Discovery and optimization of new benzofuran derivatives against p53-independent malignant cancer cells through inhibition of HIF-1 pathway

Article abstract of DOI:10.1016/j.bmcl.2016.03.112

p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors.

Full text of DOI:10.1016/j.bmcl.2016.03.112

Accepted Manuscript
Discovery and optimization of new benzofuran derivatives against p53-inde-
pendent malignant cancer cells through inhibition of HIF-1 pathway
Ying-Rui Yang, Jin-Lian Wei, Xiao-Fei Mo, Zhen-Wei Yuan, Jia-Lin Wang,
Chao Zhang, Yi-Yue Xie, Qi-Dong You, Hao-Peng Sun
PII:
S0960-894X(16)30348-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.112
BMCL 23755
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
15 January 2016
28 March 2016
31 March 2016
Please cite this article as: Yang, Y-R., Wei, J-L., Mo, X-F., Yuan, Z-W., Wang, J-L., Zhang, C., Xie, Y-Y., You,
Q-D., Sun, H-P., Discovery and optimization of new benzofuran derivatives against p53-independent malignant
cancer cells through inhibition of HIF-1 pathway, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://
dx.doi.org/10.1016/j.bmcl.2016.03.112
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Discovery and optimization of new
benzofuran derivatives against p53-
independent malignant cancer cells through
inhibition of HIF-1 pathway
Ying-Rui Yang, a, b Jin-Lian Wei, a, b Xiao-Fei Mo, a, b Zhen-Wei Yuan, a, b Jia-Lin Wang, a, b Chao Zhang, a, b
Yi-Yue Xie, a, b Qi-Dong You a, b, * Hao-Peng Suna, b, c*
a Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing
210009, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

Bioorganic & Medicinal Chemistry Letters
Discovery and optimization of new benzofuran derivatives against p53-
independent malignant cancer cells through inhibition of HIF-1 pathway
Ying-Rui Yang, a, b Jin-Lian Wei, a, b Xiao-Fei Mo, a, b Zhen-Wei Yuan, a, b Jia-Lin Wang, a, b Chao Zhang,
a, b
Yi-Yue Xie, a, b Qi-Dong You a, b,  Hao-Peng Suna, b, c, 
a a
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
p53-independent malignant cancer is still severe health problem of human beings. HIF-1
pathway is believed to play an important role in the survival and developing progress of such
cancers. In the present study, with the aim to inhibit the proliferation of p53-independent
malignant cells, we disclose the optimization of 6a, the starting compound which is discovered
in the screening of in-house compound collection. The structure-activity relationship (SAR) is
summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-
mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype
in designing potent anticancer agent especially against those p53-independent malignant tumors.
Keywords:
Benzofuran
Antitumor
2009 Elsevier Ltd. All rights reserved.
Apoptosis
Cycle arrest
HIF-1 inhibition
Cancer is a major public health problem that causes the death
of human beings worldwide. In recent years, there are increasing
