Structure-activity relationships of adenosines with heterocyclic N6-substituents

Article abstract of DOI:10.1016/j.bmcl.2007.10.028

Two series of N⁶-substituted adenosines with monocyclic and bicyclic N⁶ substituents containing a heteroatom were synthesized in good yields. These derivatives were assessed for their affinity ([³H]CPX), potency, and intrinsic activity (cAMP accumulation) at the A₁ adenosine receptor in DDT₁ MF-2 cells. In the monocyclic series, the N⁶-tetrahydrofuran-3-yl and thiolan-3-yl adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was found to be more potent. A series of nitrogen containing analogues showed varying properties, N⁶-((3R)-1-benzyloxycarbonylpyrrolidin-3-yl)adenosine (30) was the most potent at the A₁AR; IC₅₀ = 3.2 nM. In the bicyclic series, the effect of a 7-azabicyclo[2.2.1]heptan-2-yl substituent in the N⁶-position was explored. N⁶-(7-Azabicyclo[2.2.1]heptan-2-yl)adenosine (38) proved to be a reasonably potent A₁ agonist (K_i = 51 nM, IC₅₀ = 35 nM) while further substitution on the 7″-nitrogen with tert-butoxycarbonyl (31, IC₅₀ = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC₅₀ = 9.0 nM) gave highly potent A₁AR agonists.

Full text of DOI:10.1016/j.bmcl.2007.10.028

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6779–6784
Structure–activity relationships of adenosines
with heterocyclic N6-substituents
T. D. Ashton,a Kylee M. Aumann,b,c Stephen P. Baker,d
Carl H. Schiesserb,c and Peter J. Scammellsa,*
aDepartment of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381 Royal Parade,
Parkville, Vic. 3052, Australia
bSchool of Chemistry, The University of Melbourne, Vic. 3010, Australia
cBio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Vic. 3010, Australia
dDepartment of Pharmacology & Therapeutics, University of Florida College of Medicine, Box 100267, Gainesville, FL 32610, USA
Received 11 September 2007; revised 11 October 2007; accepted 11 October 2007
Available online 17 October 2007
Abstract—Two series of N6-substituted adenosines with monocyclic and bicyclic N6 substituents containing a heteroatom were syn-
thesized in good yields. These derivatives were assessed for their affinity ([3H]CPX), potency, and intrinsic activity (cAMP accumu-
lation) at the A1 adenosine receptor in DDT1 MF-2 cells. In the monocyclic series, the N6-tetrahydrofuran-3-yl and thiolan-3-yl
adenosines (1 and 26, respectively) were found to possess similar activities, whereas the corresponding selenium analogue 27 was
found to be more potent. A series of nitrogen containing analogues showed varying properties, N6-((3R)-1-benzyloxycarbonylpyrr-
olidin-3-yl)adenosine (30) was the most potent at the A1AR; IC50 = 3.2 nM. In the bicyclic series, the effect of a 7-azabicy-
clo[2.2.1]heptan-2-yl substituent in the N6-position was explored. N6-(7-Azabicyclo[2.2.1]heptan-2-yl)adenosine (38) proved to be
a reasonably potent A1 agonist (Ki = 51 nM, IC50 = 35 nM) while further substitution on the 700-nitrogen with tert-butoxycarbonyl
(31, IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34, IC50 = 9.0 nM) gave highly potent A1AR agonists.
Ó 2007 Elsevier Ltd. All rights reserved.
Adenosine is an endogenous ligand which acts in a non-
selective manner upon the four subtypes of adenosine
receptors (ARs), A1, A2A, A2B, and A3. All subtypes
are connected to the cyclic adenosine monophosphate
(cAMP) producing enzyme, adenylate cyclase, through
G-protein coupling. Activation of the A2A and A2B sub-
types leads to the stimulation of the cAMP production,
whereas activation of the A1 and A3 leads to an inhibi-
tion of this second messenger.
