Design, synthesis and in vitro cytotoxicity studies of novel β-carbolinium bromides

Article abstract of DOI:10.1016/j.bmcl.2017.02.010

A series of novel β-carbolinium bromides has been synthesized from easily accessible β-carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and 16s exhibited potent anticancer activity with IC₅₀values of <10 μM against tested cancer cell lines. The most potent analogue 16l was broadly active against all the tested cancer cell lines (IC₅₀= 3.16–7.93 μM). In order to test the mechanism of cell death, we exposed castration resistant prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of cleaved PARP1 and AO/EB staining, indicating that β-carbolinium salts induce apoptosis in these cells. Additionally, the most potent β-carbolines 16l and 16s were found to inhibit tubulin polymerization.

Full text of DOI:10.1016/j.bmcl.2017.02.010

Accepted Manuscript
Design, synthesis and in vitro cytotoxicity studies of novel β-carbolinium bro-
mides
P.O. Venkataramana Reddy, Shriprada Mishra, Mukund P. Tantak, Kumar
Nikhil, Rachna Sadana, Kavita Shah, Dalip Kumar
PII:
S0960-894X(17)30130-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.02.010
BMCL 24682
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
6 October 2016
12 January 2017
4 February 2017
Please cite this article as: Venkataramana Reddy, P.O., Mishra, S., Tantak, M.P., Nikhil, K., Sadana, R., Shah, K.,
Kumar, D., Design, synthesis and in vitro cytotoxicity studies of novel β-carbolinium bromides, Bioorganic &
Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.02.010
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Design, synthesis and in vitro cytotoxicity studies of novel β-carbolinium
bromides
a
a
a
b
c
Venkataramana Reddy P. O , Shriprada Mishra , Mukund P. Tantak , Kumar Nikhil , Rachna Sadana ,
b,∗
a,∗
Kavita Shah and Dalip Kumar
a
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India.
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
b
cDepartment of Natural Sciences, University of Houston – Downtown, Houston, TX 77002, United States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of novel β-carbolinium bromides has been synthesized from easily accessible β-
carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for
their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and
1
6s exhibited potent anticancer activity with IC50 values < 10 µM against tested cancer cell lines.
The most potent analogue 16l was broadly active against all the tested cancer cell lines (IC50
.16-7.93 µM). In order to test the mechanism of cell death, we exposed castration resistant
=
3
prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of
cleaved PARP1 and AO/EB staining, indicating that β-carbolinium salts induce apoptosis in
these cells. Additionally, the most potent β-carbolines 16l and 16s were found to inhibit
tubulin polymerization.
Keywords:
β-Carbolinium bromides
In vitro cytotoxicity
Microwave
Apoptosis
2
009 Elsevier Ltd. All rights reserved.
1
8
β-Carboline unit containing natural products and synthetic
molecules often exhibit a broad spectrum of pharmacological
properties including sedative, anxiolytic, hypnotic, antioxidant,
bromides as potent cytotoxic agents (IC50 < 5.0 µM). Zeng et al.
prepared 1-mesityl-3-(2-naphthoyl-methano)-1H-imidazo-lium
bromide 7 (IC50 = 0.3-5 µM) with interesting anticancer activity
via arresting cell cycle at G1 phase and induced apoptosis in
anticonvulsant,
antitumor,
antiviral,
antiparasitic
and
1
19
antimicrobial. Particularly, β-carboline analogues have been
K562 cells.
reported to exhibit significant antitumor activities against several
Cl
N
2
-4
human cancer cells (Fig. 1). For example, natural β-carbolines
Harmine (1) and Fascaplysin (2) exhibited interesting
antiproliferative activity through apoptosis induction, DNA
N
MeO
N
N
H
H
O
5
-10
intercalation and CDK inhibition.
Cao research group
Fascaplysin 2
Harmine 1
identified benzyl-β-carbolinium bromides 3 (IC50 = 0.8-8 µM)
and 4-5 (IC50 = 0.4-2.7 µM) as potent cytotoxic agents by
1
1, 12
modification of natural Harmine.
In 2012, Frederick and co-
Br
Br
workers prepared the trisubstituted Harmine derivative 6, with
impressive anticancer activity (IC50 = 0.7 µM; OE33).
O
N
N
1
3
N
N
CH3
Among the various ways to enhance aqueous solubility,
alkylation of azaheterocycles may lead to azolium salts with
1
4,15
enhanced water solubility.
