Thee-component, one-pot synthesis of hexahydroazepino[3,4-b]indole and tetrahydro-1H-pyrido[3,4-b]indole derivatives and evaluation of their cytotoxicity

Article abstract of DOI:10.1016/j.bmcl.2014.07.084

A three-component, four-center Ugi reaction has been developed to produce a novel class of 2-aryl-3-oxo-hexahydroazepino[3,4-b]indole and 2-aryl-3-oxo-tetrahydro-1H-pyrido[3,4-b]indole derivatives in good to high yields. A few of them exhibit moderate cyt

Full text of DOI:10.1016/j.bmcl.2014.07.084

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Thee-component, one-pot synthesis of hexahydroazepino
[3,4-b]indole and tetrahydro-1H-pyrido[3,4-b]indole derivatives
and evaluation of their cytotoxicity
a
a
b
b
B. V. Subba Reddy a, , A. Venkata Ganesh , M. Vani , T. Ramalinga Murthy , Shasi V Kalivendi ,
⇑
J. S. Yadav a
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component, four-center Ugi reaction has been developed to produce a novel class of 2-aryl-3-
oxo-hexahydroazepino[3,4-b]indole and 2-aryl-3-oxo-tetrahydro-1H-pyrido[3,4-b]indole derivatives in
good to high yields. A few of them exhibit moderate cytotoxicity against various cancer cell lines such
as HeLa (human epithelial cervical cancer), A549 (human lung carcinoma epithelial), DU145 (human
prostate carcinoma epithelial) and MCF-7 (human breast adenocarcinoma).
Received 3 February 2014
Revised 24 July 2014
Accepted 30 July 2014
Available online xxxx
Ó 2014 Published by Elsevier Ltd.
Keywords:
3CC Ugi reaction
Aldehydo acid
Aryl amine
Isonitrile
Azepinones
Pyrido[3,4-b]indoles
Multi-component reactions (MCRs) are powerful synthetic tools
for the diversity-oriented synthesis (DOS) to generate combinato-
rial libraries.1 They play a key role in drug discovery. MCRs are
highly convergent and atom efficient generating high molecular
complexity in a single-step process.2 Among MCRs, the Ugi3 and
Passerini reactions,4 are the most popular approaches for the com-
binatorial chemistry.5,6 Recently, a new version of Ugi reaction has
been developed using bifunctional substrates such as aldehydo
acid or amino acid to produce a wide range of lactams with differ-
ent ring sizes.7–9 In particular, seven-membered azepinones are
important structural motifs in some biologically active
molecules.10 In addition, they are very useful intermediates to
the preparation of various peptides and peptidomimetic ligands
for several G protein-coupled receptors.11 However, to the best of
our knowledge, there are no reports on intramolecular Ugi reaction
of 2-(2-formyl-1-methyl-1H-indol-3-yl)acetic acid (1a) or 3-(2-for-
myl-1-methyl-1H-indol-3-yl)propanoic acid (1b), aryl amine (2)
and isonitrile (3). The required starting materials 1a and 1b were
prepared using a known procedure (Scheme 1).12
O
O
n
n
OH
CHO
O
LiOH.H2O
CHO
THF:H2O (9:1)
0 - rt, 3h
N
N
1a (n = 1); 1b (n = 2)
Scheme 1. Preparation of requisite starting materials.
hexahydroazepino[3,4-b]indole and tetrahydro-1H-pyrido[3,4-
b]indole derivatives through a three-component reaction of alde-
hydo acid with aryl amine and isonitrile.
Initially, we attempted the coupling of 3-(2-formyl-1-methyl-
1H-indol-3-yl)propanoic acid (1b) with p-fluoroaniline (2) and
cyclohexyl isocyanide (3) in various solvents. Interestingly, the
reaction proceeded well in methanol at 60 °C affording the corre-
sponding hexahydroazepino[3,4-b]indole derivative 5j in 78% yield
(Table 1).
The above result provided the incentive for further study with
other substrates (Table 2). Interestingly, substituted aromatic alde-
hydes such as p-bromo-, p-chloro-, 4-fluoro-3-chloro-, m-fluoro-,
2,5-dimethyl-, p-fluoro-derivatives participated effectively in this
reaction. In all the cases, the reactions are clean affording the
Following our interest on Ugi reaction for diversity oriented
synthesis,13 we herein report a novel strategy for the synthesis of
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
http://dx.doi.org/10.1016/j.bmcl.2014.07.084
0960-894X/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Reddy, B. V. S.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.07.084

