Design, synthesis and cytotoxicity of pyrano[4,3-b]indol-1(5H)-ones: A hybrid pharmacophore approach via gold catalyzed cyclization

Article abstract of DOI:10.1016/j.bmcl.2016.03.087

Reported herein is the gold(III)-catalyzed 6-endo-dig cycloisomerization of 2-alkynyl-indole-3-carboxylic acids to form pyrano[4,3-b]indol-1(5H)-ones, which are pharmaceutically important structural motifs. The hitherto unknown substrates required for thi

Full text of DOI:10.1016/j.bmcl.2016.03.087

Accepted Manuscript
Design, synthesis and cytotoxicity of pyrano[4,3-b]indol-1(5H)-ones: A hybrid
pharmacophore approach via gold catalyzed cyclization
Chandrasekar Praveen, D. Babu Ananth
PII:
S0960-894X(16)30320-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.087
BMCL 23730
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Bioorganic & Medicinal Chemistry Letters
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25 March 2016
Please cite this article as: Praveen, C., Babu Ananth, D., Design, synthesis and cytotoxicity of pyrano[4,3-
b]indol-1(5H)-ones: A hybrid pharmacophore approach via gold catalyzed cyclization, Bioorganic & Medicinal
Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.03.087
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Design, synthesis and cytotoxicity of
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Chandrasekar Praveena,* and D Babu Ananthb

Bioorganic & Medicinal Chemistry Letters
Design, synthesis and cytotoxicity of pyrano[4,3-b]indol-1(5H)-ones: A hybrid
pharmacophore approach via gold catalyzed cyclization
Chandrasekar Praveena,* and D Babu Ananthb
aFunctional Materials Division, CSIR-Central Electrochemical Research Institute (CSIR-CECRI), Karaikudi-630003, Tamil Nadu, India
bPharmaceutical Analysis Department, EGS Pillay College of Pharmacy, Nagapattinam-611002, Tamil Nadu, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Reported herein is the gold(III)-catalyzed 6-endo-dig cycloisomerization of 2-alkynyl-indole-3-
carboxylic acids to form pyrano[4,3-b]indol-1(5H)-ones, which are pharmaceutically important
structural motifs. The hitherto unknown substrates required for this methodology were
conveniently synthesized in five steps with good overall yields. The utility of this new
cycloisomerization is demonstrated by the excellent regioselectivity obtained using a range of
substrates. The mildness of the method allowed functional group compatibility towards hydroxyl
tether, displaying exquisite chemoselectivity. All the synthesized compounds were screened for
their tumor cell growth inhibitory activity against human cervix adenocarcinoma (HeLa).
Compound 7d emerged as the most active (IC50 = 0.69 μM) among the tested series compared to
the standard cis-platin (IC50 = 0.08 μM).
Keywords:
Pyranoindolones
Cycloisomerization
Gold catalysis
Cytotoxicity
2009 Elsevier Ltd. All rights reserved.
Molecular docking
Isocoumarin and pyranone cores are structural motifs that are
featured in a large family of natural products1 and pharmaceutical
agents.2 Among several synthetic avenues, cyclization of
acetylenic acids are one of the modern approaches for the
synthesis of isocoumarins.3,4 This cyclization as allowed by
Baldwin’s rule often leads to two regioisomeric products;
isocoumarins and γ-alkylidenebutenolides via 6-endo-dig and 5-
exo-dig attack respectively (Scheme 1, eq 1). A plethora of Lewis
and Brønsted acid catalysts have been developed for the
cyclization of acetylenic acids, the results in most cases offer no
regioselectivity and lead to the formation of both γ- and δ-
lactones.3a-3t On the other hand, there are only very few reports
appeared for the selective synthesis of either δ-lactone3n-3x or γ-
lactone.4 Therefore, the regioselective synthesis of one among the
two heterocycles appeared attractive from a synthetic chemist
perspective. As part of our5 ongoing interest in homogeneous
gold catalysis6a for the construction of novel heterocycles,6b we
indoles.10b However, the substrate scope in these protocols was
limited. To this end, a gold catalytic protocol that accomplishes
the cycloisomerization of 2-alkynyl-indole-3-carboxylic acids
remains to be developed. In this context, a new synthesis of
pyrano[4,3-b]indolones, was realized through AuCl3 catalyzed
cycloisomerization of 2-alkynyl- indole-3-carboxylic acids
(Scheme 1, eq. 3) and their cytotoxic results against HeLa cells
are disclosed in this letter.
7
have previously reported the AuCl3 catalyzed 6-endo-dig
cycloisomerization of 3-alkynyl-indole-2-carboxylic acids
leading to biologically active pyrano[3,4-b]indol-1(9H)-ones
(Scheme 1, eq 2).5h As a logical speculation, we envisaged the
synthesis of corresponding positional isomer, pyrano[4,3-b]indol-
1(5H)-ones by utilising 2-alkynyl-indole-3-carboxylic acids. The
synthesis of these compounds has scarcely been investigated.
Some rare examples include [(Cp*RhCl2)2]/Cu(OAc)2 catalyzed
oxidative coupling of indole-3-carboxylic acid with internal
alkynes,8a Pd(II)-catalyzed oxidative coupling of indole-3-
carboxylic acids with styrenes,.8b, 9 CuI catalyzed tandem cross-
coupling/cyclization of iodo-heteroarenes with terminal
acetylenes10a and organocatalyzed CO2 trapping of alkynyl
Scheme 1. Baldwin’s cycloisomerization of acetylenic acids (eq 1) and AuCl3
catalyzed synthesis of isomeric pyranoindolinones (eq 2 and 3)
Our working hypothesis deals with the preparation of indole
tethered alkyne substrates, which are capable of efficiently
undergoing 6-endo-dig cyclization without the formation of 5-

