Synthesis and Biological Evaluation of Stilbene Analogues as Hsp90 C-Terminal Inhibitors

Article abstract of DOI:10.1002/cmdc.201700630

The design, synthesis, and biological evaluation of stilbene-based novobiocin analogues is reported. Replacement of the biaryl amide side chain with a triazole side chain produced compounds that exhibited good antiproliferative activities. Heat shock prot

Full text of DOI:10.1002/cmdc.201700630

Accepted Article
Title: Synthesis and biological evaluation of stilbene analogs as Hsp90
C-terminal inhibitors
Authors: katherine byrd, Caitlyn kent, and Brian Blagg
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Synthesis and biological evaluation of stilbene analogs as Hsp90
C-terminal inhibitors
Katherine M. Byrd, Caitlin N. Kent and Brian S. J. Blagg*
Anuj Khandewal and the life he lived
Abstract: The design, synthesis and biological evaluation of stilbene-
based novobiocin analogs is reported. Replacement of the biaryl
amide side chain with a triazole side chain produced compounds
that exhibited good anti-proliferative activities. Hsp90 inhibition was
observed when N-methyl piperidine was replaced with acyclic
tertiary amines on the stilbene analogs that also contain a triazole-
derived side chain. These studies revealed that ~24 Å is the optimal
length for compounds that exhibit good anti-proliferative activity as a
result of Hsp90 inhibition.
activation/maturation of more than 300 client proteins, many of
which are associated with the 10 hallmarks of cancer.[6-8] Since
Hsp90 inhibition results in the simultaneous degradation of
multiple oncogenic targets, it has emerged as a novel target for
to development of anti-cancer agents. Additionally, studies have
shown that Hsp90 is overexpressed in cancer, which provides
an additional opportunity to selectively target Hsp90 in cancer
cells versus normal tissue.[9-11]
Initial efforts to develop Hsp90 inhibitors for the treatment of
cancer focused on compounds that bind the Hsp90 N-terminus.
These efforts led to the identification of twenty Hsp90 N-terminal
inhibitors that have now been investigated in a clinical setting.[12-
15]
Introduction
To date, no Hsp90 inhibitor has been approved by the FDA
for the treatment of cancer. Unfortunately, these studies were
plagued by dosing difficulties and some toxicity issues
associated with induction of the pro-survival heat shock
response at the same concentration that inhibits client protein
folding.[16] In order to address these issues, Hsp90 isoform-
selective inhibitors have been sought to limit and identify
potential on-target toxicities.[17] Recently, it was demonstrated
that selective inhibition of Hsp90β can inhibit a number of
cancers without concomitant induction of Hsp90.[18]
Heat shock protein 90 kDa (Hsp90) is
a molecular
chaperone that folds polypeptides and denatured proteins into
their bioactive conformation.[1] In humans, Hsp90 exists as four
isoforms: Hsp90α, Hsp90β, glucose-regulated protein 94 kDa
(Grp94), and tumor necrosis receptor-associated protein 1
(Trap1). Hsp90α and Hsp90β are localized to the cytoplasm,
whereas Grp94 resides in the endoplasmic reticulum, and Trap1
is localized within the mitochondria.[2,3] Structurally, these
isoforms are homodimers, whose monomeric unit consists of an
N-terminal ATP-binding motif, a middle domain, and a C-
terminal dimerization motif.[4,5] Hsp90 is responsible for the
Figure 1. Previous Hsp90 inhibitors
Dr. K. M. Byrd, C. N. Kent and Prof. B. S. J. Blagg
Department of Chemistry and Biochemistry
University of Notre Dame
251 Nieuwland Science Hall, Notre Dame, IN 46556, USA
E-mail: bblagg@nd.edu
Phone: 574-631-6877
Supporting information for this article is given via a link at the end of
the document.
