Design, synthesis and biological evaluation of novel spiro[indole- pyridothiazine] analogs as antiproliferative agents

Article abstract of DOI:10.1039/c3ra43908a

A zeolite supported Bronsted-acid catalyst system has been developed for the synthesis of novel N-substituted spiro[indole-pyridothiazine] analogs under ultrasonication in shorter reaction times with higher yields. The antiproliferative effects of the synthesized compounds were also tested against a wide range of tumor cell lines.

Full text of DOI:10.1039/c3ra43908a

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Design, synthesis and biological evaluation of novel
spiro[indole-pyridothiazine] analogs as
antiproliferative agents†
Cite this: RSC Adv., 2014, 4, 3060
Received 25th July 2013
Accepted 29th October 2013
*
Kapil Arya, Pooja Tomar and Jyoti Singh
DOI: 10.1039/c3ra43908a
www.rsc.org/advances
A zeolite supported Brønsted-acid catalyst system has been devel- inhibits the activity of cdk2. This inhibition results in a time-
oped for the synthesis of novel N-substituted spiro[indole-pyr- dependent decrease (4–64%) in the phosphorylation of the
idothiazine] analogs under ultrasonication in shorter reaction times retinoblastoma protein pRb, an increase in caspase-3 activation
with higher yields. The antiproliferative effects of the synthesized (5–84%), and alterations in the cell cycle resulting in either a
compounds were also tested against a wide range of tumor cell lines. G0–G1 or a G2–M block.
In addition, CDK inhibitory properties in isatin derived
phenylhydrazones (3) have also been reported with IC50 values
in the range of 4.73 ꢀ 10ꢁ6 to 8.24 ꢀ 10ꢁ6 M (Scheme 1).9 Based
Introduction
on this information, Abadi et al. synthesized several 2-indolone
In the huge molecular library of heterocyclic compounds,
nitrogen and sulfur are ubiquitous elements. Spiroindoles, as
important “privileged scaffolds,” are a very attractive target for
combinatorial library synthesis because of their structure
activity relationship and are widely used as key building blocks
in the eld of drugs and pharmaceutical agents.1 Pyridothiazine
derivatives are of current interest due to their therapeutic
properties, such as their anti-inammatory, analgesic, anti-
tumor, antioxidant and antituberculosis activity, as well as their
activity as calcium channel blockers, and potential anticancer
agents, etc.2–4
imino derivatives to examine their antitumor and anti-
angiogenic properties.10 Vine et al. also synthesized several
substituted isatin analogs, and screened them against a panel
of ve human cancer cell lines.6 These authors concluded that
substituted isatins could be effective anticancer drugs.
N-Alkylated indoles are also well known to exhibit anticancer
activity.11–13 However, until recently, little had been reported on
the antineoplastic activity of N-alkyl and N-aryl isatins. In 2003,
the rst N-alkyl isatin was shown to induce apoptosis in a panel
of human cancer cell lines.11 Further screening by the National
Cancer Institute (NCI) found that the dichlorinated compound
The isatins (1H-indole-2,3-diones) are one of the most
promising new classes of heterocyclic molecules having many
interesting activity proles and being well-tolerated in human
subjects.5,6 The 2-oxoindole derivatives SU-5416 (Semaxanib,
Scheme 1) and SU-11248 (Sunitinib, Scheme 1) were reported as
having tyrosine kinase inhibitory and antiangiogenic proper-
ties.7 SU-5416 and SU-11248 treatment produced a 24% reduc-
tion in steady-state temozolomide Ct values ( p < 0.05) as well as
a 21% reduction in the tumor/plasma concentration ratio
(Ct/Cp; p ¼ 0.11–0.13) compared with controls.7 In addition, the
structurally relevant SU-9516 (Scheme 1) was reported as a
potential inhibitor of cyclin-dependent kinases (CDKs) that can
induce apoptosis in colon carcinoma cells.8 SU-9516, a novel
3-substituted indolinone compound, binds to and selectively
Department of M. Tech. Chemical Synthesis and Process Technologies, University of
Delhi, Delhi, India, 110007. E-mail: aryakapil2001@yahoo.com; Tel: +91 9310826916
† Electronic supplementary information (ESI) available: Experimental procedure
and characterization details. See DOI: 10.1039/c3ra43908a
Scheme 1 Isatin analogs with anticancer activity.