exo-dig species that would preclude any regiochemical control in
the course of the reaction.11 The required precursors were
prepared by established procedures (Scheme 2).5h, 12
catalytic efficiency of the overall process. In agreement to our
previous results,5h the cycloisomerization follows 6-endo-dig
regiochemistry13a leading to δ-lactone and no γ-lactone was
observed as evidenced by crude NMR analysis. This observation
was in sharp disagreement with other gold catalysis protocol,
where γ-lactone was formed exclusively.4c-4f This can be ascribed
to the energetic inaccessibility or greater strain of 5-5 ring
formation over 5-6 ring formation. The formation of δ-lactone
ring in all compounds was ascertained by stretching band
1
between 1695 and 1721 cm-1 in their IR spectrum. In H NMR
spectrum a singlet between δH 5.86 and 6.81 ppm were observed,
characteristic of the C4-hydrogen of 7a-j. Moreover all
compounds exhibited two characteristic peaks in their 13C NMR
spectrum at δC = 97.9-100.1 and 163.5-168.5 ppm, confirming
the presence of C4-carbon and lactone carbonyl carbon of 7a-j
respectively.
Scheme 2 (a) POBr3 (2.5 equiv.), DMF (10 equiv.), (CH2)2Cl2, 0 oC to rt, 24 h
(b) Oxone® (1.05 equiv.), MeOH, rt 3 h (c) (for 4a and 4b) NaH (2.0 equiv),
DMF, 30 min at 0 oC then R2X (3.0 equiv), 0 oC to rt, 6 h (for, 4c and 4d)
o
KOH (3.0 equiv), DMSO, 30 min at 0 C then R2X (5.0 equiv), 0 oC to rt, 6 h
(d) Pd(Ph3P)4 (5 mol%), CuI (5 mol%), terminal alkyne, (1.1 equiv), Et3N, 6
h, rt (e) NaOH (1.5 equiv), MeOH / EtOH / H2O (3:1:2), 75 oC, 1 h (f) AuCl3
(5 mol%), MeCN, reflux
Vilsmeier bromoformylation of oxindole 1a affords 2-bromo-
indole-3-carbaldehyde 2a in excellent yield.12a Oxidative
esterification of 2a with oxone in methanol gave the ester 3a.12b
N-alkylation of 3a was performed with appropriate alkyl halide
Scheme 3 Synthesis and Cyclization of N-unprotected indolyl alkyne 6k
In an effort to showcase the tolerance of our chemistry towards
challenging N-unprotected indoles, we next investigated the
cyclization of substrate 6k devoid of any substitution at the
indole nitrogen atom (Scheme 3). The synthesis of 6k was
executed essentially according to the strategy used for the
synthesis of 6a-j. Gratifyingly, a smooth cyclization of 6k to
product 7k was observed with an excellent yield, suggesting that
a free -NH group was indeed tolerated under our reaction
conditions. We consider AuCl3 only to be a precatalyst and we do
not know whether the catalytically active species is Au(III) or
Au(I), but it should be an electrophilic gold species. We
occasionally observed the precipitation of gold in the form of
gold mirror but this always occurred after the reaction was
complete. The possibility of participation of Au(I) as catalytic
species, (via redox chemistry) was ruled out by performing a
reaction with 6k using 5 mol% of AuCl in acetonitrile under
