Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine derivatives as potential cytotoxic agents

Article abstract of DOI:10.1016/j.bmcl.2016.05.019

In our endeavor towards the development of effective cytotoxic agents, a series of oxindole linked indolyl-pyrimidine derivatives were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and Mass spectral analysis. All the newly synthesized target compounds were assessed against PA-1 (ovarian), U-87MG (glioblastoma), LnCaP (prostate), and MCF-7 (Breast) cancer cell lines for their cytotoxic potential, with majority of them showing inhibitory activity at low micro-molar concentrations. Significantly, compound 8e was found to be most potent amongst all the tested compounds with an IC₅₀ value of (2.43 ± 0.29 μM) on PA-1 cells. The influence of the most active cytotoxic compound 8e on the cell cycle distribution was assessed on the PA-1 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, acridine orange/ethidium bromide staining and annexin V binding assay confirmed that compound 8e can induce cell apoptosis in PA-1 cells. These preliminary results persuade further investigation on the synthesized compounds aiming to the development of potential cytotoxic agents.

Full text of DOI:10.1016/j.bmcl.2016.05.019

Accepted Manuscript
Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine de-
rivatives as potential cytotoxic agents
Santosh Kumar Prajapti, Atulya Nagarsenkar, Sravanthi Devi Guggilapu,
Keshav Kumar Gupta, Lingesh Allakonda, Manish Kumar Jeengar, V.G.M.
Naidu, Bathini Nagendra Babu
PII:
S0960-894X(16)30505-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.05.019
BMCL 23878
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
11 December 2015
19 April 2016
6 May 2016
Please cite this article as: Prajapti, S.K., Nagarsenkar, A., Guggilapu, S.D., Gupta, K.K., Allakonda, L., Jeengar,
M.K., Naidu, V.G.M., Babu, B.N., Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine
derivatives as potential cytotoxic agents, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.bmcl.2016.05.019
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Synthesis and biological evaluation of
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a
a
a
a
Santosh Kumar Prajapti , Atulya Nagarsenkar , Sravanthi Devi Guggilapu , Keshav Kumar Gupta , Lingesh
b
Allakonda , Manish Kumar Jeengar , V. G. M. Naidu , Bathini Nagendra Babu *
b
b
a,
2

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Synthesis and biological evaluation of oxindole linked indolyl-pyrimidine
derivatives as potential cytotoxic agents
a
Santosh Kumar Prajapti , Atulya Nagarsenkar , Sravanthi Devi Guggilapu , Keshav Kumar Gupta , Lingesh
a
a
a
b
Allakonda , Manish Kumar Jeengar , V. G. M. Naidu , Bathini Nagendra Babu *
b
b
a,
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
b
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
ARTICLE INFO
ABSTRACT
Article history:
Received
In our endeavour towards the development of effective cytotoxic agents, a series of oxindole
13
1
linked indolyl-pyrimidine derivatives were synthesized and characterized by IR, H NMR,
C
Revised
NMR and Mass spectral analysis. All the newly synthesized target compounds were assessed
against PA-1 (ovarian), U-87MG (glioblastoma), LnCaP (prostate), and MCF-7 (Breast) cancer
cell lines for their cytotoxic potential, with majority of them showing inhibitory activity at low
micro-molar concentrations. Significantly, compound 8e was found to be most potent amongst
all the tested compounds with an IC50 value of (2.43±0.29 µM) on PA-1 cells. The influence of
the most active cytotoxic compound 8e on the cell cycle distribution was assessed on the PA-1
cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, acridine orange/ethidium
bromide staining and annexin V binding assay confirmed that compound 8e can induce cell
apoptosis in PA-1 cells. These preliminary results persuade further investigation on the
synthesized compounds aiming to the development of potential cytotoxic agents.
