H, S); HRMS
(ESI-MS m/z) calcd for C13H13N5O5Cl (M - H)-, 354.0605; found,
354.0622.
t, J ) 6.7 Hz), 2.97 (2H, m), 2.32 (3H, s), 1.61 (3H, s), 1.35 (3H,
s), 0.69 (3H, t, J ) 7.3 Hz); HRMS (ESI-MS m/z) calcd for
C32H33N6O7SClNa (M + Na)+, 703.1718; found, 703.1732.
(2R,3S,4S,5R)-5-Ethylcarboxyamide-2-(6′-amino-2′-(3′′-(1′′-(p-
toluenesufonyl)indolyl)ethyloxy)-purin-9′-yl)-3,4-O-isopropylidene-
tetrahydrofuran (133). A solution of 132 in saturated ammonia
ethanol solution was stirred at 120 °C overnight. The solvent was
evaporated to give an oil, which was subjected to preparative TLC
developed with a mixture of chloroform and methanol (10:1) to
1
give 133 (17 mg, 88% yield). H NMR (CDCl3) δ 7.96 (1H, d, J
) 7.7 Hz), 7.77 (2H, d, J ) 8.2 Hz), 7.68 (1H, s), 7.54-7.60 (2H,
m), 7.30 (1H, dt, J ) 1.6 and 7.7 Hz), 7.24 (1H, overlapped with
CHCl3), 7.19 (2H, d, J ) 8.5 Hz), 6.44 (1H, t, J ) 5.9 Hz), 6.07
(1H, d, J ) 1.9 Hz), 5.59 (1H, br s), 5.51 (1H, dd, J ) 1.9 and 6.0
Hz), 5.43 (1H, dd, J ) 1.8 and 6.2 Hz), 4.70 (1H, d, J ) 1.9 Hz),
4.61 (2H, m), 3.18 (2H, t, J ) 6.7 Hz), 2.96 (2H, m), 2.31 (3H, s),
1.64 (3H, s), 1.31 (3H, s), 0.69 (3H, t, J ) 7.3 Hz); HRMS (ESI-
MS m/z) calcd for C32H36N7O7S (M + H)+, 662.2397; found,
662.2374.
(2R,3S,4S,5R)-5-Ethylcarboxyamide-2-(6′-amino-2′-(3′′-(1′′-(p-
toluenesufonyl)indolyl)ethyloxy)-purin-9′-yl)-tetrahydrofuran
(134). A solution of 133 (13.4 mg, 0.0202 mmol) in 80% acetic
acid aqueous solution was stirred at 80 °C for 63 h and evaporated
to give an oil, which was subjected to preparative TLC developed
with a mixture of chloroform and methanol (8:1) to give 134 (9
mg, recovery yield 85%). 1H NMR (CD3OD) δ 8.09 (1H, s), 7.94
(1H, d, J ) 7.7 Hz), 7.69 (2H, d with small coupling, J ) 8.5 Hz),
7.56 (1H, d with small coupling, J ) 7.7 Hz), 7.52 (1H, s), 7.30
(1H, dt, J ) 1.3 and 7.7 Hz), 7.16-7.26 (3H, m), 5.93 (1H, d, J )
7.4 Hz), 4.54-4.76 (2H, m), 4.42 (1H, d, J ) 1.9 Hz), 4.31 (1H,
dd, J ) 1.8 and 4.8 Hz), 3.00-3.18 (4H, m), 2.28 (3H, s), 0.83
(3H, t, J ) 7.1 Hz); HRMS (ESI-MS m/z) calcd for C29H32N7O7S
(M + H)+, 622.2084; found, 622.2095.
2-Phenylpropoxyadenosine (8). The yield was 66%: 1H NMR
(CD3OD) δ 8.11 (1H, s), 7.10-7.28 (5H, m), 5.88 (1H, d, J ) 6.1
Hz), 4.72 (1H, t, J ) 5.5 Hz), 4.30-4.34 (1H overlaped with CH2),
4.29 (2H, t, J ) 6.6 Hz), 4.10 (1H, q, J ) 3.2 Hz), 3.85 (1H, dd,
J ) 2.9 and 12.5 Hz), 3.72 (1H, dd, J ) 3.3 and 12.4 Hz), 2.78
(2H, t, J ) 7.7 Hz), 2.06 (2H, dt, J ) 6.4 and 15.3 Hz); HRMS
(ESI-MS m/z) calcd for C19H24N5O5 (M + H)+, 402.1777; found,
402.1771; HPLC (system A) 14.1 min (99%), (system C) 10.7 min
(99%).
2-(3′′-Indolylethyloxy)adenosine (17). The yield was 72%: 1H
NMR (CD3OD) δ 8.12 (1H, s), 7.60 (1H, d with small coupling, J
) 7.7 Hz), 7.32 (1H, d with small coupling, J ) 7.7 Hz), 7.15
(1H, s), 7.07 (1H, dt, J ) 1.2 and 7.5 Hz), 7.01 (1H, dt, J ) 1.2
and 7.3 Hz), 5.90 (1H, d, J ) 5.5 Hz), 4.71 (1H, t, J ) 5.5 Hz),
4.58 (2H, m), 4.31 (1H, dd, J ) 3.6 and 5.2 Hz), 4.11 (1H, q, J )
3.2 Hz), 3.85 (1H, dd, J ) 2.8 and 12.4 Hz), 3.73 (1H, dd, J ) 3.4
and 12.2 Hz), 3.24 (2H, t, J ) 7.3 Hz); HRMS (ESI-MS m/z) calcd
for C20H23N6O5 (M + H)+, 427.1730; found, 427.1711; HPLC
(system A) 11.4 min (99%), (system C) 9.3 min (99%).
2-(3′′-(1′′-(p-Toluenesulfonyl)indolyl)ethyloxy)adenosine (18).
