SnO2 nanoparticles mediated nontraditional synthesis of biologically active 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c]-acridine derivatives

Article abstract of DOI:10.1007/s00044-010-9381-7

An efficient, practical, and eco-friendly method of preparation of 9-chloro-6,13-dihydro-7-phenyl-5H-indolo[ 3,2-c]-acridines (3a-c) is reported by Friedlander condensation of 2-amino-5-chlorobenzophenone 1 and active methylene compound 3,4-dihydro-2H-car

Full text of DOI:10.1007/s00044-010-9381-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:732–737
DOI 10.1007/s00044-010-9381-7
ORIGINAL RESEARCH
SnO2 nanoparticles mediated nontraditional synthesis
of biologically active 9-chloro-6,13-dihydro-7-phenyl-5H-indolo
[3,2-c]-acridine derivatives
•
Selvaraj Mohana Roopan
Fazlur Rahman Nawaz Khan
Received: 18 December 2009 / Accepted: 15 June 2010 / Published online: 30 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract An efficient, practical, and eco-friendly method
of preparation of 9-chloro-6,13-dihydro-7-phenyl-5H-indo-
lo[3,2-c]-acridines (3a–c) is reported by Friedlander con-
densation of 2-amino-5-chlorobenzophenone 1 and active
methylene compound 3,4-dihydro-2H-carbazol-1(9H)-ones
(2a–c) in the presence of SnO2 nanoparticles under micro-
wave irradiation. Indoloacridines, 3a–c, were screened for
their in vitro hemolytic activity, on human erythrocytes and
cytotoxicity, on HeLa and Vero cells.
(Roopan et al., 2009; Chaudhuri and Hussain, 2006). In
addition, quinolines are valuable synthons for the prepa-
ration of nano–meso structures and polymers that combine
enhanced electronic, optoelectronic, or non-linear optical
properties with different mechanical properties (Agarwal
and Jenekhe, 1991; Zhang et al., 1999, 2000). A number of
catalysts have been developed for the synthesis of quino-
lines such as AuCl3Á3H2O, FeCl3, ZnCl2, SnCl2, and ZnCl2/
triethylamine has been used for Friedlander reaction (De
and Gibbs, 2005; Hu et al., 2003).
Keywords Friedlander reaction Á SnO2 nanoparticles Á
Erythrocytes Á HeLa Á Vero cells
Solvent-free microwave-assisted chemical reactions are
gaining importance due to the advantages and environ-
mentally friendly processes they offer, as compared to
conventional reactions (Roopan et al., 2008). In recent
years organic reactions in the solid state have been
attracting the synthetic organic chemists because of their
simplicity and synthetic value (Roopan et al., 2009). Fur-
thermore, the solid state reaction has many advantages
including, reduced pollution, low costs and simplicity in
process and handling. The applications of SnO2 nanopar-
ticles in the organic transformations as explored in the
present report. To the best of our knowledge, there is no
report on the use of SnO2 in Friedlander condensation
reaction.
Introduction
Nitrogen heterocyclics are common in animal and plant
cells (Morton, 1965) and play a prominent role in biolog-
ical functions such as bioenergetic transport agents (Gupta
et al., 1979). The pharmacological, biochemical properties,
and therapeutic applications of N-heterocyclics depend on
substituents in basic structure, i.e., alterations in the
chemical structure of N-heterocyclic compounds could
influence their biological properties such as anticancer
property (Fig. 1). Among the various synthetic methods in
quinoline synthesis, Friedlander condensation was extre-
mely useful (Zolfigol et al., 2008). The solvent-free
microwave-assisted quinoline syntheses are reported
Recently, major health problems faced by mankind are
cancer diseases. Limited numbers of anticancer drugs for
the treatment of cancer are available in the market. It can
be concluded that there is urgent need to search new
anticancer agents (Da et al., 1994). Acridine derivatives are
one of the more studied chemotherapeutic compounds,
widely used as antimalarial, antiprotozoal (Gamage et al.,
1997), antibacterial (Mauel et al., 1993), and antitumor
agents (Sugaya et al., 1994). Many modifications have
been made to the acridine skeleton in the search for anti-
cancer compounds.