In the recent past, many cationic
3
(IC50 = 0.8 - 8 µM)
4 (IC50 = 1.8 -12 µM) OCH3
nitrogen heterocycles have been emerged as potent antitumor
1
6, 17
agents.
For example, Zhang group reported imidazolium
Figure 1. Representative β-carboline-based anticancer agents
—
——
∗
Corresponding author. Tel.: +91-1596-515238; fax: +91-1596-244183; e-mail: dalipk@pilani.bits-pilani.ac.in (Dalip Kumar)
∗
Corresponding author. Tel.: +001-7654969470; fax: +001-7654940239; e-mail: shah23@purdue.edu (Kavita Shah)

Recently, Xu group identified a series of novel 1-((indol-3-
prepared from the reaction of arylethanones 14 with N-bromo-
succinimide (NBS) in acetonitrile using p-toluenesulfonic acid
(PTSA) as a catalyst in good yields (Scheme 1). Finally, the
yl)methyl)–1H-imidazolium salts 8 (IC50 = 1.89 µM; HL60) as
2
0
25
apoptosis inducing potent anticancer agents.
reaction of β-carboline 13 and 1-aryl-2-bromoethanone 15 was
performed in refluxing ethanol. After refluxing the reaction
contents for 20 h, we isolated the β-carboline salt 16 only in
moderate yield (55%). In an attempt to enhance the reaction
efficiency and product yield, we performed the alkylation of β-
carboline 13 in focused microwave (MW). Reaction of 13 and 1-
aryl-2-bromoethanone 15 in focused MW led to β-carbolinium
bromide 16a with improved yield and notable reduced time (from
hour to min.). MW-assisted organic synthesis received
In an effort to identify potent cytotoxic agents, recently, we
designed and prepared synthetic indolyl heterocycles with potent
21-23
anticancer activities.
Inspired by the fascinating anticancer
properties of β-carbolines and azolium salts, in this paper we
designed a diverse series of β-carbolinium salts by incorporating
remarkable features of β-carboline and 1-aryl-2-bromoethanones
in single molecule as depicted in Figure 2.
Substituted β-carboline intermediates 13 were prepared from
2
4
L-tryptophan 9 as illustrated in Scheme 1. Firstly, the reaction
of 9 with formaldehyde solution (3.5 mL, 37%) under basic
conditions produced tetrahydro β-carboline-3-carboxylic acid 10.
However, under similar reaction conditions substituted tetrahydro
β-carboline-3-carboxylic acid 11 could not be prepared.
Alternatively, carboxylic acid 11 was prepared from the reaction
of 9 with aliphatic or aromatic aldehydes under acidic conditions.
substantial attention in pharmaceutical industry due to dramatic
26, 27
savings of reaction times and higher product yields.
Initially,
we irradiated reaction mixture in MW oven at 50 °C for 20 min
and obtained 16a in 60% yield. Notably, by increasing reaction
temperature from 50 °C to 80 °C, β-carbolinium bromide salt 16a
was produced in 89% yield. The generality of identified reaction
conditions was demonstrated by synthesizing an array of β-
carbolinium bromides 16a-t in good to excellent yields (75-
Next,
iodobenzene
diacetate-mediated
decarboxylative
aromatization of 10 or 11 led to β-carbolines 12 in good yields.
Reaction of 12 with an appropriate alkyl halide and sodium
hydride produced N-alkylated β-carbolines 13 in excellent yields.
On the other hand, required 1-aryl-2-bromoethanones 15 were
9
2%). 1-Aryl-2-bromoethanones with electron-donating (CH
3
and OCH ) and electron-withdrawing (Br) groups smoothly
3
delivered 16 in high yields.
Figure 2. Rational design for β-carbolinium bromides
COOH
NH2
COOH
NH
d
a/b
c
N
N
N
H
N
N
N
H
R
H
R
1
R
R
13a-c
L-Tryptophan 9
1
0 R = H
1a-b, R = CH /4-CH OC H
12a-c
1
1
3
3
6
4
R = CH /4-ClC H CH /
3 6 4 2
C6H5CH2
O
O
Br
N
O
f
e
Br
Ar
Ar
Ar
N
1
R
R
14a-i
15a-i
16a-t
Scheme 1. Reagents and conditions: (a) 37% formaldehyde solution, 0.4N NaOH, 37 °C, 3 days, CH
3
COOH, rt, 2 days; (b) RCHO, CH
3
COOH, 100 °C, 12 h; (c)
1
3
IBD, DMF, rt, 2 h; (d) R X, NaH, DMF, rt, 12 h. (e) NBS, CH CN, PTSA, reflux, 4-5 h; (f) 13, EtOH, MW, 80 °C, 20 min.