The yield was 60%: 1H NMR (CD3OD) δ 8.14 (1H, s), 7.93 (1H,
d with small coupling, J ) 7.4 Hz), 7.70 (2H, d with small coupling,
J ) 8.2 Hz), 7.59 (2H, m), 7.29 (1H, dt, J ) 1.7 and 8.1 Hz), 7.23
(1H, dt, J ) 1.5 and 8.1 Hz), 7.17 (2H, d, J ) 8.0 Hz), 5.90 (1H,
d, J ) 6.0 Hz), 4.73 (1H, t, J ) 5.6 Hz), 4.57 (2H, m), 4.33 (1H,
dd, J ) 3.2 and 5.1 Hz), 4.12 (1H, q, J ) 3.0 Hz), 3.88 (1H, dd,
J ) 2.8 and 12.4 Hz), 3.74 (1H, dd, J ) 3.3 and 12.4 Hz), 3.14
(2H, t, J ) 6.3 Hz); HRMS (ESI-MS m/z) calcd for C27H29N6O7S
(M + H)+, 581.1818; found, 581.1797; HPLC (system B) 16.5 min
(99%), (system C) 16.7 min (99%).
(2R,3S,4S,5R)-2-(2′-Amino-6′-chloropurin-9′-yl)-5-ethylcar-
boxyamide-3,4-O-isopropylidene-tetrahydrofuran (130). To a
solution of 129 (11.9 mg, 0.0334 mmol) in N,N-dimethylformamide
(0.8 mL) were added ethylamine hydrochloride (8.1 mg, 0.100
mmol), N,N-diisopropylethylamine (0.035 mL, 0.200 mmol), and
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophos-
phate (22.5 mg, 0.0434 mmol), and the reaction mixture was stirred
overnight. The mixture was diluted with ethyl acetate, washed with
water, dried over MgSO4, and filtered. The filtrate was evaporated
to give a crude oil, which was subjected to preparative TLC
developed with a mixture of chloroform and methanol (10:1) to
1
give 130 (10 mg, 78%). H NMR (CD3OD) δ 8.16 (1H, s), 6.27
(1H, s), 5.73 (1H, dd, J ) 1.9 and 6.3 Hz), 5.43 (1H, d, J ) 6.3
Hz), 4.62 (1H, d, J ) 1.7 Hz), 2.91 (1H, dt, J ) 6.0 and 13.3 Hz),
2.80 (1H, dt, J ) 6.0 and 13.3 Hz), 1.55 (3H, s), 1.40 (3H,s), 0.61
(3H, t, J ) 7.3 Hz); HRMS (ESI- MS m/z) calcd for C15H20N6O4-
Cl (M + H)+, 383.1235; found, 383.1229.
(2R,3S,4S,5R)-5-Ethylcarboxyamide-2-(2′-hydroxy-6′-chloro-
purin-9′-yl)-3,4-O-isopropylidene-tetrahydrofuran (131). To a
solution of 130 (10 mg, 0.026 mmol) in a mixture of 2-propanol
(0.4 mL) and water (0.4 mL) was added t-butylnitrite (13.3 µL,
0.115 mmol) at 4 °C, and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate, washed with water, dried over MgSO4, and filtered. The
filtrate was evaporated to give a crude oil, which was subjected to
preparative TLC developed with a mixture of chloroform and
1
methanol (10:1) to give 131 (5 mg, 50%). H NMR (CDCl3) δ
7.99 (1H, s), 6.37 (1H, br t, J ) 6.1 Hz), 6.11 (1H, d, J ) 1.6 Hz),
5.72 (1H, dd, J ) 1.7 and 6.1 Hz), 5.36 (1H, dd, J ) 1.7 and 6.0
Hz), 4.75 (1H, s), 3.05 (2H, m), 1.61 (3H, s), 1.41 (3H, s), 0.77
(3H, t, J ) 7.3 Hz); APCI-MS (m/z) 384.1 (M + H)+.
(2R,3S,4S,5R)-5-Ethylcarboxyamide-2-2′-(3′′-(1′′-(p-toluene-
sufonyl)indolyl)ethyloxy)-6′-chloropurin-9′-yl)-3, 4-O-isopropy-
lidene-tetrahydrofuran (132). To a solution of 131 (19.4 mg,
0.0505 mmol) in N,N-dimethylformamide (0.8 mL) was added
iodide 47 (43 mg, 0.101 mmol) and cesium carbonate (49.3 mg,
0.151 mmol), and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate, washed with water, dried over MgSO4, and filtered. The
filtrate was evaporated to give a crude oil, which was subjected to
preparative TLC developed with a mixture of toluene and acetone
(4:1) to give 132 (24 mg, 70%). 1H NMR (CDCl3) δ 7.99 (1H, s),
7.98 (1H, d, J ) 8.2 Hz), 7.77 (2H, d with small coupling, J ) 8.5
Hz), 7.61 (1H, d with small coupling, J ) 7.7 Hz), 7.56 (1H, s),
7.24-7.35 (2H, m), 7.21 (2H, d, J ) 8.5 Hz), 6.27 (1H, t, J ) 6.0
Hz), 6.14 (1H, d, J ) 2.2 Hz), 5.52 (1H, dd, J ) 1.9 and 6.1 Hz),
5.39 (1H, dd, J ) 2.1 and 6.2 Hz), 4.60-4.80 (3H, m), 3.27 (2H,
2-(3′′-Pyrrolylethyloxy)adenosine (19). The yield was 57%: 1H
NMR (CD3OD) δ 8.11 (1H, s), 6.63 (2H, d, J ) 2.2 Hz), 6.04
(1H, t, J ) 2.1 Hz), 5.88 (1H, d, J ) 5.8 Hz), 4.72 (1H, t, J ) 5.5
Hz), 4.42 (2H, t, J ) 7.4 Hz), 4.31 (1H, dd, J ) 3.4 and 5.1 Hz),
4.10 (1H, q, J ) 3.2 Hz). 3.85 (1H, dd, J ) 3.0 and 12.4 Hz), 3.73
(1H, dd, J ) 3.6 and 12.4 Hz), 2.91 (2H, t, J ) 7.3 Hz); HRMS

1824 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
(ESI-MS m/z) calcd for C16H21N6O5 (M + H)+, 377.1573; found,
377.1577; HPLC (system A) 4.5 min (99%), (system C) 4.7 min
(99%).
(3H, s); HRMS (ESI MS m/z) calcd for C27H28N6O7BrS (M + H)+,
659.0924; found, 659.0921.
