2′-O-alkyl derivatives and 5′-analogues of 5-aminoimidazole-4- carboxamide-1-β-d-ribofuranoside (AICAR) as potential Hsp90 inhibitors

Article abstract of DOI:10.1002/ejoc.200900797

Some selective preparations of AICAR-related compounds modified at the 2′- or 5′-position of the ribose moiety are reported herein. In particular, 5′-azido, 5′-amino, 5′-O-benzyl and a series of 2′-O-alkylated AICAR derivatives have been synthesized. Thes

Full text of DOI:10.1002/ejoc.200900797

FULL PAPER
DOI: 10.1002/ejoc.200900797
2Ј-O-Alkyl Derivatives and 5Ј-Analogues of 5-Aminoimidazole-4-carboxamide-
1-β- -ribofuranoside (AICAR) as Potential Hsp90 Inhibitors
D
Antonio Bracci,[a][‡] Giorgio Colombo,[b] Fiamma Ronchetti,[a] and Federica Compostella*[a]
Keywords: Antitumor agents / Ribonucleosides / Metabolism / Inhibitors
Some selective preparations of AICAR-related compounds
structural modifications on its ability to inhibit Hsp90, one of
modified at the 2Ј- or 5Ј-position of the ribose moiety are re- the biological targets for the development of anticancer
ported herein. In particular, 5Ј-azido, 5Ј-amino, 5Ј-O-benzyl
and a series of 2Ј-O-alkylated AICAR derivatives have been
synthesized. These compounds were derived from appropri-
ately functionalized inosines by opening the pyrimidine ring
at the hypoxanthine residue. The target derivatives were de-
signed with the purpose of studying the effect of AICAR
agents. Nevertheless, the development of AICAR-like com-
pounds is an appealing objective also because of their poten-
tial therapeutic application in the field of metabolic studies.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
heart,[4] or to the fact that AICAR decreases intracellular
pH by inhibition of the Na+/H+ exchanger NHE1, as has
recently been demonstrated.[5] Indeed, it is now recognized
that AICAR alters glucose uptake differently in different
tissues and cells, and some of the biological effects are inde-
pendent of AMPK activation. Furthermore, AICAR en-
hances extracellular adenosine levels under the conditions
of net ATP breakdown and, therefore, in light of the cardio-
and neuroprotective properties of adenosine, it may have
therapeutic potential for neuropsychiatric symptoms gen-
erally associated with chronically low levels of adenosine.[6]
However, the usefulness of AICAR to treat human diseases
is limited by its poor bioavailability[7] and non-specificity[8]
and the development of AICAR-related more specific and
cell-permeable AMPK activators is required to investigate
the cellular functions of AMPK or to develop novel leads
with improved therapeutic profiles.
Introduction
In recent years there has been considerable interest in
5-aminoimidazole-4-carboxamide-1-β--ribofuranoside
(AICAR, AICA riboside, acadesine; see 1 in Figure 1),
which is a structural analogue of adenosine nucleotide
(AMP). Indeed, this molecule has a number of effects on
cell metabolism. Some are related to its ability to activate
AMP-activated protein kinase (AMPK), an energy-sensing
enzyme that controls glucose and lipid metabolism.[1] In
this context, AICAR can enter most cell types where it is
phosphorylated to AICA ribotide (ZMP), which mimics the
effect of AMP, increasing the activity of AMPK. The acti-
vation of AMPK promotes ATP-generating pathways and
results in decreased hepatic glucose production, reduced
fatty acid synthesis, increased muscle glucose disposal and
improved insulin sensitivity.[2] As a consequence, AICAR,
as an AMPK activator, is a promising therapeutic for meta-
bolic diseases such as type 2 diabetes and obesity in which
glucose uptake and use are impaired. Moreover, AICAR
can enter cardiac cells and improves heart recovery after
ischemia, even if the precise mechanism of the cardioprotec-
tion remains uncertain.[3] The benefits might arise from
AMPK activation, which induces glucose uptake in the
[a] Dipartimento di Chimica, Biochimica e Biotecnologie per la
Medicina, Università di Milano,
Via Saldini 50, 20133 Milano, Italy
Fax: +39-02-50316036
E-mail: federica.compostella@unimi.it
[b] Istituto di Chimica del Riconoscimento Molecolare, CNR,
Via Mario Bianco 9, 20131 Milano, Italy
Figure 1. Structures of AICAR (1) and AICAR derivatives 2–7.
[‡] Present address: Dipartimento di Scienze Chimiche, Alimentari,
Farmaceutiche e Farmacologiche, Università del Piemonte Ori-
entale, Via Bovio 6, 28100 Novara, Italy
More recently, within the frame of AMPK activation,
AICAR has been proposed as an anticancer agent.[9] Never-
theless, a different study revealed that AICAR could exert
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900797.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Bracci, G. Colombo, F. Ronchetti, F. Compostella
FULL PAPER
antitumour activity through a different biological pathway group points directly towards a hydrophobic channel that
in cancer cells.[10] In particular, AICAR emerged as an an- could be occupied by a hydrophobic moiety (Figure 2).
tagonist of Heat Shock Protein 90 (Hsp90), an ATPase- Consequently, the presence of an apolar substituent should
driven molecular chaperone that oversees the correct con- improve the hydrophobic contribution to the free energy of
formational development of polypeptides and protein re- association.
folding.[11] Hsp90 has recently attracted increasing attention
Besides being of interest as possible new Hsp90 inhibi-
in the development of rational cancer therapy due to its role tors, these new compounds can allow the metabolic studies
at the crossroads of multiple signalling pathways associated of pathways described previously and open the way to the
with cancer cell proliferation and cell viability. AICAR anti- correlation of metabolic profiles and the functional–struc-
cancer activity reflects the inhibition of the chaperone func- tural properties of small molecule effectors.
tion by the destabilization of multiple Hsp90 client proteins
with a cell killing effect selective for tumour cells in which
Hsp90 concentration and ATPase activity are highly upreg-
ulated.[12] Computational studies, confirmed by binding ex-
Results and Discussion
periments and the evaluation of AICAR effects on cancer
and normal cells,[10] have shown that AICAR engages the
The synthetic approach that we proposed for the prepa-
ATP-binding pocket of the N-terminal domain of Hsp90 ration of AICAR derivatives 2–7 was based on the obtain-
and highlighted AICAR/Hsp90 interactions to evidence ment of these compounds not by derivatization of AICAR
possible structural determinants for inhibitory activity, thus itself (see for example ref.[13]) but from properly function-
suggesting sites for structural modifications that could be alized and more manageable inosine derivatives. The syn-
useful for the development of improved Hsp90 antagonists thesis of AICAR from N1-substituted inosine is in fact now-
(Figure 2).
adays utilized and preferred over other older protocols[14]
due to its higher yields and easier isolation procedures.[15]
According to the literature, when the N1-position of the hy-
poxanthine ring is substituted with a 2,4-dinitrophenyl[16]
or a (2-methoxyethoxy)methyl (MEM)[17] group, treatment
with alkali, aqueous NaOH or ethylenediamine, respec-
tively, allows the simultaneous opening of the pyrimidine
ring and removal of the N1 substituent to afford AICAR.
