Gold(III) chloride catalyzed regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones and evaluation of anticancer potential towards human cervix adenocarcinoma

Article abstract of DOI:10.1016/j.bmcl.2011.05.088

A highly regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones via gold(III) chloride catalyzed cycloisomerization of 3-ethynyl-indole-2-carboxylic acid was achieved in good to excellent yields. These compounds were screened for their in vitro cytotoxicity against human cervical (HeLa) cell lines. Out of ten compounds, three compounds (7d, 7e and 7j) showed comparable proliferation inhibitory activity against the standard drug cisplatin. Compound 7d was found to be the most efficacious with IC₅₀ value of 0.22 μM.

Full text of DOI:10.1016/j.bmcl.2011.05.088

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4170–4173
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Gold(III) chloride catalyzed regioselective synthesis of pyrano[3,4-b]indol-1(9H)-
ones and evaluation of anticancer potential towards human cervix
adenocarcinoma
Chandrasekaran Praveen a, Asairajan Ayyanar b, Paramasivan Thirumalai Perumal a,
⇑
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamilnadu, India
b Department of Pharmaceutical Chemistry, Arulmigu Kalasalingam College of Pharmacy, Krishnankoil 626 190, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones via gold(III) chloride catalyzed cyclo-
isomerization of 3-ethynyl-indole-2-carboxylic acid was achieved in good to excellent yields. These com-
pounds were screened for their in vitro cytotoxicity against human cervical (HeLa) cell lines. Out of ten
compounds, three compounds (7d, 7e and 7j) showed comparable proliferation inhibitory activity against
the standard drug cisplatin. Compound 7d was found to be the most efficacious with IC50 value of
Received 5 April 2011
Revised 22 May 2011
Accepted 24 May 2011
Available online 30 May 2011
0.22 lM.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Pyrano[3,4-b]indol-1(9H)-ones
Regioselectivity
Gold(III) chloride
Anticancer
HeLa
Cervical cancer, a slow growing squamous cell carcinoma
caused by human papillomavirus (HPV), is the second most com-
mon cancer that affects women after breast cancer.1 The mortality
rate of cervical cancer is high even though the percentage of cure is
nearly 100%. For example, the mortality of cervical cancer was
about 37% in the United States in 2006. The clinical therapy of cer-
vical cancer includes surgery, radiotherapy, and chemotherapy. For
example, cisplatin is a common chemotherapeutic drug for cervical
cancer. However, patients often develop resistance to cisplatin at
the later stages of therapy. Only two prophylactic vaccines have
been developed and approved by FDA; GardasilÒ (Merck) and
CervarixÒ (GlaxoSmithKline).2 Therefore, it seems necessary to de-
velop new drugs to complement the present chemotherapeutic
strategies. Recently, different authors have reported the anticancer
cycloisomerization strategy has been frequently applied for the
synthesis of isocoumarins, there has been no precedent for the
synthesis of pyranoindolones. Further in continuation to our
previous studies on the synthesis of heterocycles7 through gold
catalysis,7a–e,j we planned to synthesise pyrano[3,4-b]indol-1(9H)-
ones via gold catalyzed cycloisomerization of 3-(ethynyl)-indole-2-
carboxylic acid. Herein, we report on the gold(III) chloride catalyzed
synthesis and biological evaluation of pyrano[3,4-b]indol-1(9H)-
ones as promising cytotoxic agents towards HeLa cell lines.
Synthesis of the requisite 3-(ethynyl)-indole-2-carboxylic acid
6a–j was achieved as depicted in Scheme 1. Indole-2-carboxylic acid
1a,b was esterified with methanol using catalytic sulphuric acid to
afford the corresponding methyl ester 2a,b.8 The esters were then
subjected to C3-iodination using molecular iodine to afford
3-iodo-indole-2-carboxylate 3a,b.9 N-Alkyl-3-iodo-indole-2-carbo-
xylate 4a–g was obtained by N-alkylation of 3a,b using respective
alkyl halide and base.10 3-(Ethynyl)-indole-2-carboxylate 5a–j was
obtained by coupling terminal alkynes with 3-iodo indoles 3a,b
and 4a–j under standard Sonogashira condition.11 Hydrolysis of
5a–j was achieved using aqueous sodium hydroxide in an
potential of indole3 and
a
-pyrone derivatives.4 On the basis of
these studies it was speculated that combining the structural char-
acteristics of both these moieties could produce substantial
enhancement in the anticancer activity of such compounds. This
prompted us to design molecules wherein the pyrone moiety is
angularly fused to the C2 and C3 carbon of the indole ring (viz.,
pyrano[3,4-b]indol-1(9H)-one, Fig. 1).
On the other hand, cycloisomerization5 and oxidative
O
coupling6 strategies have received considerable attention for the
+
O
synthesis of isocoumarin and a-pyrone scaffolds. Even though the
N
O
N
H
H
O
⇑
Corresponding author.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Figure 1. Structure and retro-synthesis of targeted pyrano[3,4-b]indol-1(9H)-one.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.088