2
B. V. Subba Reddy et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1
Table 3
Optimization of reaction conditions in the formation of 5j
Anti-proliferative activity (IC50 values
DU145, MCF7
l
Mb) of indole derivatives on HeLa, A549,
Entry
Solvent
T (°C)
Time (h)
Yielda (%)
Compounda
HeLa
A549
DU145
MCF7
1
2
3
4
5
6
7
8
Benzene
Toulene
Toulene
THF
Dioxane
MeOH
40
40
1110
66
101
40
12
12
12
12
12
10
10
11
—
—
4a
4b
4c
4d
4e
4f
4g
4h
4i
5j
5k
5l
5m
5n
5o
5p
5q
5r
11 0.9
49 2.8
55 2.8
25 2.5
>100
26 2.4
83 2.9
>100
95 3.8
48 2.5
63 2.6
12 1.1
>100
62 2.4
>100
59 2.5
85 2.4
>100
47 2.6
45 2.5
42 2.2
>100
>100
78 3.4
>100
95 3.5
63 2.8
90 3.2
55 2.1
13 1.6
82 2.5
52 2.8
>100
50 2.7
52 2.7
>100
95 2.8
95 2.8
61 2.2
96 2.1
>100
87 2.7
50 1.6
78 3.2
29 1.2
54 2.4
94 2.8
>100
<10
20
35
55
65
78
CH3CN
MeOH
82
60
>100
63 2.8
80 2.7
49 2.9
59 2.6
>100
27 2.1
>100
>100
a
Isolated yield after column chromatography.
hexahydroazepino[3,4-b]indole derivatives (5j–r, Table 2) in good
yields. The reactions proceeded well with both cyclohexyl- and
t-butyl-isocyanides. Inspired by above results, we further extended
this process to the synthesis of 2-aryl-3-oxo-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b]indole derivatives. Accordingly, treatment of
2-(2-formyl-1-methyl-1H-indol-3-yl)acetic acid (1a) with p-fluo-
roaniline (2) and cyclohexylisocyanide (3) afforded the
corresponding tetrahydro-1H-pyrido[3,4-b]indole 4a in 81% yield
(Table 2). Similarly, various aryl amines and isonitriles reacted well
with aldehydo acid (1a) to provide the corresponding tetrahydro-
1H-pyrido[3,4-b]indole derivatives (4a–i, Table 2) reasonably in
good yields.
All the synthesized compounds were evaluated for their anti-
proliferative activity against a panel of four different human cancer
cell lines; HeLa (cervical cancer), A549 (lung carcinoma), DU145
(prostate carcinoma) and MCF7 (breast adenocarcinoma). The
growth inhibition values for the cells were expressed in IC50
44 2.5
>100
46 2.2
13 1.7
67 2.8
>100
>100
18 1.1
35 2.4
70 2.6
21 1.4
56 2.8
50 2.3
18 0.8
>100
a
Cell lines were treated with different concentrations of compounds for 48 h as
described in experimental section.
b
IC50 values are indicated as mean of three independent experiments.
O
R2
n
C
D
N
A
B
NH
R1
N
O
CH3
n = 1, 2
(lM) and are summarized in the Table 3. The Ugi products consist
Figure 1.
of four rings (A, B, C and D) apart from different amide linkers on C-
ring. In addition, the C-ring was modified as six- (4a–i) and seven-
membered rings (5j–r).
To study the structure and activity relationship (SAR) for these
compounds, we have modified the D-ring with different substitu-
ents like F, Cl, Br and CH3 (Fig. 1). Based on the screening results,
the compounds with seven-membered C-ring (5j–r) are more
active than six-membered C-ring compounds (4a–i). Among the
compounds (5j–r), 5l and 5q were found to exhibit significant
growth inhibitory effect on the tested cell lines with IC50 values
Table 2
ranging from 12 lM–29 lM. The effect of 5l and 5q on cell viability
Synthesis of tetrahydro-1H-pyrido[3,4-b]indole and hexahydroazepino[3,4-b]indole
derivatives
was shown in the Figure 2 (Supporting information). In particular,
the lead compound 5l bearing cyclohexyl amide linker on C-ring
and 4-chloro substituent on D-ring inhibited the growth of HeLa
O
CO2H
Ar
( )n
( )n
H2N
N
Ar
MeOH, 60 o
C
2
and DU145 cancer cells with the IC50 values of 12
13 M, respectively. However, 5l showed moderate cytotoxicity
