Synthesis of 5,6-dihydro-4H-benzo[d]isoxazol-7-one and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-one Derivatives as Potential Hsp90 Inhibitors

Article abstract of DOI:10.1111/cbdd.12570

A novel class of 5,6-dihydro-4H-benzo[d]isoxazol-7-ones and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones was designed, synthesized, and assayed to investigate the affinity toward Hsp90 protein. The synthetic route was based on a 1,3-dipolar cycloaddition of nitriloxides, generated in situ from suitable benzaldoximes, with 2-bromocyclohex-2-enones or 3-bromo-5,6-dihydro-1H-pyridin-2-ones. Whereas all the compounds bearing a benzamide group on the bicyclic scaffold were devoid of activity, the derivatives carrying a resorcinol-like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme. A series of 5,6-dihydro-4H-benzo[d]isoxazol-7-ones and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones was designed, synthesized, and assayed to investigate affinity toward Hsp90 protein. Compounds carrying a resorcinol-like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme.

Full text of DOI:10.1111/cbdd.12570

Chem Biol Drug Des 2015; 86: 1030–1035
Research Letter
Synthesis of 5,6-dihydro-4H-benzo[d]isoxazol-7-one
and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-one
Derivatives as Potential Hsp90 Inhibitors
1
,
1
Loana Musso *, Raffaella Cincinelli , Giuseppe
The discovery and characterization of natural compounds
inhibiting Hsp90, such as geldanamycin (GDA) and radici-
col (Figure 1), has validated this molecular chaperone as
a therapeutic target. GDA (4) inhibitory activity is mainly
due to a competition with the ATP binding within the N-
terminus of the protein. Radicicol (5), a natural macrocy-
clic antifungal antibiotic, inhibits Hsp90 by interacting
within the same site of action of GDA. Due to its chemi-
cal instability, this compound could not be developed,
but served as a template for the discovery of new Hsp90
inhibitors. In particular, the presence of a resorcinol-like
fragment was found to be extremely important to drive its
binding mode and to get a strong interaction with the
enzyme. This mode of binding has also been verified with
other synthetic series of compounds (6–8).
2
3
Giannini , Fabrizio Manetti and Sabrina
1
Dallavalle
1
Department of Food, Environmental and Nutritional
Sciences, Division of Chemistry and Molecular Biology,
University of Milano, via Celoria 2, Milan I-20133, Italy
R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,
via Pontina Km 30,400, Pomezia I-00040, Italy
Dipartimento di Biotecnologie, Chimica e Farmacia,
Universit aꢀ degli Studi di Siena, via A. Moro 2, Siena
I-53100, Italy
*Corresponding author: Loana Musso,
loana.musso@unimi.it
2
3
A novel class of 5,6-dihydro-4H-benzo[d]isoxazol-7-
ones and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones
was designed, synthesized, and assayed to investigate
the affinity toward Hsp90 protein. The synthetic route
was based on a 1,3-dipolar cycloaddition of nitriloxides,
generated in situ from suitable benzaldoximes, with
The investigation and clinical development of Hsp90 inhibi-
tors continue to progress. Currently, a number of highly
specific compounds are undergoing clinical trials (i.e.
SNX5422, NVP-AUY922, and STA9090; Figure 1), and an
impressive growth in scientific literature confirms the great
interest toward this target (9). However, to date, there are
still no FDA approved Hsp90-targeting agents. For all
these reasons, the finding of novel chemotypes that fully
satisfy requisites of safety and stability, moving forward the
knowledge in this field, still remains an interesting and
promising goal.
2
1
-bromocyclohex-2-enones or 3-bromo-5,6-dihydro-
H-pyridin-2-ones. Whereas all the compounds bearing
a benzamide group on the bicyclic scaffold were devoid
of activity, the derivatives carrying a resorcinol-like frag-
ment showed a remarkable inhibitory effect on Hsp90.
Docking calculations were performed to investigate the
orientation of the new compounds within the binding
site of the enzyme.
Previous reports supported the hypothesis that the pres-
ence of the isoxazole nucleus could exert a key role in
the docking of compounds to the ATP binding site of the
enzyme. In fact, synthetic compounds containing this het-
erocyclic moiety have shown potent and selective inhibi-
tion of Hsp90, see NVP-AUY922 and SST0116CL1
Key words: anticancer, docking calculations, Hsp90 inhibi-
tors, isoxazoles, synthesis
Received 19 March 2015 and accepted for publication 3 April
2
015
(6,10–12).
Heat-shock protein 90 (Hsp90) is a molecular chaperone,
which is essential for a wide range of protein assembly,
trafficking, folding, and degradation processes (1). Multiple
signal transduction pathways implicated in the regulation
of cell proliferation and survival are dependent on Hsp90
Recently, a structural investigation on the isoxazole scaf-
fold led us to discover a new class of 4,5,6,7-tetrahyd-
roisoxazolo-[4,5-c]pyridines containing an isoxazole
nucleus fused with a tetrahydropyridine ring (13). Other
structures described in recent papers, containing con-
densed bicyclic groups, have been very successful in tar-
geting Hsp90 (7,8,14). Thus, we envisaged that the
isoxazole scaffold could be fused to other rings to build
novel series of potential Hsp90 inhibitors with a bicyclic
core structure.
(2). Several Hsp90 client proteins are involved in critical
processes, including cell-cycle regulation and apoptosis.
The heat-shock proteins are often overexpressed in tumor
cells, and this supports their ability to survive under unfa-
vorable stress conditions (e.g., hypoxia and acidosis), as
well as to facilitate rapid somatic evolution (3).
1
030
ª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12570