C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4170–4173
4171
I
R1
R1
R1
b)
a)
c)
COOH
COOMe
COOMe
N
H
N
H
N
H
1a: R1 = H
3a: R1 = H
2a: R1 = H
1b: R1 = MeO
3b: R1 = MeO
2b: R1 = MeO
d)
R3
R3
I
R1
R1
R1
d)
e)
COOMe
COOMe
COOH
N
N
N
R2
R2
R2
4a: R1 = H; R2 = Me
5a: R1 = H; R2 = Me; R3 = Ph
5b: R1 = H; R2 = Et; R3 = Ph
5c: R1 = H; R2 = Bu; R3 = Ph
6a: R1 = H; R2 = Me; R3 = Ph
6b: R1 = H; R2 = Et; R3 = Ph
6c: R1 = H; R2 = Bu; R3 = Ph
6d: R1 = OMe; R2 = Me; R3 = Ph
6e: R1 = OMe; R2 = Et; R3 = Ph
6f: R1 = OMe; R2 = Bu; R3 = Ph
6g: R1 = OMe; R2 = Bn; R3 = Ph
6h: R1 = H; R2 = H; R3 = Bu
6i: R1 = H; R2 = H; R3 = Ph
4b: R1 = H; R2 = Et
4c: R1 = H; R2 = Bu
4d: R1 = OMe; R2 = Me
4e: R1 = OMe; R2 = Et
4f: R1 = OMe; R2 = Bu
4g: R1 = OMe; R2 = Bn
5d: R1 = OMe; R2 = Me; R3 = Ph
5e: R1 = OMe; R2 = Et; R3 = Ph
5f: R1 = OMe; R2 = Bu; R3 = Ph
5g: R1 = OMe; R2 = Bn; R3 = Ph
5h: R1 = H; R2 = H; R3 = Bu
5i: R1 = H; R2 = H; R3 = Ph
5j: R1 = OMe; R2 = H; R3 = Ph
6j: R1 = OMe; R2 = H; R3 = Ph
7a: R1 = H; R2 = Me; R3 = Ph
7b: R1 = H; R2 = Et; R3 = Ph
7c: R1 = H; R2 = Bu; R3 = Ph
7d: R1 = OMe; R2 = Me; R3 = Ph
7e: R1 = OMe; R2 = Et; R3 = Ph
7f: R1 = OMe; R2 = Bu; R3 = Ph
7g: R1 = OMe; R2 = Bn; R3 = Ph
7h: R1 = H; R2 = H; R3 = Bu
7i: R1 = H; R2 = H; R3 = Ph
R3
R1
f)
O
O
N
R2
7j: R1 = OMe; R2 = H; R3 = Ph
Scheme 1. Reagents and conditions: (a) H2SO4 (catalytic), MeOH, reflux, 24 h; (b) I2 (1.2 equiv), KOH (3.0 equiv), DMF, rt, 6 h; (c) (for 4a,b, and 4d,e) NaH (2.0 equiv), DMF,
30 min at 0 °C then R2X (3.0 equiv), 0 °C to rt, 6 h (for 4c, 4f and 4g) KOH (3.0 equiv), DMSO, 30 min at 0 °C then R2X (5.0 equiv), 0 °C to rt, 6 h; (d) PdCl2(Ph3P)2 (5 mol %), CuI
(5 mol %), alkyne, (1.1 equiv), Et3N, 6 h, rt; (e) NaOH (1.5 equiv), MeOH/EtOH/H2O (3:1:2), 75 °C, 1 h; (f) AuCl3 (5 mol %), MeCN, reflux.
ethanol–methanol solution to give 3-(ethynyl)-indole-2-carboxylic
acid 6a–j.5c Having synthesized the starting materials in satisfactory
yields, we then focused our attention on the cyclization of substrates
6a–j. The synthetic utility of gold catalysts in the cycloisomerization
of acetylenic acids5c,12 coupled with our research experience in gold
catalyzed organic transformations prompted us to use gold(III) chlo-
ride for the cyclization of substrates 6a–j. The gold-catalyzed cyclo-
isomerization of all substrates was achieved in the presence of