The first time we tackled the synthesis of these derivatives
we explored these two different approaches. However, after
preliminary attempts, in spite of slightly lower yields, we
preferred the synthesis via the N-MEM-inosine because
product purification was feasible and easier.
Our synthetic efforts for the preparation of the target de-
rivatives started with the synthesis of the 5Ј-modified com-
pounds 2 and 3, which were obtained from the known
azido-inosine 8, in turn derived from commercially available
Figure 2. AICAR (yellow) in the active site of Hsp90.
In this paper we report the synthesis of AICAR deriva- 9, as reported previously.[18] The reaction of inosine 8 with
tives 2–7 (Figure 1),[13] designed to examine possible struc- MEMCl in a mixture of dichloromethane and dimethyl-
ture–activity relationships that modulate the interaction of formamide in the presence of Hünig’s base afforded the N1-
AICAR with the Hsp90 receptor. In particular, the modifi- MEM-inosine derivative 10 (Scheme 1). At this stage we de-
cations planned at the 5Ј-position of the riboside, where the cided first to perform the opening of the pyrimidine ring
5Ј-OH group has been replaced with an azido or an amino and then to remove the 2Ј,3Ј-protecting group in order to
group (compounds 2 and 3, respectively), were based on the simplify the purification of the AICAR derivative. Thus,
fact that the 5Ј-OH is in direct contact with an aspartate treatment of 10 with 0.2  NaOH at 80 °C gave intermedi-
residue (D93 on Hsp90; Figure 2), which suggests that the ate 11 in 44% yield. The opening of the pyrimidine ring is
1
substitution of this functional group with other polar ones supported by the disappearance from the H NMR spec-
may modulate the molecular recognition interaction. In trum of the singlet corresponding to the 2-H hypoxanthine
contrast, modification of the 5Ј-position with a bulky group hydrogen at around 8 ppm and the appearance of two
such as benzyl (compound 4) should have an opposite ef- broad singlets corresponding to the CONH2 and NH2 pro-
fect: steric hindrance and the disruption of hydrogen-bond- ton signals. The desired 5Ј-azido-AICAR 2 was finally ob-
ing potential would in fact oppose the favourable interac- tained after high-yielding deprotection of the isopropylidene
tion with D93.
acetal mediated by aqueous HCl. Compound 2 was in turn
Compounds 5–7 are all ethers in which the 2Ј-OH group subjected to hydrogenolysis at atmospheric pressure to give
of the furanoside has been alkylated with a methyl, butyl the 5Ј-amino-AICAR 3 in a quantitative yield. Compounds
or benzyl residue, respectively. Analysis of the structure of 2 and 3 were both purified by column chromatography,
the AICAR/Hsp90 complex has shown that this hydroxy which ensured the high quality of the final derivatives.
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AICAR Derivatives as Potential Hsp90 Inhibitors
Scheme 1. Reagents and conditions: i. ref.[18]; ii. MEMCl, DIPEA, DCM/DMF, 0 °C, 30 min, 45%; iii. NaOH, EtOH/H2O, 80 °C, 8 h,
44%; iv. HCl, THF/H2O, 24 h, 96%; v. H2, Pd/C, 18 h, quant.; vi. Ac2O, Py, 0 °C, 3 h, then MEMCl, DIPEA, DCM, 0 °C, 2 h, 44 %;
vii. NH3, MeOH, 1 h, then NaH, BnBr, DMF, 0 °C, 1 h, 76%; viii: NaOH, EtOH/H2O, 80 °C, 3 h, 47%; ix. HCl, THF/H2O, 18 h, 83%.
We then turned our attention to the 5Ј-O-benzyl deriva- lows the simultaneous protection of the 3Ј and 5Ј functions
tive 4, which was also obtained from 9 after initial conver- of the ribose unit and is widely used in nucleotide chemis-
sion to the N-MEM-protected inosine 12 by acetylation fol- try.[19] Thus, triol 15 was regioselectively protected in high
lowed by the introduction of the MEM group onto the hy- yield by reaction with the TIPDSCl2 silylating agent in di-
poxanthine ring by standard procedures. Compound 12 was methylformamide to give 16, which was converted into the
then deacetylated and etherified in good yield with benzyl desired 2Ј-O-alkylated compounds 17–19 by treatment with
bromide in dimethylformamide to give 13, which was sub- the corresponding alkyl halides and sodium hydride in di-
jected to the alkaline hydrolytic ring-opening of the hetero- methylformamide. The target ethers 5–7 were finally reco-
cycle to give product 14 in quite a satisfactory yield. Finally, vered in an acceptable yield by treatment with aqueous
acidic cleavage of the isopropylidene group allowed the 5Ј- NaOH, which allows simultaneously both the pyrimidine
O-benzyl-AICAR 4 to be obtained in high yield and purity. ring-opening and the TIPDS removal.
The other series of AICAR analogues, namely the 2Ј-O-
alkyl derivatives (Scheme 2), were obtained starting from
the known N1-MEM-inosine 15.[17] The protection of the
Conclusions
purine N1 atom was necessary to avoid unwanted derivati-
We have reported new syntheses of AICAR-related com-
zation in the subsequent alkylation step and, at the same
pounds based on consistent protocols that ensure easy man-
time, the MEM group provides the necessary activation for
agement of these otherwise difficult-to-handle compounds.
the subsequent cleavage of the pyrimidine ring. The desired
Targets 2–7 were designed with the purpose of studying the
selective 2Ј-O-alkylation was ensured by the use of the
effect of structural modifications on the molecular recogni-
1,1,3,3-tetraisopropyldisiloxane (TIPDS) group, which al-
tion of Hsp90. The binding of the new derivatives to the N-
terminal domain of Hsp90 is presently being investigated
by NMR techniques with the aim of defining the most im-
portant binding poses and the effect of different ligands on
the dynamics of the receptor. Note that, besides our current
interest in the Hsp90 protein, the preparation of AICAR-
like compounds is an appealing objective because of their
potential therapeutic application in the field of metabolic
studies, as described in the Introduction. Moreover, having
new manageable ways to access a set of chemically diverse
but related compounds can allow the effects of structural
and functional modification on the metabolic pathways of
small molecule effectors to be ascertained. As a conse-
quence, there is a clear interest in identifying procedures for
their preparation.[20] As an example, the ether derivatives
5–7 display increased oral bioavailability and/or brain pene-
tration with respect to AICAR,[13] whereas the azido deriv-
ative 2 or the 5Ј-O-benzyl-AICAR 4 could be useful tools
for understanding whether the biological pathway in which
AICAR is involved necessarily requires the initial phos-
phorylation to ZMP.