2-(3′′-(6′′-Chloro-indolyl)ethyloxy)adenosine (27). The yield
was 54%: 1H NMR (CD3OD) δ 8.08 (1H, s), 7.52 (1H, d, J ) 8.5
Hz), 7.27 (1H, d, J ) 1.7 Hz), 7.13 (1H, s), 6.95 (1H, dd, J ) 1.9
and 8.5 Hz), 5.86 (1H, d, J ) 6.0 Hz), 4.67 (1H, t, J ) 5.5 Hz),
4.51 (2H, m), 4.28 (1H, dd, J ) 3.4 and 5.1 Hz), 4.07 (1H, q, J )
3.2 Hz), 3.81 (1H, dd, J ) 2.8 and 12.4 Hz), 3.69 (1H, dd, J ) 3.3
and 12.4 Hz), 3.14 (2H, t, J ) 7.0 Hz); HRMS (ESI-MS m/z) calcd
for C20H22N6O5Cl (M + H)+, 461.1340; found, 461.1339; HPLC
(system A) 15.7 min (99%), (system C) 11.9 min (99%).
2-(3′′-(6′′-Bromo-indolyl)ethyloxy)adenosine (28). The yield
was 71%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.52 (1H, d, J ) 8.5
Hz), 7.48 (1H, d, J ) 1.7 Hz), 7.17 (1H, s), 7.12 (1H, dd, J ) 1.7
and 8.5 Hz), 5.90 (1H, d, J ) 5.8 Hz), 4.71 (1H, t, J ) 5.5 Hz),
4.56 (2H, m), 4.31 (1H, dd, J ) 3.3 and 5.2 Hz), 4.11 (1H, q, J )
3.2 Hz), 3.85 (1H, dd, J ) 3.4 and 12.2 Hz), 3.73 (1H, dd, J ) 3.4
and 12.2 Hz), 3.21 (2H, t, J ) 7.2 Hz); HRMS (ESI-MS m/z) calcd
for C20H22N6O5Br (M + H)+, 505.0835; found, 505.0840; HPLC
(system A) 18.1 min (98%), (system C) 12.6 min (98%).
2-(3′′-(4′′-Bromo-indolyl)ethyloxy)adenosine (29). The yield
was 44%: 1H NMR (CD3OD) δ 8.11 (1H, s), 7.31 (1H, dd, J )
0.8 and 8.0 Hz), 7.24 (1H, s), 7.16 (1H, dd, J ) 0.8 and 7.4 Hz),
6.93 (1H, t, J ) 7.8 Hz), 5.89 (1H, d, J ) 6.0 Hz), 4.71 (1H, t, J
) 5.5 Hz), 4.60 (2H, m), 4.31 (1H, dd, J ) 3.6 and 5.0 Hz), 4.10
(1H, q, J ) 3.2 Hz), 3.85 (1H, dd, J ) 2.9 and 12.5 Hz), 3.73 (1H,
dd, J ) 3.4 and 12.5 Hz), 3.47 (1H, t, J ) 7.1 Hz); HRMS (ESI-
MS m/z) calcd for C20H22N6O5Br (M + H)+, 505.0835; found,
505.0843; HPLC (system A) 15.3 min (99%), (system C) 11.7 min
(99%).
2-(3′′-(7′′-Bromo-indolyl)ethyloxy)adenosine (30). The yield
was 27%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.60 (1H, d, J ) 8.0
Hz), 7.25 (1H, d, J ) 7.4 Hz), 7.24 (1H, s), 6.95 (1H, t, J ) 7.8
Hz), 5.90 (1H, d, J ) 5.8 Hz), 4.71 (1H, t, J ) 5.6 Hz), 4.58 (2H,
m), 4.31 (1H, dd, J ) 3.6 and 4.9 Hz), 4.11 (1H, q, J ) 3.2 Hz),
3.85 (1H, dd, J ) 2.9 and 12.2 Hz), 3.73 (1H, dd, J ) 3.3 and
12.4 Hz), 3.20 (2H, t, J ) 6.9 Hz); HRMS (ESI-MS m/z) calcd for
C20H22N6O5Br (M + H)+, 505.0835; found, 505.0837; HPLC
(system A) 15.9 min (99%), (system C) 12.1 min (99%).
2-(3′′-(5′′-Methoxy-2′′-methylindolyl)ethyloxy)adenosine (31).
The yield was 29%: 1H NMR (CD3OD) δ 8.13 (1H, s), 7.10 (1H,
dd, J ) 0.6 and 8.8 Hz), 6.96 (1H, d, J ) 2.2 Hz), 6.65 (1H, dd,
J ) 2.3 and 8.7 Hz), 5.90 (1H, d, J ) 5.8 Hz), 4.68 (1H, t, J ) 5.5
Hz), 4.47 (2H, m), 4.30 (1H, dd, J ) 3.6 and 5.2 Hz), 4.10 (1H, q,
J ) 3.2 and 6.5 Hz), 3.84 (1H, dd, J ) 2.9 and 12.2 Hz), 3.72
(1H, dd, J ) 3.3 and 12.4 Hz), 3.13 (2H, t, J ) 7.3 Hz), 2.37 (3H,
s); HRMS (ESI-MS m/z) calcd for C22H26N6O8Na (M + Na)+,
493.1812; found, 493.1792; HPLC (system A) 11.8 min (98%),
(system C) 9.4 min (98%).
2-(3′′-(5′′-Methoxy-2′′-methyl-1′′-(p-toluenesulfonyl)indolyl)-
ethyloxy)adenosine (32). The yield was 71%: 1H NMR (CD3OD)
δ 8.12 (1H,s), 7.96 (1H, d, J ) 9.1 Hz), 7.52 (2H, d, J ) 8.5 Hz),
7.11 (2H, d, J ) 8.5 Hz), 6.92 (1H, d, J ) 2.5 Hz), 6.82 (1H, dd,
J ) 2.5 and 9.1 Hz), 5.87 (1H, d, J ) 6.0 Hz), 4.66 (1H, t, J ) 5.6
Hz), 4.41 (2H, m), 4.29 (1H, dd, J ) 3.2 and 5.1 Hz), 4.10 (1H, q,
J ) 2.9 Hz), 3.82 (1H, dd, J ) 2.8 and 12.4 Hz), 3.77 (3H, s),
3.70 (1H, dd, J ) 3.2 and 12.5 Hz), 3.06 (2H, t, J ) 6.6 Hz), 2.56
(3H, s), 2.21 (3H, s); HRMS (ESI-MS m/z) calcd for C29H33N6O8S
(M + H)+, 625.2081; found, 625.2079; HPLC (system B) 17.3 min
(99%), (system C) 17.6 min (99%).