5 mol % of AuCl3 in refluxing acetonitrile, which gave the pyranoin-
dolones 7a–j with good to excellent yields as single regioisomer.
The results were shown in Table 1, which indicates that the
reaction proceeded at a short reaction time in N-alkyl indoles than
unsubstituted indoles. Significant increase in yield of the product
was observed in N-alkyl indoles 7a–g, whereas a slight decrease
in the product yield was observed in N-unsubstituted indoles
7h–j. These observations suggest that the presence of electron
releasing N-alkyl group enhances the electron density of the triple
bond, thus complexing with the Lewis acidic AuCl3 with ease. The
presence of electron releasing substituent (MeOÀ) in the aryl ring
also enhances the reaction as evidenced by the short reaction time
and excellent yield 7d–g.
The structures of all the synthesized compounds were
confirmed by spectral data (FTIR, 1H NMR, 13C NMR and EI-MS)
and elemental analyses. Pyrano[3,4-b]indol-1(9H)-one derivatives
7a–j showed C@O stretching bands in the region of 1666–1714
cmÀ1 in their IR spectrum, indicating the presence of
a
d-lactone ring. In 1H NMR spectrum, a prominent singlet at
dH = 6.62–7.76 ppm ascertained the presence of C4-hydrogen of
the indolone ring. In 13C NMR spectrum the lactone carbonyl and
C4-carbon resonated at dC = 155.2–163.6 and 97.1–98.5 ppm,
respectively. All these findings confirmed the formation of prod-
ucts (see Supplementary data for experimental procedure and
spectral data).
Table 1
AuCl3 catalyzed synthesis of pyrano[3,4-b]indol-1(9H)-ones
Entry
Substrate
Producta
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
7g
7h
7i
20
20
30
05
05
15
15
20
45
40
84
85
83
92
91
88
87
79
75
77
A plausible mechanism for the formation of pyrano[3,4-b]indol-
1(9H)-ones was given in Scheme 2. According to which, the soft
acidic gold(III) chloride activates the soft basic alkyne to form
p-complex 6I. Nucleophilc attack of the tethered carboxyl group
leads to the 6-endo-dig intermediate 6II, which upon subsequent
proto-deauration leads to the product 7. A 5-exo-dig intermediate
6III, although allowed by Baldwin’s rule, was not observed in
the present case because of the greater strain associated with the
5–5 ring formation rather than the 5–5 ring.
10
6j
7j
a
All the Products were characterized by IR, 1H NMR, 13C NMR and MS.
Isolated yield after column chromatography.
b