fect of adenosine has seen its utilization in the treatment
of paroxysmal supraventricular tachycardia (PSVT).4
However, as a result of adenosine’s short plasma half-
life, up to 35% of tachycardias have been reported to re-
cur within 2 min of termination. Accordingly, much re-
search has been undertaken in the development of
potent A1AR agonists with longer plasma half-lives.2,3
One of these agents, Tecadenoson (CVT-510, 1), is cur-
rently in Phase III clinical trials for the treatment of
PSVT.5,6
The A1AR has been implicated in many tissue types with
various physiological effects. In the cardiovascular sys-
tem, A1ARs mediate negative chronotropic, dromotro-
pic, and inotropic effects as well as having
cardioprotective effects.1–3 Activation decreases trans-
mitter release and locomotor activity in the central ner-
vous system (CNS); they also have anti-lipolytic
effects.1–3 Exploitation of the negative dromotropic ef-
High potency and selectivity for the A1AR can be
achieved through mono-substitution of exo-cyclic nitro-
gen of adenosine with a hydrophobic group. Adenosine
analogues with carbocyclic, heterocyclic or bicyclic N6-
substituents are among the more potent A1AR agonists
known [e.g., Tecadenoson (1) and ENBA (2),7 Fig. 1].
Substitution of this position also renders the molecule
more stable towards deamination by adenosine deami-
nase,8 and subsequently, improves half-life. The incor-
poration of a halogen in the 2-position9 and certain 50-
modifications such as the replacement of the hydroxyl
group with fluoro or chloro7 have also been found to
Keywords: Adenosine; A1AR agonist.
*
Corresponding author. Tel.: +61 3 9903 9542; fax: +61 3 9903
9582; e-mail: peter.scammells@vcp.monash.edu.au
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.028

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T. D. Ashton et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6779–6784
O
(i)
S
S
HO
HO
88%
NH2
NH2
5
6
(ii), 31%
S
(iii)
O
Ph
S
N
92%
NH2
7
(R)-8
Scheme 1. Reagents and conditions: (i) NaBH4, I2, THF, 66 °C; (ii)
ZnBr2, PhCN, 120 °C; (iii) a—conc. HCl, AcOH, 100 °C; b—KOH,
H2O, 100 °C.
tions to give 10 in excellent yield (94%) using methane-
sulfonyl chloride and triethylamine in CH2Cl2 (Scheme
2).19 Selenium was incorporated as a selenolane via tan-
dem nucleophilic displacement of the mesylate groups
using sodium selenide which was generated in situ from
selenium powder and NaBH4 in EtOH. Finally, the boc-
group was removed using 2 M HCl in Et2O to give the
(R)-3-aminoselenolane (12) as the hydrochloride salt in
quantitative yield.
Figure 1. A1 Adenosine receptor agonists.
be favorable for A1AR activity. Alternative substituent
patterns are well known to confer selectivity for the
other receptor subtypes.10–12
Commercially available (R)-3-aminopyrrolidine (13)
was used for the preparation of nitrogen analogues of
1. Conversion of the 13 to the corresponding Boc carba-
mate 14 was achieved as per Fujimoto and Hoshino
(Scheme 3).20 Replacement of di-tert-butyl dicarbonate
with dibenzyl dicarbonate gave the benzyl carbamate
15. The use of acetic anhydride gave the N-protected
acetamide 16. Due to the water solubility of acetyl
amine and the bis-acetylated by-product it was neces-
sary to purify this amine via column chromatography
whereas the others were obtained from extraction.
Previous work in our laboratory has demonstrated high
activities at the A1AR when a sulfur atom is present in
the N6-substituent (e.g. thiirane 3).13 Based on these
findings we investigated sulfur, selenium, and nitrogen
isosteres of other N6-substituted adenosines with high
affinity for the A1AR. Isosteres of Tecadenoson (1)
and 7-oxabicyclo[2.2.1]heptan-2-yl adenosine (4)14 were
targeted.
Adenosines bearing an N6-substituent are readily syn-
thesized from an appropriately functionalized purine
riboside and the corresponding amine. Accordingly,
we required the amines necessary to generate the target
compounds.
The nitrogen isosteres of ENBA (2) required a slightly
more involved synthesis of the amine synthons. The
extensive SAR data available on A1AR agonists indicate
the norborn-2-yl N6-substitution with the endo-confor-
mation in the 2-position leads to higher affinities.7 As
The synthesis of optically pure (R)-3-aminothiolane (8)
was prepared using the approach developed by Dehm-
low and Westerheide for the synthesis of the corre-
sponding (S)-isomer (Scheme 1).15 (R)-Methioninol (6)
was prepared smoothly in 88% yield via NaBH4/I2
reduction of D-methionine (5). Subsequent zinc bromide
catalyzed condensation in neat benzonitrile gave the re-
quired 4,5-dihydrooxazole (7) in low yield (31%), how-
ever this gave sufficient quantities to continue. Reflux
in harsh acidic conditions (conc. HCl in AcOH) cyclized
7 to give 8 as a phenyl amide which was subsequently
hydrolyzed, in the same pot, under basic conditions to
give the desired (R)-aminothiolane (8) in excellent yield
(92%).