2-(3′′-(5′′-Methoxy-indolyl)ethyloxy)adenosine (33). The yield
was 54%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.20 (1H, d, J ) 8.8
Hz), 7.12 (1H, s), 7.05 (1H, d, J ) 2.5 Hz), 6.73 (1H, dd, J ) 2.5
and 8.8 Hz), 5.89 (1H, d, J ) 5.8 Hz), 4.71 (1H, t, J ) 5.5 Hz),
4.56 (2H, t, J ) 7.1 Hz), 4.31 (1H, dd, J ) 3.3 and 5.2 Hz), 4.10
(1H, q, J ) 3.2 Hz), 3.84 (1H, dd, J ) 2.8 and 12.4 Hz), 3.72 (1H,
dd, J ) 3.3 and 12.4 Hz), 3.18 (2H, t, J ) 7.1 Hz); HRMS (ESI-
MS m/z) calcd for C21H25N6O6 (M + H)+, 457.1836; found,
457.1815; HPLC (system A) 10.7 min (98%), (system C) 8.8 min
(98%).
2-(2′′-Indolylethyloxy)adenosine (20). The yield was 32%: 1H
NMR (CD3OD) δ 8.08 (1H, s), 7.37 (1H, d with small couplings,
J ) 7.4 Hz), 7.25 (1H, d with small coupling, J ) 8.0 Hz), 6.97
(1H, dt, J ) 1.4 and 7.1 Hz), 6.88 (1H, dt, J ) 1.1 and 7.2 Hz),
6.21 (1H, d, J ) 0.8 Hz), 5.86 (1H, d, J ) 5.8 Hz), 4.69 (1H, t, J
) 5.5 Hz), 4.57 (2H, t, J ) 6.6 Hz), 4.30 (1H, dd, J ) 3.3 and 5.2
Hz), 4.08 (1H, q, J ) 3.3 Hz), 3.83 (1H, dd, J ) 2.9 and 12.2 Hz),
3.72 (1H, dd, J ) 3.3 and 12.4 Hz), 3.18 (2H, t, J ) 6.7 Hz);
HRMS (ESI-MS m/z) calcd for C20H23N6O5 (M + H)+, 427.1730;
found, 427.1735; HPLC (system A) 14.6 min (99%), (system C)
10.9 min (99%).
2-(2′′-(1′′-(p-Toluenesulfonyl)indolyl)ethyloxy)adenosine (21).
The yield was 55%: 1H NMR (CDCl3) δ 8.10 (1H, d, J ) 8.2
Hz), 7.57-7.64 (3H, m), 7.37 (1H, d, J ) 7.7 Hz), 7.11-7.26 (4H,
m), 6.52 (1H, s), 5.71 (1H, d, J ) 6.9 Hz), 5.66 (2H, br s), 5.03
(1H, t, J ) 6.9 Hz), 4.62 (1H, m), 4.46 (2H, m), 4.27 (1H, s), 3.89
(1H, d, J ) 11.5 Hz), 3.74 (1H, d, J ) 11.5 Hz), 3.43 (2H, m),
3.19 (1H, br s), 2.30 (3H, s); HRMS (ESI-MS m/z) calcd for
C27H29N6O7S (M + H)+, 581.1818; found, 581.1802; HPLC (system
A) 23.0 min (99%), (system C) 16.7 min (99%).
2-(3′′-(5′′-Fluoro-indolyl)ethyloxy)adenosine (22). The yield
was 80%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.20∼7.30 (3H, m),
6.83 (1H, dt, J ) 2.5 and 9.1 Hz), 5.89 (1H, d, J ) 5.8 Hz), 4.72
(1H, t, J ) 5.5 Hz), 4.55 (2H, t, J ) 7.0 Hz), 4.31 (1H, dd, J ) 3.3
and 5.2 Hz), 4.11 (1H, q, J ) 3.3 Hz), 3.86 (1H, dd, J ) 2.8 and
12.4 Hz), 3.73 (1H, dd, J ) 3.6 and 12.4 Hz), 3.16 (2H, t, J ) 7.1
Hz); HRMS (ESI-MS m/z) calcd for C20H21N6O5FNa (M + Na)+,
467.1455; found, 467.1479; HPLC (system A) 13.1 min (99%),
(system C) 10.2 min (99%).
2-(3′′-(5′′-Chloro-indolyl)ethyloxy)adenosine (23). The yield
was 54%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.55 (1H, d, J ) 1.9
Hz), 7.28 (1H, dd, J ) 0.5 and 8.5 Hz), 7.22 (1H, s), 7.03 (1H, dd,
J ) 1.9 and 8.5 Hz), 5.89 (1H, d, J ) 6.0 Hz), 4.71 (1H, t, J ) 5.5
Hz), 4.56 (2H, t, J ) 7.0 Hz), 4.31 (1H, dd, J ) 3.6 and 5.2 Hz),
4.11 (1H, q, J ) 3.2 Hz), 3.86 (1H, dd, J ) 2.9 and 12.5 Hz), 3.73
(1H, dd, J ) 3.3 and 12.4 Hz), 3.17 (2H, t, J ) 7.0 Hz); HRMS
(ESI-MS m/z) calcd for C20H22N6O5Cl (M + H)+, 461.1340; found,
461.1332; HPLC (system A) 16.6 min (99%), (system C) 11.8 min
(99%).