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C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4170–4173
R3
R3
R1
R1
O
COOH
N
AuCl3
O
6
N
R2
7
R2
Cl3Au
AuCl3
R3
R3
R3
AuCl3
N
H
O
a
R1
H
R1
O
O
..
b
R1
OH
O
b
N
6I
N
6III
R2
O
6II
R2
a
R2
Scheme 2. Tentative mechanism for the formation of pyrano[3,4-b]indol-1(9H)-ones.
The MTT [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl-tetrazo-
lium bromide] cell proliferation assay13 was used to evaluate the
cytotoxic activity of the synthesized compounds against HeLa (hu-
man cervix adenocarcinoma) cell lines. Results of the in vitro anti-
cancer activity were compared with reference drug cisplatin. The
without 6-MeO groups showed a significant loss of potency. A
small substituent like methyl on the nitrogen atom 7d
(IC50 = 0.22
analogues. Replacement of the N-methyl group with an N-ethyl
group 7e (IC50 = 1.20 M) decreased the potency appreciably,
whereas N-butyl group 7f (IC50 = 5.00 M) showed even much re-
lM) exhibited maximum potency compared to other
l
cells were seeded into 96-well plates in 100
l
L of medium contain-
l
ing 5% fetal bovine serum (FBS), at plating density of 10,000 cells/
well and incubated at 37 °C, 5% CO2, 95% air and 100% relative
humidity for 24 h prior to addition of samples. The samples were
solubilized in DMSO and diluted in serum free medium. After
duced inhibitory potency. The loss of activity was observed due
to the increase on group size from methyl to ethyl to butyl for com-
pounds 7d–f. However, similar behaviour was not observed in
molecules devoid of 6-MeO group like 7a–c as evidenced by the
inconsistent IC50 values (1.90, 11.31 and 3.20, respectively).
Although the reason was not clear, it was attributed to the favour-
able structural combination of 6-MeO and N-alkyl groups to exhi-
bit better anticancer activity. Interestingly, the absence of alkyl
24 h, 100 lL of the medium containing the samples at various con-
centrations were added and incubated at 37 °C, 5% CO2, 95% air and
100% relative humidity for 48 h. Triplicate was maintained and the
medium containing without samples were served as control. After
48 h, 15
l
L of MTT (5 mg/mL) in Dulbecco’s phosphate buffered
substituent on the indolic nitrogen 7j (IC50 = 0.33
be the second most active among the tested compounds. In con-
trast, the related compound 7i (IC50 = 19.1 M) emerged as the less
lM) seems to
saline (DPBS) was added to each well and incubated at 37 °C for
4 h. The medium with MTT was then flicked off and the formed for-
l
mazan crystals were solubilized in 100
l
L of DMSO and then the
attractive compound in this series showing poor activity. A moder-
absorbance was measured at 570 nm using micro plate reader.
The percentage growth of inhibition was calculated by comparing
the results of the test with those of the control using the formula: %
inhibition = (AC À AT)/AC Â 100, where AC is the absorbance of con-
trol and AT is the absorbance of test. From the results nonlinear
regression graph was plotted between % cell growth inhibition
ate cytotoxity was observed for compound with 3-butyl group 7h
(IC50 = 2.60 lM).
In summary gold(III) chloride catalyzed synthesis of pyrano
[3,4-b]-indol-1(9H)-ones via cycloisomerization of 3-(ethynyl)-in-
dole-2-carboxylic acid has been achieved. Excellent regioselectivi-
ty, good chemical yields and short reaction time are the significant
advantages of this method. All the synthesized compounds were
screened for their anticancer potential against HeLa cells. This ef-
fort has led to the identification of three compounds (7d, 7e and
7j), which showed good anticancer activity over other compounds.
The anticancer potency of these compounds could be attributed to
the favourable structural combination of the pyranoindolone
framework and their substituents. We also believe that an in depth
QSAR study is necessary to reason out the observed activity. The
mechanism of apoptosis induced by these compounds in HeLa cell
lines is currently under investigation.
and Log10 concentration (lM). The half maximal inhibitory concen-
tration (IC50 value) was determined using GraphPad Prism soft-
ware. Analysis of the screening data (Table 2) revealed that
compounds 7d, 7e and 7j showed comparable anticancer potency
with IC50 values of 0.22, 1.2 and 0.33
to the reference drug, cisplatin (IC50 = 0.08
l
M, respectively, with respect
M). The results indi-
l
cated that the presence of methoxy substituent on the C-6
position was found to be essential for activity, since compounds
Table 2
Anticancer potency of compounds 7a–j in HeLa cell lines
Acknowledgments
Entry
Compound
IC50 (lM)
The author C.P. thank CSIR, New Delhi, India, for the research
fellowship. A.A. thanks Mr. T.H. Babu, Mr. K. Ramachandran and
Mr. A. Nandakumar, the research scholars of Organic Chemistry
Division, Central Leather Research Institute, Chennai for recording
NMR spectrum.
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
1.90
11.31
3.20
0.22
1.20
5.00
6.70
2.60
19.11
0.33
0.08
Supplementary data
7i
7j
10
11
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.05.088.
Cisplatin

C. Praveen et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4170–4173
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