Structures of all the synthesized β-carbolinium bromides 16a-t
when compared to compound 16a. 2-Naphthyl analogue 16g
showed improved activity with IC50 values ranging 11.1-
40.4 µM ((16g vs 16a). Replacement of an aryl group with
heteroaryl (furyl and thienyl) moiety led to compounds 16h-
1
13
were confirmed by IR, NMR ( H & C) and mass spectral data.
1
In H NMR spectrum, two characteristic singlets appeared at ~9.5
2
and ~6.6 ppm due to C-1 proton of β-carboline and CH - of
2
13
arylacyl moiety at N , respectively. C NMR of 16 showed a
i
with weak cytotoxicity or inactive against the tested cell
lines except 16i with moderate cytotoxicity towards kidney
(HEK293T) cells (IC50 18.2 µM). -Methylated
derivatives 16j-k showed moderate cytotoxicity (IC50 = 14-
65 µM) towards tested cancer cell lines. -(4-Chlorobenzyl)
unit is reported to be beneficial for the potency of various
characteristic signal at ~190 ppm for the carbonyl carbon (C=O).
-
1
A band at 1690 cm in IR spectra of 16 indicated the presence of
C=O functional group. The purity of carbolinium bromides 16a-t
was found to be greater than 97% by HPLC analysis.
=
N
N
In vitro cytotoxicity of
β-carbolinium bromides 16a-t
2
8, 29
was evaluated against pancreatic (BxPC-3), cervical cancer
indole-based anticancer lead molecules.
improve anticancer activity of the -carbolinium bromides,
we prepared -(4-chloro-benzyl) -carbolinium bromides
16l-n with significant enhanced cytotoxicity against the
tested cancer cells compared to -carbolines with free -H.
In an efforts to
(
(
HeLa), castration-resistant prostate (C4-2), human prostate
PC-3), human embryonic kidney 293 (HEK293T) and
β
β
N
breast carcinoma (MDA-MB-231) cells by MTT assay.
Doxorubicin was used as the reference drug. Activity results
in terms of IC50 values are summarized in Table 1.
β
N
Notably, compound 16l found to be the most potent
analogue of the series with broad cytotoxicity against all the
tested cell lines (IC50 3.2-7.9 µM). Incorporation of methyl
Structure–activity relationship study was carried out by
1
varying substituents on
β
-carboline (R and R ) and 1-aryl-2-
bromoethanone (Ar) moieties. Compound 16a without any
substituent on -carboline and arylacyl moieties was found
to be moderately active against a panel of cancer cell lines
IC50 = 21.6-74.9 µM). Replacement of phenyl with a -tolyl
led to 16b with slightly improved
cytotoxicity (IC50 = 18.4-31.9 µM, 16a 16b). Similarly,
and
-carboline further increased the growth inhibitory potency
(IC50 = 8.7-49.2 µM) when compared to 16c 16e and 16g
(IC50 = 11.1-116.3 µM). -Benzylation of 16q led to 16t
with moderate cytotoxicity (IC50 = 12.6-94.1 µM). Overall,
most of the -carbolinium bromides proved to be active
p-metho-xyphenyl substituents at position 1 (16o-s) of
β
β
,
(
p
N
2
ring in arylacyl part at
N
vs
p
-
β
methoxyphenyl analogue 16c, slightly augmented the
growth inhibitory potency when compared to 16a and 16b
against kidney cells (HEK293T, IC50 = 3.7-67.8 µM).
Activity results suggest that substituents at positions 1, 2 and
(IC50 = 13.2-55.8 µM). Dimethoxyphenyl (16d) and
9 of β-carboline and arylacyl part bearing 4-methoxyphenyl
trimethoxyphenyl (16e) derivatives were found to be weakly
cytotoxic against kidney cells (IC50 = 67.8 and 28.6 µM;
and 2-naphthyl groups are beneficial for the anticancer
activity. Notably, the most potent compound 16l with
moderate water solubility (86 µg/mL) was found to be 95%
stable at pH 4.5 up to 24 h.