S. M. Roopan Á F. R. N. Khan (&)
Organic & Medicinal Chemistry Research Laboratory,
Organic Chemistry Division, School of Advanced Sciences,
VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
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Med Chem Res (2011) 20:732–737
733
Fig. 1 Quinoline fused
biologically important
compounds
N
N
N
O
O
HO
N
O
O
O
N
N
N
N
O
N
O
O
HO
Camptothecin
O
HO
Topotecan
O
OH O
Irinotecan
In continuation of our interest in synthesis of biologi-
cally active heterocyclics (Roopan et al., 2008; Manivel
et al., 2008), a number of 9-chloro-6,13-dihydro-7-phenyl-
5H-indolo [3,2-c] acridine analogues has been synthesized
and examined for their bioactivities. In the present inves-
tigation, the hemolytic and cytotoxicity potential of
9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c] alcidine
analogues against human erythrocytes, HeLa and Vero
cells were explored.
microwave irradiated for 2–4 min at 500 W. The repro-
ducibility of the whole experiment in the microwave con-
dition was ensured by carrying out every reaction three
times on reproducible positions marked in the microwave
oven. The progress of the reaction was monitored by thin-
layer chromatography (TLC). The reaction mixture was
diluted with chloroform and then centrifuged to remove the
nanoparticles. Evaporation of the organic solvent gives the
titled compound (3) (Scheme 2).
Under solid-phase grinding conditions
Materials and methods
The title compounds (3) were also synthesized using grind
stone methodology. A mixture of 2-amino-5-chlor-
Structural investigation
obenzophenone (1 mmol) (1), 3,4-dihydro-2H-carbazol-
1(9H)-one (1 mmol) (2a–c), tin oxide nanoparticles
(5 mol%), and drop of Conc. H2SO4 was ground by a mortar
and pestle at room temperature for 15 min and was kept aside
overnight. The completion of the reaction was monitored by
TLC. The reaction mixture was work up as before.
The 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c]
alcidines were denoted by specific codes for identity (3a, 3b,
and 3c). SnO2 nanoparticles were prepared by the reported
method (Jie et al., 2006). Synthesized tin oxide nanoparticles
size of 25 0.5 nm was confirmed by HRSEM image. TLC
was performed using silica gel-TLC, mobile phase: ethyl
acetate: Pet. ether (1:9). Domestic microwave SANYO EM-
G3586W was used for the synthesis. Melting points were
measured in open capillary tubes and are corrected with
reference to benzoic acid. IR spectra in KBr pellets were
recorded on Nucon Infrared spectrophotometer. Nuclear
Magnetic Resonance (1H) spectra were recorded on a
300 MHz spectrometer. Chemical shifts are reported in parts
per million (d) downfield from an internal tetramethylsilane
reference. High Resolution Scanning Electron Microscope
(HRSEM) spectra were recorded on FEI Quanta FEG 200.
Spectral data of synthesized compounds as follows
9-Chloro-6,13-dihydro-1-methyl-7-phenyl-5H-indolo
[3,2-c]acridine (3a)
Yield, 82.5% as orange needles; m.p., 282°C; FTIR tmax
(cm-1, KBr): 3453 (NH); 1H NMR (300 MHz; DMSO-d6):
11.51 (s, 1H, –NH indole ring), 8.08–8.11 (d, J = 9.2 Hz,
1H, ArH), 7.60–7.54 (m, 4H, ArH), 7.37–7.45 (m, 3H),
7.16 (s, 1H), 6.94–7.01 (m, 2H), 2.92(s, 3H, –CH3), 2.46–
2.58 (m, 4H, 2X–CH2); LCMS (m/z): calc. mass = 394,
actual mass = 395.0 (M ? 1), 396.0 (M ? 2).