a
result, endo-7-azabicyclo[2.2.1]heptan-2-yl amines
(i)
OH
OMs
HO
MsO
NHBoc
NHBoc
94%
9
10
(ii), 93%
Se
(iii)
Se
100%
NH2.HCl
NHBoc
11
The analogous selenolane was also conveniently ac-
cessed from an amino acid precursor. The conversion
of D-asparagine to the boc-protected D-asparagininol
(9) was achieved via known procedures.16–18 The diol
was then mesylated at the two terminal hydroxy posi-
12
Scheme 2. Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 °C, rt;
(ii) a—Se, NaBH4, EtOH, 78 °C; b—10, THF, 66 °C; (iii) HCl, Et2O,
30 °C.

T. D. Ashton et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6779–6784
6781
R
diation for 2 h. In instances when pressure in the micro-
wave vessel exceeded 13 bar, heating was ceased and the
reaction vessel was cooled and vented before being
heated again. This was sufficient to avoid a cumulative
build up in pressure. Benzyloxycarbonyl substituents
were subsequently introduced using either Cbz2O (for
22) or the relevant succinimide carbamate reagent (for
23 and 24).
HN
(i)
N
NH2
(R)-13
NH2
14
15
16
R = Boc 70%
R = Cbz 81%
R = Ac 97%
Scheme 3. Reagents and condition: (i) R2O, HCl, MeOH, 0 °C.
With the required amine synthons in hand, the corre-
sponding N6-substituted adenosines could be routinely
prepared from the commercially available 6-chloropu-
rine riboside (25) using standard SNAr conditions [N(i-
Pr)2Et, t-BuOH, Scheme 5]. Tecadenoson (1) was syn-
thesized using the aforementioned conditions with com-
mercially available (R)-(+)-3-aminotetrahydrofuran
toluene-4-sulfonate. In the case of the acetamide ana-
logue 29, difficulties with the separation of the N(i-
Pr)2Et from the product lead to the use of NH4OH solu-
tion as an alternative acid scavenger. Yields of the SNAr
reactions ranged from 67% to 99%.
were targeted. The synthesis of the ( )-methyl endo-7-
(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptyl-2-carbox-
ylate (17) has already been reported and provided an
ideal starting point as it contains the aza-bridge and
the 2-substituent in endo-stereochemistry.21,22 Basic
hydrolysis (LiOHÆH2O in MeOH:H2O) of the methyl es-
ter, 17, followed by acidification gave the free carboxylic
acid 18 in excellent yield (96%, Scheme 4). Further elab-
oration, through two complimentary synthetic routes,
provided our desired amine synthons. The tert-butoxy-
carbonyl substituted amine 20 was prepared in two
steps. This initially involved conversion of the carbox-
ylic acid 18 to the corresponding acyl azide using diph-
enylphosphorylazide (DPPA) and Et3N, followed by
Curtius rearrangement and trapping of the intermediate
isocyanate with benzyl alcohol to give the benzyl carba-
mate 19. Selective cleavage of the benzyl carbamate
(Pd–C under H2 atmosphere) afforded the target amine
( )-20 in 53% yield.
Successful deprotection of the secondary amine was of-
ten precluded by the sensitivity of the glycosidic bond.
Consequently,
6-chloro-9-(2,3,5-tris-O-(tert-butyldi-
methylsilyl)-b-D-ribofuranosyl)-9H-purine (35)23 was
used to form the per-silylated adenosine derivative 36
under standard SNAr conditions (Scheme 6). The use
of the TBS-protecting groups facilitated ZnBr2 pro-
moted deprotection of the boc-group by instating solu-
bility in the reaction media (CH2Cl2).24 This gave the
free amine 37 in good yield (78%) following partitioning
between CH2Cl2 and satd NaHCO3. Full deprotection,
to give the adenosine analogue 38, was then achieved
in 85% yield by warming in MeOH in the presence of
ammonium fluoride.