reflux, which led to the formation of only 20% of the product 7k.
We reasoned out that AuCl could not be electrophilic enough to
allow for cycloisomerization, thus demonstrating that the
catalytic activity of AuCl3 is superior to that of AuCl in this
reaction. It is pertinent to note that, our approach is devoid of any
Ag-additive; the Reader will be reminded that these air-, light-
and moisture-sensitive Ag salts of type AgX (X = BF4, SbF6, PF6,
NTf2) are usually employed to generate the cationic Au(I) species
from LAuCl (L = phosphine or NHC).14a
and base which results in the formation of N-alkyl derivatives 4a-
12d
d.12c,
By subjecting 4a-d and terminal acetylenes under
standard Sonogashira cross-coupling reaction yields the
acetylenic derivatives 5a-j,12e which upon alkaline hydrolysis3a of
5a-j affords the requisite 2-(ethynyl)-indole-3-carboxylic acid
6a-j. Guidelines for searching of a suitable catalyst for the
cyclization of substrates 6a-j came from our previous studies,5h
where it was shown that AuCl3 was effective in this sort of
transformation. Towards this end, we subjected the acetylenic
synthons 6a-j with 5 mol% of AuCl3 in acetonitrile under
refluxing condition. Under this condition, all substrates
underwent
cyclization
and
afforded
the
expected
pyranoindolones 7i-7j in moderate to good yields (Table 1).
Table 1 AuCl3 catalyzed cyclization of 6a to 7a
Entry
Substrate
6a
6b
6c
6d
6e
6f
6g
6h
6i
Producta
7a
7b
7c
7d
7e
7f
7g
7h
7i
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
50
60
90
40
90
90
90
90
90
90
80
78
75
81
74
73
67
65
59
62
We were also intrigued by the prospect of applying this
methodology to substrate possessing
a
labile electron
withdrawing group at the nitrogen atom (Scheme 4). The
precursor required for this study was prepared starting from the
Sonogashira coupling of 2a to give 2b. Subsequent mesylation,
where tBuOK was used as base, delivered the mesyl aldehyde 2c
in 74% yield. A clean oxidation of the aldehyde 2c was
conducted with oxone to afford the acid precursor 6l. Subjecting
6l under our standard condition led to a sluggish reaction and
affords only 21% yield of the product 7l. This diminution in yield
could be attributed to the electron withdrawing nature of mesyl
group which decreases electron density of the triple bond, thus
lowering the coordination ability of the acetylenic moiety
towards Au(III). Results from Scheme 1 to 3 suggested that
6j
7j
a All the Products were characterized by IR, 1H NMR, 13C NMR and MS
b Isolated yield after column chromatography
It is noteworthy to mention that precursors, 6a-j led to reasonable
conversion with only an increase of the reaction time and this can
be attributed to the reduced electrophilicity of carboxylic acid in
C3-indole. The low yield observed in compounds 6i and 6j can
be rationalized by the decrease in Lewis acidity of the catalyst by
coordinating with the hydroxyl function and eventually the

