Hybrids of the benzofuran core from natural products and the 2,4-dihydroxy-5-isopropylbenzene fragment as potent Hsp90 inhibitors: Design, synthesis and bioevaluation

Article abstract of DOI:10.1002/minf.201300182

Several chemical fragments have been confirmed as highly efficient cores for the design of Hsp90 inhibitors. Molecular hybridization of potent fragments has been widely used as a rational drug discovery strategy. In this study, a novel class of hybrids of benzofuran, a privileged core from natural products, and 2,4-dihydroxy-5-isopropyl phenyl, an efficient fragment in Hsp90 inhibitors, were designed and synthesized. Subsequent evaluation confirmed they inhibited cell proliferation and regulated the level of client proteins through Hsp90 inhibition. Some of the hybrids can serve as leads to obtain novel chemotypes of Hsp90 inhibitors. The methods reported here may expand the range of known structural types accommodated by the ATP binding site of Hsp90.

Full text of DOI:10.1002/minf.201300182

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DOI: 10.1002/minf.201300182
Hybrids of the Benzofuran Core from Natural Products and
the 2,4-Dihydroxy-5-isopropylbenzene Fragment as Potent
Hsp90 Inhibitors: Design, Synthesis and Bioevaluation
[
a, b]
[a, b]
[a, b]
[a, b]
[a, b]
[a, b]
[a, b]
Jian-Min Jia,
Fang Liu,
Xiao-Li Xu,
Xiao-Ke Guo,
Fen Jiang,
Hao-Zhe Huang,
Yang Pan,
[
a, b]
[a, b, c]
[a, b]
Bahidja Cherfaoui,
Hao-Peng Sun,*
and Qi-Dong You*
Abstract: Several chemical fragments have been confirmed
as highly efficient cores for the design of Hsp90 inhibitors.
Molecular hybridization of potent fragments has been
widely used as a rational drug discovery strategy. In this
study, a novel class of hybrids of benzofuran, a privileged
core from natural products, and 2,4-dihydroxy-5-isopropyl
phenyl, an efficient fragment in Hsp90 inhibitors, were de-
signed and synthesized. Subsequent evaluation confirmed
they inhibited cell proliferation and regulated the level of
client proteins through Hsp90 inhibition. Some of the hy-
brids can serve as leads to obtain novel chemotypes of
Hsp90 inhibitors. The methods reported here may expand
the range of known structural types accommodated by the
ATP binding site of Hsp90.
Keywords: Hybrid · Molecular design · Benzofuran · 2,4-Dihydroxy-5-isopropylbenzene · Hsp90 inhibitor
1
Introduction
The 90 kDa heat shock protein (Hsp90) is a molecular chap-
erone whose association is required for the stability and
function of multiple mutated, chimeric and over-expressed
semi-synthetic inhibitors such as 17-AAG (Figure 1) and 17-
DMAG (Figure 1) which progressed into clinical evalua-
[16,17]
tion.
Subsequently, many small molecule inhibitors of
[1,2]
[18]
signalling proteins named client proteins.
To date, over
Hsp90 have been reported and entered into clinical trials.
However, to date, no Hsp90 inhibitors are in the market
and no inhibitors in clinical trials fully satisfy the requisites
of safety and stability. Therefore, the identification of new
inhibitors that are more potent and selective remains an in-
teresting and promising goal.
2
00 client proteins have been identified, (for a list see
[3]
Picard ) among the plethora of which are involved in path-
ways associated with cancer pathology and the hallmark
[4–6]
[7]
traits of cancer. Several Hsp90 clients are notorious onco-
genes (Raf-1, Akt, Cdk4, Src, Flt-3, hTert, c-Met, etc.), and
five of them are clinically validated cancer targets: HER-2/
neu, Bcr-Abl, estrogen receptor, androgen receptor, and
VEGFR (the full names of the Hsp90 clients were listed in
Hit identification remains a significant challenge in drug
discovery campaign. The molecular hybridization strategy,
[8–11]
the Supplementary data).