HEK293T) and inactive against other cell lines.
6f with electron-withdrawing ( -bromophenyl) substituent
displayed improved cytotoxicity (IC50 = 18.8-44.1 µM)
β-Carboline
1
p
Table 1. In vitro cytotoxicity of β-carbolinium bromides 16a-t against a panel of cancer cells (IC50 in µM)
O
Br
Ar
N
N
R1
R
16a-t
1
R
Compd
R
Ar
BxPC-3
HeLa
C4-2
PC-3
HEK293T MDA-MB-231
1
1
1
6a
6b
6c
H
H
H
H
H
H
C
4-CH
4-CH
6
H
5
27.8±2.7
19.9±2.3
> 100
37.7±3.4
27.5±3.1
48.7±2.9
74.9±5.5
31.9±3.5
45.7±5.4
59.6±5.3
39.1±3.1
55.8±4.9
21.6±2.8
18.4±4.1
13.2±2.6
37.2±4.1
29.2±2.2
> 100
3
3
C
OC
6
H
4
6
H
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
H
H
H
H
H
H
H
H
H
H
H
CH
CH
CH
4-CH
4-CH
H
H
H
H
H
H
CH
CH
4-ClC
4-ClC
4-ClC
H
3,4-(CH
3,4,5-(CH
4-BrC
2-Naphthyl
2-Furyl
3
O)
2
C
6
H
3
> 100
> 100
24.5±3.9
15.1±2.4
> 100
38.8±4.9
18.0±2.1
64.9±4.3
6.3±1.0
35.3±2.9
36.9±3.6
26.6±1.8
30.9±3.2
12.3±2.0
20.0±2.5
12.2±1.6
> 100
> 100
> 100
> 100
33.3±2.9
40.4±3.9
> 100
> 100
> 100
43.2±5.2
35.8±3.0
> 100
67.8±7.9
> 100
> 100
3
O)
3
C
6
H
2
28.6±3.8
18.8±3.1
11.1±2.2
> 100
18.2±2.6
14.2±2.8
17.6±3.0
3.8±1.1
11.5±3.1
10.6±2.8
9.5±1.1
18.9±2.0
17.7±2.8
17.8±2.0
11.6±1.9
6
H
4
44.5±5.0
35.2±2.6
> 100
65.0±4.6
55.6±5.4
33±3.2
3.2±0.9
13.16±2.5
14.2±2.2
23.9±2.9
54±6.2
44.1±5.3
25.1±3.6
> 100
48.9±5.8
38.1±2.9
54.2±5.4
7.9±1.1
37.0±4.0
16.2±1.8
16.8±3.1
40.2±5.2
14.1±2.1
22.4±2.7
14.1±2.1
2-Thienyl
> 100
> 100
3
4-CH
2-Naphthyl
4-CH OC
3,4,5-(CH
2-Naphthyl
4-CH OC
3,4,5-(CH
2-Naphthyl
4-CH OC
3
OC
6
H
4
37.9±4.3
25.4±2.2
7.4±1.2
41.0±3.8
11.6±2.1
28.1±2.6
49.2±3.4
17.7±1.9
22.1±2.9
8.7±1.5
35.2±4.1
43.8±3.9
5.4±0.8
36.5±3.4
15.2±2.7
26.7±2.0
39.5±3.3
19.5±2.1
28.1±3.4
10.1±1.1
3
6
6
6
H
4
H
4
H
4
CH
CH
CH
2
2
2
3
6
H
O)
4
3
3
C
6
6
H
2
2
3
3
3
3
6 4
H
H
H
H
H
3
O)
3
C
H
13±2.6
26.4±1.4
15.5±2.0
3
OC
OC
6
H
H
4
3
6
H
4
3
6
4
2-Naphthyl
1
6t
CH
3
C
6
H
4
CH
2
2-Naphthyl
94.1±6.4
14.3
37.6±2.4
4.85
12.6±2.3
2.5
15.3±1.4
14.3±2.3
29.0±4.2
4.8±1.2
44.1±6.3
2.5±0.8
Doxorubicin
The activity data represent mean IC50 values of experiments conducted in triplicates

To determine the preliminary mechanism of action of β-
carbolinium bromides, PARP1 cleavage assay for the active
compounds 16l and 16s was performed. C4-2 Cells were treated
with 16l and 16s for 48 h, and cleaved PARP1 levels was
analyzed using immunoblotting. As shown in Figure 3, exposure
of C4-2 cells by either 16l or 16s enhanced the levels of PARP1
cleavage as indicating apoptotic induced cell death in C4-2 cells.