either free NH or NR (where, R is any electron releasing group)
of indole is necessary to realize effective cyclization, whereas a
deactivating group at the nitrogen reduces the efficiency of the
cyclization.
showed an IC50 value of 0.08 μM.17 The tested compounds
exhibited maximum cytotoxicity against HeLa cells at a
concentration of 0.69 to 2.25 μM (Table 2).18 From the analysis
of the observed data, it was found that compound 7d possessing
C3-phenyl and N-benzyl substituent showed highest activity
(IC50 = 0.69 μM). Compound 7c which contains butyl chain at C3
and indolic nitrogen emerged as the second most active in the
series (IC50 = 1.11 μM). However, replacement of N-butyl by a
small group like methyl (7a) marginally reduced the inhibitory
potency to 1.24 μM. By increasing the chain length to ethyl at the
nitrogen atom (7b), a slight decrease in activity was observed
(IC50 = 1.41 μM). Switching from phenyl to aliphatic chains such
as butyl and pentyl as a C3-substituent (7e-h) exhibited only
moderate potency with the IC50 values ranging between 1.63 and
1.92 μM. Compounds possessing tertiary and primary hydroxyl
(7i and 7j) emerged as the least active among the tested series
(IC50 = 2.02 and 2.25 μM respectively) suggesting the intolerance
of polar substituent at the C3-site. Likewise, compound 7k,
possessing no substitution at indolic nitrogen exhibited poor
cytotoxicity among the screened series. These qualitative
assessments revealed that the presence of C3-phenyl substituent
(as in 7a-d) is essential for exhibiting good inhibitory potency.
Scheme 4 Synthesis and cyclization of N-protected indolyl alkyne 6l
Up to this point, we merely uncovered the scope of substrates
possessing internal alkynes. To gain insight into the influence of
the electronic nature of alkyne, a control experiment with
substrate possessing terminal alkyne was envisaged. For this
study, the requisite alkyne 6m was prepared through K2CO3
promoted tandem desilylation/hydrolysis of silyl ester 5l
(Scheme 5). By subjecting 6m under our reaction conditions, no
ring-closing event to product 7m was observed and almost 80%
of the starting material 6m was recovered. Such evidence can be
ascribed to the reduced electrophilicity of the terminal sp-carbon
of the alkyne. Therefore, the only possibility for the carboxyl
function is to attack the remote sp-carbon of the Au-complexed
alkyne, but this scenario would lead to 5-5 ring fusion, which in
the present case is energetically unfavorable. It is also worth
noting that this substrate did not afforded the lactone dimer
neither through Glaser-type homocoupling, as it was the case
observed with several terminal alkynes under Au(III)-catalysis3d
or through oxidative coupling of the vinylgold-intermediates.14b
Table 2 Cytotoxicity of compounds 7a-7j against HeLa cells
Entry
1
Compound
IC50 (μM)
1.24
7a
2
3
4
5
6
7
8
9
7b
7c
7d
7e
7f
7g
7h
7i
1.41
1.11
0.69
1.92
1.89
1.75
1.63
2.02
2.25
2.55
0.08
10
11
12
7j
7k
cis-platin
Scheme 5 Reaction with terminal alkyne 6m
A reaction mechanism for the formation of 7 was proposed
(Scheme 6).14c According to which, π-electrophilic AuCl3
activates the C-C triple bond of 6 leading to the π-complex 6I. As
per Baldwin’s rule, the later could undergo either 6-endo-dig (via
path a) or 5-exo-dig (via path b) cyclization to form complexes 6I
and 6III respectively. On the grounds of energetic inaccessibility
of 5-5 ring formation, the regiochemistry would be directed
towards 6-endo-dig (against 5-exo-dig) to form the cyclized
intermediate 6II. Protodeauration, where the labile C-Au bond of
intermediate 6II14d,14e was replaced by C-H bond results in the
formation of product 7 along with the regeneration of AuCl3.
In pharmaceutical drug design, the discovery of small
molecules that predominantly undergo non-covalent interactions
such as hydrogen bonding, van der Waals, π-π and π-cationic
interactions in protein-ligand binding is an important concept.19
This in silico approach involves the docking of synthesized
compounds into the active site of the 3D structure of the target,
followed by the calculation of free energy of binding (FEB) of
the protein-ligand complex. The binding mode of the potent
inhibitors was investigated using AutoDock Tools (ADT) version
1.5.6 and AutoDock version 4.2.5.1 docking program to
rationalize the pharmacological results.20 To gain insights of the
observed activity, we docked all the compounds to Vaccinia H1-
Related (VHR) Phosphatase receptor (PDB ID: 3F81) crystal
structures available in the Protein Data Bank. A link between
VHR and cervical cancer was well established. Compared to
normal keratinocytes, VHR protein levels are found to be up
regulated in several cervix cancer cell lines including human
papillomavirus (CaSki, HeLa, SiHa, HT3 and C33). Biopsies of
the primary cervix cancer, squamous intraepithelial lesions and
squamous cell carcinomas of the uterine cervix revealed the
higher expression levels of VHR protein level. This clearly
suggests that in the treatment of cervical cancer, VHR might be a
promising drug target and VHR inhibiting small-molecules could
be a potential drug to cure the cervical cancer.21 To start with, the
reproducibility of docking calculations was verified by extracting
the co-crystallized ligand from the complexes and submitted for
one-ligand run calculation. This reproduced top scoring
Scheme 6 Plausible mechanism for the AuCl3 catalyzed formation of 7
In pursuance of our on-going project on bio-active
5h, 15
heterocycles,3o,
an attempt has been made to evaluate the
cytotoxicity of compounds
(7a-7k) against human
adenocarcinoma cell lines (HeLa) by MTT assay.16 The cytotoxic
results were compared with reference drug cis-platin, which