Thus, inhibition of Hsp90 si-
[a] J.-M. Jia, F. Liu, X.-L. Xu, X.-K. Guo, F. Jiang, H.-Z. Huang, Y. Pan,
multaneously incapacitates multiple client proteins, provid-
ing a combinatorial attack on cellular oncogenic processes.
Additionally, the prevalence of a high affinity form of
Hsp90 in tumor cells and the greater reliance of cancer
cells on oncogenic client proteins provide a selective profile
B. Cherfaoui, H.-P. Sun, Q.-D. You
Jiang Su Key Laboratory of Drug Design and Optimization, China
Pharmaceutical University
Nanjing 210009, P. R. China
tel/fax: +8602583271216; +8602583271351
*e-mail: sunhaopeng@163.com
[12,13]
of Hsp90 inhibitors for the treatment of cancers.
As
youqidong@gmail.com
a result, Hsp90 has become an attractive and validated
target.
[b] J.-M. Jia, F. Liu, X.-L. Xu, X.-K. Guo, F. Jiang, H.-Z. Huang, Y. Pan,
B. Cherfaoui, H.-P. Sun, Q.-D. You
The Hsp90 protein folding process is ATP dependent. In-
hibition of the ATPase activity of Hsp90 disrupts an ongo-
ing “folding” cycle, including multiple co-chaperone pro-
teins, and in turn leads to the destabilization, ubiquitina-
tion, and ultimately proteasomal degradation of client pro-
State Key Laboratory of Natural Medicines, China Pharmaceutical
University
Nanjing 210009, P. R. China
[c] H.-P. Sun
Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University
Nanjing 210009, P. R. China
[14]
teins. The discovery and studies of the natural products
geldanamycin (GA, Figure 1) and radicicol (RD, Figure 1) as
competitive binders to an ATP site on the N-terminal
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/minf.201300182.
[15]
domain of Hsp90 paved the way for the identification of
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however, has emerged as an efficient method for the devel-
opers. Molecular hybridization involves the rational design
of new chemical entities by the fusion of two or more
[19]
drugs. Combining molecular hybridization with structure-
based design can provide a powerful strategy for drug dis-
[
20]
covery. Indeed molecular hybridization approaches have
been successfully used in Hsp90 discovery programs. Re-
[21]
cently, Blagg et al. reported a hybrid inhibitor radamide
RDA, Figure 1) that contained both the quinone ring from
(
geldanamycin and the resorcinol moiety of radicicol. The
two active fragments, whose binding poses are exemplified
by the co-crystal structures, are merged in RDA in an at-
tempt to enhance the hydrogen bonding interactions with
Hsp90.
2
-Phenyl-3-alkylbenzofuran serves as a privileged core
which is frequently imbedded in anti-cancer natural prod-
[22,23]
ucts (as shown pink shadows in Figure 2).
Meanwhile,
this core possesses similar molecular weight and shape to
the cores that are used in Hsp90 inhibitors, such as isoindo-
line in AT-13387, purine in BIIB021 and 4-phenylisoxazole
Figure 1. The 2D chemical structures of geldanamycin, radicicol,
radamide, 17-AAG and/or 17-DMAG.
Figure 2. Design of the novel hybrid compound 1a based on representative structures of natural products containing benzofuran and
Hsp90 inhibitors containing 2,4-dihydroxy-5-isopropylphenyl.
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in NVP-AUY922. 2,4-Dihydroxy-5-isopropylphenyl (as
With the aim of discovering novel scaffolds as Hsp90 in-
hibitor, in this study, we fused the 2-phenyl-3-alkylbenzofur-
an core with 2,4-dihydroxy-5-isopropylphenyl fragment to
design the initial compound 1a. The compound was
docked into the ATP binding site of Hsp90. The conforma-
tion and the orientation of the docked pose could be su-
perimposed very well to the bound ligand AT-13387 (PBD
shown blue shadows in Figure 2) is proved to be a highly
[24,25]
efficient fragment as Hsp90 inhibitor.