2-(3′′-(5′′-Bromo-indolyl)ethyloxy)adenosine (24). The yield
was 70%: 1H NMR (CD3OD) δ 8.12 (1H, s), 7.70 (1H, d, J ) 1.9
Hz), 7.24 (1H, d, J ) 8.8 Hz), 7.20 (1H, s), 7.15 (1H, dd, J ) 1.8
and 8.7 Hz), 5.89 (1H, d, J ) 5.8 Hz), 4.71 (1H, t, J ) 5.5 Hz),
4.56 (2H, t, J ) 7.0 Hz), 4.32 (1H, dd, J ) 3.6 and 5.2 Hz), 4.11
(1H, q, J ) 3.2 Hz), 3.86 (1H, dd, J ) 2.8 and 12.4 Hz), 3.73 (1H,
dd, J ) 3.6 and 12.4 Hz), 3.17 (2H, t, J ) 6.9 Hz); HRMS (ESI-
MS m/z) calcd for C20H22N6O5Br (M + H)+, 505.0835; found,
505.0822; HPLC (system A) 15.2 min(98%), (system C) 12.2 min
(98%).
2-(3′′-(5′′-Iodo-indolyl)ethyloxy)adenosine (25). The yield was
56%: 1H NMR (CD3OD) δ 8.12 (1H, s) 7.89 (1H, dd, J ) 0.6 and
1.7 Hz), 7.32 (1H, dd, J ) 1.7 and 8.5 Hz), 7.16 (1H, s), 7.15 (1H,
dd, J ) 0.6 and 8.5 Hz), 5.89 (1H, d, J ) 5.8 Hz), 4.71 (1H, t, J
) 5.5 Hz), 4.55 (2H, t, J ) 7.0 Hz), 4.32 (1H, dd, J ) 3.6 and 5.2
Hz), 4.11 (1H, q, J ) 3.2 Hz), 3.86 (1H, dd, J ) 2.8 and 12.4 Hz),
3.73 (1H, dd, J ) 3.3 and 12.4 Hz), 3.16 (2H, t, J ) 6.9 Hz);
HRMS (ESI-MS m/z) calcd for C20H22N6O5I (M + H)+, 553.0696;
found, 553.0681; HPLC (system A) 19.0 min (98%), (system C)
13.1 min (98%).
2-(3′′-(5′′-Bromo-1′′-(p-toluenesulfonyl)indolyl)ethyloxy)aden-
osine (26). The yield was 68%: 1H NMR (CD3OD) δ 8.14 (1H,
s), 7.86 (1H, dd, J ) 0.6 and 8.8 Hz), 7.68-7.74 (3H, m), 7.63
(1H, s), 7.40 (1H, dd, J ) 1.8 and 8.8 Hz), 7.18 (2H, d with small
coupling, J ) 8.5 Hz), 5.89 (1H, d, J ) 6.0 Hz), 4.73 (1H, t, J )
5.6 Hz), 4.55 (2H, t, J ) 6.3 Hz), 4.33 (1H, dd, J ) 3.3 and 5.2
Hz), 4.12 (1H, q, J ) 3.0 Hz), 3.89 (1H, dd, J ) 2.9 and 12.5 Hz),
3.74 (1H, dd, J ) 3.3 and 12.4 Hz), 3.11 (2H, t, J ) 6.2 Hz), 2.27

Adenosine DeriVatiVes with Potent ActiVity
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1825
2-(3′′-(5′′-Hydroxyindolyl)ethyloxy)adenosine (34). The yield
was 31%; H NMR (CD3OD) δ 8.12 (1H, s), 7.15 (1H, dd, J )
0.261 mmol) was added, and the reaction mixture was stirred for
42 h at 80 °C. The solvent was evaporated to give a crude solid
that was subjected to preparative TLC developed with a mixture
of chloroform and methanol (5:1) to give 39 (2.2 mg, 28% yield in
1
0.6 and 8.8 Hz), 7.09 (1H, s), 7.01 (1H, dd, J ) 0.5 and 2.5 Hz),
6.65 (1H, dd, J ) 2.3 and 8.4 Hz), 5.90 (1H, d, J ) 5.8 Hz), 4.72
(1H, t, J ) 5.6 Hz), 4.54 (2H, t, J ) 7.4 Hz), 4.31 (1H, dd, J ) 3.3
and 5.2 Hz), 4.11 (1H, q, J ) 3.2 Hz), 3.86 (1H, dd, J ) 2.7 and
12.4 Hz), 3.74 (1H, dd, J ) 3.3 and 12.4 Hz), 3.13 (2H, t, J ) 7.3
Hz); HRMS (ESI-MS m/z) calcd for C20H22N6O6Na (M + Na)+,
465.1499; found, 465.1471; HPLC (system A) 5.5 min (98%),
(system C) 5.3 min (98%).
1
two steps). H NMR (CD3OD) δ 8.05 (1H, s), 7.60 (1H, d with
small coupling, J ) 7.1 Hz), 7.32 (1H, d with small coupling, J )
7.7 Hz), 7.14 (1H, s), 7.07 (1H, dt, J ) 1.3 and 7.6 Hz), 7.00 (1H,
dt, J ) 1.1 and 7.4 Hz), 5.87 (1H, d, J ) 6.0 Hz), 4.71 (1H, t, J )
5.6 Hz), 4.60 (2H, t, J ) 7.0 Hz), 4.30 (1H, dd, J ) 3.2 and 5.1
Hz), 4.11 (1H, q, J ) 3.0 Hz), 3.86 (1H, dd, J ) 2.6 and 12.5 Hz),
3.73 (1H, dd, J ) 3.2 and 12.5 Hz), 3.50-3.66 (2H, br m), 3.22
(2H, t, J ) 7.1 Hz), 1.26 (3H, t, J ) 7.3 Hz); HRMS (ESI-MS
m/z) calcd for C22H27N6O5 (M + H)+, 455.2043; found, 455.2063;
HPLC (system A) 19.5 min (99%), (system C) 13.5 min (99%).