General procedure for the synthesis of 9-chloro-6,13-
dihydro-7-phenyl-5H-indolo [3,2-c] acridine (3a–c)
9-Chloro-6,13-dihydro-2-methyl-7-phenyl-5H-indolo
[3,2-c]acridine (3b)
Under solid-phase MWI conditions
A mixture of 2-amino-5-chlorobenzophenone (1 mmol)
(1), 3,4-dihydro-2H-carbazol-1(9H)-one (1 mmol) (2), tin
oxide nanoparticles (5 mol%), and drop of Conc. H2SO4
was ground in a beaker until a homogeneous powder was
formed. The reaction flask was held inside an alumina bath,
Yield, 81.0% as orange needles; m.p., 250°C; FTIR tmax
(cm-1, KBr): 3433 (NH); 1H NMR (300 MHz; DMSO-d6):
11.55 (s, 1H, –NH indole ring), 8.00–8.03 (d, J = 8.8 Hz,
1H, ArH), 7.54–7.70 (m, 4H, ArH), 7.39–7.44 (m, 2H,
ArH), 7.27–7.31 (m, 1H), 7.14–7.28 (m, 1H), 6.72–7.07
123

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Med Chem Res (2011) 20:732–737
(m, 2H), 3.17–3.21 (t, 2H, –CH2), 2.90 (s, 3H, –CH3),
2.40–2.57 (t, 2H, –CH2); LCMS (m/z): calc. mass = 394,
actual mass = 395.0 (M ? 1).
of mouse and human erythrocytes in 0.85% saline con-
taining 10 mM CaCl2. After 30 min incubation at room
temperature, centrifuged, and the supernatant was used to
measure the absorbance of the liberated hemoglobin at
540 nm. The average value was calculated from triplicate
assay.
9-Chloro-6,13-dihydro-3-methyl-7-phenyl-5H-indolo[3,2-
c]acridine (3c)
Yield, 84.4% as orange needles; m.p., 231°C; FTIR tmax
(cm-1, KBr): 3421 (NH); 1H NMR (300 MHz; DMSO-d6):
11.58 (s, 1H, –NH indole ring), 8.00–8.03 (d, J = 8.9 Hz,
1H, ArH), 7.56–7.69 (m, 4H, ArH), 7.32–7.41 (m, 4H,
ArH), 7.15 (s, 1H), 7.01–7.03 (d, J = 8.6 Hz, 1H), 2.91 (s,
3H, –CH3), 1.89–2.49 (m, 2H, 2X–CH2); LCMS (m/z):
calc. mass = 394, actual mass = 395.0 (M ? 1).
Cell culture
HeLa and Vero cell lines were obtained from ATCC and
maintained in DMEM and RPMI 1640 (Himedia, Mumbai,
India) medium supplemented with 10% FBS (v/v) and
100 mg/l streptomycin and 100 IU/ml penicillin (Himedia,
India) at 37°C in a CO2 incubator with 5% CO2.
Biological activity
The 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c]
acridines such as 3a, 3b, and 3c (1 mg) were dissolved in
1 ml of DMSO solution. The appropriate concentrations of
the compounds were made by serial dilution in culture
medium.
MTT cell proliferation assay
The cytotoxic activity of the compounds (diluted in DMSO 0
to 100 lg/ml) on HeLa and Vero cells (1 9 105 cells/well)
were tested by using the CellQuanti-MTT cell viability
assay kit (Bioassay Systems). The wells with only culture
medium or cells treated with 0.1% of DMSO served as
control. The graph was plotted with cell viability against
the time period in hours at increasing concentrations of
secondary metabolite. The mean and the IC50 value was
calculated by non-linear regression analysis using the
data analysis software (Prism) from three independent
experiments.
In vitro hemolytic assay
Hemolytic effect of the compounds on human erythrocytes
was evaluated by using washed erythrocytes (RBCs).
For the preparation of mouse and human erythrocytes
(Suthindhiran and Kannabiran, 2009; Roopan et al., 2009)
Blood samples from the rats were collected from Charles
foster strain (each weighing 130–180 g) in citrated tubes.
The cells were then washed three times with 20 mM Tris–
HCl containing 144 mM NaCl (pH 7.4) and 2% erythro-
cyte suspension was prepared. Human erythrocytes were
obtained from the peripheral blood (O?) of healthy vol-
unteer. The blood was used within 24 h after bleeding and
washed three times in 9 volumes of sterile 0.9% NaCl
saline solution. After each washing, cells were centrifuged
1509g for 5 min and the supernatant was discarded. The
final pellet was diluted 1:9 (v/v) in sterile 0.9% NaCl saline
solution then 1:24 (v/v) in sterile Dulbecco’s phosphate
buffer saline (D-PBS), pH 7.0 containing 0.5 mM boric
acid and 1 mM calcium chloride.