Benzyloxycarbonyl substituted amines 22–24 were also
prepared from the carboxylic acid 18. In this case it
was envisaged that acid hydrolysis of the isocyanate
formed in the Curtius rearrangement would also lead
to the removal of the boc-group from the 7-position to
give the diamine, 21. Our initial attempts at heating in
1 M HCl solution overnight were sufficient for removal
of the protecting group, but not harsh enough to fully
convert the isocyanate to the corresponding amine.
Eventually, full conversion to the 2-amine was achieved
using 4 M HCl, heating at 130 °C under microwave irra-
The affinity of the compounds was determined by their
ability to displace [3H]CPX binding at the A1AR in
DDT1 MF-2 cell membranes and also [3H]ZM241385
BocN
BocN
(iii)
65%
NH2
20
NHCbz
19
(ii)
75%
BocN
BocN
(i)
96%
COOMe
COOH
18
17
(iv)
HN
RN
76%
(v)
NH2.2HCl
21
NH2
22 R = Cbz
53%
23 R = 2-Cl-Cbz 25%
24 R = 2-Br-Cbz 56%
Scheme 4. Reagents and conditions: (i) LiOHÆH2O, MeOH:H2O (1:1), rt; (ii) a—DPPA, Et3N, Toluene 100 °C; b—BnOH, 100 °C; (iii) H2, Pd–C
(10%), MeOH, rt; (iv) a—DPPA, Et3N, MeCN; b—4 M HCl, MW, 130 °C, 2 h; (v) NaHCO3, MeOH:H2O (2:1), 0 °C, Cbz2O for 22; Z[2-Cl]-OSu for
23; Z[2-Br]-OSu for 24.

6782
T. D. Ashton et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6779–6784
X
*
68%
68%
96%
93%
67%
86%
X = O
1
* = R
HN
N
X = S
26 * = R
27 * = R
28 * = R
29 * = R
30 * = R
N
N
N
X = Se
X = NBoc
X = NAc
X = NCbz
HO
(i)
(i)
O
Cl
N
HO OH
N
N
N
HO
O
NR
HO OH
*
25
HN
31 * = endo
32 * = endo
33 * = endo
34 * = endo
R = Boc
R = Cbz
98%
91%
N
N
HO
R = 2-Cl-Cbz 75%
R = 2-Br-Cbz 87%
N
O
N
HO OH
Scheme 5. Reagents and conditions: (i) amine or amine salt, N(i-Pr)2Et, t-BuOH, 83 °C (for 29; NH4OH, t-BuOH, 83 °C).
ents exhibited a larger range and interesting properties
NBoc
at the A1AR. When the secondary amine of the N6-pyr-
rolidinyl group was tert-butoxycarbonyl substituted
(compound 28), it displayed poor affinity and potency
(Ki = 929 nM, IC50 = 380 nM). However, when an acet-
amide was present (compound 29), the affinity was sim-
ilar (Ki = 803 nM) but the potency increased five-fold
(IC50 = 85 nM). Even more significant, the benzyl carba-
mate 30 showed a three-fold improvement in affinity
(Ki = 288 nM, cf. 28) and over two orders of magnitude
enhancement in potency, with an IC50 of 3.2 nM. The
differential between affinity and potency may be due
to structurally related alterations in the efficacy of the
compounds. According to receptor occupation theory,
the potency of an agonist is dependent upon both affin-
ity and efficacy where the latter is estimated from the
relationship between receptor occupancy and response.
Thus there will be an increase in efficacy and hence po-
tency when a fewer number of receptors are activated
to produce a given level of response. All of the pyrrol-
idine derivatives were full agonists at the A1AR as they
produced the same maximal inhibition of (ꢀ)-isoprote-
renol-stimulated cAMP accumulation as did CPA. The
N6-monocyclic adenosine analogues had relatively
weak affinity for the A2AAR, with only 26 and 27
(Ki = 9700 and 5500 nM, respectively) possessing a Ki
below 100,000 nM. Thus the A1AR selectivity versus
the A2AAR ranged from about 140-fold for 26 to over
4700-fold for compounds 1 and 28–30.