Scheme 2. Reagents and conditions: i. TIPDSDCl2, Im, DMF, 5 h,
0 °C, 93%; ii. NaH, DMF, RX, 40–60%; iii. NaOH, EtOH/H2O,
80 °C, 2–8 h, 25–58%.
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A. Bracci, G. Colombo, F. Ronchetti, F. Compostella
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(s, 3 H, CH3), 1.35 (s, 3 H, CH3) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 166.9, 142.6, 128.1, 115.8, 115.0, 90.7, 82.9, 82.6, 80.3,
51.8, 27.1, 25.2 ppm. MS (ESI, positive-ion mode): m/z (%) = 669.0
(100) [2M + Na]+, 346.1 (40) [M + Na]+. C12H17N7O4 (323.31):
calcd. C 44.58, H 5.30, N 30.33; found C 44.73, H 5.31, N 30.48.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
AVANCE-500 spectrometer at a sample temperature of 298 K.
Chemical shifts are reported on the δ (ppm) scale and were mea-
sured relative to TMS as the internal reference. Optical rotations
were measured with a Perkin–Elmer 241 polarimeter at 20 °C. MS
spectra were recorded with a Thermo Quest Finnigan LCQdeca
ion trap mass spectrometer equipped with a Finnigan ESI interface
using positive electrospray ionization as indicated. All reactions
were monitored by TLC on silica gel 60 F-254 plates, spots being
developed with 5% sulfuric acid in methanol/water (1:1) or with
a phosphomolybdate reagent. Flash column chromatography was
performed on silica gel 60 (230–400 mesh). Organic solutions were
dried with sodium sulfate. All evaporations were carried out under
reduced pressure at 40 °C. All reagents were bought at the highest
commercial quality and used without further purification except
where noted. Dry solvents were distilled prior to use. THF was
distilled from sodium, dichloromethane and pyridine were distilled
from calcium hydride and DMF was dried with molecular sieves
(4 Å). NaH was washed three times with hexane prior to use.
5-Amino-1-(5Ј-azido-5Ј-deoxy-1-β-D-ribofuranosyl)imidazole-4-carb-
oxamide (2): Compound 11 (0.21 g, 0.65 mmol) was treated with a
solution of THF/1  aq. HCl (1:1, 6.5 mL) for 24 h and then
NaHCO3 was added portionwise until the solution reached a basic
pH value. The crude was diluted with EtOH (20 mL) and, after
filtration through a pad of Celite, the solvent was evaporated under
reduced pressure. Product 2 (0.17 g, 96%) was recovered as a white
foam after purification by flash chromatography (CHCl3/MeOH,
9:1). [α]2D0 = +1.1 (c = 1.0, MeOH). 1H NMR (500 MHz, CD3OD):
δ = 7.39 (s, 1 H, arom.), 5.56 (d, J1Ј,2Ј = 5.6 Hz, 1 H, 1Ј-H), 4.46–
4.37 (m, 1 H, 2Ј-H), 4.21–4.11 (m, 2 H, 3Ј-H, 4Ј-H), 3.70 (dd, J4Ј,5Јa
= 3.1, J5Јa,5Јb = 13.3 Hz, 1 H, 5Ј-Ha), 3.60 (dd, J4Ј,5Јb = 3.6, J5Јa,5Јb
= 13.3 Hz, 1 H, 5Ј-Hb) ppm. 13C NMR (125.8 MHz, CD3OD): δ
= 169.3, 145.4, 129.8, 113.6, 89.5, 84.6, 75.0, 72.1, 53.4 ppm. MS
(ESI, positive-ion mode): m/z (%) = 589.0 (100) [2M + Na]+, 306.1
(45) [M + Na]+. C9H13N7O4 (283.24): calcd. C 38.16, H 4.63, N
34.62; found C 38.04, H 4.65, N 34.52.
5Ј-Azido-5Ј-deoxy-2Ј,3Ј-O-isopropylidene-1-[(2-methoxyethoxy)meth-
yl]inosine (10): DIPEA (0.72 mL, 4.12 mmol) was added in one
portion to a solution of azido-inosine 8[18] (1.14 g, 3.44 mmol) in
DCM/DMF (3:1, 34 mL) and the mixture was cooled to 0 °C.
MEMCl (0.43 mL, 3.78 mmol) was then added dropwise over a
period of 20 min. After 30 min, the reaction was quenched by the
addition of brine and the aqueous phase extracted with DCM
(2ϫ30 mL). The combined organic layers were dried with sodium
sulfate and the solvents evaporated to dryness. The crude was puri-
fied by flash chromatography (DCM/acetone, 6:4) after filtration
through a short column (CHCl3/MeOH, 92:8) to afford compound
10 (0.65 g, 45%) as a white foam. [α]2D0 = +47.5 (c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 8.13 (s, 1 H, arom.), 7.91 (s, 1
H, arom.), 6.06 (d, J1Ј,2Ј = 2.6 Hz, 1 H, 1Ј-H), 5.52 (m, 2 H,
NCH2O), 5.25 (dd, J1Ј,2Ј = 2.6, J2Ј,3Ј = 6.4 Hz, 1 H, 2Ј-H), 4.95 (dd,
J3Ј,4Ј = 3.8, J2Ј,3Ј = 6.4 Hz, 1 H, 3Ј-H), 4.37–4.31 (m, 1 H, 4Ј-H),
5-Amino-1-(5Ј-amino-5Ј-deoxy-1-β-D-ribofuranosyl)imidazole-4-carb-
oxamide (3): Pd/C (1:5, w/wsubstrate) was added to a solution of
compound 2 (0.050 g, 0.18 mmol) in MeOH (2 mL) and the mix-
ture left under hydrogen overnight. The reaction was filtered
through a pad of Celite and the solvent was evaporated to give
compound 3 (0.045 g, quant.) as a white foam. 1H NMR
(500 MHz, D2O): δ = 7.36 (s, 1 H, arom.), 5.50 (d, J1Ј,2Ј = 5.9 Hz,
1 H, 1Ј-H), 4.48–4.42 (m, 1 H, 2Ј-H), 4.12–4.07 (m, 1 H, 3Ј-H),
4.00–3.94 (m, 1 H, 4Ј-H), 2.82 (dd, J4Ј,5Јa = 4.5, J5Јa,5Јb = 13.8 Hz,
1 H, 5Ј-Ha), 2.73 (dd, J4Ј,5Јb = 7.0, J5Јa,5Јb = 13.8 Hz, 1 H, 5Ј-
Hb) ppm. 13C NMR (125.8 MHz, D2O): δ = 168.3, 143.9, 129.8,
112.1, 86.8, 85.4, 73.1, 70.9, 42.8 ppm. MS (ESI, positive-ion
mode): m/z (%) = 589.0 (100) [2M + Na]+, 306.1 (45) [M + Na]+.