New Scaffolds as Hsp90 Inhibitors
Figure 1: Hsp90 inhibitors.
Based on preliminary computational studies on isoxazole-
based molecules using Hsp90 X-ray structure, we selected
compounds with a 5,6-dihydro-4H-benzo[d]isoxazol-7-one
nitriloxides, generated in situ from suitable benzaldoximes
to 2-bromocyclohex-2-enones or 3-bromo-5,6-dihydro-
1H-pyridin-2-ones. (Scheme 1).
(
1, X = CH
2
, Scheme 1) or a 5,6-dihydro-4H-isoxazolo
[
5,4-c]pyridin-7-one (1, X = NH, Scheme 1) scaffold as
Literature reports (16) show that cycloaddition of arylnitril-
oxides to cyclohexenones affords 4-acylisoxazolines. Simi-
larly, cycloaddition to a,b-unsaturated lactams affords
mainly 4-carboxamidoisoxazolines with high regioselectivity
(17). Thus, to reverse the regiochemistry of the reaction,
we planned to use lactams and ketones with a bromine
atom in alpha position with respect to the carbonyl group.
Following this strategy, the isoxazole could be obtained in
one step, due to the spontaneous isoxazoline dehydrobro-
mination.
starting points for further investigation. Our exploration
was focused on the expansion of the core structure within
the ATP binding site, by adding groups aimed at improving
the fitting to the pocket. In particular, we planned to link
the bicyclic system either to a resorcinol-like group or to a
primary benzamide moiety, being both these fragments
able to confer tight binding into the ATP binding pocket
(
15).
The synthetic route used for the preparation of
compounds 1 was based on a 1,3-dipolar cycloaddition of
The key fragment 5 was obtained in three steps, starting
from commercially available 2,4-dihydroxybenzaldehyde 4
(Scheme 2). Chlorination of 4 with NCS, protection of the
phenol groups with 2-methoxyethoxymethyl chloride, fol-
lowed by reaction with hydroxylamine hydrochloride in eth-
anol, in the presence of pyridine, gave the oxime 5.
Compound 7a was obtained starting from N-methylpiperi-
done, which was brominated to obtain 1-methyl-3,3-dibro-
3
mo-2-piperidone (18). Dehydrobromination with CaCO in
DMF at 80 °C gave 7a in good yield (19). Similarly, 7b
was obtained from d-valerolactone (20). Cycloaddition of 5
to 7a and 7b was performed in dichloromethane at room
temperature by generating the nitriloxide in situ with NCS
Scheme 1: Retrosynthetic approach to compound 1.
Chem Biol Drug Des 2015; 86: 1030–1035
1031

