Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2013.01.045

A series of novel indole-imidazole derivatives have been prepared and evaluated in vitro on the aromatase inhibitory activities. The results suggested that proton or a small electron-withdrawing group at para-position of the phenyl ring would enhance the inhibitory activities and any bulky group should be avoided in order to keep a relative small volume for this kind of molecules.

Full text of DOI:10.1016/j.bmcl.2013.01.045

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1760–1762
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and aromatase inhibitory activities
of novel indole-imidazole derivatives
⇑
Rui Wang, Hong-Fan Shi, Jing-Feng Zhao, Yan-Ping He, Hong-Bin Zhang, Jian-Ping Liu
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel indole-imidazole derivatives have been prepared and evaluated in vitro on the aroma-
tase inhibitory activities. The results suggested that proton or a small electron-withdrawing group at
para-position of the phenyl ring would enhance the inhibitory activities and any bulky group should
be avoided in order to keep a relative small volume for this kind of molecules.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 31 October 2012
Revised 9 January 2013
Accepted 15 January 2013
Available online 26 January 2013
Keywords:
Indole-imidazole derivatives
Breast cancer
Aromatase inhibitor (AI)
Structure–activity relationship
Synthesis
A great majority of breast cancers are hormone-dependent,1
and it is widely accepted that estrogen plays an important role in
the genesis and evolution of breast tumors.2 Aromatase (CYP19),
a cytochrome P450 enzyme, is responsible for the conversion of
androgens including androstenedione and testosterone into estro-
gens,3 therefore it is considered as a particularly attractive target
for inhibition in the endocrine treatment of hormone-dependent
breast cancer. Non-steroidal aromatase inhibitors (NSAIs, Fig. 1),
such as aminoglutethimide (1),4 anastrozole (2, Arimidex™)5 and
letrozole (3, Femara™),6 competitively inhibit the enzymatic activ-
ity of aromatase in a reversible manner and play an important role
in the endocrine treatment for hormone-dependent breast cancers.
Potent AIs still remain an attractive subject, and lots of interest-
ing compounds have been developed by different groups working
in this field.7–10 Recently, with letrozole as led compound, we de-
signed and prepared several series of potential AI compounds. In
order to find some more suitable structures for AI activities, com-
pared with the led compound, our research focused on the geom-
etry and molecular flexibility changes of the designed compounds.
We also made an imidazole group in our designed molecules to
keep it connected with oxyferryl of the haem group in the structure
of aromatase according to Ghosh’s discovery.11
as compound 4 (Fig. 1),18 showed a high potent as aromatase
inhibitors. Compared with letrozole and compound 4, phenyl
group was moved from central methine to the nitrogen atom in in-
dole ring. This movement would make two hydrophobic aromatic
rings closer, and at the same time newly formed methylene group
in the molecules 10a–s would make the connected angles and pos-
sible configurations between two hydrophobic aromatic rings and
imidazole group more flexible. Here we reported the synthesis and
primary aromatase inhibitory activities of the new derivatives and
to the best of our knowledge, there were no such compounds
reported.
Our synthesis journey was shown in Scheme 1. The precursors
6a–d were synthesized by aldol condensation of ethyl azidoacetate
and commercially available 4-substituted benzaldehydes 5a–d in
the presence of sodium ethoxide.20 The key step in the formation
of the 6-substituted indoles skeleton intermediates 7a–d was read-
ily accomplished by using Rh2(OAc)4 as a catalyst,21,22 refluxing in
toluene. The corresponding compounds 8a–s were prepared from
precursors 7a–d by arylation with a set of 4-substituted bromo-
benzenes,23 and further reduced to corresponding alcohols 9a–s.
Finally, the target compounds 10a–s were prepared by treatment
of N-phenyl-indole alcohols 9a–s with 1,10-carbonyldiimidazole
(CDI) in dry acetonitrile.24,25 The structures of all target com-
pounds, as well as main intermediates, were confirmed mainly
by proton and carbon-13 NMR spectroscopy. Compound 10d was
further verified by the single X-ray crystallography (Fig. 2).26 The
crystal structure of compound 10d had been deposited at the Cam-
bridge Crystallographic Data Centre and allocated the deposition
number CCDC 869637.
In this Letter, we designed a novel class of indole-imidazole
derivatives (10a–s, Fig. 1) based on some structure–activity rela-
tionship studies12–19 which reported that indole derivatives, such
⇑
Corresponding author. Tel.: +86 871 5031119; fax: +86 871 5035538.
E-mail address: jpliu@ynu.edu.cn (J.-P. Liu).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.045

R. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1760–1762
1761
N
N
N
N
N
N
O
N
H
O
NC
CN
NC
CN
Letrozole
Anastrozole
Aminoglutethimide
2
3
1
N
N
N
2
N
N
1
1'
N
H
Cl
6
R1
R2
4'
4
10a-s
Figure 1. Non-steroidal aromatase inhibitors (NSAIs).
O
OEt
O
CHO
i
ii
OEt
R1
N
H
N3
R1
R1
7a-d
6a-d
5a, 6a, 7a,
5a-d
1
R =H
5b, 6b, 7b, R1=CH3
5c, 6c, 7c, R1=OCH3
5d, 6d, 7d, R1=Cl
iii
N
O
N
R1
R1
N
OH
N
OEt
R1
v
N
iv
R2
R2
R2
8a-s
10a-s
9a-s
1
2
1
2
8a, 9a, 10a,
8k, 9k, 10k,
R =OCH3, R =H
R =H, R =F
8b, 9b, 10b, R1=H, R2=CH3
8c, 9c, 10c, R1=H, R2=OCH3
8d, 9d, 10d, R1=H, R2=CF3
8l, 9l, 10l, R1=OCH3, R2=F
8m, 9m, 10m, R1=OCH3, R2=CF3
8n 9n, 10n, R1=OCH3, R2=CN
1
2
1
2
8e, 9e, 10e,
8f, 9f, 10f,
8o, 9o, 10o,
8p, 9p, 10p,
R =H, R =H
R =OCH3, R =CH3
1
2
1
2
R =CH3, R =H
R =OCH3, R =OCH3
8g, 9g, 10g, R1=CH3, R2=CH3
8h, 9h, 10h, R1=CH3, R2=OCH3
8i, 9i, 10i, R1=CH3, R2=F
8q, 9q, 10q, R1=Cl, R2=OCH3
8r, 9r, 10r, R1=Cl, R2=CH3
8s, 9s, 10s, R1=Cl, R2=Cl
1
2
8j, 9j, 10j,
R =CH3, R =CN
Scheme 1. Synthesis of indole-imidazole derivatives. Reagents and conditions: (i) N2CH2COOEt, NaOEt, ꢀ50 °C, 8–12 h, 38.6–59.4%; (ii) Rh2(OAc)4, toluene, reflux, 1–2 h,
51.7–58.6%; (iii) BrC6H4R2, K3PO4, CuI, N,N0-dimethylehtylenediamine, toluene, reflux, 24 h, 50.7–81.6%; (iv) LAH, THF, 0 °C to rt, 0.5–4 h, 51.3–87.9%; (v) CDI, CH3CN, 48–72 h,
71.6–89.1%.
The primary aromatase inhibitory activities of all new com-
pounds were determined according to the reported method,27–29
with human placental microsomes served as source of P450 arom,
and ELISA assay (EIA method) was used to measure the estrone le-
vel with commercial estrone ELISA kit.30 The results were summa-
10d, with trifluoromethyl (CF3) group at C-40, showed the highest
potent inhibitory activity against aromatase and over 3-fold higher
than that of letrozole. Trifluoromethyl group, an interesting build-
ing block in the drug constructions,31–33 which possiblely in-
creased aromatase–small molecule interaction with its electron-
withdrawing and metabolic stability properties, is worth further
studies and should be pay more attention in the future AI drug can-
didates. It was observed from Table 1 that the compounds with
proton or a small electron-withdrawing group at C-40 tended to en-
hance the inhibitory activities while those with electron-donating
group exhibited lower activities. Generally AI activities of the com-
pounds decreased when proton at C-6 position of the indolyl group
was replaced by other bulky groups, but 10k exhibited an excep-
rized in Table
1 (IC50 value, defined as the concentrations
corresponding to 50% activity inhibition).
As shown in Table 1, potential AI efficacies of structural varia-
tion in the C-6 position of the indole ring and para-position of
the phenyl group were explored. Most of the test compounds
exhibited moderate activities in the aromatase inhibition assay.
Compound 10e, with no substituted group in both C-6 and C-40,
showed nearly the same AI activity as letrozole, while compound

1762
R. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1760–1762
Acknowledgments
This research was supported by the National Natural Science
Foundation of China (Grant No. 20562012, 21162033) and the Na-
tional Basic Research Program of China (973 Program:
2009CB522300). We would like to acknowledge Dr. Meng-Xiang
Su, China Pharmaceutical University, Mr. Hong-Jun Kang, Kunming
Baker Norton Pharmaceutical Co., Ltd, for their great help and dis-
cussion in vitro AI tests.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.01.
045.
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CF3
H
148.93 12.61
77.36 6.31
4.93 0.23
16.58 1.39
21.39 1.76
164.01 14.63
138.72 11.46
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