C9H15N5O4 (275.25): calcd. C 42.02, H 5.88, N 27.22; found C
42.16, H 5.69, N 27.14.
3.81–3.77 (m, 2 H, CH2-MEM), 3.60 (dd, J4Ј,5Јa = 4.6, J5Јa,5Јb
=
13.0 Hz, 1 H, 5Ј-Ha), 3.56 (dd, J4Ј,5Јb = 5.5, J5Јa,5Јb = 13.0 Hz, 1 H,
5Ј-Hb), 3.52–3.48 (m, 2 H, CH2-MEM), 3.35 (s, 3 H, OCH3), 1.60
(s, 3 H, CH3), 1.37 (s, 3 H, CH3) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 156.6, 147.6, 146.9, 139.0, 125.2, 115.1, 90.3, 84.9,
84.4, 81.5, 75.1, 71.5, 69.3, 59.0, 52.2, 27.2, 25.3 ppm. MS (ESI,
positive-ion mode): m/z (%) = 865.1 (100) [2M + Na]+, 444.2 (45)
[M + Na]+. C17H23N7O6 (421.41): calcd. C 48.45, H 5.50, N 23.27;
found C 48.29, H 5.52, N 23.21.
5Ј-O-Acetyl-2Ј,3Ј-O-isopropylidene-1-[(2-methoxyethoxy)methyl]in-
osine (12): A solution of inosine 9 (0.53 g, 1.71 mmol) in dry pyr-
idine (10 mL) was treated with Ac2O (0.30 mL) at 0 °C. After 3 h
the reaction was quenched by the addition of MeOH (6 mL) and
the mixture was evaporated to dryness. Purification by flash
chromatography (DCM/MeOH, 95:5) afforded 5Ј-O acetylated in-
osine in a nearly quantitative yield. The acetylated product was
dissolved in DCM (18 mL) and DIPEA (0.45 mL, 2.57 mmol) was
5-Amino-1-(5Ј-azido-5Ј-deoxy-2Ј,3Ј-O-isopropylidene-1-β-D-ribofur- added. The solution was cooled to 0 °C and MEMCl (0.23 mL,
anosyl)imidazole-4-carboxamide (11): A solution of compound 10
(0.65 g, 1.54 mmol) in EtOH/H2O (1:1, 15 mL) and containing dis-
solved NaOH (0.13 g, 3.23 mmol) was heated at 80 °C for 8 h. Af-
ter cooling, the solution was concentrated to half of its volume and
then brine (10 mL) and CHCl3 (30 mL) were added. After separa-
tion, the aqueous phase was extracted with chloroform
(2ϫ30 mL). The combined organics were dried with sodium sul-
fate and the solvent evaporated under reduced pressure to leave a
crude that was purified by flash chromatography (CHCl3/MeOH,
96:4) to afford product 11 (0.22 g, 44%) as a foam. [α]2D0 = –31.2 (c
2.05 mmol) was slowly added. The reaction was quenched after 2 h
by the addition of water/brine (1:1, 15 mL) and, after separation,
the aqueous layer was extracted with DCM (2ϫ30 mL). The com-
bined organics were dried, evaporated to dryness and purified by
flash chromatography (DCM/MeOH, 97.5:2.5) to afford com-
pound 12 (0.33 g, 44%) as an oil. [α]2D0 = –19.2 (c = 1.00, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 8.10 (s, 1 H, arom.), 7.85 (s, 1
H, arom.), 6.05 (d, J1Ј,2Ј = 1.8 Hz, 1 H, 1Ј-H), 5.51 and 5.49 (2 d,
Jgem = 10.5 Hz, 2 H, NCH2O), 5.22 (dd, J1Ј,2Ј = 1.9, J2Ј,3Ј = 6.3 Hz,
1 H, 2Ј-H), 4.91 (dd, J3Ј,4Ј = 3.6, J2Ј,3Ј = 6.3 Hz, 1 H, 3Ј-H), 4.49–
= 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.07 (s, 1 H, 4.40 (m, 1 H, 4Ј-H), 4.29 (dd, J4Ј,5Јa = 4.2, J5Јa,5Јb = 12.0 Hz, 1 H,
arom.), 6.57 (br. s, 2 H, CONH2), 5.57 (d, J1Ј,2Ј = 3.7 Hz, 1 H, 1Ј- 5Ј-Ha), 4.17 (dd, J4Ј,5Јb = 5.9, J5Јa,5Јb = 12.0 Hz, 1 H, 5Ј-Hb), 3.76–
H), 5.35 (br. s, 2 H, NH2), 5.01 (dd, J1Ј,2Ј = 3.7, J2Ј,3Ј = 6.8 Hz, 1
H, 2Ј-H), 4.82 (dd, J3Ј,4Ј = 4.1, J2Ј,3Ј = 6.8 Hz, 1 H, 3Ј-H), 4.25–
4.20 (m, 1 H, 4Ј-H), 3.75 (dd, J4Ј,5Јa = 3.4, J5Јa,5Јb = 13.2 Hz, 1 H,
5Ј-Ha), 3.65 (dd, J4Ј,5Јb = 3.2, J5Јa,5Јb = 13.2 Hz, 1 H, 5Ј-Hb), 1.57
3.71 (m, 2 H, CH2-MEM), 3.49–3.45 (m, 2 H, CH2-MEM), 3.28
(s, 3 H, OCH3), 1.97 (s, 3 H, COCH3), 1.56 (s, 3 H, CH3), 1.33 (s,
3 H, CH3) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 170.2, 156.4,
147.4, 146.6, 138.8, 125.0, 114.7, 90.6, 84.5, 84.4, 81.2, 75.0, 71.3,
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AICAR Derivatives as Potential Hsp90 Inhibitors
69.1, 63.8, 58.8, 27.0, 25.2, 20.5 ppm. MS (ESI, positive-ion mode):
1 H, 2Ј-H), 4.26–4.21 (m, 1 H, 3Ј-H), 4.16–4.15 (m, 1 H, 4Ј-H),
m/z (%) = 898.9 (100) [2M + Na]+, 461.1 (45) [M + Na]+. 3.78 (dd, J4Ј,5Јa = 2.3, J5Јa,5Јb = 10.7 Hz, 1 H, 5Ј-Ha), 3.68 (dd, J4Ј,5Јb
C19H26N4O8 (438.43): calcd. C 52.05, H 5.98, N 12.78; found C
51.90, H 6.16, N 12.83.
