2-Phenylbenzo[b]furans: Synthesis and promoting activity on estrogen biosynthesis

Article abstract of DOI:10.1016/j.bmcl.2016.10.013

Estrogen biosynthesis is pivotal to many physiological processes of human. Aberrant estrogen level is closely related to a variety of diseases, including breast cancer and osteoporosis. Previously we found that 2-phenylbenzo[b]furan glycosides could promote estrogen biosynthesis. To find high active 2-phenylbenzo[b]furans, fifty-four 2-phenylbenzo[b]furans were prepared via four strategies according to corresponding substrate scopes. Biological evaluation in HEK293A cells showed that some compounds exhibited promotive activity on estrogen biosynthesis. 2-(4-Chlorophenyl)-7-methoxybenzo[b]furan possessed the highest activity with EC₅₀value of 14.68?μM. Furthermore, these compounds did not affect aromatase expression in HEK292A cells, indicating that these 2-phenylbenzo[b]furans might enhance estrogen biosynthesis via directly allosteric regulation of aromatase or indirectly via posttranslational modification.

Full text of DOI:10.1016/j.bmcl.2016.10.013

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Phenylbenzo[b]furans: Synthesis and promoting activity
on estrogen biosynthesis
Wenchen Pu a,b, Yun Yuan a,c, Danfeng Lu a, Xin Wang a, Hanwei Liu d, Chun Wang a, Fei Wang a,
Guolin Zhang a,
⇑
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b University of Chinese Academy of Sciences, Beijing 100049, China
c School of Materials and Science Engineering, Southwest University of Science and Technology, Mianyang 621010, China
d Ningbo Entry-Exit Inspection and Quarantine Bureau Technical Center, Ningbo 315012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Estrogen biosynthesis is pivotal to many physiological processes of human. Aberrant estrogen level is clo-
sely related to a variety of diseases, including breast cancer and osteoporosis. Previously we found that 2-
phenylbenzo[b]furan glycosides could promote estrogen biosynthesis. To find high active 2-phenylbenzo
[b]furans, fifty-four 2-phenylbenzo[b]furans were prepared via four strategies according to correspond-
ing substrate scopes. Biological evaluation in HEK293A cells showed that some compounds exhibited
promotive activity on estrogen biosynthesis. 2-(4-Chlorophenyl)-7-methoxybenzo[b]furan possessed
Received 9 May 2016
Revised 26 September 2016
Accepted 7 October 2016
Available online xxxx
Keywords:
the highest activity with EC50 value of 14.68 lM. Furthermore, these compounds did not affect aromatase
Estrogen biosynthesis
2-Phenylbenzo[b]furan
Decarboxylative coupling
McMurry reaction
expression in HEK292A cells, indicating that these 2-phenylbenzo[b]furans might enhance estrogen
biosynthesis via directly allosteric regulation of aromatase or indirectly via posttranslational
modification.
Ó 2016 Elsevier Ltd. All rights reserved.
Estrogens are steroidal hormones that exert extensive biological
effects in the cardiovascular, musculoskeletal, immune and central
nervous systems in both men and women.1 Epidemiological stud-
ies have suggested the involvement of partial estrogen excess in
breast, ovarian and endometrial cancer, and estrogen insufficiency
in osteoporosis, neurodegenerative diseases and cardiovascular
diseases.2 Estrogens are synthesized in all vertebrates and cat-
alyzed by aromatase (CYP19A1), which is the key enzyme respon-
sible for binding of the C19 androgenic steroid substrate and
catalyzing the key reactions to form the aromatic ring characteris-
tic of estrogens.3 Aromatase inhibitors, such as anastrozole, letro-
zole, and exemestane, have been developed for the treatment of
hormone-dependent breast cancer in postmenopausal women.4
In comparison, the efforts toward small molecules that promote
estrogen biosynthesis have been limited. Although stimulative
activities on aromatase expression in a cAMP-dependent or -inde-
pendent manner have been found in some herbicides, fungicides,
and insecticides, but small molecules with less side effects are still
to be concerned.5 For the established estrogen therapy, recent evi-
dence indicated that the long-term use of estrogens accompanied
by side effects such as increased risks of breast, ovarian, and
endometrial cancer.6 Thus, alternative methods that improve the
therapeutic efficacy and safety by promoting estrogen biosynthesis
should be developed for the prevention and treatment of the dis-
eases caused by estrogen deficiency.