Accepted
Available online
Keywords:
Indole
Oxindole
Indolyl-pyrimidine
Cell cycle analysis
Cytotoxicity
Knoevenagel
2015 Elsevier Ltd. All rights reserved.
In recent decades, cancer has achieved an unambiguous
distinction for being one of the leading causes of death reported
worldwide. About 8.2 million people lost their fight to this
dreadful disease in 2012 and the figure has been feared to touch
Br
N
HO
O
N
H2
N
NH
N
N
N
OH
Y
NH2
O
N
1
N
the 14 million mark by 2030. The present scenario highlights the
N
S
N
H
HO
O
N
N
X
need for the discovery and development of novel drugs with new
2
modes of action. The recognition of new molecule that can be
X
H
N
H
N
H
(
d)
Meridianins
Psammopemmins
(b)
(a)
Hyrtinadine
c)
more effectual and reliable is still a major challenge for a
medicinal chemist. Hence, this has led several research groups
endeavouring for highly potent, effective and economical
molecules as anticancer agents, which undoubtedly, is need of the
hour. In the last one decade pyrimidine, indole and oxindole
derivatives have surfaced up as a diverse class of heterocyclic
compounds, reported with a multitude of activities, such as,
anticancer, anti-inflammatory, anti-malarial, antifungal, antiviral,
anti-HIV, anti-microbial, anti-tubercular, anti-adrenergic, anti-
(
O
N
O
S
N
O
O
F
N
H
N
N
HN
HN
O
O
N
H
N
H
N
H
Semaxinib
Sunitinib
(AZ20)
e)
(
(f)
(g)
Figure 1. Structure of some representative indolyl-pyrimidine and
oxindole derivatives as potential anticancer agents.
3
leishmanial, anti-psychotics and lipid lowering agents.
Numerous drugs are available in the market containing either of
these privileged scaffolds such as, imatinib, sunitinib, dabrafenib,
Indole linked pyrimidines are probably one of the most
important heterocyclic scaffold present in nature bestowed with
significant cytotoxic activity. Extensive database exploration has
led to the findings of various naturally occurring indolyl-
3
c,4
vinca alkaloids displaying potent anticancer activity.
It is
evidenced from the literatures that scores of pyrimidine, indole
and oxindole inhibits the growth of various types of cancer
namely, breast, bladder, lung, colon etc. These motifs have been
extensively accounted for their ability to target multiple proteins,
3a,3b
pyrimidines
hyrtinadine and aplicyanin with anticancer potentials (Figure
such as meridianin, psammopemmins,
6,7
). Owing to the importance of indole linked pyrimidines in the
1
4
,5
required at various stages of cancer progression.
field of cancer research, various researchers are keenly involved
in the development of novel indolyl-pyrimidine derivatives as
Corresponding
author.
Dr.
B.
Nagendra
Babu,
E-mail:
8
promising cytotoxic agents (Figure 1). However, till now only
one indole linked pyrimidine containing molecule Cediranib
bathini.niperhyd@gov.in; Tel: +9140 23073740.
3

O
O
(
Recentin), a very potent inhibitor of VEGFR tyrosine kinase,
Br
9a
Br
Br
(i)
(ii)
was under phase III clinical trial by AstraZeneca.
N
N
N
H
H
O
H
N
1
2
3
Despite of the great advances in cancer therapy, there has been
tremendous growth in the number and types of new anticancer
agents containing indolyl-pyrimidine pharmacophore. Since,
interesting biological activities are shown by indolyl-pyrimidine
derivatives, there has been a considerable curiosity in the
synthesis of new hybrid molecules containing indolyl-pyrimidine
alongwith oxindole unit, as oxindole containing molecules have
N
(v)
N
N
O
N
R
NH2
O
R1
7
(a-j)
(iii)
(iv)
R
N
R
N
(vi)
4
(a-j)
5(a-j)
O
6(a-j)
NH
H
N
9
b
N
shown potent cytotoxic activity. Thus, our objective is to
synthesize indolyl-pyrimidine derivatives with an array of
substitutions at it, which may lead us towards an enhancement in
cytotoxic activity. In order to develop pertinent leads for
prospective antineoplastics, we have introduced appropriate
substitutions at C-3 and C-5 positions of indole with oxindole
and aminopyrimidines, respectively as well as aromatic
substitutions at C-4 position of the aminopyrimidine ring.
Furthermore, these compounds have been evaluated for their
cytotoxicity. The most active cytotoxic compound was further
tested via acridine orange staining, annexin V binding assay and
cell cycle analysis.
N
N
R
8(a-j)
R =
(a)
(
b)
(c)
OMe (d)
OH (e)
Cl
Cl
(i)
(j)
(f)
F
(g)
CF3 (h)
N
S
Cl
Scheme 1: Synthetic scheme for the synthesis of oxindole linked indolyl-
pyrimidine derivatives: (i) POCl , DMF, 0-75 °C; (ii) CH I, NaOH, ACN, rt,
h; (iii) DMF-DMA, xylene, reflux, 48 h; (iv) guanidine nitrate, NaOH, n-
butanol, reflux, 12 h; (v) CuI, DMEDA, Cs CO , 1,4-dioxane, reflux, 20 h;
vi) oxindole, piperidine, EtOH, reflux, 6 h.