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Figure 2. Initial analogs of 2
Hsp90 C-terminal inhibitors have been shown to induce
Hsp90 client protein degradation without concomitant induction
Synthesis of ring-constrained analogs
of the heat shock response.[19]
Therefore, this approach
Synthesis of 3 commenced via a Suzuki coupling between
vinyl triflate 8[27] and 4-hydroxyphenylboronic acid to produce 9
in 45% yield (Scheme 1). N-methyl-4-piperidinol (10) was then
coupled with 9 via a Mitsunobu etherification.[28] Following
removal of the Boc-protecting group, the resulting aniline was
coupled with acid chloride 12 to yield 3 in 39% over both steps.
Compound 3 was subsequently subjected to hydrogenation
conditions to yield the saturated derivative, 13.
represents an attractive alternative to Hsp90 N-terminal
inhibition. Although there is no co-crystal structure of the Hsp90
C-terminus bound to inhibitors,[20] drug discovery efforts have led
to the identification of Hsp90 C-terminal inhibitors that exhibit
excellent anti-proliferative activity against a variety of cancers.[21]
Those Hsp90 C-terminal inhibitors have been developed by
elucidation and evaluation of structure-activity relationship (SAR)
studies on novobiocin (1), which was the first Hsp90 C-terminal
inhibitor identified.[22-24] Previous studies also determined the
optimal distance and angle between the N-methyl piperidine and
biaryl amide side chain[25] which revealed that the most
efficacious anti-proliferative and Hsp90 inhibitory activities were
obtained when the distance was between 7.7 to 11.8 Å and the
angle was ~180° (Figure 1). In fact, stilbene 2 was identified as
the most efficacious inhibitor that exhibited both potent anti-
proliferative and Hsp90 inhibitory activity. Therefore, the focus
of this work was to optimize 2, identify structure-activity
relationships, and obtain more efficacious compounds.
Preparation of
4
was initiated by installation of
a
methoxymethyl (MOM) protecting group onto 6-hydroxy-2-
Results and Discussion
Synthesis and biological evaluation of stilbene core analogs
Initial efforts to modify 2 consisted of three approaches
(Figure 2): The first approach was to restrict rotation of the
phenyl rings within the stilbene core, thus prohibiting the
entropic penalty observed upon binding. Such compounds
could provide insight into preferred orientation of the phenyl ring
upon binding Hsp90. The first ring-constrained analogs were
comprised of a 6-phenyl-7,8-dihydronaphthalene core, which
allowed rotation of one phenyl ring. The second approach
sought to investigate the electronic effects by enlisting a Topliss
tree approach[26] to dictate subsequent modification. The final
approach was to modify orientation of the N-methyl piperidine
and biaryl amide side chain through the incorporation of a
cyclopropane ring or inclusion of a saturated phenyl ring.
Scheme 1. Synthesis of 3
tetralone (Scheme 2). Tetralone 14 was first converted to the
vinyl triflate and then immediately coupled with 4-
nitrophenylboronic acid, to form 16. Upon removal of the
protecting group present in 16, the resulting phenol was coupled
with N-methyl-4-piperidinol through a Mitsunobu etherification
reaction. Following reduction of the nitro group in 17 to the
corresponding aniline, the aniline was treated with acid chloride
12 to form 4 in 50% yield. Hydrogenation of 4 led to saturated
derivative 18, in 58% yield.
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Stilbenes 20a/b were synthesized via a Heck coupling between
styrene 19[29] and the corresponding nitrobenzenes. Upon
reduction of the nitro groups in 20a/b, the resulting anilines were
coupled with carboxylic acid 21 to form amides 22a/b. Following
removal of the MOM group, the corresponding phenols were
coupled with N-methyl-4-piperidinol.
Synthesis of saturated analogs of 2
Synthesis of the cyclopropane analog[30] began via
cyclopropanation of stilbene 24.[31,32] (Scheme 4) Following
demethylation of 25, a methoxymethyl group was placed onto
the resulting phenol. Aryl bromide 26 was coupled[33] with amide
27 via Hartwig-Buchwald amidation to form 28. After removal of
the methoxymethyl ether, the corresponding phenol was coupled
with N-methyl-4-piperidinol to form the final product, 6.