16s trigger apoptosis in C4-2 cells, thereby confirming the PARP
cleavage data.
Figure 3. PARP1 cleavage (in C4-2 cells) induced by 16l and 16s
Furthermore, we also conducted acridine orange/ethidium
bromide assay to investigate the mechanism of cell death.
Acridine orange (AO) stains both live and dead cells, whereas
30
ethidium bromide (EB) only stains dead cells. Therefore,
AO/EB staining is used to examine whether cell death occurred
via apoptosis or necrosis. Effect of β-carbolinium salts on the
morphological changes of C4-2 cells is illustrated in Figure 4.
Incubation of compounds 16s (IC50 = 8 µM) and 16l with C4-2
cells (IC50 = 7 µM) for 24 h resulted in typical nuclear
fragmentation (red), whereas no visible changes in cell nucleus
and cell membrane integrity was observed for the control cells.
The results of AO/EB staining revealed that compounds 16l and
Figure 4. Apoptosis inducing effects of 16l and 16s in C4-2 cells.
Figure 5. Binding interactions of 16l and 16s in the colchicine-binding site of tubulin. Hydrogen bonds (green and blue dotted lines) and steric interactions (red
dotted lines) are outlined.

In the recent past, indole-based compounds have been
reported for their significant anticancer activity through
modulation of tubulin-heterodimer dynamics and binding at
potent cytotoxicity against the tested cancer cell lines with IC50
values ranging 3.16-7.93 µM. The preliminary mechanism of
action study revealed that compounds 16l and 16s induced
apoptotic cell death by enhancing the level of cleaved PARP1 in
C4-2 cells and exhibited their activity through the inhibition of
tubulin polymerization. This class of compounds can be further
exploited for obtaining highly potent cytotoxic compounds.
3
1
colchicine binding sites. In order to find the theoretical binding
sites of novel β-carboline bromides, a docking study for the
identified potent compounds 16l and 16s was performed by
3
2
Molegro Virtual docker program according to reported high-
resolution crystal structure of the tubulin-DAMA-colchicine
3
3
(
CN-2) complex (PDB ID: 1SA0). Scoring functions and
hydrogen bond formed with the surrounding amino acids
predicted the binding affinities for 16l and 16s with MolDock
Scores of -151.18 and -167.90, respectively. The docking poses
of the molecule with the receptor are detailed in Figure 5.
Binding interactions for 16l are strongly stabilized by two
hydrogen bonds; first interaction between C=O and Asp251 with
hydrogen bond distance of 3.0616 Å; the second one between
oxygen of 4-methoxyphenyl group and Cys241 with the bond
length of 2.6103 Å. Similarly, compound 16s also showed
hydrogen-bonding interactions between the oxygen of 1-(4-
methoxyphenyl)-β-carboline and Cys241 with 3.207Å distance of
hydrogen bond. Apart from hydrogen bonding interactions,
compounds 16l and 16s also strongly stabilized by steric
interactions (red dotted lines) as illustrated in Figure 5.
Additionally, the hydrophobic interactions in the colchicine-
binding domain of the tubulin for β-carbolines 16l and 16s are
shown in Figure 6.
Figure 7. Effect of compounds 16l and 16s on in vitro tubulin polymerization
Acknowledgments
This work was supported by grants from Department of
Biotechnology (No. BCIL/NER-BPMC/2012/1549), New Delhi,
India (to DK) and by National Institute of Health (R03 CA
166912 to KS).
Supplementary data
Supplementary data (experimental procedures for the
synthesis of compounds 10, 11, 12, 13, 15 and 16a-t, protocol for
cytotoxicity assay and analytical spectra of final compounds 16a-
t) associated with this article can be found, in the online version,
at http://dx.doi.org/
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*Graphical Abstract
Graphical Abstract
Design, synthesis and in vitro cytotoxicity studies of
novel β-carbolinium bromides
a
a
Venkataramana Reddy P. O , Shriprada Mishra ,
a
b
c
Mukund P. Tantak , Kumar Nikhil , Rachna Sadana ,
Kavita Shah * and Dalip Kumar *
b,
a,