Several candi-
dates in clinical trial contain this fragment, such as NVP-
AUY922, AT-13387, STA-9090 and KW-2478. A series of co-
crystal structures reveal that the fragment deeply inserted
into the polar hinge region of the ATP binding site of
Hsp90. The two hydroxyl groups form strong H-bonds di-
rectly to the key residues Asp93, Asn51 and Thr184 or indi-
rectly to the conserved water molecules in the binding site.
These H-bonds lead to the critical intermolecular recogni-
tion, and thus stabilize the binding of the inhibitors.
[24]
code: 2xjx),
indicating a potentially rational binding
mode of 1a (Figure 3). Encouraged by the results, we syn-
thesized 1a and performed molecular modifications accord-
ing to the structure-based information revealed by molecu-
lar modeling. The hybridization strategy can be expanded
Figure 3. The binding mode between compound 1a and Hsp90. (A) 1a is shown as stick colored in orange, the key residues in the active
site is shown as grey stick, conserved water molecules is shown as red ball, H-bonds are as green dot lines. Molecular surface is added and
colored according to the H-bond state of the residues. (B) The comparison of the docked pose of 1a (yellow stick) and the bound pose of
AT-13387 (PBD code: 2xjx, green stick).
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to other active fragments to obtain more promising scaf-
folds as Hsp90 inhibitors.
on the proposed Hsp90-binding the hybrid compound 1a
were carried out using GOLD. Molecular docking studies
proposed that 1a (Figure 3A) interacted with the ATP-bind-
ing site of Hsp90 in a similar manner to the resorcinol class
of inhibitors. The 2,4-dihydroxy-5-isopropylphenyl of 1a lo-
cated deeply in the binding groove, the hydroxyl groups
were close to the key residues Asp93 and Asn51 to directly
form H-bonds interactions, or indirectly interacted with the
2
Molecular Modeling and Designing
To explore potential binding interactions with the N-termi-
nal ATP-binding site of Hsp90, molecular modelling studies
Scheme 1. Synthesis of compounds 1a–1k. Reagents and conditions: (a) BnBr, K CO , acetone, reflux, 4 h, 92%; (b) Ph3 MePBr, (CH ) COK,
2
3
3 3
THF, 0–258C, 1 h, 75%; (c) Pd/C, THF, rt, 12 h, 75%; (d) BF Et O, Ac O, reflux, 3h, 61.5%; (e) Br , Et O, rt, 30 min, 81%; (f) suitable salicylalde-
3
2
2
2
2
hyde, K CO , acetone, rt, 12h, 90%; (g) Fe, HCl, MeOH, reflux, 3h, 87%; (h) MeI, K CO , EtOH, 12h, 43%; (i) 150 8C, mechlorethamine hydro-
2
3
2
3
chloride; (j) BBr , dichloromethane, 08C, 3 h, 42%.
3
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conserved water molecules in the active site. The benzofu-
ran ring was anchored in the hydrophobic cleft surrounded
by Asp54, Ala55, Lys58, Ile96 and Thr109. The carbonyl of
3 Synthetic Chemistry
The strategy adopted for the synthesis of the target com-
pounds has been outlined in Scheme 1, where the key in-
termediate 6 was synthesized from the starting material 2
according to the reported methods. The intermediate 6
was reacted with the bromine in diethyl ether to give the
compound 7. The compound 7 was treated with the substi-
tuted salicylaldehydes in the presence of potassium car-
bonate and the resulted compounds were reduced by Pd/C
1a, which linked the two fragments, acting as an anchor of
H-bonds with the side chain of Thr184 and water molecules
around (Figure 3A). These interactions ensured the intermo-
lecular recognition of compound 1a by Hsp90 and stabi-
lized the binding pose. At the edge of the binding cavity,
the benzofuran ring faced into solvent region, indicating
proper hydrophilic groups can be introduced to adjust the
physicochemical properties of the compound. Taking all
these observations into consideration, we designed and
synthesized ten analogs of 1a (Scheme 1, ranging from 1b–
[25]
under H atmosphere to afford 1a–1h. The compound 7
2
was added to 2-hydroxy-5-nitrobenzaldehyde in the pres-
ence of potassium carbonate and the resulted compound
was reduced by Fe/HCl to give the intermediate 8. The
compound 1i was synthesized through methylation and re-
1k).