Scheme 2. Synthesis of 4
Synthesis of analogs to study electronic effects
The first stilbene derivatives synthesized contained
a
chloride group in the ortho- or meta-position of the amide
substituted phenyl ring (See supporting information for
synthesis). Since the chloro-containing derivatives were less
active than the parent compound, methoxy-substituted stilbenes
were synthesized according to the Topliss approach (Scheme 3).
Scheme 4. Synthesis of cyclopropane analog
Preparation of the saturated analog of 2 commenced via a
Horner-Wadsworth-Emmons reaction between phosphonate 29
and aldehyde 30,[34] to form 31 (Scheme 5). After removal of the
ketal on 31, the resulting ketone 32 was subjected to a
deprotection-protection protocol to produce 33. Syn alcohol 34
was obtained via the treatment of 33 with L-Selectride.
Following activation of the alcohol with methanesulfonyl chloride,
the resulting mesylate was displaced to form azide 35. Amide
36 was then formed by reduction of azide 35 to form the
corresponding amine, which was subsequently coupled with
carboxylic acid 21 to give 36. Removal of the toluenesulfonate
ester and coupling of the resulting phenol with N-methyl-4-
piperidinol completed the preparation of 7.
Scheme 3. Synthesis of 23a/b
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Scheme 5. Synthesis of saturated analog of 2
Table 1. Evaluation of anti-proliferative activity
OMe
OMe
H
N
O
O
N
H3C
X = Red
Y = Green
Compound
2
Structure
MCF-7 [a]
1.3±0.59
SKBr3 [a]
HCT-116 [a]
3.68±0.41
Y
Y
Y
Y
Y
Y
0.68±0.10
X
3
>50
>50
>50
>50
>50
X
13
>50
X
X
X
4
2.61±0.98
7.36±0.82
3.54±0.43
10.59±1.61
3.64±0.20
>50
3.57±0.19
6.43±0.18
4.50±0.99
>50
18
23a
23b
37a
37b
3.59±0.068
>50
OCH3
X
Y
OCH3
X
Y
>50
>50
>50
Cl
X
Y
>50
27.46±0.057
>50
Cl
X
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Y
6
7
2.64±1.04
1.31±0.251
2.90±0.69
X
Y
0.814±0.126
0.894±0.004
0.801±0.091
X
[a] = Values are in µM, which represent mean standard deviation for at least two separate experiments performed in triplicate.
These initial analogs were evaluated against three cancer
Investigation of replacements for the N-methyl piperidine and
cell lines: MCF-7 (estrogen receptor positive breast cancer cells), biaryl amide side chain
SKBr3 (estrogen receptor negative, HER2 overexpressing
breast cancer cells) and HCT-116 (human colon cancer cells).
(Table 1) Restriction of rotation of either phenyl ring resulted in
a significant or complete loss of anti-proliferative activity across
all three cancer cell lines. These results suggest that the
addition of two carbons at the center of the stilbene core may
cause a steric clash with Hsp90. The addition of a chloro or
methoxy group also caused a significant loss in anti-proliferative
activity, as compared to the parent compound. The saturated
analogs manifested the most efficacious anti-proliferative
activities, and the activity of 7 was comparable to parent
compound 2. In order to determine whether the anti-proliferative
activities manifested by the saturated analogs were the result of
Hsp90 inhibition, western blot analyses were performed on
MCF-7 cell lysates treated with 6 and 7 for 24 hours (Figure 1S).
Neither compound was able to induce Hsp90 dependent client
protein degradation at concentrations that mirror the IC50 values.
Overall, the results from these compounds show that stilbene 2
remains the optimal core for the design of future analogs.