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exerted a cytostatic effect (inhibiting cell growth by 50–100%) on pyridothiazine] analogs were prepared (Scheme 2 and Table 1)
40 out of the 48 cell lines tested, at a concentration of 10 mM. At in shorter reaction times in good yields. Encouraging results
10 times this concentration however, the compound exhibited obtained from our previous work17 prompted us to develop
100% cytotoxicity on virtually all cell lines, suggesting that this some new analogous of this series to search for better medicinal
effect may be due to non-specic toxicity.11 Later in 2003, Liu agents.
et al.,12 identied a class of N-acyl isatins that selectivity
A typical experimental procedure was chosen: N-substituted
inhibited neuronal ubiquitin C-terminal hydrolase (UCH-L1) at indole-2,3-dione (1, 1.0 mmol), various amines (2, 1.0 mmoꢁl),
sub-micromolar concentrations in the H1299 lung cancer cell 2-mercaptonicotinic acid (3, 1.0 mmol) and ZSM-5-([MIM]+BF4
)
line. Despite being linked to Parkinson's disease, UCH-L1 is Brønsted acid catalyst (1.5 g). Using this system, we synthesized a
also expressed in many primary lung tumours and lung cancer small library of novel N-substituted spiro[indole-pyridothiazine]
cell lines, but not normal lung tissue,14,15 where it is proposed to analogous under ultrasound irradiation and the results are
be linked to tumour progression upon upregulation.12
summarized in Table 1. The new series of compounds (4a–o) were
Based on these prior observations, we postulated that a fully characterized by means of spectroscopic techniques such as
compound containing both N-alkyl and N-acyl isatins and pyr- IR, 1H NMR, 13C NMR and EI-MS.
idothiazine pharmacophores could be very effective for anticancer
activity. The synthesis of isatin–pyridothiazine conjugates could
be possible by a pharmacophore hybrid approach. Hybridization
Anticancer activity
of two different bioactive molecules with complementary phar- The anticancer activity of the novel spiro[indole-pyr-
macophoric functions or with different mechanisms of action idothiazines] (4a–o) was tested using ve different cell lines in a
oen results in synergistic effects.16 Therefore, we synthesized cell toxicity assay and the percentage of cells that survived at the
hybrid compounds by linking the main structural unit of the dose level of 50 mM was determined. The potential effects on cell
isatin ring system with the pyridothiazine ring system by a Schiff viability were also investigated by using the MTT assay23 for
base reaction, and then examined their antiproliferative effects on compounds 4a–o against normal skin broblast cells, epider-
a wide range of tumor cell lines.
moid carcinoma of nasopharynx (KB) cells, lung carcinoma
In spite of the immense biological activities of pyridothiazines (A-549) cells, ileocecal carcinoma (HCT-8) cells, renal cancer
and spiroindoles, still no report is available on the synthesis of (CAKI-1) cells and breast cancer (MCF-7) cells. The results are
spiro[indole-pyridothiazines] except for the one from our labora- summarized in Table 2.
tory.17 In our earlier study, we developed a novel one-pot synthesis
Compounds 4g and 4h, having electron withdrawing groups,
of spiro[3H-indole-3,20-[4H]pyrido[3,2-e]-1,3-thiazine]-2,40(1H)dio- showed higher activity against all cell lines compared to
nes] by reaction of 2-mercaptonicotinic acid with various aromatic 5-uorouracil, which is used as a standard positive control drug.
amines and carbonyl compounds. This reaction proceeded Among the tested compounds, a maximum inhibitory activity of
through the in situ-generated imine intermediate, which was 21.76% was shown by 4g against the lung carcinoma (A-549) cell
demonstrated as a microwave-tolerable species in the literature.18 line. Compound 4e exhibited 23.45% antiproliferation against
As a consequence of our interest to develop new selective envi- ileocecal (HCT-8) carcinoma cells. Similarly, compound 4a
ronmentally friendly methodologies for the preparation of phar- showed 23.95% antiproliferation against renal (CAKI-1) carci-
maceutically important scaffolds,19,20 and as an extension of our noma cell lines.
current research we have developed a small library of novel
Compounds 4a, 4e, 4g, 4h, 4k and 4l exhibited good inhibi-
N-methyl substituted spiro[indole-pyridothiazine] analogs in tion compared to other tested compounds. The maximum
water as a solvent under ultrasonication using a zeolite supported inhibition by compound 4a (22.84%) could be attributed to the
Brønsted-acid as a catalyst (Scheme 1).