= 2.0, J5Јa,5Јb = 10.7 Hz, 1 H, 5Ј-Hb) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 169.3, 145.3, 138.9, 131.1, 129.6 (2 C), 129.3 (2 C),
129.2, 113.4, 90.7, 86.0, 74.7, 74.1, 72.5, 70.9 ppm. MS (ESI, posi-
tive-ion mode): m/z (%) = 719.1 (100) [2M + Na]+, 371.3 (45) [M
+ Na]+. C16H20N4O5 (348.35): calcd. C 55.17, H 5.79, N 16.08;
found C 55.36, H 5.61, N 16.03.
5Ј-O-Benzyl-2Ј,3Ј-O-isopropylidene-1-[(2-methoxyethoxy)methyl]in-
osine (13): Compound 12 (0.14 g, 0.31 mmol) was dissolved in
MeOH (2 mL) and treated with a commercial aqueous ammonia
solution (32%, 0.36 mL). The reaction was stirred for 30 min and
then the solvent was removed under reduced pressure and the crude
diluted with BuOH and concentrated to coevaporate residual traces
of volatile impurities (2ϫ5 mL). Flash column chromatography
(CHCl3/MeOH, 97:3) afforded the deprotected compound, which
was diluted in DMF (3 mL). The solution was cooled to 0 °C, 60%
NaH (0.024 g, 0.61 mmol) was added in one portion and then, after
2 min, BnBr (0.072 mL, 0.61 mmol) was added dropwise. The mix-
ture was quenched after 30 min with satd. NH4Cl/H2O solution
1-[(2-Methoxyethoxy)methyl]-3Ј,5Ј-O-(tetraisopropyldisiloxane-1,3-
diyl)inosine (16): Compound 15[17] (1.7 g, 4.73 mmol) and imid-
azole (1.4 g, 20.83 mmol) were dissolved in dry DMF (95 mL). Af-
ter cooling to 0 °C, TIPDSCl2 (1.7 mL, 5.44 mmol) was slowly
added and the solution maintained at this temperature for 5 h, then
warmed to room temperature and stirred overnight. The solvent
was removed under reduced pressure and the crude dissolved in
DCM (75 mL) and washed with a 0.5  HCl/brine solution (1:1,
(1:1, 3 mL) and diluted with DCM (5 mL). After separation, the 70 mL). After separation, the aqueous phase was extracted with
aqueous phase was extracted with DCM (2ϫ5 mL). The combined DCM (1ϫ70 mL) and the combined organics dried and the sol-
organics were dried and the solvent evaporated to dryness. Purifica-
tion by flash chromatography (CHCl3/MeOH, 97.5:2.5) afforded
13 (0.11 g, 76%) as a foam. [α]2D0 = –51.8 (c = 0.5, CHCl3). 1H
vents evaporated. Purification by flash chromatography (petroleum
ether/AcOEt/MeOH, 75:20:5) afforded pure 16 (2.6 g, 93%) as a
foam. [α]2D0 = –33.1 (c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3):
NMR (500 MHz, CDCl3): δ = 8.06 (s, 1 H, arom.), 8.01 (s, 1 H, δ = 8.06 (s, 1 H, arom.), 7.93 (s, 1 H, arom.), 5.94 (s, 1 H, 1Ј-H),
arom.), 7.40–7.20 (m, 5 H, arom.), 6.13 (d, J1Ј,2Ј = 2.1 Hz, 1 H, 1Ј- 5.58–5.52 (m, 2 H, NCH2O), 4.92–4.79 (m, 1 H, 3Ј-H), 4.45 (d,
H), 5.56 and 5.50 (2 d, Jgem = 10.5 Hz, 2 H, NCH2O), 5.17 (dd,
J2Ј,3Ј = 5.3 Hz, 1 H, 2Ј-H), 4.16–4.01 (m, 3 H, 4Ј-H, 5-H), 3.83–
J1Ј,2Ј = 2.3, J2Ј,3Ј = 6.0 Hz, 1 H, 2Ј-H), 4.93 (dd, J3Ј,4Ј = 1.6, J2Ј,3Ј 3.75 (m, 2 H, CH2-MEM), 3.55–3.47 (m, 2 H, CH2-MEM), 3.34
= 6.0 Hz, 1 H, 3Ј-H), 4.55–4.43 (m, 3 H, 4Ј-H, CH2Ph), 3.79 (m,
2 H, CH2-MEM), 3.68 (dd, J4Ј,5Јa = 3.1, J5Јa,5Јb = 10.5 Hz, 1 H, 5Ј-
Ha), 3.61 (dd, J4Ј,5Јb = 3.8, J5Јa,5Јb = 10.5 Hz, 1 H, 5Ј-Hb), 3.55–
(s, 3 H, OCH3), 3.12 (br. s, 1 H, OH), 1.17–0.97 (m, 28 H,
CHMe2) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 156.7, 147.3,
146.7, 138.8, 125.2, 89.5, 82.1, 75.2, 75.0, 71.5, 70.4, 69.3, 61.4,
3.48 (m, 2 H, CH2-MEM), 3.35 (s, 3 H, OCH3), 1.62 (s, 3 H, CH3), 59.0, 18.3–12.6 (12 C) ppm. MS (ESI, positive-ion mode): m/z (%)
1.39 (s, 3 H, CH3) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 162.4, = 1219.3 (100) [2M + Na]+, 621.3 (35) [M + Na]+. C26H46N4O8Si2
156.5, 147.2, 146.9, 138.5, 136.9, 128.3 (2 C), 127.8 (2 C), 124.5, (598.84): calcd. C 52.15, H 7.74, N 9.36; found C 52.05, H 7.76, N
114.0, 91.4, 85.7, 85.1, 81.7, 74.9, 73.5, 71.4, 70.0, 69.0, 58.8, 27.1, 9.39.