Musso et al.
Scheme 2: Synthesis of compounds 9a,b. Reagents and conditions: (a) NCS, CHCl
3
, 6h, reflux, 89%; (b) 2-methoxyethoxymethyl
, Br , CHCl , 0 °C, r.t., 54% from 6a and 60%
2
, r.t., 67% for 8a and 57% for 8b; (g) HCl (10%),
chloride, iPr
from 6b; (e) CaCO
CH OH, reflux, 43% for 9a and 76% for 9b.
2
EtN, THF, 24 h, r.t.; (c) NH
2
OHÁHCl, py, EtOH, 4h, reflux, 71%; (d) PCl
5
, ZnCl
Cl
2
2
3
3
, DMF, 80 °C, 88% for 7a and 69% for 7b; (f) NCS, Al
O
2 3
, CH
2
3
Scheme 3: Synthesis of compounds 13-16. Reagents and conditions: (a) Br
r.t., 49%; (c) HCl (10%), CH OH, reflux, 61%; (d) CeCl O, NaBH , CH OH, HCl (10%), 55%; (e) NH
Á7H
CH Cl , 75%; (g) NH OCH CH NH HCl, py, EtOH, reflux, 44%.
2
, TEA, CH
2
Cl
2
, 0 °C then rt, 86%; (b) NCS, Al
2 3 2 2
O , CH Cl ,
3
3
2
4
3
2
OHÁHCl, py, EtOH, reflux; (f) TFA,
2
2
2
2
2
2
1
032
Chem Biol Drug Des 2015; 86: 1030–1035