bromo and acetyl groups present in the indole moiety at the
In the eld of chemotherapeutic drugs, the search for new, 5-position. The compound 4e exhibited 22.24% maximum
more active, selective and less toxic compounds is still in progress inhibition, which may be due to the presence of electron with-
and promising new anticancer approaches are being pursued.21,22 drawing NO2 and COCH3 groups in the indole moiety. This
In view of this, structure-based combinatorial libraries of novel activity might be related to the reduction of the nitro group to
N-substituted spiro[indole-pyridothiazine] analogs have been an electrophilic nitrogen that induces oxidative damage of DNA
designed and synthesized in the presence of water as a solvent with a relatively high AT content.24 In addition, 4g showed high
under ultrasonication and the potential in vitro antiproliferative inhibition due to the presence of a N-acetyl group in the indole
activity of this class of compounds against ve human tumor cell moiety, whereas 4b, 4i, 4j, 4m, 4n and 4o, having electron
lines has been described for the rst time. At the outset, synthesis donating groups, showed weak activity against all cancer cell
of N-substituted spiro[indole-pyridothiazine] analogs via a multi- lines. It can be concluded that the inhibition of cell prolifera-
component approach zeolite supported Brønsted-acid catalyst tion increases with the electron withdrawing groups, whereas in
system, as shown in Scheme 2, was envisaged.
the presence of electron donating groups, the inhibition is not
signicant.
The een compounds (4a–o) proposed for screening were
selected, and a preliminary evaluation was made against 60
Results and discussion
The library of tested molecules was developed around a pyr- tumor cell lines at a single dose of 1.0 mM. The output from the
idothiazine core. Small libraries of N-substituted spiro[indole- single dose screening was reported as a mean graph available for
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Scheme 2 Synthesis of spiro[indole-pyridothiazine] analogs.
Table 2 Evaluation of the cytotoxicity towards tumor cells (% cell
survival) for the synthesized compounds (4a–o)
analysis by the COMPARE program. The results of the rst assay
showed that compounds 4a–j were active. Then, the active
compounds were passed to a second stage in order to determine
their cytostatic activity. They were evaluated at ve concentration
levels against various tumor cell lines including melanoma,
leukemia and cancers of the lung, colon, brain, breast, ovary,
kidney or prostate. The test consisted of a 48 h continuous drug
exposure protocol using a sulforhodamine B (SRB) protein assay
to estimate cell growth. Details of this evaluation method and the
complementary information related with the activity pattern over
all cell lines have been published.25–27 Compound 4a exhibited
activity against the 60 human tumor cell lines, with low values of
GI50 ꢂ 10ꢁ6 M in all cell lines, e.g. GI50 ¼ 2.36 ꢀ 10ꢁ6 M for A-549
(non-small cell lung), and GI50 ¼ 1.94 ꢀ 10ꢁ6 M for KB, and
generally interesting LC50 values higher than 1 ꢀ 10ꢁ4 M. In a
similar way, compound 4e also showed an interesting activity
against CAKI-1 with GI50 ¼ 2.01 ꢀ 10ꢁ6 M. Consequently,
compound 4g exhibited signicant activity, with GI50 values
ranging from 1.97 ꢀ 10ꢁ6 to 5.22 ꢀ 10ꢁ6 M. The cytotoxicities
associated with the latter compounds, measured as LC50, are
around 100 mM for most cell lines, indicating a low toxicity of
such compounds for normal human cell lines, as is required for
potential antitumor agents (see Table 3).
Normal cell
Entry
line
KB
A-549 HCT-8 CAKI-1 MCF-7
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
22.84
32.89
33.89
31.95
22.95
34.20
21.34
21.39
37.83
38.75
21.25
22.08
38.7
24.20 21.98 23.03 23.95
31.76 30.68 39.03 38.50
32.94 30.65 34.96 37.05
30.53 33.06 37.83 37.93
23.72 22.24 23.45 23.72
31.86 35.09 38.41 34.95
22.02 21.76 22.96 22.09
22.73 22.05 23.02 22.78
36.99 31.83 32.07 34.79
34.61 37.81 34.07 39.03
22.85 23.02 23.51 24.15
22.91 23.49 23.12 24.02
34.32 31.29 38.42 32.98
32.09 33.75 38.25 34.21
39.82 31.32 33.71 35.64
23.85 21.43 22.56 23.49
25.21
41.02
38.33
40.34
24.95
36.03
23.21
23.42
39.29
34.22
21.45
23.91
35.85
38.97
34.16
24.81
42.8
40.2
5-Fluorouracila 22.32
a
Used as a positive control.
activity compared with previous compounds. Raja Solomon
et al.28 reported anti breast cancer activity of isatin–benzothia-
zole analogs with IC50 values of 20–110 mM against
MCF-7 cancer cell lines, while Kalman et al.29 reported
Finally, the antiproliferative activities of the isatin–pyr-
idothiazine conjugates were compared with previously reported
isatin based analogs and were found to have enhanced
Table 1 Cyclocondensation reaction of arylimines with 2-mercaptonicotinic acid under ultrasonication
S. no.
Producta
R
X
Y
Time (min)
Yieldb (%)
M.p. (ꢃC)
1.
2.
3.
4.