3
3
3
2
3
(
The synthetic protocol to achieve target molecule involved six
steps (Scheme 1), which instigates from commercially accessible
The IC50 (µM) values (concentration required to achieve 50%
5
-bromoindole 1 to obtain 5-bromoindole-3-carbaldehyde 2 in
inhibition of the tumor growth) of the tested compounds are
listed in Table 1. Preliminary cytotoxicity screening of the
compounds 8(a-j) was carried out at 100 µM concentration to
determine cell death. The IC50 values were not determined for the
compound displaying poor activity at this concentration. It is
evident from the preliminary results that some of the compounds
have shown significant cytotoxicity on human cancer cell lines
such as PA-1, U-87 MG and LnCaP. From the close analysis of
IC50 values (Table 1), it was observed that, oxindole linked
indolylpymidine with phenyl substitution 8a displayed
substantial inhibitory activity against all tested cancer cell lines
while the phenyl substituted with electron donating groups such
as –Me 8b and –OMe 8c at para position led to loss in
cytotoxicity against all cancer cell lines. Enhancement in
cytotoxicity was observed against all cancer cell lines, when the
phenyl ring is introduced with free hydroxyl group at para
position of the phenyl ring 8d. Notably, it showed enhanced
inhibitory activity against U-87MG and LnCaP cells as compared
to the reference drugs. Interestingly, the compound substituted
with a chloro group at para position of phenyl ring 8e has led to
further improvements in cytotoxic activity and has displayed
enhanced activity against all tested cancer cell lines as compared
to the reference drug. Moreover, cytotoxicity was decreased
while substituting the phenyl ring with halogen groups such as p-
quantitative yield, by utilizing Vilsmeier reagent i.e.,
chloroiminium salt for the formylation at electron rich third
position of indole under Vilsmeier-Haack reaction parameters.
1
0
This was followed by N-methylation to acquire 5-bromo-1-
methyl-1H-indole-3-carbaldehyde 3 in high yield, using reported
procedure. On the other hand, different substituted aromatic and
heteroaromatic enaminones 5(a-j) were synthesised by
employing respective acetophenones 4(a-j) and refluxing it with
1
1
1
2
DMF-DMA to obtain desired products in quantitative yields.
During the course of product formation, methanol was also
formed as a by-product which was distilled off at regular
intervals, as it interfered with the proceedings of reaction. The
synthesized enaminone intermediates 5(a-j) were then subjected
to reflux with guanidine nitrate in n-butanol under basic
condition to afford respective aminopyrimidines 6(a-j) in high
13
yields. Presence of electron withdrawing groups on the ring
afforded high yields, as compared to electron donating groups in
both the aforementioned reactions. The two privileged moieties 3
and 6(a-j) were subsequently linked in the penultimate step
involving Ullmann type C-N bond coupling reaction to afford
compounds 7(a-j). In this reaction, CuI was utilized to carry out
the coupling under strict anhydrous atmosphere, as the presence
of moisture hindered the progress of reaction. As
aminopyrimidines are very weak nucleophiles, a strong electron
donating agent such as DMEDA was added under basic condition
14
3
F 8f and p-CF 8g on phenyl ring, although compound 8f showed
promising results against U-87MG cells as compared to their
reference drugs. Furthermore, the indolyl-pyrimidine substituted
with 2,4 dichlorophenyl 8h was shown to be specifically active
against U-87MG cancer cells. Replacement of phenyl group with
the heterocyclic substituents such as pyridine 8i and thiophene 8j,
displayed improved cytotoxicity towards all the tested cancer cell
lines. Fascinatingly, compound 8j displayed excellent cytotoxic
activity against all tested cancer cells, while compound 8i
showed good activity against U-87MG and LnCaP cells.
Significantly, compound 8e was found to be most potent among
all the tested compounds with an IC50 value (2.43±0.29 µM) on
PA-1 cells, while majority of the compounds showed excellent
cytotoxic activity against prostate cancers cells.
of Cs
single chemical entity. Finally, the desired product 8(a-j) was
2 3
CO , to carry out the merging of both the motifs in to a
1
5a,b
achieved by Knoevenagel condensation
(a-j) and oxindole under basic condition, to acquire target
compounds. The stereochemistry of the final product was
of coupling product
7
1
15c-g
confirmed by H NMR and the previous literature reports.