Previous optimization studies on the noviose sugar and
prenylated amide side chain of novobiocin (1) provided insight
towards the inclusion of N-methyl piperidine and the biaryl amide
side chain. For example, such studies revealed that the best
anti-proliferative activities were obtained when the noviose sugar
was replaced with a tertiary amine.[22b] Subsequent studies have
shown that the tertiary amine (cyclic versus acyclic) can play a
significant role in binding the Hsp90 C-terminal domain.[35]
Therefore, various acyclic tertiary amines were investigated with
this stilbene core. In terms of the biaryl amide side chain, work
has been done to probe the utility of each aromatic ring on the
amide side chain and alternative aromatic systems have been
identified that can replace the biaryl amide side chain. Of the
systems investigated from the literature, a triazole-containing
amide side chain was shown to manifest the most efficacious
activity against multiple cancer cell lines.[22c] Therefore, triazole-
based amide side chains were investigated as replacements for
the biaryl amide side chain in this study.
Scheme 6 illustrates the general synthetic route used to
Second-generation stilbene analogs
construct the triazole-based stilbene analogs.
4-Nitro-4’-
It was important to change either the N-methyl piperidine
or biaryl amide side chain based on the information gained from
hydroxystilbene was protected with a methoxymethyl group to
yield 39. Next, the nitro group was reduced to the corresponding
aniline, which was then coupled with the requisite carboxylic
acid to form the resulting amide. The protecting group on the
amide was removed before the appropriate tertiary amine was
then coupled with the phenol via a Mitsunobu etherification or
SN2 reaction.
the first generation of compounds.
Since the N-methyl
piperidine and biaryl amide side chain were optimized for the
coumarin and biphenyl scaffold, appendages on both sides of
the stilbene core were investigated.
Scheme 6 General Scheme for the preparation of second-generation stilbene analogs
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Table 2. Evaluation of biological activities of second-generation stilbene analogs
Compound
R4
X
X
X
Y
Y
Z
R2
A
B
C
B
C
B
C
A
MCF-7 [a]
SKBr3 [a]
HCT-116 [a]
3.68±0.41
2
1.3±0.59
0.68±0.10
44
45
46
47
48
49
50
0.326±0.081
0.092±0.005
0.325±0.034
0.494±0.053
0.234±0.052
0.150±0.008
5.86±1.23
0.231±0.035
0.099±0.020
0.382±0.101
0.184±0.071
0.183±0.003
0.141±0.028
9.68±0.209
0.301±0.043
0.186±0.035
0.350±0.064
0.740±0.164
0.350±0.064
0.179±0.050
5.51±0.225
Z
Y
[a] = Values are in µM, which represent mean standard deviation for at least two separate experiments performed in triplicate.
Replacement of the biaryl amide side chain with the triazole
moiety caused a significant increase in anti-proliferative activity
against all of the investigated cell lines (Table 2). Regardless of
R, compounds containing the triazole and 4-methylbenzyl group
(C) were more potent than the benzyl (B) substituted derivatives.
When N-methyl-piperidine (X) was replaced with 3-
(dimethylamino)propane (Y), the activity decreased as in 47,
while the activity of 46 was similar to 44. Interestingly, when the
shorter 2-(dimethylamino)ethane (Z) was added onto the
stilbene core, an improvement in anti-proliferative activity was
observed for both triazole-containing compounds (48 and 49).
This data suggests that a limited amount of space exists within
the binding pocket. Once a compound exceeds that defined
terminal binding pocket. As shown in Figure 5, the best
compounds (46 and 49) are ~ 24 Å in length. If the compound is
too long (47) or too short (48), then the compound is unable to
inhibit Hsp90 and induce client protein degradation. The
improvement in Hsp90 inhibition by 46 and 49 reveals that the
incorporation of a flexible 3-(dimethylamino)alkyl group can
produce better interactions with Hsp90 for this particular scaffold.
A.
space, then the anti-proliferative activities decrease.
example, the activities manifested by 49 are better than the
activities exhibited by 47, suggesting that 47 is too large to fit
For
Cyclin D1
CDK4
within the Hsp90 C-terminal binding pocket.
In order to
independently probe the effect of the acyclic amine on anti-
proliferative activity, 50 was tested against all of the cancer cell
lines. Since 50 is significantly less active than 2, it is clear that
the increase in anti-proliferative activity is due to replacement of
the biaryl amide side chain with the triazole moiety.