Trypan blue dye exclusion assay
Cell viability assay was done by Trypan blue dye exclusion
assay. The cells were incubated with or without compound.
After 24 h of incubation cells were trypsinised, centrifuged
for 5 min at 1009g, and the pellet was resuspended in 1 ml
PBS. Trypan blue (0.4%) 10 ll was added with 10 ll of cell
suspension and incubated for 3–5 min. Trypan blue/cell
mixture (10 ll) was placed in a haemocytometer and a total
of 100 cells were counted and the number of viable and non-
viable cells was recorded. The assay was done in triplicates.
The hemolytic activities of the compounds were tested
by the method of Malagoli under in vitro conditions in 96-
well plates. Each well received 100 ll of 0.85% NaCl
solution containing 10 mM CaCl2. The first well served as
negative control contained only water, and from the second
well 100 ll of compound of various concentrations
(5–500 lg/ml) were added. The last well served as positive
control containing 20 ll of 0.1% Triton X-100 in 0.85%
saline. Then, each well received 100 ll of a 2% suspension
Results and discussion
Chemistry
Retro synthetic analysis
A retro synthetic analysis (Scheme 1) approach has been
employed in designing a multistep synthesis of the target
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Med Chem Res (2011) 20:732–737
735
Scheme 1 Retrosynthetic
pathway to synthesis 9-chloro-
6,13-dihydro-7-phenyl-5H-
indolo [3,2-c] acridine (3)
+
Path I
Cl
O
+
N
H
O
NH2
O
NH2
5
4
2
1
Cl
N
HN
Path II
Cl
Cl
3
NH
NH2
O
+
+
N
O
NH2
O
O
9
6
7
8
molecule such as 9-chloro-6,13-dihydro-7-phenyl-5H-indolo
[3,2-c] acridine (3). Two pathways can be utilized for the
construction of target molecule. However, based on the
availability and cost of the materials we proposed path I for
the target compound (3). The quinoline ring ‘AB’ can be
formed through Friedlander reaction of ring ‘C’ of the
carbazole ‘CDE’ (2). Similarly the carbazole ring ‘CDE’
(2) can be obtained from aniline (4) and cyclohexanone (5)
by reported method (Roopan et al., 2008) (Scheme 1).
carbazol-1(9H)-one (2a–c) was also attempted under
grinding conditions using SnO2 nanoparticles as solid sup-
port (Table 1). To our delight, the product was formed in
comparable yields ([80%). The desired product in signifi-
cant purity was obtained by simple aqueous work-up.
These conditions were applied for the preparation of a
series of substituted 9-chloro-6,13-dihydro-7-phenyl-5H-
indolo[3,2-c]-acridine (3a–c). To optimize the reaction
conditions, reaction was carried out in the presence and
absence of nanoparticles, H2SO4 for the synthesis of titled
compounds 3a (Table 2). The results suggested that, mix-
ture of nanoparticles and H2SO4 provided the products 3a
(Table 2, Entry 4), whereas in the absence of nanoparticles
the reaction was not proceeded (Table 2, Entry 1, 3). Same
reaction when carried in the presence of nanoparticles and
absence of H2SO4 (Table 2, Entry 2) was not futile. Further
an optimized amount of 5 mol% tin oxide nanoparticles
were required for the reaction.
Synthesis of 9-chloro-6,13-dihydro-7-phenyl-5H-indolo
[3,2-c] acridine compounds (3a–c)
A green chemical method for the synthesis of biologically
active indoloacridine is reported. In the present study, syn-
thesis of 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c]
acridine using tin oxide nanoparticles under mild condition
has been reported and compared the results to the reported
literature (Sridharan et al., 2009) Initially, efforts were
focused on optimizing the microwave conditions for the
formation of substituted 9-chloro-6,13-dihydro-7-phenyl-
5H-indolo [3,2-c] acridine analogues (3a–c) by condensing
2-amino-5-chlorobenzophenone (1) and 3, 4-dihydro-2H-
carbazol-1(9H)-one (2a–c) in the presence of SnO2 nano-
particles as catalyst (Scheme 2). The title compounds (3a–c)
were formed in good yield ([80%) in less time (5 min)
(Table 1). The preparation of 9-chloro-6,13-dihydro-7-
phenyl-5H-indolo [3,2-c] acridine analogues (3a–c) on solid
support has not been reported so far. Then, the condensation
of 2-amino-5-chlorobenzophenone (1) with 3,4-dihydro-2H-
The diverse hemolytic and cytotoxic activity profile of
the synthesized title compounds has also been obtained
with a view to seek the structural requirements for potential
drug candidates with a high therapeutic index.