25.2 ppm. MS (ESI, positive-ion mode): m/z (%) = 995.5 (100) [2M
1-[(2-Methoxyethoxy)methyl]-2Ј-O-methyl-3Ј,5Ј-O-(tetraisopropyl-
disiloxane-1,3-diyl)inosine (17): NaH (60 %, 0.037 g, 0.93 mmol)
was added in one portion to a solution of compound 16 (0.37 g,
+ Na]+, 509.4 (40) [M + Na]+. C24H30N4O7 (486.52): calcd. C
59.25, H 6.22, N 11.52; found C 59.45, H 6.13, N 11.49.
5-Amino-1-(5Ј-O-benzyl-2Ј,3Ј-O-isopropylidene-1-β-D-ribofuranosyl)- 0.62 mmol) in dry DMF (6 mL) at 0 °C and a few minutes later
imidazole-4-carboxamide (14): Compound 13 (0.11 g, 0.23 mmol)
was treated as reported for the synthesis of 11. The reaction was
heated at 80 °C for 3 h and the work-up was carried out with brine
(10 mL) and AcOEt (30 mL) instead of chloroform. Purification
by flash chromatography (AcOEt/MeOH, 98:2) afforded 14
(0.041 g, 47%) as a foam. [α]2D0 = –47.0 (c = 0.5, CHCl3). 1H NMR
iodomethane (0.12 mL, 1.85 mmol) was added dropwise. The reac-
tion was quenched after 1 h with a satd. NH4Cl/H2O solution (1:1,
6.0 mL) and diluted with DCM (10 mL). After separation the
aqueous layer was extracted with DCM (1ϫ10 mL). The combined
organics were dried and the solvent evaporated under reduced pres-
sure. Purification by flash chromatography (petroleum ether/Ac-
(500 MHz, CDCl3): δ = 7.40–7.25 (m, 5 H, arom.), 7.05 (s, 1 H, OEt/MeOH, 80:15:5) gave 17 (0.22 g, 60%) as an oil. [α]2D0 = –22.5
1
arom.), 5.59 (m, J1Ј,2Ј = 3.8 Hz, 1 H, 1Ј-H), 5.57–5.51 (m, 2 H, (c = 0.5, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.12–8.04 (m,
NH2), 5.03 (dd, J2Ј,3Ј = 3.8, J1Ј,2Ј = 6.6 Hz, 1 H, 2Ј-H), 4.94 (dd,
J3Ј,4Ј = 3.4, J2Ј,3Ј = 6.6 Hz, 1 H, 3Ј-H), 4.56 and 4.51 (2 d, J = 11.6,
2 H, arom.), 5.97 (s, 1 H, 1Ј-H), 5.57 and 5.54 (2 d, Jgem = 10.5 Hz,
2 H, NCH2O), 4.62 (dd, J2Ј,3Ј = 4.6, J3Ј,4Ј = 9.3 Hz, 1 H, 3Ј-H), 4.20
J = 27.7 Hz, 1 H, CH2-Ph), 4.32–4.26 (m, 1 H, 4Ј-H), 3.80 (dd, (br. d, J5Јa,5Јb = 13.3 Hz, 1 H, 5Ј-Ha), 4.11 (br. d, J3Ј,4Ј = 9.3 Hz, 1
J4Ј,5Јa = 2.2, J5Јa,5Јb = 10.5 Hz, 1 H, 5Ј-Ha), 3.66 (dd, J4Ј,5Јb = 1.8, H, 4Ј-H), 4.02 (dd, J4Ј,5Јb = 2.1, J5Јa,5Јb = 13.3 Hz, 1 H, 5Ј-Hb), 3.93
J5Јa,5Јb = 10.5 Hz, 1 H, 5Ј-Hb), 1.58 (s, 3 H, CH3), 1.35 (s, 3 H, (br. d, J2Ј,3Ј = 4.6 Hz, 1 H, 2Ј-H), 3.84–3.78 (m, 2 H, CH2-MEM),
CH3) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 166.5, 143.0, 136.4, 3.67 (s, 3 H, OCH3), 3.54–3.51 (m, 2 H, CH2-MEM), 3.34 (s, 3 H,
128.7 (2 C), 128.5, 128.4, 128.1 (2 C), 115.0, 113.5, 92.0, 84.0, 82.6,
80.2, 73.9, 68.9, 27.2, 25.2 ppm. MS (ESI, positive-ion mode): m/z
(%) = 799.0 (100) [2M + Na]+, 411.3 (45) [M + Na]+. C19H24N4O5
(388.42): calcd. C 58.75, H 6.23, N 14.42; found C 58.59, H 6.41,
N 14.47.
OCH3), 1.17–0.88 (m, 28 H, CHMe2) ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 156.7, 147.3, 146.5, 138.3, 125.0, 88.2, 84.1, 81.5, 75.0,
71.5, 69.3 (2 C), 59.0, 59.7, 59.5, 17.5–12.5 (12 C) ppm. MS (ESI,
positive-ion mode): m/z (%) = 635.3 (100) [M + Na]+, 613.3 (40)
[M + 1]+. C27H48N4O8Si2 (612.86): calcd. C 52.91, H 7.89, N 9.14;
found C 52.79, H 7.91, N 9.11.
5-Amino-1-(5Ј-O-benzyl-1-β-D-ribofuranosyl)imidazole-4-carbox-
amide (4): Compound 14 (0.039 g, 0.10 mmol) was treated as re-
ported for the preparation of 2. Purification by flash chromatog-
raphy (AcOEt/MeOH, 95:5) afforded 4 (0.029 g, 83%) as a foam.
2Ј-O-Butyl-1-[(2-methoxyethoxy)methyl]-3Ј,5Ј-O-(tetraisopropyl-
disiloxane-1,3-diyl)inosine (18): A solution of compound 16 (0.30 g,
0.50 mmol) in dry DMF (5 mL) was added at –60 °C to 60% NaH
1H NMR (500 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H, arom), 7.26 (0.029 g, 0.75 mmol) and, after 30 min, butyl bromide (0.070 mL,
(s, 1 H, arom.), 5.55 (d, J1Ј,2Ј = 6.7 Hz, 1 H, 1Ј-H), 4.59 and 4.56
(2 d, Jgem = 11.6 Hz, 2 H, CH2Ph), 4.48 (dd, J1Ј,2Ј = J2Ј,3Ј = 6.7 Hz,
0.65 mmol) was added dropwise. The reaction was quenched after
2 h with a satd. NH4Cl/H2O solution (1:1, 5.0 mL) and diluted with
Eur. J. Org. Chem. 2009, 5913–5919
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Bracci, G. Colombo, F. Ronchetti, F. Compostella
FULL PAPER
DCM (8 mL). After separation the aqueous layer was extracted
with DCM (2ϫ8 mL). The combined organics were dried and the
solvent evaporated under reduced pressure. Purification by flash
chromatography (petroleum ether/AcOEt/MeOH, 5:4:1) gave 18
1 H, 4Ј-H), 3.82–3.73 (m, 2 H, 5Ј-H), 3.69–3.61 (m, 1 H, OCHa-
HbCH2), 3.47–3.40 (m, 1 H, OCHaHbCH2), 1.56–1.46 (m, 2 H,
CH2), 1.35–1.24 (m, 2 H, CH2), 0.86 (s, 3 H, CH3) ppm. 13C NMR
(125.8 MHz, CD3OD): δ = 168.0, 144.0, 129.9, 111.9, 87.7, 86.6,
79.3, 70.3, 69.5, 61.2, 31.3, 18.6, 12.7 ppm. MS (ESI, positive-ion
(0.13 g, 40%) as an oil. [α]2D0 = –13.8 (c = 0.5, CHCl3). H NMR
1
(500 MHz, CDCl3): δ = 8.39 (s, 1 H, arom.), 8.11 (s, 1 H, arom.), mode): m/z (%) = 337.3 (100) [M + Na]+, 651.0 (70) [2M + Na]+.