pre-clinical and clinical achievements in the treatment of cancers.
Among these discoveries, p53 signaling pathway attracts the
attention of researchers all over the world. It induces cell cycle
arrest and apoptosis in the presence of metabolic disorder or
genetic damage. Activating the function of p53, which is mainly
achieved by blocking the p53-MDM2 protein-protein interaction
with small molecules such as Nutlin-3a,1 is considered to be a
promising therapeutic strategy. However, for those malignant
cancer cell lines, especially the ones that are independent of p53
because of mutation or deletion of p53, there have been only
minimal therapeutic improvements. Mutation or deletion of p53
occurs in approximately 50 % of cancers. That will cause the loss
of tumor suppressor function of p53, and what's worse, will lead
to new oncogenic gain-of-function properties in the cancer cells
including tumorigenesis, invasion, and metastasis2. As a result,
obtaining efficient inhibitors against p53-independent cells is still
an emergent task for medicinal chemists.
outcome.6 At the molecular level, the transcription factor hypoxia
inducible factor-1 (HIF-1) has been recognized as the key
modulator of the response to hypoxia in malignant cells. It
enhances the transactivation of many genes that are involved in
cell survival, metabolism, angiogenesis and invasion.7 Therefore,
inhibition of HIF-1 function is considered as an attractive
strategy for the malignant cancer therapy.8-10
As a key functional moiety, benzofuran appears in the
structures of many natural products and approved drugs.
Recently, benzofuran derivatives have been verified to exert
antiproliferative activity through multiple mechanisms, such as
tubulin polymerization inhibition,11,12 multi-drug resistance
(MDR) reversal activity13 and HIF-1 inhibition.14 For instance,
moracin family are bioactive benzofuran derivatives isolated
from species of the moraceae family. Moracin O and Moracin
P were reported for their ability to inhibit HIF-1 activation, with
IC50 values of 0.14 and 0.65 M, respectively.14,15 Another
benzofuran derivative BNC-105P, a tubulin polymerization
inhibitor, is being developed in early clinical development at
Bionomics for the treatment of progressive or metastatic clear
cell renal cell carcinoma (Phase II),16 asbestos-related
mesothelioma (Phase II)17 and ovarian cancer (Phase I/II).18
A unique feature of malignant cancers is that the rapid growth
of the cells often resulted in hypoxia microenvironment, leading
to reduced oxygen availability of the cells due to the formation of
inadequate or aberrant vasculature.3 The hypoxic condition can
reduce the sensibility of cancer cells to radiotherapy4 and
conventional chemotherapy5, thus leading to poor therapeutic
———
 Corresponding author. Tel.: +86-25-83271351; fax: +86-25-83271351; e-mail: sunhaopeng@163.com
 Corresponding author. Tel.: +86-25-83271216; fax: +86-25-83271216; e-mail: youqd@163.com