Cl
N
HN
N
N
N
N
N
N
N
(i)
TBSO
TBSO
O
O
84%
TBSO OTBS
TBSO OTBS
35
36
(ii), 78%
NH
NH
HN
N
HN
N
N
N
N
(iii)
HO
TBSO
N
N
N
O
O
85%
HO OH
38
TBSO OTBS
37
Scheme 6. Reagents and conditions: (i) 20, N(i-Pr)2Et, t-BuOH, 83 °C;
(ii) ZnBr2, CH2Cl2, rt; (iii) NH4F, MeOH, 55 °C.
binding at the A2AAR in PC-12 membranes (Tables 1
and 2).25,26 These assays contained 50-guanylyl-imidodi-
phosphate to maintain the receptor in the agonist low
affinity state. Using intact DDT cells, each compound
was tested for potency to inhibit (ꢀ)-isoproterenol-stim-
ulated cAMP accumulation. The maximal inhibition of
cAMP accumulation (intrinsic activity) by the com-
pounds was also determined by comparison to the clas-
sical A1 agonist, N6-cyclopentyladenosine (CPA).
The N6-aza-bicyclic analogues showed considerable
variation in interaction with and agonist effect at the
A1AR (Table 2). The free amine analog 38 exhibited
relatively high affinity and potency (51 and 35 nM,
respectively). The tert-butyl carbamate 31 has about
the same affinity as 38 but a 14-fold higher potency
whereas the Cbz analogue 32 has a two- to three-fold
decrease in both affinity and potency as compared to
38. 2-Chloro substitution of Cbz (compound 33) re-
sulted in a 4.8- and 3.7-fold decrease in affinity and po-
tency, respectively, in relation to the unsubstituted
analogue 32. In contrast, 2-bromo substitution of
Cbz (34) showed a 7.8-fold increase in affinity and
Consistent with a previous report, Tecadenoson (1)
showed nanomolar affinity and potency at the A1AR
and was a full agonist as compared to CPA.5 When a
chalcogen is present as part of the cyclic N6-substituent
high affinity for the A1AR is observed. N6-(R-Thiolan-3-
yl)adenosine (26) possessed similar affinity and potency
to 1. The corresponding selenolane 27 also showed low
nanomolar affinity with a Ki = 8 nM as well as high po-
tency (IC50 = 1.9 nM). Pyrrolidine based N6-substitu-

T. D. Ashton et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6779–6784
Table 1. Ki, IC50 and intrinsic activity (IA) of N6-monocyclic adenosine derivatives
6783
X
*
HN
N
N
N
N
HO
O
HO OH
Entry
X
No.
A1AR Dataa
A2AAR Datab
Ki (nM)
IC50 (nM)
IA
Ki (nM)
1
2
3
4
5
6
O
1
26
27
28
29
30
65 16 (3)
70 9 (3)
8.2 1.2 (3)
5.3 2 (4)
1.00 0.02 (3)
0.98 0.01 (4)
1.01 0.02 (4)
0.99 0.04 (3)
1.00 0.05 (4)
0.99 0.03 (3)
>100,000 (4)
9700 1200 (4)
5500 500 (3)
>100,000 (4)
>100,000 (4)
>100,000 (4)
S
Se
8
2 (4)
1.9 0.1 (4)
380 84 (3)
85 24 (4)
3.2 0.4 (3)
NBoc
NAc
NCbz
929 397 (3)
803 341 (4)
288 127 (3)
a The Ki values were calculated from the concentration of the compounds that initiated [3H]CPX binding by 50%. The assays were performed in the
presence of Gpp(NH)p and therefore the Ki values represent the agonist low affinity binding state. IC50 values are concentrations of compounds
that inhibited (ꢀ)-isoproterenol (1 lM)-stimulated cAMP accumulation by 50% in DDT cells. The IA is the maximal inhibition of (ꢀ)-isopro-
terenol-stimulated cAMP accumulation as compared to the maximum inhibition by CPA which was set at 1.00. Numbers in parentheses are the n.
b The Ki values were calculated from the concentration of compounds that inhibited [3H]ZM241385 binding by 50%. Numbers in parentheses are the
n. The notation of >100,000 indicates that at the highest concentration of the compounds used (100,000 nM), less than 50% inhibition of
[3H]ZM241385 binding was observed. NECA was included as a standard and was found to have a Ki of 110 10 nM in this assay.
Table 2. Ki, IC50 and intrinsic activity (IA) of N6-bicyclic adenosine derivatives
NR
*
HN
N
N
HO
N
N
O
HO OH
Entry
R
No.