5.
6.
7.
8.
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
COCH3
CH3
COCH3
CH3
COCH3
CH3
COCH3
CH3
COCH3
CH3
CH3
COCH3
CH3
COCH3
CH3
5-Br
5-Br
5-Cl
5-Cl
5-NO2
5-NO2
H
H
H
H
H
H
H
H
H
H
H
6
8
8
7
10
8
10
8
7
10
9
8
93
90
85
88
92
85
87
85
88
85
88
90
92
90
93
210
245
203
198
176
258
246
222
269
189
169
201
211
203
256
4-OCH3
4-OCH3
4-CH3
4-CH3
4-NO2
4-NO2
4-Cl
4-Cl
4-Br
9.
10.
11.
12.
13.
14.
15.
H
5-Br
5-Br
H
8
7
10
a
ꢁ
Experimental conditions: an equimolar mixture (1 mmol) of N-substituted indole, amines, 2-mercaptonicotinic acid, and ZSM-5-([MIM]+BF4
)
b
Brønsted acidic ionic liquid (0.3 mol%) in 5 mL of water was irradiated under ultrasonication at 95 ꢃC. Isolated yields.
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Table 3 In vitro testing expressed as growth inhibition of cancer cell lines for compounds 4a–ja
Panel/cell line
Non-small cell
Nasopharynx (KB)
lung (A-549)
Ileocecal (HCT-8)
Renal (CAKI-1)
Breast (MCF-7)
b
c
c
b
c
c
Entry
GI50 (mM) LC50 (mM) GI50b (mM) LC50 (mM) GI50b (mM) LC50c (mM) GI50 (mM) LC50 (mM) GI50b (mM) LC50 (mM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.94
5.19
7.45
4.42
2.13
5.32
1.99
3.34
9.84
5.07
>100
>100
>100
>100
>100
>100
>100
>81
2.36
5.96
7.92
8.71
2.25
4.65
5.22
4.87
9.34
7.32
2.41
>100
>100
>100
>100
>100
>92
>100
>100
>100
>100
>100
2.19
3.14
4.65
5.69
2.20
3.35
2.25
5.38
6.23
7.11
2.22
>100
>92
2.08
5.51
4.97
3.96
2.01
3.47
1.97
8.36
4.52
3.61
2.05
>100
>100
>100
>100
>100
>100
>100
>100
>88
2.13
5.23
3.69
5.32
2.03
8.96
2.08
5.21
4.78
6.89
2.15
>100
>100
>76
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
4j
>100
>100
5-Fluorouracild 2.01
a
b
Data obtained from NCI's in vitro disease-oriented human tumor cell lines screen.33 GI50 is the drug concentration resulting in a 50% reduction
in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. Determined at ve concentration levels (100,
c
d
10, 1.0, 0.1 and 0.01 mM). LC50 is a parameter of cytotoxicity and reects the molar concentration needed to kill 50% of the cells. Used as a
positive control.
indolo[3,2-g]pteridine-7-one analogs with anticancer activity were able to identify a few biologically active molecules that are
against murine leukemia L1210 cells in vitro with IC50 values of capable of inhibiting the growth of human cancer cell lines in
4 to 24 mM. Cai et al.30 reported indoline–benzohydrazides as vitro.34–38 An attempt to understand the mechanism of action of
new apoptosis inducers with GI50 values of 0.056 mM against this series of new antiproliferative agents is being further studied
human colorectal carcinoma HCT 116 cells. Various spiroindole in our laboratory.
thiazolidinone and thiazine compounds were screened against
three human cancer cell lines (HT-29, H460 and MDA-MB-231)
by MTT assays and exhibited IC50 values of 0.025, 0.075 and
Acknowledgements
0.77 mM, respectively. The SAR study showed that substitution
with smaller electron withdrawing uorine atoms at the
5-position of the indolin-2-one ring and a 3-(diethylamino)
propyl group at the 3-position of the 4-thiazolidinone ring had a
positive contribution for increasing antitumor activity. Gouda
et al. reported DNA degradative capacity of thiazolidinone
derivatives. Only a few of the synthesized derivatives showed
complete degradation of calf thymus DNA.31,32
KA acknowledge the D.S.T. (SR/FT/CS-69/2013), New Delhi,
India and the University of Delhi, Delhi, India for nancial
support.
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The present synthetic methodology for the multicomponent one
pot cyclocondensation reaction of 2-mercaptonicotinic acid with
aromatic amines and N-substituted indole-2,3-dione using water
as a greener solvent under ultrasonication is a simple, convenient
and environmentally friendly method and will be applicable for
the library synthesis of spiro-ring systems in good yield without
using any dehydrating agents or solvents, with easy purication.
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