The synthesized oxindole linked indolyl-pyrimidine
derivatives 8(a-j) were evaluated for their in vitro cytotoxicity
against cancer cell lines such as breast cancer (MCF-7), prostate
cancer (LnCaP), ovarian teratocarcinoma (PA-1), brain
glioblastoma (U-87 MG) and human normal prostate epithelial
(
RWPE-1) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-
16
diphenyltetrazolium bromide (MTT) assay. 5-Fluorouracil (5-
FU) and Sunitinib were taken as the reference in this study.
4

Table 1. In vitro cytotoxic activity of oxindole linked indolyl-pyrimidine which has lost membrane integrity and stain the nucleus red. It
derivatives.
can be inferred from Figure 4 that the control cells showed
a
IC50 (µM)
Co
normal morphology and appeared green in colour. Fluorescence
microscopic images of cells treated with 2.5 µM of compound 8e
clearly showed the morphological changes such as cell shrinkage,
membrane blebbing, chromatin condensation and apoptotic body
formation, suggesting that the compound 8e induced cell death in
PA-1 cancer cells via apoptosis (Figure 4).
mp.
PA-1
U-87MG
LnCaP
MCF-7
RWPE-1
8
8
a
17.27±1.07 14.13±0.54
13.42±0.9
>100
42.88±2.20
>100
95.63±1.89
nd
b
>100
>100
>100
>100
8
c
>100
>100
nd
8
d
9.27±0.99
2.43±0.29
13.15±0.32
5.82±0.69
10.8±0.41
6.59±0.66
39.63±0.42
23.51±1.72
58.42±2.97
41.05±5.37
168.45±3.78
nd
8
e
8
f
31.75±0.91 16.42±0.91 16.34±0.66 48.10±2.04
8
8
g
63.94±0.83
>100
25.97±0.8
>100
>100
65.2±12.63
>100
h
36.79±0.44
nd
8
8
i
18.1±1.82
7.94±0.38
8.51±0.31
7.97±1.33
14.84±0.77 14.15±0.67 46.59±1.74
7.18±1.54 10.35±0.31 30.75±2.27
69.83±2.98
64.89±6.52
nd
j
b
F
15.48±3.50 47.18±2.32 32.27±4.33
59.75±3.06 12.61±0.99 23.76±0.42
c
S
23.0±1.23
a
5
0% inhibitory concentration and mean ± SD of three individual experiments
b
performed in triplicate; 5-Fluorouracil was included as reference standard;
c
nd
Sunitinib; not determined.
Figure 3. Morphological changes in PA-1 cells. Light microscopy: (a) not
treated with compound 8e was used as control for 24 h; (b) treatment with
compound 8e (1 µM) for 24 h; (c) treatment with compound 8e (2.5 µM) for
24 h.
To check the safety and selectivity of the synthesized
compounds towards normal cells, we have further performed
MTT assay on normal prostate epithelium cells (RWPE-1) for
compounds which showed IC50 less than 20 µM on LnCaP
(
prostate cancer) cells. It was quite interesting to observe that the
tested compounds displayed more cytotoxicity towards LnCaP
cancer cells as compared to RWPE-1 cells (Figure 2). From
Table 1 it is clear that compound 8f was highly selective toward
LnCaP cell line (IC50 was almost 10.3 fold higher in RWPE-1
cells), when compared to the normal prostate epithelial cells. The
highest cytotoxicity of compound 8e was observed on PA-1
cancer cell line with IC50 of 2.43±0.29 µM; hence this compound
was selected for further mechanistic analysis on PA-1 cell line.
These preliminary results of biological screening of the tested
compounds could offer an encouraging support in this field that
may lead to the discovery of novel cytotoxic agent.
Figure 4. AO/EB staining of compound 8e in PA-1 cells. Fluorescence
microscopy (a) Not treated with compound 8e was used as control for 24 h;
(b) treatment with compound 8e (1 µM) for 24 h; (c) treatment with
compound 8e (2.5 µM) for 24 h.