6.11 (br. s, 1 H, 1Ј-H), 5.58 and 5.54 (2 d, Jgem = 10.5 Hz, 2 H,
NCH2O), 4.57–4.51 (m, 1 H, 3Ј-H), 4.22–4.16 (m, 1 H, 5Ј-Ha),
4.14–4.05 (m, 3 H, 2-H, 4Ј-H, 5Ј-Hb), 3.88–3.78 (m, 3 H, OCH-
aHbCH2, CH2-MEM), 3.67–3.60 (m, 1 H, OCHaHbCH2), 3.55–3.50
(m, 2 H, CH2-MEM), 3.35 (s, 3 H, OCH3), 1.66–1.57 (m, 2 H,
CH2), 1.44–1.34 (m, 2 H, CH2), 1.13–0.82 (m, 31 H, CH3,
CHMe2) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 155.6, 147.5,
146.7, 138.7, 124.3, 86.8, 84.8, 83.0, 75.1, 71.5, 71.2, 69.3, 68.0,
60.8, 59.0, 31.6, 19.1, 17.3–12.6 (13 C) ppm. MS (ESI, positive-ion
mode): m/z (%) = 677.4 (100) [M + Na]+, 655.4 (50) [M + 1]+.
C30H54N4O8Si2 (654.94): calcd. C 55.02, H 8.31, N 8.55; found C
55.21, H 8.28, N 8.57.
C13H22N4O5 (314.34): calcd. C 49.67, H 7.05, N 17.82; found C
49.78, H 7.05, N 17.76.
5-Amino-1-(2Ј-O-benzyl-1-β-D-ribofuranosyl)imidazole-4-carbox-
amide (7): Compound 7 was obtained by following the same pro-
cedure reported for the preparation of 5 starting from 19 (0.12 g,
0.17 mmol), heating the reaction at 80 °C for 2 h. Product 7
(0.018 g, 30%) was recovered as a white solid after purification by
flash chromatography (AcOEt/MeOH, from 95:5 to 9:1). 1H NMR
(500 MHz, [D6]DMSO): δ = 7.37–7.22 (m, 6 H, arom.),6.88–6.58
(m, 2 H, CONH2), 5.95 (br. s, 2 H, NH2), 5.70 (d, J1Ј,2Ј = 6.2 Hz,
1 H, 1Ј-H), 5.31 (d, J3Ј,OH = 4.9 Hz, 1 H, OH), 5.29–5.24 (m, 1 H,
OH), 4.67 and 4.48 (2 d, Jgem = 12.0 Hz, 2 H, CH2Ph), 4.33–4.23
(m, 2 H, 2Ј-H ,3Ј-H), 3.99–3.93 (m, 1 H, 4Ј-H), 3.65–3.55 (m, 2 H,
5Ј-H) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ = 167.2, 143.2,
138.4, 129.9–127.9 (6 C), 113.2, 86.4, 86.3, 80.3, 71.5, 69.1,
61.4 ppm. MS (ESI, positive-ion mode): m/z (%) = 719.1 (100) [2M
+ Na]+, 371.2 (30) [M + Na]+. C16H20N4O5 (348.35): calcd. C
55.17, H 5.79, N 16.08; found C 55.00, H 5.81, N 16.12.
2Ј-O-Benzyl-1-[(2-methoxyethoxy)methyl]-3Ј,5Ј-O-(tetraisopropyl-
disiloxane-1,3-diyl)inosine (19): Compound 19 (0.13 g, 41%) was
obtained by following the same procedure used for the preparation
of 18. The product was recovered after flash chromatography (pe-
troleum ether/AcOEt/MeOH, 80:15:5) as an oil. [α]2D0 = –20.5 (c =
0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.11–8.04 (m, 2 H,
arom.), 7.43–7.23 (m, 5 H, arom.), 6.05 (br. s, 1 H, 1Ј-H), 5.58 and
5.53 (2 d, Jgem = 10.5 Hz, 2 H, NCH2O), 5.03 and 4.84 (2 d, Jgem
= 12.2 Hz, 2 H, CH2Ph), 4.62 (dd, J2Ј,3Ј = 4.5, J3Ј,4Ј = 9.3 Hz, 1 H,
3Ј-H), 4.28–4.20 (m, 2 H, 4Ј-H, 5Ј-Ha), 4.15 (br. d, J2Ј,3Ј = 4.5 Hz,
1 H, 2Ј-H), 4.07–4.02 (m, 1 H, 5Ј-Hb), 3.85–3.80 (m, 2 H, CH2-
MEM), 3.56–3.52 (m, 2 H, CH2-MEM), 3.35 (s, 3 H, OCH3), 1.72–
0.89 (m, 28 H, CHMe2) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
156.6, 147.3, 146.4, 138.2, 137.2, 128.4–127.6 (6 C), 88.6, 81.7, 81.4,
75.1, 72.7, 71.5, 69.3, 69.1, 59.7, 59.0, 17.5–12.7 (12 C) ppm. MS
(ESI, positive-ion mode): m/z (%) = 711.3 (100) [M + Na]+, 689.3
(45) [M + 1]+. C33H52N4O8Si2 (688.96): calcd. C 57.53, H 7.61, N
8.13; found C 57.32, H 7.63, N 8.16.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of compounds 2–7, 10–14
and 16–19.
Acknowledgments
The University of Milan is gratefully acknowledged for financial
support. G. C. acknowledges the Associazione Italiana per la
Ricerca sul Cancro (AIRC) for financial support.