(2R,3S,4S,5R)-6-Amino-5-ethylcarboxyamide-2-(3′′-indolyl)-
ethyloxy)-purin-9-yl)-tetrahydrofuran (40). Potassium hydroxide
(12.6 mg, 0.025 mmol) was added to a solution of 134 (7.0 mg,
0.0112 mmol) in methanol (1.5 mL), and the reaction mixture was
stirred at 70 °C overnight. The mixture was evaporated to a small
amount of solution that was subjected to preparative TLC developed
with a mixture of chloroform and methanol (5:1) to give 40 (1.7
2-(3′′-(Benzoimidazole-1′′-yl)ethyloxy)adenosine (35). The yield
was 57%: 1H NMR (CD3OD) δ 8.22 (1H, s), 8.10 (1H, s), 7.62
(2H, d with small coupling, J ) 8.2 Hz), 7.31 (1H, dt, J ) 1.2 and
7.6 Hz), 7.24 (1H, dt, J ) 1.3 and 7.6 Hz), 5.84 (1H, d, J ) 5.8
Hz), 4.63 - 4.74 (5H, m), 4.31 (1H, dd, J ) 3.2 and 5.1 Hz), 4.11
(1H, q, J ) 3.0 Hz), 3.86 (1H, dd, J ) 2.8 and 12.4 Hz), 3.73 (1H,
dd, J ) 3.0 and 12.4 Hz); HRMS (ESI-MS m/z) calcd for
C19H22N7O5 (M + H)+, 428.1682; found, 428.1691; HPLC (system
A) 4.9 min (99%), (system D) 8.3 min (99%).
2-(3′′-(Benzotriazole-1′′-yl)ethyloxy)adenosine (36). The yield
was 40%: 1H NMR (CD3OD) δ 8.10 (1H, s), 7.93(1H, dt, J ) 1.0
and 7.4 Hz), 7.80 (1H, dt, J ) 0.8 and 8.2 Hz), 7.52 (1H, ddd, J
) 1.0, 7.1 and 8.1 Hz), 7.38 (1H, ddd, J ) 1.0, 7.1 and 8.1 Hz),
5.83 (1H, d, J ) 5.8 Hz), 5.13 (2H, m), 4.82-4.92 (2H, m,
overlapped with HDO), 4.64 (1H, t, J ) 5.6 Hz), 4.31 (1H, dd, J
) 3.3 and 5.2 Hz), 4.10 (1H, q, J ) 3.1 Hz), 3.83 (1H, dd, J ) 2.8
and 12.6 Hz), 3.72 (1H, dd, J ) 3.3 and 12.4 Hz); HRMS (ESI-
MS m/z) calcd for C18H21N8O5 (M + H)+, 429.1635; found,
429.1642; HPLC (system A) 4.7 min (99%), (system C) 4.8 min
(99%).
1
mg, 33% yield). H NMR (CD3OD) δ 8.06 (1H, s), 7.56 (1H, d
with small coupling, J ) 8.0 Hz), 7.32 (1H, d with small coupling,
J ) 8.0 Hz), 7.11 (1H, s), 7.08 (1H, dt, J ) 1.2 and 8.1 Hz), 7.00
(1H, dt, J ) 1.1 and 8.1 Hz), 5.91 (1H, d, J ) 7.4 Hz), 4.74 (1H,
dd, J ) 4.8 and 7.3 Hz), 4.61 (2H, m), 4.41 (1H, d, J ) 1.9 Hz),
4.30 (1H, dd, J ) 1.7 and 4.9 Hz), 3.15-3.26 (4H, m), 0.99 (3H,
t, J ) 7.2 Hz); HRMS (ESI MS m/z) calcd for C22H26N7O5 (M +
H)+, 468.1995; found, 468.2015; HPLC (system A) 15.7 min (98%),
(system C) 11.4 min (98%).
Pharmacological Methods. [125I]N6-(4-amino-3-iodobenzyl)-
adenosine-5′-N-methyluronamide (I-AB-MECA; 2000 Ci/mmol),
[3H]CCPA (2-chloro-N6-cyclopentyladenosine, 42.6 Ci/mmol), [3H]-
CGS21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylcar-
boxamido-adenosine, 47 Ci/mmol), and [3H]cyclic AMP (40 Ci/
mmol) were from Amersham Pharmacia Biotech (Buckinghamshire,
U.K.).
Cell Culture and Membrane Preparation. CHO (Chinese
hamster ovary) cells expressing the recombinant human ARs26 were
cultured in DMEM supplemented with 10% fetal bovine serum,
100 units/mL penicillin, 100 µg/mL streptomycin, 2 µmol/mL
glutamine, and 800 µg/mL geneticin. Cells were harvested by
trypsinization. After homogenization and suspension, cells were
centrifuged at 500 g for 10 min, and the pellet was resuspended in
50 mM Tris-HCl buffer (pH 8.0) containing 10 mM MgCl2, 1 mM
EDTA, and 0.1 mg/mL CHAPS. The suspension was homogenized
with an electric homogenizer for 10 s and was then recentrifuged
at 20 000 g for 20 min at 4 °C. The resultant pellets were
resuspended in buffer in the presence of 3 units/mL adenosine
deaminase, and the suspension was stored at -80 °C until the
binding experiments. The protein concentration was measured using
the Bradford assay.43
Binding Assay. Human A1 and A2A Receptors: For binding
to human A1 receptors, [3H]CCPA (1 nM) was incubated with
membranes (40 µg/tube) from CHO cells stably expressing human
A1 receptors at 25 °C for 60 min in 50 mM Tris-HCl buffer (pH
7.4; MgCl2, 10 mM) in a total assay volume of 200 µL. Nonspecific
binding was determined using 10 µM of CPA. For human A2A
receptor binding, membranes (20 µg/tube) from HEK-293 cells
stably expressing human A2A receptors were incubated with 15 nM
[3H]CGS21680 at 25 °C for 60 min in 200 µL of 50 mM Tris-
HCl, pH 7.4, containing 10 mM MgCl2. NECA (10 µM) was used
to define nonspecific binding. Reaction was terminated by filtration
with GF/B filters.
Human A3 Receptor: For competitive binding assay, each tube
contained 100 µL of membrane suspension (20 µg protein), 50 µL
of [125I]I-AB-MECA (0.5 nM), and 50 µL of increasing concentra-
tions of the nucleoside derivative in Tris-HCl buffer (50 mM, pH
7.4) containing 10 mM MgCl2 and 1 mM EDTAPRIVATE.
Nonspecific binding was determined using 10 µM of Cl-IB-MECA
in the buffer. The mixtures were incubated at 25 °C for 60 min.
6-Guanidino-2-(3′′-indolylethyloxy)adenosine (37) and 6-Guani-
dino-2-(3′′-(1′′-(p-toluenesulfonyl)indolyl)ethyloxy)adenosine (38).