2-Phenylbenzo[b]furans and their analogues, including both
natural and synthetic origins, are of particular interest because of
their broad range of biological activities and significant pharmaco-
logical potentials.7 We found that egonol gentiobioside (EGB) and
egonol gentiotrioside (EGT) (Fig. 1) from Styrax perkinsiae could
promote the biosynthesis of 17b-estradiol in both human ovarian
granulosa KGN cells and mouse 3T3-L1 preadipocyte cells. Pharma-
cological studies suggested that the effects of these two com-
pounds on 17b-estradiol biosynthesis may be generated through
the allosterical regulation of aromatase rather than the modulation
of aromatase expression. Although EGT increases serum estrogen
level in vivo, a partial hydrolysis of oligosaccharide chain in EGT
during gastrointestinal absorption may occur.8 In-depth research
on 2-phenylbenzo[b]furan promoting estrogen biosynthesis would
pave the way to find efficient and safe alternative to estrogen ther-
apy without an influence of aromatase expression. To simplify the
structure such as removal of the oligosaccharide or the side chain
at C-5 of EGT or EGB, and to find more potent compounds, we
established a fifty-four membered 2-phenylbenzo[b]furan library
via four effective synthetic strategies including derivatization of
⇑
Corresponding author. Tel./fax: +86 28 82890333.
E-mail address: zhanggl@cib.ac.cn (G. Zhang).
http://dx.doi.org/10.1016/j.bmcl.2016.10.013
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pu, W.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.10.013

2
W. Pu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
R1
R1
HOH2C
HO
Phenyl
O
CuCl2, Phen, NaOH
DMSO, MS, air, 150oC
Phenyl
O
HO
O
O
O
O
H2C
OH
HO
O
R2
R2
HOH2C
HO
O
O
O
HO
O
OH
O
R1
Cl
Cl
H
H
H
H
H
Br
Cl
Cl
R2
Cl
Cl
H
H
H
H
H
Phenyl
2'-methoxyl
HO
R1
H
H
H
H
R2
Phenyl
CH2
OH
HO
15
EGB
EGT
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
3',4'-dimethoxyl
4'-methoxyl
3'-methoxyl
30
31
32
33
34
35
36
37
38
39
40
41
42
43
OCH3
O
O
16
17
18
19
20
21
22
23
24
25
26
27
28
29
HO
O
H2C
3',4'-dimethoxyl
4'-methoxyl
3'-methoxyl
OH
HO
O
O
O
HO
H
H
4'-chloro
4'-fluoro
OH
O
OCH3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3',4'-dimethoxyl
4'-methoxyl
2'-methoxyl
3',4',5'-trimethoxyl
4'-chloro
4'-fluoro
3',4'-dimethoxyl
OCH3
OCH3
OCH3
Figure 1. Egonol gentiobioside and egonol gentiotrioside.
4'-chloro
4'-chloro
4'-fluoro
4'-fluoro
2',5'-dimethoxyl
egonol (Scheme 1), copper-catalyzed decarboxylative intramolecu-
lar C-O formation (Scheme 2), McMurry reaction based strategy
(Scheme 3 and 4) and benzylation-intramolecular condensation
based strategy (Scheme 5). In aromatase-overexpressing human
embryonic kidney 293 (HEK293A) cells, thirteen synthetic 2-
phenylbenzo[b]furans showed promotive activity on the biosyn-
SCH3 OCH3
Cl OCH3
SCH3 OCH3
Cl OCH3
H
Cl
Cl
Cl
4'-benzyloxy
3',4'-dimethoxyl
4'-methoxyl
3'-methoxyl
Scheme 2. Compounds 15–43 synthesized via Copper-catalyzed decarboxylative
intramolecular C-O formation.
thesis of estrogen with EC50 value from 14.68 to 30.86 lM. The
results suggested that the oligosaccharide or the side chain at C-
5 in 2-phenylbenzo[b]furans as the case in EGT or EGB was not
necessary and the introduction of halogen atom at C-4, 5 or 40
was favorable for the estrogen biosynthesis-promoting effect.
Additionally, these compounds did not affect aromatase expression
in HEK293A cells, providing the evidence that they might enhance
estrogen biosynthesis via directly allosteric regulation of aro-
matase or indirectly via posttranslational modification.