5-Amino-1-(2Ј-O-methyl-1-β-D-ribofuranosyl)imidazole-4-carbox-
[1] B. Guigas, K. Sakamoto, N. Taleux, S. M. Reyna, N. Musi, B.
Viollet, L. Hue, IUBMB Life 2009, 61, 18–26.
amide (5): Compound 17 (0.22 g, 0.37 mmol) in EtOH/H2O (1:1,
5 mL) was treated with NaOH (0.44 g, 1.10 mmol) and heated at
80 °C for 8 h. After cooling, the reaction was neutralized with 2 
HCl and then concentrated under reduced pressure. The crude was
dissolved in warmed EtOH (4 mL), silica gel was added and the
solvent evaporated under reduced pressure. Purification by flash
chromatography (AcOEt/MeOH, 85:15) gave 5 (0.058 g, 58%) as a
white solid. 1H NMR (500 MHz, [D6]DMSO): δ = 7.35 (s, 1 H,
arom.), 6.85–6.56 (m, 2 H, CONH2), 5.96 (br. s, 2 H, NH2), 5.59
(d, J1Ј,2Ј = 6.5 Hz, 1 H, 1Ј-H), 5.31–5.25 (m, 1 H, OH), 5.22 (d,
J3Ј,OH = 4.8 Hz, OH), 4.28–4.21 (m, 1 H, 3Ј-H), 4.11–4.06 (m, 1 H,
2Ј-H), 3.93–3.88 (m, 1 H, 4Ј-H), 3.63–3.53 (m, 2 H, 5Ј-H), 3.31 (s,
3 H, CH3) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ = 167.2,
143.3, 129.0, 113.2, 86.3, 86.1, 82.1, 69.0, 61.5, 57.9 ppm. MS (ESI,
positive-ion mode): m/z (%) = 566.9 (100) [2M + Na]+, 295.2 (70)
[M + Na]+. C10H16N4O5 (272.26): calcd. C 44.12, H 5.92, N 20.58;
found C 44.27, H 5.89, N 20.63.
[2] A. Sriwijitkamol, N. Musi, Expert Opin. Drug Discover 2008,
3, 1167–1176.
[3] C. Ségalen, S. L. Longnus, D. Baetz, L. Counillon, E. Van Ob-
berghen, Endocrinology 2008, 149, 1490–1498.
[4] N. Fujii, N. Jessen, L. J. Goodyear, Am. J. Physiol. Endocrinol.
Metab. 2006, 291, E867–E8772.
[5] T. R. Moopanar, X. H. Xiao, L. Jiang, Z. P. Chen, B. E. Kemp,
D. G. Allen, Pflugers Arch. – Eur. J. Physiol. 2006, 453, 147–
156.
[6] D. R. Lara, O. P. Dall’Igna, E. S. Ghisolfi, M. G. Brunstein,
Prog. Neuropsychopharmacol. Biol. Psychiatry 2006, 30, 617–
629.
[7] R. Dixon, J. Gourzis, D. McDermott, J. Fujitaki, P. Dewland,
H. Gruber, J. Clin. Pharmacol. 1991, 31, 342–347.
[8] M. F. Vincent, M. D. Erion, H. E. Gruber, G. Van Den Berghe,
Diabetologia 1996, 39, 1148–1155.
[9] R. Rattan, S. Giri, A. K. Singh, I. Singh, J. Biol. Chem. 2005,
280, 39582–39593.
[10] M. Meli, M. Pennati, M. Curto, M. G. Daidone, J. Plescia, S.
Toba, D. C. Altieri, N. Zaffaroni, G. Colombo, J. Med. Chem.
2006, 49, 7721–7730.
[11] L. Whitesell, S. Lindquist, Nat. Rev. Cancer 2005, 5, 761–772.
[12] L. Neckers, S. P. Ivy, Curr. Opin. Oncol. 2003, 15, 419–424.
[13] A different approach to compounds 2, 3, 5 and 6 has been
described, see: D. T. Mangano, Methods, Compositions and For-
mulations for Preventing or Reducing Adverse Effects in a Pa-
tient, PTC Int. Appl., WO 2006105167, 2006.
5-Amino-1-(2Ј-O-butyl-1-β-D-ribofuranosyl)imidazole-4-carbox-
amide (6): Compound 6 was obtained by following the same pro-
cedure reported for the preparation of 5 starting from compound
18 (0.12 g, 0.18 mmol), heating the reaction at 80 °C for 2 h. Prod-
uct 6 (0.014 g, 25%) was recovered as a white solid after purifica-
tion by flash chromatography (AcOEt/MeOH, 95:5). 1H NMR
(500 MHz, CD3OD): δ = 7.34 (s, 1 H, arom.), 5.63 (d, J1Ј,2Ј
=
6.7 Hz, 1 H, 1Ј-H), 4.37–4.29 (m, 2 H, 2Ј-H, 3Ј-H), 4.11–4.06 (m,
5918
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5913–5919

AICAR Derivatives as Potential Hsp90 Inhibitors
[14] a) J. P. Ferris, B. Devadas, C. H. Huang, W. Y. Ren, J. Org.
Chem. 1985, 50, 747–754; b) Y. Suzuki, Bull. Chem. Soc. Jpn.
1974, 47, 898–903.
[15] See, for example: a) E. Casanova, A.-I. Hernández, E.-M. Pri-
ego, S. Liekens, M.-J. Camarasa, J. Balzarini, M.-J. Pérez-Pérez,
J. Med. Chem. 2006, 49, 5562–5570; b) M. D. Erlacher, K.
Lang, B. Wotzel, R. Rieder, R. Micura, N. Polacek, J. Am.
Chem. Soc. 2006, 128, 4453–4459.
Oliviero, J. Amato, N. Borbone, S. D’Errico, G. Piccialli, L.
Mayol, Tetrahedron Lett. 2007, 48, 397–400.
N. Kohyama, Y. Yamamoto, Synthesis 2003, 2639–2642.
[17]
[18]
F. Liu, D. J. Austin, J. Org. Chem. 2001, 66, 8643–8645.
[19] W. T. Markiewicz, J. Chem. Res. (S) 1979, 24–25.
[20] G. Oliviero, J. Amato, N. Borbone, S. DЈErrico, G. Piccialli, E.
Bucci, V. Piccialli, L. Mayol, Tetrahedron 2008, 64, 6475–6481.
Received: July 16, 2009
[16] a) L. De Napoli, A. Messere, D. Montesarchio, G. Piccialli, M.
Varra, J. Chem. Soc. Perkin Trans. 1 1997, 2079–2082; b) G.
Published Online: October 15, 2009
Eur. J. Org. Chem. 2009, 5913–5919
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5919