A1AR Dataa
A2AAR Datab
Ki (nM)
IC50 (nM)
IA
Ki (nM)
1
2
3
4
5
H
Boc
38
31
32
33
34
51 16 (5)
32 8 (5)
35 9 (4)
2.5 0.5 (4)
68 13 (6)
254 58 (6)
9.0 2.7 (6)
1.02 0.04 (4)
1.01 0.02 (4)
1.01 0.02 (6)
0.86 0.04 (6)
0.97 0.02 (6)
7800 1500 (3)
34,700 3,900 (3)
>100,000
Cbz
2-Cl-Cbz
2-Br-Cbz
164 9 (3)
783 73 (3)
21 4 (3)
>100,000
>100,000
a The Ki values were calculated from the concentration of the compounds that initiated [3H]CPX binding by 50%. The assays were performed in the
presence of Gpp(NH)p and therefore the Ki values represent the agonist low affinity binding state. IC50 values are concentrations of compounds
that inhibited (ꢀ)-isoproterenol (1 lM)-stimulated cAMP accumulation by 50% in DDT cells. The IA is the maximal inhibition of (ꢀ)-isopro-
terenol-stimulated cAMP accumulation as compared to the maximum inhibition by CPA which was set at 1.00. Numbers in parentheses are the n.
b The Ki values were calculated from the concentration of compounds that inhibited [3H]ZM241385 binding by 50%. Numbers in parentheses are the
n. The notation of >100,000 indicates that at the highest concentration of the compounds used (100,000 nM), less than 50% inhibition of
[3H]ZM241385 binding was observed. NECA was included as a standard and was found to have a Ki of 110 10 nM in this assay.
7.6-fold increase in potency as compared to 32. As with
the pyrrolidine analogues, all of the N6-aza-bicyclic
derivatives produced the same maximal inhibition of
cAMP accumulation as CPA indicating that these
compounds acted as full agonists at the A1AR. As ob-
served for the monocyclic series, the adenosines with
bicyclic N6-substituents also proved to be selective for
the A1AR over the A2AAR.
a heteroatom were synthesized and evaluated as A1AR
agonists. In the monocyclic series, it was found that
N6-((R)-seleolan-3-yl)adenosine (27) had the highest
affinity, potency and selectivity. In the bicyclic
series, N6-(7-azabicyclo[2.2.1]heptan-2-yl)adenosine
(38) proved to be a reasonably potent A1 agonist
(Ki = 51 nM, IC50 = 35 nM) while further substitution
on the bridging nitrogen with tert-butoxycarbonyl (31,
IC50 = 2.5 nM) and 2-bromobenzyloxycarbonyl (34,
IC50 = 9.0 nM) gave highly potent and selective (as com-
pared to the A2A) A1AR agonists.
In summary, two series of N6-substituted adenosines
with monocyclic and bicyclic N6-substituents containing

6784
T. D. Ashton et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6779–6784
10. Baraldi, P. G.; Fruttarolo, F.; Tabrizi, M. A.; Romagnoli,
Acknowledgments
R.; Preti, D.; Bovero, A.; Pineda de Las Infantas, M. J.;
Moorman, A.; Varani, K.; Borea, P. A. J. Med. Chem.
2004, 47, 5535.
The authors wish to thank the ARC Centre for Free
Radical Chemistry and Biotechnology for financial sup-
port and Dr. Simon Egan and Dr. Jenny Taylor for the
acquisition of the MS data.
11. Baraldi, P. G.; Preti, D.; Tabrizi, M. A.; Fruttarolo, F.;
Romagnoli, R.; Carrion, M. D.; Cara, L. C. L.; Moor-
man, A. R.; Varani, K.; Borea, P. A. J. Med. Chem. 2007,
50, 374.
12. Adachi, H.; Palaniappan, K. K.; Ivanov, A. A.; Bergman,
N.; Gao, Z-G.; Jacobson, K. A. J. Med. Chem. 2007, 50,
1810.
Supplementary data
13. Hutchinson, S. A.; Baker, S. P.; Linden, J.; Scammells, P.
J. Bioorg. Med. Chem. 2004, 12, 4877.
14. Hutchinson, S. A.; Baker, S. P.; Scammells, P. J. Bioorg.
Med. Chem. Lett. 1999, 9, 933.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.10.028.
15. Dehmlow, E. V.; Westerheide, R. Synthesis 1992, 10, 947.
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