To a solution of guanidine hydrochloride (98 mg, 1.02 mmol) in
acetonitrile (2.2 mL) and N,N-dimethylformamide (1.1 mL) was
added sodium hydride (60%; 41.2 mg, 1.02 mmol) at room
temperature, and the reaction mixture was stirred overnight. This
guanidine solution was added to a mixture of compound 102 (46
mg, 0.0633 mmol) and 1,4-diazabicyclo[2.2.2]octane (14 mg,
0.0126 mmol), and the resulting mixture was stirred overnight at
110 °C and filtered. The filtrate was evaporated to give a crude
oil, which was subjected to preparative TLC developed with a
mixture of chloroform, methanol, and saturated aqueous ammonia
(2:1:0.3) to give 37 (2.3 mg, 8%) and 38 (9 mg, 23%) as an
amorphous solid.
1
37: H NMR (CD3OD) δ 8.09 (1H, s), 7.60 (1H, d with small
coupling, J ) 7.7 Hz), 7.32 (1H, d with small coupling, J ) 7.2
Hz), 7.16 (1H, s), 7.08 (1H, dt, J ) 1.3 and 7.6 Hz), 7.01 (1H, dt,
J ) 1.2 and 7.3 Hz), 5.90 (1H, d, J ) 6.0 Hz), 4.73 (1H, t, J ) 5.5
Hz), 4.54 (2H, t, J ) 7.1 Hz), 4.32 (1H, dd, J ) 3.3 and 4.9 Hz),
4.12 (1H, q, J ) 3.0 Hz), 3.87 (1H, dd, J ) 2.8 and 12.6 Hz), 3.73
(1H, dd, J ) 3.3 and 12.4 Hz), 3.24 (2H, t, J ) 7.4 Hz); HRMS
(ESI-MS m/z) calcd for C21H25N8O5 (M + H)+, 469.1948; found,
469.1952; HPLC (system B) 8.9 min (97%), (system D) 7.5 min
(97%).
1
38: H NMR (CD3OD) δ 8.25 (1H, s), 7.93 (1H, dd, J ) 1.4
and 7.4 Hz), 7.71 (2H, d with small coupling, J ) 8.5 Hz), 7.61
(1H, dd, J ) 1.4 and 7.1 Hz), 7.59 (1H, s), 7.30 (1H, dt, J ) 1.2
and 7.6 Hz), 7.24 (1H, dt, J ) 1.2 and 7.6 Hz), 7.18 (2H, d with
small coupling, J ) 8.5 Hz), 5.96 (1H, d, J ) 6.0 Hz), 4.74 (1H,
t, J ) 5.5 Hz), 4.59 (2H, t, J ) 6.5 Hz), 4.35 (1H, dd, J ) 3.4 and
5.1 Hz), 4.13 (1H, q, J ) 3.2 Hz), 3.89 (1H, dd, J ) 2.9 and 12.5
Hz), 3.76 (1H, dd, J ) 3.6 and 12.4 Hz), 3.18 (2H, t, J ) 6.5 Hz),
3.26 (3H, s); HRMS (ESI-MS m/z) calcd for C28H31N8O7S (M +
H)+, 623.2036; found, 623.2045; HPLC (system A) 16.3 min (97%),
(system C) 8.7 min (97%).
6-Ethylamino-2-(3′′-indolyl)ethyloxy)adenosine (39). To a
solution of 102 (28.3 mg, 0.0389 mmol) in DMF (1.4 mL) in a
sealed tube were added ethylamine hydrochloride (63.5 mg, 0.779
mmol) and N,N-diisopropylethylamine (0.271 mL), and the reaction
mixture was stirred at 140 °C overnight and evaporated to give an
oil. The oil was dissolved in methanol (1 mL), KOH (14.6 mg,

1826 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Adachi et al.
(5) Harada, H.; Asano, O.; Hoshino, Y.; Yoshikawa, S.; Matsukura, M.;
Kabasawa, Y.; Niijima, J.; Kotake, Y.; Watanabe, N.; Kawata, T.;
Inoue, T.; Horizoe, T.; Yasuda, N.; Minami, H.; Nagata, K.;
Murakami, M.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S.
2-Alkynyl-8-aryl-9-methyladenines as novel adenosine receptor
antagonists: Their synthesis and structure-activity relationships
toward hepatic glucose production induced via agonism of the A2B
receptor. J. Med. Chem. 2001, 44, 170-179.
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Preiss, B.; Schumacher, B.; Daly, J. W.; Mu¨ller, C. E. 1,8-
Disubstituted xanthine derivatives: Synthesis of potent A2B-selective
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(7) Elzein, E.; Kalla, R.; Li, X.; Perry, T.; Parkhill, E.; Palle, V.;
Varkhedkar, V.; Gimbel, A.; Zeng, D.; Lustig, D.; Leung, K.;
Zablocki, J. Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-
4-yl)-xanthine derivatives as high affinity and selective A2B receptor
antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 302-306.
(8) Varani, K.; Gessi, S.; Merighi, S.; Vincenzi, F.; Cattabriga, E.; Benini,
A.; Klotz, K.-N.; Baraldi, P. G.; Tabrizi, A. M.; Lennan, S. M.;
Leung, E.; Borea, P. A. Pharmacological characterization of novel
adenosine ligands in recombinant and native human A2B receptors.
Biochem. Pharmacol. 2005, 70, 1601-1612.
(9) Feoktistov, I.; Ryzhov, S.; Zhong, H.; Goldstein, A. E.; Matafonov,
A.; Zeng, D.; Biaggioni, I. Hypoxia modulates adenosine receptors
in human endothelial and smooth muscle cells toward an A2B
angiogenic phenotype. Hypertension 2004, 44, 649-654.
(10) Eltzschig, H. K.; Ibla, J. C.; Furuta, G. T.; Leonard, M. O.; Jacobson,
K. A.; Enjyoji, K.; Robson, S. C.; Colgan, S. P. Coordinated adenine
nucleotide phosphohydrolysis and nucleoside signaling in post-
Binding reactions were terminated by filtration through Whatman
GF/B filters under reduced pressure using a MT-24 cell harvester
(Brandell, Gaithersburgh, MD). Filters were washed three times
with 9 mL of ice-cold buffer. Radioactivity was determined in a
Beckman 5500B γ-counter.