against A549 and MCF7 with IC50 value 27 M and 29 M. Further-
lM and
+
CN
R
NH
R
8-14h,
l
61-85%
N
N
O
O
l
l
3
1a (n = 1); 1b (n = 2)
4
5
(n = 1)(a-i); (n = 2)(j-r)
more, 5q that possesses tert-butyl amide linker on C-ring and 4-
chloro group on the D-ring showed potential antiproliferative
Entry
n
Ar
Ar
Producta
Time (h)
Yieldb (%)
activity against HeLa cells with an IC50 value 13
5q showed significant cytotoxic effect towards A549 (18
DU145 (21 M) and MCF7 (18 M) cells. The compounds 4d and
lM. In addition,
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
p-F-C6H4
p-Br-C6H4
p-Cl-C6H4
m-F-C6H4
2,5-Me2-C6H3
p-F-C6H4
C6H11
C6H11
C6H11
C6H11
C6H11
C4H9
C4H9
C4H9
C4H9
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
C4H9
4a
4b
4c
4d
4e
4f
4g
4h
4i
5j
5k
5l
5m
5n
5o
5p
5q
5r
9
8
10
11
14
9
10
10
14
12
11
11
10
14
14
11
12
14
81
85
74
72
65
82
79
76
68
78
81
70
65
70
63
74
72
61
lM),
l
l
4f that possess six-membered C-ring and fluoro substituted D-ring
have shown moderate cytotoxicity against HeLa cells with an IC50
value 25
uro substituent on the D-ring inhibited the growth of Hela cells
with the IC50 value 11 M and also showed moderate cytotoxicity
lM and 26 lM, respectively. Interestingly, 4a with 4-flo-
p-Cl-C6H4
3-Cl-4-F-C6H3
2,5-Me2-C6H3
p-F-C6H4
p-Br-C6H4
p-Cl-C6H4
3-Cl-4-F-C6H3
m-F-C6H4
2,5-Me2-C6H3
p-F-C6H4
p-Cl-C6H4
3-Cl-4-F-C6H3
l
on other cell lines investigated in this study. Therefore, the lead
compounds 5l, 5q, 4a, 4d and 4f showed significant cytotoxic effi-
cacy on cervical cancer cells. Overall, the structure activity rela-
tionship with respect to their anticancer activity reveals that
chloro substituted seven-membered lactams (azepinones) (5l, 5q
and 5r) are more active than chloro substituted six-membered
lactams (4c, 4g, and 4h). In particular, 5l showed better activity
compared to its six-membered counterpart (4c). Similarly, seven-
membered lactam 5q displayed better activity than six-membered
lactam 4g. On the other hand, six-membered lactams (4a–i), fluoro
C4H9
C4H9
a
All products were characterized by NMR, IR and mass spectrometry.
Isolated yields after column chromatography.
b
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B. V. Subba Reddy et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
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general, halo substituted compounds are more active when com-
pared to methyl substituted compounds.
In conclusion, we have demonstrated a novel approach for the
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b]indole
and
2-aryl-3-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole derivatives through a Ugi four-center three-component
reaction. This method is simple, convenient and catalyst-free to
produce the structural diversity in a one-pot process. Of various
products, five compounds (5l, 5q, 4a, 4d and 4f) showed moderate
cytotoxicity against different cancer cell lines.
Acknowledgments
A.V.G. thanks CSIR, New Delhi for the award of a fellowship. The
authors thank to SMiLE, CSIR, New Delhi, India for financial
assistance.
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Supplementary data
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A.; Van Duppen, J.; Lai, J.; Varga, E.; Porreca, F.; Schiller, P. W.; Vanden Broeck,
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.07
.084.
References and notes
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Please cite this article in press as: Reddy, B. V. S.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.07.084