We started with the direct functionalization of egonol 1, the
aglycon of EGB and EGT in Styrax perkinsiae.9 As shown in Scheme 1,
substitution of the hydroxyl group with chlorine, bromine and
iodine gave compounds 2–4 successively using relevant halogen
source with almost quantitative yields. Under the treatment of
pyridinium chlorochromate, egonol was smoothly oxidized into
corresponding aldehyde 5 with 95% yield. Selective aromatic
bromination of 1 in acetonitrile afforded 6–8 by using different
equivalents of N-bromosuccinimide. In addition, reaction between
egonol and acyl chloride gave ester 9–12. Compounds 13–14 were
further prepared from 9 through Vilsmeier–Haack reaction in the
presence of phosphorus oxychloride and N,N-dimethylformamide.
R5
R4
R1
R1
CHO
OH
1. TiCl4, Zn,
THF, reflux
R5
+
O
2. I2, K2CO3,
THF, 25oC
OHC
R3
R4
R3
R2
R2
Compound R1
R2
R3
H
H
H
H
H
R4
R5
Yield(%)
44
45
46
47
48
H
H
H
-OCH2O-
-OCH2O-
-OCH2O-
31
37
33
42
48
OCH3
Br OCH3
Br OCH3
Br OCH3
H
OCH3
H
OCH3
Scheme 3. Synthesis of 44–48 by McMurry reaction based strategy. The yields were
isolated yields.
Copper-catalyzed decarboxylative intramolecular carbon–oxy-
gen cross-coupling developed by our group is one of the most effi-
O
O
OHC
R1
: R1 = Cl (95%)
: R1 = Br (92%)
2
3
O
O
O
O
4: R1 = I (96%)
OCH3
OCH3
R4
5
(95%)
b
a
R3
O
HO
O
H
H
O
R5
O
c
HO
O
OCH3
O
: R = H, R4 = Br, R5 = H (1.1 equiv. NBS, 85%)
H
3
6
7
: R = Br, R4 = Br, R5 = H (2.1 equiv. NBS, 76%)
OCH3
3
1
8: R3 = Br, R4 = Br, R5 = Br (3.1 equiv. NBS,
52%)
d
O
R4
O
R3
O
O
O
R2
O
:
R
2 = methyl
e
O
O
O
O
OCH3
OCH3
9
: R2 = propyl (91%)
: R2 = phenyl (85%)
R
2 = methyl (96%)
13
14
: R3 = CHO, R4 = H (14%)
: R3 = H, R4 = CHO (63%)
11
12
: R2 = vinyl (89%)
10
Scheme 1. Derivatization of egonol (1). (a) for 2: PPh3, CCl4, reflux; for 3: PPh3, DDQ, TBAB, CH2Cl2; for 4: PPh3, DDQ, TEAI, CH2Cl2. (b) PCC, CH2Cl2. (c) NBS, CH3CN. (d) Acyl
chloride, TEA, THF. (e) POCl3, DMF. DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBAB: tetrabutyl ammonium bromide, TEAI: tetraethylammonium iodide, PCC:
pyridinium chlorochromate, NBS: N-bromosuccinimide, TEA: triethylamine, DMF: N,N-dimethylformamide. The values in parenthesis were isolated yields.
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W. Pu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
H3CO
BnO
CHO
A HEK293A cell line stably transfected with aromatase expres-
sion vector was established as described in the materials and
methods. 2-Phenylbenzo[b]furans at a concentration of 50 lM
H3CO
HO
CHO
b, c
a
were evaluated in aromatase-overexpressing HEK293A cells for
their promoting activity on estrogen biosynthesis with EGB as pos-
itive control and DMSO as negative control. As shown in Fig. S1,
nineteen 2-phenylbenzo[b]furans (2, 6, 12, 19, 24, 26, 29, 34–36,
41, 43, 45, 47, 48, 50 and 54) were found to have good promotive
effect on estrogen biosynthesis (the ratios with positive control
were more than 0.6). Moreover, nine test compounds (21, 22, 33,
37, 39, 40, 44, 51 and 53) were shown inhibitory activities on
estrogen biosynthesis, indicating their potential to be aromatase
Br
Br
OH
OCH3
d
OBn
O
OCH3
O
OCH3
49
(23%)
OCH3
Br
OCH3
50
O
OH
OCH3
(21%)
inhibitors. All compounds at 50 lM and 10 lM showed no effect
on the proliferation of aromatase-overexpressing HEK293A cells
(data not shown).