Figure 1. Representation of benzofuran derivatives
Our research groups focused on the discovery and optimization
of new therapeutic agents against malignant cancers for over a
decade.19-22 Previously, we performed cell-based screenings of in-
house compound collections with the aim to identify new
compounds against p53-independent malignant cancer cell lines.
During screening, compound 6a showed moderate inhibition of
two human colorectal carcinoma cell lines, HCT116 (with wild-
type p53) and HCT116–/–(with p53 deleted), with IC50 value of
9.46 ± 1.01 and 8.70 ± M, respectively. Considering that
the compound showed better inhibitory activity on p53-
independent cell HCT116–/– than traditional p53-MDM2 inhibitor
Nutlin-3a, we infer that 6a may be more sensitive to p53-
independent cells. Therefore, the compound was selected as the
starting compound for further optimization.
Scheme 1. Reagents and conditions: (a) BrCH2COOEt, KI, K2CO3, acetone,
reflux, 2h, 91%; (b) K2CO3, DMF, microwave (350W, 145 C, 7 min) 59%;
o
(c) 3M HCl, EtOH, reflux, 6-8 h, 63%; (d) pyridine, substituted
benzenesulfonyl chloride, DCM, r.t., 6h, 41-82%; (e) R2Br or R2Cl, K2CO3,
KI, acetone, reflux, 2-8 h, 41-90%; (f) NaOH/EtOH, reflux, 2 h, 69-85%; (g)
o
EDCI, HoBt, DIPEA, RNH2, r.t., overnight, 43-88%; (h) CF3COOH, 30 C,
overnight, 98%.
Table 1. Antiproliferative activities of the synthesized analogs of
6a against human colorectal carcinoma cells
IC50(M)
Compd.
R1
R2
R3
HCT116
9.46 ± 1.01
>40
HCT116-/-
8.70 ± 1.76
>40
6a
6b
6c
6d
6e
6f
6g
6h
6i
4-Br
3-Br
2-Br
4-CH3
4-OMe
4-NO2
4-CF3
4-Cl
3-Cl
4-F
H
4-Br
4-Cl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
4-Br-benzyl
4-Cl-benzyl
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
>40
>40
>40
>40
>40
>40
>40
>40
26.7 ±1.8
4.86 ±0.56
>40
12.7 ± 2.6
23.2 ± 1.1
>40
6j
6k
6l
5.82 ± 0.73
>40
33.1 ± 3.6
>40
Figure 2. Structural optimization strategy of the starting compound
6a.
10.9 ± 1.7
9.48 ± 0.84
5.22 ± 1.41
9.64 ± 1.43
6m
In order to identify the key component of compound 6a, the
scaffold of this compound was firstly analyzed. Two series of
analogues 6a~p and 7a~g were synthesized (Scheme 1) in order
to evaluate the importance of the two aromatic ring (ring A and B,
respectively). Additionally, we observed that 6a contained
several hydrophobic rings, which can lead to the poor solubility
of the compound (cLogP of 6a was 6.14 calculated by Discovery
Studio 4.0). To solve this problem, the ester group (Region III)
was replaced by other polar groups to explore their effects on
antitumor activities as well as the physicochemical properties.
Compound 1 was prepared as described in literature23 with p-
anisidine as the starting material. In the presence of potassium
carbonate, 1 was alkylated with ethyl bromoacetate to give 2.
Cyclization of 2 in the presence of potassium carbonate under
microwave irradiation afforded benzofuran 3.24 Hydrolysis of 3
6n
6o
4-Cl
4-Cl
OEt
OEt
14.1 ±1.5
>40
>40
CH(CH3)2
7.83 ± 1.71
6p
18.3 ± 2.5
>40
5a
5g
5h
5j
7a
7b
7c
7d
7e
7f
4-Br
4-CF3
4-Cl
4-F
4-Br
4-Br
4-Cl
4-Cl
4-F
H
H
H
OEt
OEt
OEt
OEt
OH
OH
OH
OH
OH
OH
9.31 ± 0.75
5.03 ± 0.50
24.3 ± 1.08
10.5 ± 1.0
7.09 ± 0.48
8.58 ± 0.82
9.13 ± 0.93
3.67 ± 0.20
>40
>40
24.2 ± 1.1
>40
>40
20.0 ± 2.3
>40
33.4 ± 2.0
27.2 ± 2.7
>40
H
Benzyl
4-Br-benzyl
Benzyl
4-Cl-benzyl
Benzyl
Benzyl
4-CF3
4.13 ± 0.94
21.1 ± 1.4
with HCl gave 4. Sulfonylation of
4 with substituted
benzenesulfonyl chloride and pyridine generated analogues 5. 25
N-alkylation of 5 led to analogues 6. Hydrolysis of carboxylic
ester 6 with sodium hydroxide led to 7. 8a~c and 9a~c were
obtained by amidation of 7 and substituted amine. Deprotection
of Boc group in 8c and 9c gave 8d and 9d.
Nutlin-
3a
5.21 ± 0.39
21.5 ± 3.7