Cyclic AMP Accumulation Assay. Intracellular cyclic AMP
levels were measured with a competitive protein binding method.44,45
CHO cells that expressed recombinant human A3ARs were
harvested by trypsinization. After centrifugation and resuspension
in medium, cells were plated in 24-well plates in 1.0 mL of medium.
After 24 h, the medium was removed and cells were washed three
times with 1 mL of DMEM, containing 50 mM HEPES, pH 7.4.
Cells were then treated with agonists and/or test compounds in the
presence of rolipram (10 µM) and adenosine deaminase (3 units/
mL). After 45 min, forskolin (10 µM) was added to the medium,
and incubation was continued an additional 15 min. The reaction
was terminated upon removal of the supernatant, and cells were
lysed upon the addition of 200 µL of 0.1 M ice-cold HCl. The cell
lysate was resuspended and stored at -20 °C. For determination
of cyclic AMP production, protein kinase A (PKA) was incubated
with [3H]cyclic AMP (2 nM) in K2HPO4/EDTA buffer (K2HPO4,
150 mM; EDTA, 10 mM), 20 µL of the cell lysate, and 30 µL of
0.1 M HCl or 50 µL of cyclic AMP solution (0-16 pmol/200 µL
for standard curve). Bound radioactivity was separated by rapid
filtration through Whatman GF/C filters and washed once with cold
buffer. Bound radioactivity was measured by liquid scintillation
spectrometry.
hypoxic endothelium: Role of ectonucleotidases and adenosine A2B
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receptors. J. Exp. Med. 2003, 198, 783-796.
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J.; Gause, W. C.; Tone, M.; Pacher, P.; Vizi, E. S.; Hasko´, G.
Adenosine augments IL-10 production by macrophages through an
A2B receptor-mediated posttranscriptional mechanism. J. Immunol.
2005, 175, 8260-8270.
Statistical Analysis. Binding and functional parameters were
calculated using Prism 4.0 software (GraphPAD, San Diego, CA).
IC50 values obtained from competition curves were converted to
Ki values using the Cheng-Prusoff equation.46 Data were expressed
as mean ( standard error.
(12) Wang, L.; Kolachala, V.; Walia, B.; Balasubramanian, S.; Hall, R.
A.; Merlin, D.; Sitaraman, S. V. Agonist-induced polarized trafficking
and surface expression of the adenosine 2b receptor in intestinal
epithelial cells: Role of SNARE proteins. Am. J. Physiol. 2004, 287,
G1100-G1107.
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Sitaraman, S. V. Interferon-gamma down-regulates adenosine 2b
receptor-mediated signaling and short circuit current in the intestinal
epithelia by inhibiting the expression of adenylate cyclase. J. Biol.
Chem. 2005, 280, 4048-4057.
(14) Lazarowski, E. R.; Tarran, R.; Grubb, B. R.; van Heusden, C. A.;
Okada, S.; Boucher, R. C. Nucleotide release provides a mechanism
for airway surface liquid homeostasis. J. Biol. Chem. 2004, 279,
36855-36864.
(15) Auchampach, J. A.; Jin, J.; Wan, T. C.; Caughey, G. H.; Linden, J.
Canine mast cell adenosine receptors: Cloning and expression of
the A3 receptors and evidence that degranulation is mediated by the
A2B receptor. Mol. Pharmacol. 1997, 52, 846-860.
Molecular Modeling. A published molecular model of the
human A2BAR in which (S)-PHP-NECA was docked38 was utilized
to study the binding mode of 28. Toward this goal, the ribose and
adenine moieties of 28 were superimposed upon the corresponding
moieties of (S)-PHP-NECA located inside the binding site. Then
(S)-PHP-NECA was removed from the receptor. The obtained
complex of the A2BAR with 28 was subjected to MCMM calcula-
tions using MacroModel software.39 The MCMM calculations were
performed for 28 and all residues located within 5 Å from the
ligand, using a shell of residues located within 2 Å. The following
parameters were used: MMFFs force field, water was used as an
implicit solvent, a maximum of 1000 iterations of the Polak-Ribier
conjugate gradient (PRCG) minimization method was used with a
convergence threshold of 0.05 kJ‚mol-1‚Å-1, the number of
conformational search steps ) 100, and the energy window for
(16) Feoktistov, I.; Ryzhov, S.; Goldstein, A. E.; Biaggioni, I. Mast cell-
mediated stimulation of angiogenesis: Cooperative interaction
between A2B and A3 adenosine receptors. Circ. Res. 2003, 92, 485-
492.
saving structures ) 1000 kJ‚mol-1
.
Acknowledgment. We thank Dr. John W. Daly, Dr. Peiran
Chen, Dr. Hea Ok Kim, and Dan Margulies (NIDDK) for helpful
discussions and Dr. John Lloyd (NIDDK) for mass spectral
determinations. We are grateful to the Cystic Fibrosis Founda-
tion and Microbial Chemistry Research Foundation for financial
support provided to H. Adachi. This research was supported
by the Intramural Research Program of the NIH, National
Institute of Diabetes and Digestive and Kidney Diseases.
(17) Yan, L.; Burbiel, J. C.; Maass, A.; Mu¨ller, C. E. Adenosine receptor
agonists: From basic medicinal chemistry to clinical development.
Expert Opin. Emerging Drugs 2003, 8, 537-576.
(18) Clancy, J. P.; Ruiz, F. E.; Sorscher, E. J. Adenosine and its nucleotides
activate wild-type and R117H CFTR through an A2B receptor-coupled
pathway. Am. J. Physiol. 1999, 276, C361-C369.
(19) Dubey, R. K.; Gillespie, D. G.; Mi, Z.; Jackson, E. K. Adenosine
inhibits PDGF-induced growth of human glomerular mesangial cells
via A2B receptors. Hypertension 2005, 46, 628-634.
(20) Mohsenin, A.; Blackburn, M. R. Adenosine signaling in asthma and
chronic obstructive pulmonary disease. Curr. Opin. Pulm. Med. 2006,
12, 54-59.
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