Raf-1
Western blot analyses of MCF-7 cell lysates incubated with
44 and 45 for 24 hours were conducted to determine whether
the observed anti-proliferative activities resulted from Hsp90
inhibition (Figure 3). For 44, a dose-dependent degradation of
Hsp90-dependent client proteins was observed, whereas no
degradation of Hsp90 client proteins was observed for 45. The
western blot analysis of 46 and 47 showed that 46, but not 47,
induced client protein degradation (Figure 4). On the other hand,
western blot analysis of 48 and 49 revealed that 49 was able to
induce Hsp90 client protein degradation. This data supports that
there is an overall optimal length for occupancy of the Hsp90 C-
Hsp90
Actin
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B.
B.
HER 2
CDK4
Cyclin D1
CDK4
Raf-1
Akt-1
Hsp90
Actin
Hsp90
Actin
Figure 3 Western blot analysis of Hsp90 client protein degradation in MCF-7
cells. Geldanamycin (GDA 500 nm) represents a positive control, while DMSO,
represents the negative control. A. Analysis of cells treated with 44. B.
Analysis of cells treated with 45.
Figure 4 Western blot analysis of Hsp90 client protein degradation in MCF-7
cells treated with (A) 37 and 38 or (B) 39 and 40. Geldanamycin (GDA 500
nm) represents a positive control, while DMSO, represents the negative
A.
control. L represents a concentration 1/2XIC
concentration of 5XIC value.
50
value while H represents a
50
Conclusions
Cyclin D1
In an effort to optimize 2, structure-activity relationships were
elucidated for 17 analogs, which revealed the stilbene core to be
optimal for these compounds. Replacement of the biaryl amide
side chain with a triazole-containing group improved anti-
proliferative activity. In addition, replacement of the N-methyl
piperidine with a (dimethylamino)alkyl group led to Hsp90
inhibition. The overall length of the best Hsp90 inhibitors was 24
Å.
CDK4
Raf-1
Experimental Section
Hsp90
Actin
1H NMR were recorded at 400 or 500 MHz (Bruker DRX- 400 Bruker with
a H/C/P/F QNP gradient probe) spectrometer and 13C NMR spectra were
recorded at 125 MHz (Bruker DRX 500 with broadband, inverse triple
resonance, and high resolution magic angle spinning HR-MA probe
spectrometer); chemical shifts are reported in δ (ppm) relative to the
internal reference CDCl3 (CDCl , 7.26 ppm). FAB (HRMS) spectra were
3
recorded with a LCT Premier (Waters Corp., Milford, MA) spectrometer
and IR spectra were recorded on a Magna FT-IR spectrometer (Nicolet
Instrument Corporation, Madison, WI). The purity of all compounds was
determined to be >95% as determined by 1H NMR and 13C NMR spectra,
unless otherwise noted. TLC was performed on glass- backed silica gel
plates (Uniplate) with spots visualized by UV light. All solvents were
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reagent grade and, when necessary, were purified and dried by standard
methods. Concentration of solutions after reactions and extractions
involved the use of a rotary evaporator operating at reduced pressure.
Detailed experimental procedures can be found in the supporting
information.
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Keywords: Heat Shock Protein 90 • Stilbene • C-terminal
inhibitors • Anti-cancer agents
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10.1002/cmdc.201700630
ChemMedChem
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This work focused on the
design and biological
Byrd, K. M., Kent, C. N., Blagg,
B. S. J.*
N
N
N
H
N
O
evaluation of stilbene-based
novobiocin analogs. Intial
This Work
N
Pg. 1 – 9
O
OCH3
efforts revealed the stilbene
H
N
Synthesis and biological
evaluation of stilbene-based
analogs as Hsp90 inhibitors
OCH3
moiety as the optimal core.
These studies revealed that
replacement of the biaryl
amide side chain with triazole
containing analogs and
O
2
O
OH
OH
O
H
N
N
CH3
O
O
O
tertiary amines on the stilbene
core produced more
O
MeO
O
Novobiocin (1)
O
OH
efficacious compounds as
confirmed by EC50 values and
western blot analyses.
NH2
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Author(s), Corresponding Author(s)*
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Title
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