conformation falling within root-mean-square deviation (RMSD)
value of 1.04 Å with bound X-ray conformation for 3F81,
suggesting this method is valid enough to be used for docking
studies of other compounds (Figure 1). Docking simulation of all
the synthesized compounds was performed in the same active site
using the same protocol used for the validation study (Figure 2).
For each of the test molecules, dockings were performed by taken
into 2.5 million energy evaluations. The conformations of docked
ligand with VHR receptor were analyzed in terms of energy,
hydrogen bonding, hydrophobic and π-π interaction. The final
coordinates of the ligand and receptor were saved after the clear
analysis of ligand-receptor interactions. To investigate the
interactions of ligand and receptor simulated conformations
output was exported to PyMOL software. The free energy of
binding (FEB) of all compounds were calculated from the
docking scores (Table 3).
The results revealed that all the docked compounds bind with the
receptor and exhibits free energy of binding value between -5.00
and -7.27 kcal/mol. All the compounds binds in the active site
and the simulated conformation exhibits various interactions with
16 amino acids namely LEU-25, PRO-26, PHE-68, MET-69,
ASP-92, CYS-124, ARG-125, GLU-126, GLY-127, TYR-128,
SER-129, ARG-130, ARG-158, GLY-161, PRO-162 and ASN-
163 with non-covalent interactions such as hydrophobic,
hydrophilic, π-π interaction and hydrogen bonding. Among all
compounds docked, 7d exhibits high binding with 3F81 receptor
and forms hydrogen bonding with GLY-161 amino acid which
resulted in binding energy of -7.27 kcal/mol (Figure 3). The
benzyl moiety exhibits hydrophobic interaction with GLY-126,
in addition to the CH-π interaction with the phenyl ring of TYR-
128. It is to be noted that compound 7d with highest binding
energy (-7.27 kcal/mol) did exhibited significant IC50 value (0.69
μM), thus establishing a correlation with the biological results.
Table 3 FEB values of compounds on VHR phosphatase
receptor
In summary, syntheses of pyrano[4,3-b]indol-1(5H)-ones through
gold(III)-catalyzed 6-endo-dig cycloisomerization of 2-alkynyl-
indole-3-carboxylic acids have been developed. The current
method has promising advantage toward practical uses because
of the high regioselectivity, short reaction time, high atom-
economy, modest chemical yield and functional group
compatibility. In view of a large number of bioactivities
involving fused-indole scaffolds, we screened the synthesized
compounds for cytotoxicity against HeLa cells. The results of
which indicated that compound 7d emerged as the most active
with an IC50 of 0.69 μM (FEB = -7.27 kcal.mol). We expect that
these potential special structures will have wide applicability in
medicinal chemistry. Further studies to extend the scope of this
procedure to other heterocycles and DFT computational studies
are underway in our laboratory and will be reported shortly.
Entry
Compound
FEB (kcal/mol)a
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
-5.89
-5.86
-6.10
-7.27
-5.17
-5.00
-6.31
-6.47
-6.77
-6.51
-5.89
9
10
11
7j
7k
aFree energy of binding (PDB ID: 3F81)
Figure 1 Validation using crystallized and docked ligand with 3P9J receptor

Figure 2 Docking mode of all the compounds in the active site of 3P9J receptor
Figure 3 Docking mode of the most active compounds 7d in the active site of 3P9J
Phytopathol. Mediterr. 2003, 42, 191; (d) Yoshikawa, M.; Matsuda,
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The work has been financially supported by a fast track grant for
young scientists (Grant no: SERB/F/5666/2015-16) from Science
and Engineering Research Board (SERB), India. C. P. is grateful
to Dr. Vijayamohanan K. Pillai, Director, CSIR-CECRI for
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Supplementary data
Experimental procedure for the synthesis of starting materials,
cytotoxicity evaluation, molecular docking, H NMR, 13C NMR
1
and mass spectra were provided in the supplementary material.
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