All the compounds were assessed in vitro against HCT116
and HCT116-/- (p53-null) cell lines. Nutlin-3a was used as the
positive control. For the structure-activity relationship (SAR) of
these compounds, we firstly observed that the substituted
position of ring A played critical role for the compounds.
Changes from 4-bromine to 3- or 2-bromine (6b or 6c) led to the
completely loss of antitumor activity. Similar manner was
observed in -Cl substitution (6h and 6i). The results indicated
that para substitution of ring A was one of the determinants for
the antiproliferative activity. As a result, we then introduced
other groups at the para position of ring A. The bromine atom
was replaced by different kinds of substituent, including electron-
donating groups (6d, 6e) and electron-withdrawing groups (6f, 6g,
6j). We found electron-donating groups were not preferred, as 6d
and 6e completely loss their antiproliferative activity. While
electron-withdrawing groups slightly reduced the activity, with
an exception of 6f, this can be explained by its poor solubility
during the assay. When we removed the substituent of ring A
(6k), the activity was completely lost, indicating appropriate
group at para position of ring A was necessary. When halogen
atom was introduced (6l, 6m), the activity was slightly improved.
Additionally, we found the 6l showed improved potency on
HCT116-/- cells, indicating that bromine at para position of ring
B was preferred in designing potent compounds against p53-
supported the conclusion mentioned above. To further evaluate
the importance of benzofuran core, we replaced it by benzene
(6p). The compound also lost the activity on HCT116-/- cells,
indicating the benzofuran core need to be retained.
We then optimized region III by replacing the ester with
carboxyl group (7a~7f) to improve the aqueous solubility of the
compounds. The activities of compounds 7a~7f on HCT116 cells
were retained, however, the HCT116-/- inhibition remarkably
decreased. We inferred that the carboxyl group may be too polar
to permeate the cell membrane of HCT116-/- cells. Compounds
with both high cell permeability and good aqueous solubility
were more likely to show good inhibitory activities. As a result,
we then replaced the carboxyl group with N containing alkyl
chains (8a, 8b, 8d, 9a, 9b, and 9d). We observed that all these
six compounds exhibited obviously improved antiproliferative
activity on HCT116-/- cells compared to carboxyl substituted
compounds. To further verify that compounds were active in a
p53-independent manner, we evaluated the antiproliferative
activities of the compounds on two breast cancer cell lines.
MCF7 was p53 wild type while MDA-MB-435s was more
malignant with p53 mutation. We observed that all the
compounds showed good antiproliferative activities on MDA-
MB-435s cells, while the positive control, Nutlin-3a, exhibited
about 5-fold decrease in inhibiting MDA-MB-435s cells
compared to MCF7 cells. The most potent compound 8d and 9d,
showed IC50 against the four cell lines in a low micromolar range,
indicating that they can serve as the starting compounds for
further optimization.
independent cells. When ring
B
was replaced by
cyclohexylmethyl (6n) or isopropyl (6o), the activity on wild
type HCT116 cells was retained, however, they completely loss
the activities on HCT116-/- cells, indicating the benzene ring was
important in designing potent compounds targeting p53-
independent cells. Similar manner was observed when the
benzene ring was removed (5a, 5g, 5h, 5j). The results further
Table 2. Antiproliferative activities against five cancer cell lines and physicochemical properties of derivatives of 6h and 6m
Antiproliferative activity, IC50 (M)
Compd.
X
R3
HIF-1 IRa at 20 M (%)
HCT116
HCT116-/-
MCF7
MDA-MB-435s
<10
8a
8b
8d
H
H
H
7.06 ± 0.51
6.31 ± 0.54
6.72 ± 1.69
9.24 ± 2.74
17.1 ± 4.9
5.00 ± 0.08
2.91 ± 0.73
31.8 ± 5.24
4.56 ± 0.27
5.60 ± 0.65
4.71 ± 0.26
32.3 ± 6.0
47.3 ± 5.7
3.00 ± 0.86
5.38 ± 0.49
2.43 ± 0.61
1.81 ± 0.33
5.21 ± 0.39
3.87 ± 0.33
1.89 ± 0.26
4.03 ± 0.85
21.5 ± 3.7
5.84 ± 0.89
>40
10.8 ± 0.5
7.25 ± 0.80
1.63 ± 0.06
29.6 ± 5.3
12.7 ± 4.4
27.0 ± 9.1
9a
9b
Cl
Cl
Cl
-
5.67 ± 0.75
5.01 ± 0.05
22.2 ± 3.8 ( 10 M)b
<10
9d
Nutlin-3a
-
a inhibitory rate; b 9d caused completely cell death at a concentration of 20 M.
Considering HIF-1 signaling pathway played an important
role in malignant cancers, we then evaluated whether the
compounds exerted their p53-independent antiproliferative
effects through HIF-1 pathway. We initially assayed the
compounds by a cell-based luciferase reporter assay on the basis
of evaluating the hypoxia response elements (HREs). 8d showed
47.3 ± 5.7 % inhibition of HRE at the concentration of 20 μM,
while 9d showed 22.2 ± 3.8 % inhibition at 10 μM. These data
suggested that the compounds, at least partially, exerted their
antiproliferative activities through HIF-1 inhibition. To further
support the conclusion, we next selected 8d to determine whether
it could inhibit the gene level of endothelial growth factor
(VEGF), a well-known downstream target gene of HIF-1. 8d
reduced the expression of VEGF gene in a dose dependent
manner based on real-time PCR (rt-PCR, Fig. 3). The data were
consistent with HRE assay, confirming that 8d inhibited HIF-1
pathway, which would enhance the antitumor activity of the
compound under hypoxia condition.