Table 1. Antiproliferative activity in different cell lines and Hsp90 ATPase activity inhibition of 1a–1k.
Compd. no.
R
Hsp90-ATPase activity inhibition (FP, IC , mM) [a]
Antiproliferative activity cell lines (IC , mM) [a]
50
50
SK-Br-3
MCF-7
HCT116
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
ÀH
0.32Æ0.11
0.28Æ0.20
0.20Æ0.07
0.30Æ0.11
0.29Æ0.13
0.37Æ0.22
0.41Æ0.03
1.14Æ0.28
0.17Æ0.01
5.49Æ0.62
7.04Æ1.31
4.93Æ0.71
5.01Æ1.52
1.01Æ0.02
2.13Æ0.44
1.72Æ0.51
10.74Æ0.83
2.13Æ1.32
7.17Æ1.14
5.35Æ0.82
3.88Æ1.29
6.76Æ2.38
3.10Æ0.88
1.91Æ0.21
2.05Æ1.03
24.13Æ2.42
3.08Æ1.11
4.67Æ0.91
4.83Æ0.15
5.13Æ0.63
4.33Æ1.31
2.21Æ0.47
2.24Æ0.63
0.91Æ0.12
18.31Æ3.11
3.14Æ0.15
ÀMe
ÀtBu
ÀOMe
ÀCl
ÀBr
ÀF
ÀNH
2
ÀN(CH )
3
2
1
j
0.09Æ0.04
0.53Æ0.07
0.11Æ0.05
0.76Æ0.11
1
k
–ÀOH
2.13Æ0.08
12.11Æ2.01
22.31Æ0.33
28.51Æ2.12
AT-13387
0.03Æ0.02
0.08Æ0.01
0.07Æ0.06
0.05Æ0.03
[
a] Values shown are mean ÆSD (n=3).
Figure 4. The biological evaluation of the most potent compound 1j. (A) The gene expression of Hsp70 in MCF-7 cell induced by 1j. (B)
Western-Blot analysis of the expression level of Hsp90, Hsp70 and several client proteins of Hsp90 after incubation with 1j in MCF-7 cells.
AT-13387 was used as a positive control at 0.50 mM. 0.1% DMSO was used as a negative control. 1j was incubated with MCF-7 cancer cells
at indicated concentrations (mM) for 36 h. Cell extracts were prepared and equivalent amounts of protein were separated by SDS-PAGE and
subsequently western-blotted for the indicated proteins.
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duction of the intermediate 8. The compound 1j was ob-
4 Biological Evaluation
tained using the intermediate 8 and mechlorethamine hy-
[26]
drochloride according to the reported methods.
The
The Hsp90 binding affinities of hybrids 1a–1k (Scheme 1)
were first evaluated using Hsp90 recombinant human pro-
tein and determined by the fluorescent polarization assay
compound 1k was synthesized by demethylation of com-
pound 1d.
(
FP assay), based on the ability of the compound to com-
[27]
pete with the probe geldanamycin for Hsp90 binding.
Figure 5. The binding mode between compound 1j and Hsp90. (A) The detailed binding information in the active site is shown as stick
colored in orange, the key residues in the active site is shown as grey stick, conserved water molecules is shown as red ball, H-bonds are
as green dot lines. Molecular surface is added and colored according to the H-bond state of the residues. (B) The comparison of the
docked pose of 1j (yellow stick) and the bound pose of AT-13387 (PBD code: 2xjx, green stick).
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The eleven analogs 1a–1k showed encouraging activity
with IC50 values ranging from 0.09 to 2.13 mM (Table 1). The
results suggested that simple modifications such as intro-
duction of methyl, methoxyl and halogens at the 5 position
of the benzofuran (compounds 1b, 1d, 1e, 1f and 1g) were
tolerated, maintaining enzyme activity compared as 1a. The
steric substituents on the benzofuran ring were favorable,
exhibiting more or less increase in potency (1j>1c~1i~
of the binding pocket, interacted with the water molecules,
which enhanced polar interaction and improved the solu-
bility. The docking results proposed a rational binding pat-
tern of 1j with Hsp90, which could explain the activity of
the compound against Hsp90.