Subsequently, nineteen 2-phenylbenzo[b]furans with promo-
tive activities at 50 lM were submitted to identify their EC50 val-
Scheme 4. Synthesis of 49 and 50. (a) Benzyl chloride, K2CO3, DMF, 80 °C. (b) TiCl4,
Zn, THF, reflux. (c) I2, K2CO3, THF, 25 °C. (d) TiCl4, THF, 25 °C. The values in
parenthesis were isolated yields.
ues. As shown in Table 1, fifteen EC50 values were finally
obtained. Compounds 19, 26, 29, 35 and 43 exhibited potent pro-
motive activity with successive EC50 values of 14.68, 17.23,
cient methods for the synthesis of 2-phenylbenzo[b]furan. Starting
from 3-phenylcoumarin, 2-phenylbenzo[b]furans could be easily
prepared with good yield in one pot. In the presence of cupric chlo-
ride, 1,10-phenanthroline and sodium hydroxide, 2-phenylbenzo
[b]furans 15–43 were successfully prepared under air for 24 h in
dimethyl sulfoxide with the yields from 26% to 82%. This method,
however, is not promising to synthesize 5-bromo-2-phenylbenzo
[b]furan as a result of the activation of aromatic C-Br bond by cop-
per catalyst. Instead, 5-chloro and 5-methylthio 2-phenylbenzo[b]-
furans (38–43) were obtained through this side reaction
(Scheme 2).10
To obtain 5-bromo-2-phenylbenzo[b]furan, McMurry reaction
based strategy was employed, which was an available two-step
route developed by Duan’s group.11 Via low valent titanium pro-
moted selective McMurry reaction and subsequent oxidative
cyclization, salicylaldehydes and benzaldehydes were cross-cou-
pled and the corresponding products sequentially converted to 2-
phenylbenzo[b]furans without the disassociation of aromatic C-
Br bond. 5-Bromo-2-phenylbenzo[b]furans 46–48 as well as 44–
45 were directly synthesized based on this strategy (Scheme 3).
Hydroxyl 2-phenylbenzo[b]furans could not be directly
obtained through McMurry reaction. Therefore, benzyl protective
group was employed and benzylated benzaldehyde substrate was
successfully converted into corresponding 2-phenylbenzo[b]furan.
After deprotection using titanium tetrachloride, 2-phenylbenzo[b]-
furan 49 was obtained with acceptable overall yield. 5-(5-Bromo-
7-methoxybenzo[b]furan-2-yl)-2-methoxyphenol (50) was also
synthesized via this method (Scheme 4).
19.58, 15.53 and 19.42
more than 20 M. Comparing with the EC50 value of EGB
(15.72 M), these results indicated that the promotive activities
lM. The values of the rest compounds were
l
l
on estrogen biosynthesis could be maintained or even enhanced
by simplifying EGB or EGT motifs.
Based on our experimental data, the structure activity relation-
ship was speculated (Fig. 2). Introduction of bromine at C-4 was
favorable, which could be explained by the highest activity of com-
pound 6 among the egonol derived compounds (1–14). It is
promising that the alkyl group at C-5 of egonol could be replaced
with halogen. By this modification, the performance of 24, 26, 29,
41, 43, 47, 50 and 54 were maintained or even enhanced. The intro-
duction of fluorine or chlorine into C-40 was another favorable
strategy to increase the activity (19, 36 and 41). No obvious influ-
ence was observed toward the substituent at C-7.
Small molecules with promotive activities on estrogen biosyn-
thesis as well as their mechanisms were merely reported. We dis-
covered several 2-phenylbenzo[b]furans with promotive activities
on estrogen biosynthesis, but how they upregulated estrogen level
were still unknown. Aromatase expression in HEK293A cell was
analyzed by western blotting with aromatase antibody. Compound
19, 26 and 35 had no remarkable effects on aromatase expression
at the concentrations of 10 lM and 50 lM (Fig. 3), which were in
accord with the phenomenon of EGB and EGT, indicating that these
compounds might promote estrogen biosynthesis via directly
allosteric regulation of aromatase or indirectly via posttransla-
tional modification, which needs to be further studied.