New Scaffolds as Hsp90 Inhibitors
and Al
2
O
3
, to obtain 8a and 8b, respectively (21). Finally,
according to a protocol described previously (25). The
results are summarized in Table 1.
deprotection of the phenol groups gave compounds 9a-b.
Cycloaddition of 5 with 11, on its turn obtained from
cyclohexen-2-one (22), afforded 12, which was deprotect-
ed by 10% HCl to give 13 (Scheme 3). To investigate the
role of the carbonyl group of 13, a series of analogs were
prepared starting from the intermediate 12. Treatment with
The most disappointing result was the lack of activity
showed by compounds carrying the benzamide moiety
(20, 21a-c, 22). The compounds with a resorcinol-like moi-
ety appeared more promising. In fact, almost all the tested
molecules showed inhibitory activity with IC50 < 10 lM.
Compound 15, with an oxime group, showed a notable
binding ability (IC50 = 0.8 lM). The reduction of the car-
bonyl group (as in 14) caused a decrease of activity
(IC50 = 26 lM), similarly to the introduction of a methyl
group on the dihydropyridone moiety (9b versus 9a).
NaBH
4 3
and CeCl , followed by HCl, gave the reduced
compound 14. Reaction of 12 with hydroxylamine hydro-
chloride or O-(2-aminoethylhydroxylamine) gave the oximes
15 and 16, respectively.
A series of analogs with the benzamide moiety were pre-
pared following the same synthetic strategy (Scheme 4).
The 4-(hydroxyiminomethyl)benzonitrile 18 was prepared
from 4-cyanobenzaldehyde 17 by reaction with hydroxyl-
amine hydrochloride in ethanol, in the presence of pyridine
According to the previous data, the compounds with the
resorcinol fragment (9a-b, 13-16) showed the most inter-
esting profile, and two of them (namely, 9b and 15) had
ability to bind Hsp90 comparable to or slightly better than
that of the reference compound 17-AAG (1.6 and 0.8 lM
versus 1.1 lM, respectively).
(23). The cycloaddition reaction, performed following the
conditions previously described, afforded 19 in 30% yield.
The yield was increased to 38% when the 4-cyanobenzal-
dehye chlorooxime obtained reacting 19 with N-chlorosuc-
cinimide in DMF was reacted with the dipolarophile 11 in
To gain a more precise picture of the interaction mode of
these compounds with Hsp90, a computational protocol
consisting in molecular docking calculations and energy
minimization of the resulting complexes was set up. For this
purpose, the structure of Hsp90 was taken from the crystal-
lographic co-ordinates of its complex with NVP-AUY933
(PDB entry 2VCI) (6) and used as a template. Docking simu-
lations and energy minimization were performed as previ-
ously described for other Hsp90 triazole inhibitors (26).
3 2
the presence of (Bu Sn) O at room temperature (24).
Amide 20 was obtained by reaction of 19 with H O2 and
2
NaOH. Similarly to compound 12, compound 20 was con-
verted to oximes 21a-c by reaction with suitable hydroxyl-
amines, whereas compound 22 was obtained by
reduction with NaBH
and NaOH.
4 2 2
, followed by treatment with H O
The binding affinity of these compounds to Hsp90 was
determined by a fluorescence polarization (FP) assay,
Analysis of the complexes resulting from docking calcula-
tions showed that the orientation of the new compounds
Scheme 4: Synthesis of compounds 21a-c and 22. Reagents and conditions: (a) NH
r.t.; (c) 11, (Bu Sn) O, CH Cl , rt, 38%; (d) H , 6N NaOH, EtOH, 57%; (e) NH
ORÁHCI, py, EtOH, reflux, 58%; 21a: 58%, 21b: 41%,
1c: 50%; (f) CeCl O, NaBH , CH OH, HCl (10%), 55%; (g) H , 6N NaOH, EtOH, 94%.
Á7H
2
OHÁHCl, py, EtOH, reflux, 71%; (b) NCS, CH
2 2
Cl ,
3
2
2
2
2
O
2
2
2
3
2
4
3
2 2
O
Chem Biol Drug Des 2015; 86: 1030–1035
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Musso et al.
Table 1: Binding affinity to Hsp90 of synthesized compounds
p-hydroxy group makes a water-mediated (HOH2232,
another structural water molecule present in the binding
site) hydrogen bond with the carbonyl group of Leu48.
The chlorine atom is accommodated in a large hydropho-
bic cavity delimited by Phe138 and Leu107 side chains.
Moreover, also the isoxazole nitrogen atom interacts with
the carboxyl terminus of Asp93 through a water-mediated
Compound
Hsp90 (FP) (IC50, lM)
1
9
9
1
1
1
1
2
2
2
2
2
7-AAG
a
1.09 Æ 0.05
10.0 Æ 0.8
1.60 Æ 0.04
4.8 Æ 0.1
26 Æ 1
b
3
4
(HOH2233) hydrogen bond. The oxime nitrogen of the
5
0.8 Æ 0.1
6.3 Æ 0.1
>100
most active compound (15) interacts with the ammonium
group of the Lys58 side chain, whereas the endocyclic
oxygen is involved in an intramolecular hydrogen bond
with the terminal OH group of the oxime moiety. The satu-
rated portion of the six-membered condensed ring does
not show any significant hydrophobic interaction with the
protein.
6
0
1a
1b
1c
2
>100
>100
>100
>100
In summary, we have designed and synthesized a novel
class of 5,6-dihydro-4H-benzo[d]isoxazol-7-ones and 5,6-
dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones to investigate
their affinity toward Hsp90 protein. Whereas all the com-
pounds having a benzamide group on the bicyclic scaffold
were devoid of activity, all the derivatives carrying a resor-
cinol-like fragment showed inhibitory effect on the enzyme.
In particular, 15 possessed a remarkable binding ability
(IC50 = 0.8 lM), slightly better than that of the reference
compound (17-AAG). On this basis, it could be considered
as a useful starting point for medicinal chemists involved in
designing new scaffolds in the field of Hsp90 inhibitors.
Work is in progress to investigate structural changes of
the resorcinol portion, as well as of the bicyclic moiety, to
enhance the fitting into the Hsp90 ATP binding pocket,
and to improve the activity of the compounds.
Figure 2: Graphical representation of the complex between
Hsp90 and 15 (ball and stick notation) as derived from molecular
docking calculations and energy minimization. The resorcinol
hydroxy groups and the isoxazole nitrogen atom make hydrogen
bond interactions mediated by water molecules (W). The carboxy
terminus of Asp93 interacts directly with the o-hydroxy group of
the ligand. The oxime OH group makes an intramolecular
hydrogen bond with the heterocyclic oxygen, while the oxime
nitrogen atom interacts by hydrogen bond with the terminal
ammonium group of Lys58 side chain. Hydrophobic contacts
between the chlorine substituent and the side chains of Phe138
and Leu107 are also found. For the sake of clarity, only few
amino acid residues are displayed and labeled, while hydrogen
bonds are depicted as dashed black lines.
Acknowledgments
Authors wish to thank Dr. Claudio Pisano and Dr. Massi-
mo Castorina (Sigma-tau Italia, Pomezia) for the biological
data (binding affinity to Hsp90) and Professor L. Merlini for
his helpful suggestions and discussions. They are also
grateful to Dr. Gilles Pain (Sigma-tau Italia, Pomezia) for
critical revision of the manuscript. This work was sup-
ported by grants from Sigma-Tau Research Switzerland
S.A. (Dr. Alessandro Noseda).
Conflict of Interest
9
a-b, 13-16 within the binding site is very similar to that
The authors declare that there are no conflict of interests.
previously found for different Hsp90 inhibitors (26), with
the resorcinol moiety deeply located within the cavity,
while the remaining part of the molecule pointed toward
the solvent (Figure 2). In further detail, the o-hydroxy group
is involved in a direct and in a water-bridged (HOH2233,
one of the four structural water molecules accommodated
within the Hsp90 binding site) hydrogen bond with the
terminal carboxyl group of Asp93. On the other hand, the
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Appendix S1. Experimental details for synthesis and eval-
uation of new compounds. NMR spectral data of new
compounds.
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