In vitro hemolytic assay
As described earlier quinoline ring appears to be essential
for both cytotoxic and hemolytic activities, suggesting that
the mechanism of action is connected with the redox
Scheme 2 Synthesis of 9-
chloro-6,13-dihydro-7-phenyl-
5H-indolo [3,2-c] acridine
compounds (3a–c)
Cl
Cl
SnO2 nanoparticles
+
O
H2SO4
N
NH2
O
MW 500W
HN
HN
R
R
3a-c
1
2a-c
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Med Chem Res (2011) 20:732–737
Table 1 Synthesis of 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c] acridine (3a–c) under solvent free, SnO2 nanoparticles as catalyst
Sl.no. Reactants Reaction carried out in the presence of SnO2 nanoparticles
Time taken (min)
MW
Product, 3a–c
Yielda %
MW
Grinding
30 min
Grinding
85
1
1, 2a
3 min
4 min
4 min
82.5
Cl
N
HN
3a
2
3
1, 2b
30 min
47
81
Cl
N
HN
3b
1, 2c
30 min
64
84.4
Cl
N
HN
3c
1 (1 mmol), 2 (1 mmol), tin oxide nanoparticles (5 mol%), drop of Con.H2SO4, at RT for the specified period of time
a
Isolated yields
peroxidation chain reactions, neutralizing active forms of
oxygen and thus protecting cell membranes from the
damaging actions of free radicals (Muller et al., 1987).
The total hemolysis was obtained with 20 ll of Triton
X-100 (0.1%) and 1 h incubation. The EC50, IC50, and 95%
confidence interval (CI 95%) was obtained by non-linear
regression analyses. EC50 value lower than 250 lg/ml was
considered as active for hemolytic activity. As shown in
Table 2, compound (3c) showed good hemolytic activity
while other compounds (3a and 3b) displayed moderate
hemolytic activities.
Table 2 In vitro hemolytic on human erythrocytes and cytotoxicity
on HeLa and vero cells of compounds (3a–c)
Compounds
Hemolytic
activity
Cytotoxicity
on HeLa
Cytotoxicity
on Vero
EC50 (lg/ml)
IC50 (lg/ml)
IC50 (lg/ml)
3a
458.0
408.6
212.0
429.9
[100
[100
[100
0.28
[100
[100
[100
58.0
3b
3c
Camptothecin
properties of quinines. It is known that the most important
reaction of quinones is their reversible reduction to the
corresponding hydroquinones via semiquinone free radi-
cals (Bentley and Campbell, 1974). These semiquinone
radicals cause one electron reduction of oxygen (O2) to
superoxide radical anions, which interact with H2O to form
H2O2 and highly reactive hydroxyl radicals. Hydroxyl free
radicals generated may cause damage to oxidative cells,
particularly erythrocytes (or red blood cells) (Papas, 1999).
Evidence has been presented that none of the synthetic
quinoline has showed remarkable hemolytic and cytotoxic
activity when compared to the standard. But it has seen that
the compound 3c has shown hemolytic activity to some
extend but not much enough for the formation of cytotoxic
oxidation products to accumulate and show cytotoxic activ-
ity. It can be suggested that substances able to suppress
Cytotoxic activity
IC50 value lower than 50 lg/ml was considered as active for
cytotoxicity on HeLa and Vero cells. As shown in Table 2,
compounds (3a, 3b, and 3c) have inactive on both cells.
Acknowledgement We gratefully acknowledge financial support
from the Department of Science and Technology, Government of
India (Grant No. SR/FTP/CS-99/2006).
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