with annexin-V/propidium iodide (PI) was performed on
HCT116-/- cells. After treatment with 5, 10 or 20 μM of 8d for 48
h, the early apoptotic rates in control and treated HCT116-/- cells
were 6.96, 15.42, 55.86 and 62.28%, respectively, and the late
apoptotic rates were 3.11, 6.74, 14.99, and 34.63% respectively
(Fig. 4C). These results demonstrated that 8d treatment induced
both early and late apoptosis in a concentration-dependent
manner. To determine whether the suppression of HCT116-/- cell
by compound 8d was caused by a regulation of the cell cycle
progress, a cell-cycle cytotoxicity assay was performed by
treating HCT116-/- cells at different concentrations of compound
8d (0, 5, 10, 20 M) for 12 h . Cells in the G1 phase increased
from 27.78% in control to 36.24%, 52.82% and 59.67%.
Therefore, compound 8d induced cell cycle arrest at the G1
phase in a concentration manner (Fig. 4D).
Finally, we evaluated the expression of apoptosis related
proteins procaspase-3 and procaspase-9 after the treatment of 8d
in HCT116-/- cells by western blot analysis (Fig. 5). The
expression levels of the two proteins were remarkably decreased,
indicating an activation of apoptosis. While p53 wild-type
dependent compound Nutlin-3a did not show such effect. Taken
together, compound 8d induced cell apoptosis in a p53-
independent manner.
Figure 3. VEGF mRNA was measured by real-time PCR analyses in MCF7
cell line after 8d (0, 5, 10, 20 μM) treated for 24 h under hypoxic condition.
GAPDH expression was used as control. All error bars are SD. *Represents a
significant difference compared to hypoxia control, p < 0.05.
We next evaluated whether 8d could induce cell apoptosis
through inhibiting HIF-1 pathway. After 48 h treatment of 8d in
HCT116-/- cells,
a significantly morphologic change was
observed, indicating that 8d strongly induced the death of
HCT116-/- cells (Fig. 4A and 4B). To characterize the mode of
cell death induced by 8d, biparametric flow cytometric analysis
Figure 4. (A) Morphologic changes and (B) the nuclei of HCT116-/- (p53-null) cells were treated with 0, 5, 10 and 20 μM compound 8d for 48h. (C) Apoptosis
analysis of HCT116-/- (p53-null) cells was performed by flow cytometer after 8d treatment for 48 h. (D) Cell cycle analysis of HCT116-/- (p53-null) cells was
performed by flow cytometer after 8d treatment for 12 h.

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Acknowledgments
This work is supported by 2013ZX09402102-001-005 of the
National Major Science and Technology Project of China
(Innovation and Development of New Drugs); 2012AA020301 of
863 key program.
25. Yang, L.; Lei, H.; Mi, C. G.; Liu, H.; Zhou, T.; Zhao, Y. L.; Lai,
X. Y.; Li, Z. C.; Song, H.; Huang, W. C. Bioorg. Med. Chem. Lett.
2011, 21, 5389.
Supplementary data
The structure determination and the methods for biological
evaluation are supplied in supplementary data.
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