The positive allosteric effect has been widely found in ligand-
binding receptors and enzyme catalysis.13 In our previous study,
we found that EGB and EGT could significantly promote the sub-
strate conversion catalyzed by purified aromatase in vitro, indicat-
ing that these compounds may modulate the aromatase
conformation and enhance its substrate conversion efficiency.8
40-Nitro-2-phenylbenzo[b]furans were prepared via a one-pot
strategy from salicylaldehyde and 4-nitrobenzylbromide owing
to the withdrawing effect of 4-nitrophenyl group.12 Starting mate-
rials were easily transformed into compounds 51–54 through ben-
zylation and successive intramolecular condensation with the yield
from 59% to 71% in the presence of potassium carbonate in DMF
(Scheme 5).
Table 1
R1
CHO
OH
R1
The promotive activity of 2-phenylbenzo[b]furans on estrogen biosynthesis
NO2
Compound
EC50
(l
M)
Compound
EC50 (lM)
O
R2
R2
R1
H
R2
OCH3 (62%)
K2CO3, DMF
reflux
6
22.12
14.68
29.44
17.23
19.58
20.78
15.53
36
41
43
47
50
54
EGB
24.95
20.05
19.42
20.85
25.53
30.86
15.72
+
19
24
26
29
34
35
51
NO2
52 Cl
53 Cl
54 Br
H
Cl
(71%)
(66%)
Br
OCH3 (59%)
Scheme 5. Synthesis of 51–54 by benzylation-intramolecular condensation based
The values are mean SEM (n = 3).
strategy. The values in parenthesis were isolated yields.
Please cite this article in press as: Pu, W.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.10.013

4
W. Pu et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
thetic strategies were used to establish a fifty-four membered 2-
phenylbenzo[b]furan library. 2-Phenylbenzo[b]furans had good
promotive activity on estrogen biosynthesis with the EC50 values
R1 = Br and R2 = Br or Cl
are favorable
from 14.68 lM to 30.68 lM without the influence of aromatase
R1
R3
expression. It could be concluded that the promotive activity could
be maintained by removing the side chain at C-5 and the oligosac-
charide motif, and the presence of halogen is superior to the activ-
ity. This work illustrated the excellent pharmacological potential of
2-phenylbenzo[b]furans for the therapy of estrogen deficiency-
associated diseases.
R8
R7
R2
R6 = F or Cl
is favorable
R6
O
R4
R5
No obvious influcence
Acknowledgement
Figure 2. Structure activity relationship of the promotive effect on estrogen
biosynthesis of 2-phenylbenzo[b]furans.
This work was supported by the National Natural Science Foun-
dation of China (No. 21372213, 21372214, 21172214 and
21561142003), the Pillar Program of Science & Technology Depart-
ment of Sichuan Province (No. 2012SZ0219), and the Sichuan
Youth Science & Technology Foundation (No. 2014JQ0028), and
Research Foundation of State General Administration of The Peo-
ple’s Republic of China for Quality Supervision and Inspection
and Quarantine (No. 2015IK180).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.10.
013.
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HEK293A cell.
Recently, Barone et al. found that protein tyrosine phosphatase-1B
(PTP1B) can dephosphorylate aromatase and decrease aromatase
activity. ERɑ-induced phosphoinositide 3-kinase (PI3K) activation
would impair the ability of PTP1B and promote aromatase activ-
ity.14 Thus, target inhibition of PTP1B has the potential to upregu-
late estrogen biosynthesis. Whether 2-phenylbenzo[b]furans may
induce a conformational change of aromatase to directly enhance
its activity or inhibit PTP1B to upregulate aromatase phosphoryla-
tion does need to be studied.
13. Changeux, J. P.; Edelstein, S. J. Science 2005, 308, 1424.
14. Barone, I.; Giordano, C.; Malivindi, R.; Lanzino, M.; Rizza, P.; Casaburi, I.;
Bonofiglio, D.; Catalano, S.; Ando, S. Endocrinology 2012, 153, 5157.
In summary, to find 2-phenylbenzo[b]furans with enhancive
activity toward aromatase and without hydrolysis issue, four syn-
Please cite this article in press as: Pu, W.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.10.013