The apoptosis inducing effect of compound 8e on PA-1 cancer
cells was further investigated using annexin V-FITC/propidium
1
9
iodide staining assay. PA-1 cells were treated with two
concentrations of 1 and 2.5 µM of compound 8e for 24 h and
further stained with Annexin V-FITC and propidium iodide. As
shown in Figure 5, compound 8e increased the percentage of
early apoptotic cells (from 1.65% (ctrl) to 16.68% (1 µM),
25.18% (2.5 µM) respectively) which indicate that 8e induced
apoptosis of PA-1 cancer cells in a dose dependent manner.
Figure 2. Specificity of compounds 8a, 8d, 8e, 8f, 8i and 8j towards normal
prostate epithelial cells (RWPE-1) compared to cancer cells.
The induction of apoptotic bodies formation (consist of
damaged organelles and DNA) by anticancer agents, has always
been a preferred choice in developing anti-cancer therapeutics.
To observe whether the treatment with the compounds could lead
to loss of cell viability and induction of apoptosis, PA-1 cells
were treated with the most active compound 8e. Phase contrast
microscopy of compound 8e treated PA-1 cells showed cell
shrinkage, cell wall deformation and resulted in reduced number
of viable cells, whereas these distinctive morphological features
were absent in control as shown in Figure 3.
Figure 5. Flow cytometry analysis of apoptotic cells after Annexin V-
FITC/propidium iodide (PI) staining (representative result of three
independent experiments); L: Live, EA: Early Apoptotic, LA: Late Apoptotic,
D: Dead. (a) PA-1 cells without treatment; (b) PA-1 cells treated with 1 µM
of 8e for 24 h; (c) PA-1 cells treated with 2.5 µM of 8e for 24 h.
Many of the cytotoxic compounds exert their growth inhibitory
2
0
effect by arresting the cell cycle at a specific checkpoint. In
vitro screening results revealed that compound 8e showed
significant activity against PA-1 cells. Therefore, we examined
the effect of compound 8e on cell cycle using flow cytometry.
PA-1 cells were treated with various concentrations of compound
Acridine orange/ethidium bromide (AO/EB) fluorescent
staining assay was performed to differentiate the live, apoptotic
8
e for 24 h, stained with propidium iodide and samples were
1
7,18
and necrotic cells. AO permeates the intact cell membrane
and stains the nuclei green, whereas EB can stain only cells
analysed by using flow cytometry. The data obtained from the
study indicated that majority of control cells (without treatment)
5

were in G1 phase (73.23%). Treatment with compound 8e
resulted in dose dependent accumulation of cells in G2/M phase.
For instance 17.55% and 31.13% of cells were in G2/M phase
after treatment with 1 and 2.5 µM concentrations (Figure 6).
These results clearly indicate the G2/M phase cell cycle arrest.
8.
(a) Finlay, M. R. V.; Buttar, D.; Critchlow, S. E.; Dishington, A. P.;
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Figure 6. Effect of compound 8e on cell cycle progression of PA-1 cells, (a)
control cells, (b) Cells treated with 1 µM for 24 h, (c) Cells treated with 2.5
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In present study, a panel of oxindole linked indolyl-pyrimidine
derivatives were synthesized and evaluated for their in vitro
cytotoxic potential against four cancer cell lines. The compounds
showing promising results (8a, 8d, 8e, 8f, 8i, 8j) were also
evaluated for the cytotoxicity on normal prostate epithelial cell
line (RWPE-1). Interestingly, the tested compounds showed
more selectivity toward LnCaP cancer cell as compared to the
normal prostate epithelial cells. Notably, compound 8e was found
to be most potent amongst all the tested compounds, having IC50
value (2.43±0.29 µM) on PA-1 cells, while most of the tested
compounds showed enhanced cytotoxicity against prostate
cancers cells compared to the reference drugs. The cell cycle
analysis results revealed that compound 8e arrested the PA-1 cell
cycle at G2/M phase in dose dependent manner. Furthermore, the
apoptotic potential of the most active cytotoxic compound 8e was
assessed by acridine orange/ethidium bromide (AO-EB) staining
and annexin binding assay on PA-1 cells. These preliminary
results encourage further investigation on synthesized
compounds aiming to the development of new potential cytotoxic
agents.
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1. Typical reaction procedure, experimental data for all the compounds
and general methods are provided in the supporting information.
2
Acknowledgments
We thank the Department of Pharmaceuticals (Ministry of
Chemicals and Fertilizers, Govt. of India) for providing funds
and also CSIR-Indian Institute of Chemical Technology,
Hyderabad for providing the facilities.
References and notes
1
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