1b~1a). In contrast, the polar groups (1h and 1k) on the
5
Conclusions
benzofuran ring was unfavorable, displaying a reduction
IC50 compared to 1a. This reduction in binding affinity may
be explained by that the substituents at this position point-
ed toward the solvent exposed surface of the protein. As
we expected, these new hybrids showed potent Hsp90 in-
hibition activity with nanomolar IC50 values. The most
promising compound 1j exhibited comparable potency to
AT-13387, with IC50 value of 0.09Æ0.04 mM.
In the present study, a novel scaffold containing benzofu-
ran and resorcinol has been developed by molecular hy-
bridization strategy. Eleven hybrids were synthesized and
evaluated for their activities against Hsp90. The target-
based and cell-based assays confirmed the hybrids as
potent Hsp90 inhibitors. The most potent derivative 1j
showed comparable potency to AT-13387. It displayed sig-
nificant inhibition of Hsp90 with an IC50 of 0.09Æ0.04 mM
and an IC50 value of 0.11Æ0.05 mM in an antiproliferative
assay using MCF-7 human breast cancer cells. It could also
regulate the client proteins of Hsp90 in a dose-dependent
manner in MCF-7 cells. This is the first report to use benzo-
furan core as Hsp90 inhibitor. Further optimization of this
core will be meaningful. The hybridization strategy we re-
ported here can be applied to other efficient fragments of
Hsp90 inhibitors to expand the range of chemotypes that
can accommodate well to the ATP binding site of Hsp90.
The antiproliferative activity of these compounds were
evaluated in various cell lines including HCT116 colon cells,
MCF-7 breast cancer cells and SKBr-3 breast cancer cells.
From Table 1, most compounds showed potent anti-prolif-
erative effects with IC50 values of ranging from 0.11–
2
4.13 mM. Among all the compounds, 1e, 1f and 1g having
halogens groups at the 5 position of benzofuran ring
showed good antiproliferative activity. In contrast, com-
pounds 1a–1d, especially for the amino substituent com-
pound 1h and the hydroxy substituent compound 1k,
showed inferior antiproliferative activity against a range of
cell lines, this might result from the unfavorable physico-
chemical properties. 1j displayed the most potent antiproli-
ferative activity against all the cell lines. The data was con-
sistent with the result of FP assay.
To further characterize these new hybrids as potential
Hsp90 inhibitors, the most potent compound 1j was select-
ed for the evaluation of its effect on expression level of the
client protein of Hsp90. We first evaluated the expression
level of Hsp70, a key Hsp family member that was upregu-
lated when Hsp90 was inhibited, by luciferase reporter
assay. As expected, 1j exhibited obvious Hsp70 induction in
a dose-dependent manner, it showed over 3 times induc-
tion of Hsp70 at the concentration of 1.0 mM (Figure 4A).
The result confirmed the Hsp90 inhibitory activities of 1j in
cell-based level. We further determined the ability of 1j to
affect turnover of several Hsp90 client proteins in MCF-7
cells. As shown in Figure 4B, 1j dose-dependently downre-
gulated the Hsp90 client proteins Her2, Akt, Erk and Raf-1.
At the same time, 1j dose-dependently up-regulated
Hsp70.
Acknowledgements
This work is supported by the Project 81230078 (key pro-
gram), 81202463 (youth foundation) and 91129732 of the
National Natural Science Foundation of China, 863 of the
State Key Program, Program of State Key Laboratory of Nat-
ural
Medicines,
China
Pharmaceutical
University
(No. JKGQ201103), 2008ZX09401-001 and 2009ZX09501-003
of National Major Science and Technology Project of China
(Innovation and Development of New Drugs). The authors
declare no other conflicts of interest.
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Received: December 25, 2013
Accepted: April 21, 2014
Published online: July 2, 2014
[
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