Synthesis and preliminary evaluation of difluorinated 1,3-propanediones as potential agents in the treatment of breast cancer

Article abstract of DOI:10.1007/s00044-011-9561-0

A series of difluorinated propanediones were synthesized and evaluated for in vitro cytotoxic activity by Sulforhodamine B (SRB) assay against a panel of four human cancer cell lines. Though the compounds showed varying degrees of cytotoxicity in the test

Full text of DOI:10.1007/s00044-011-9561-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:584–589
DOI 10.1007/s00044-011-9561-0
ORIGINAL RESEARCH
Synthesis and preliminary evaluation of difluorinated
1,3-propanediones as potential agents in the treatment
of breast cancer
•
Tabreskhan Pathan Sachin Ingale
•
•
Ashish Sharma Rhea Mohan C. S. Ramaa
•
Received: 21 July 2010 / Accepted: 11 January 2011 / Published online: 29 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of difluorinated propanediones were
synthesized and evaluated for in vitro cytotoxic activity by
Sulforhodamine B (SRB) assay against a panel of four
human cancer cell lines. Though the compounds showed
varying degrees of cytotoxicity in the tested cell lines, most
marked effect was observed in breast cancer cell line
(MCF7), wherein nine of the ten synthesized chalcones
showed good antiproliferative activity.
and, most importantly, the development of tumor resis-
tance. Therefore, there is an urgent need for novel and
effective therapies against breast cancer (Chopin et al.,
2004).
It has long been recognized that infections and inflam-
mation are related to cancer, and strong correlations
between the presence of inflammation and development of
precancerous lesions at various anatomic sites have been
established (Rayburn et al., 2009). As tumor develops, it
expresses phenotypes similar to inflammatory cells (Arias
et al. 2007). For example, numerous cancer cells express
cytokines and chemokines and their receptors. These
molecular mediators and their respective receptors have a
significant impact on angiogenesis, cell migration and
metastasis (Coussens and Werb, 2002). In a study con-
ducted by (Chavey et al., 2007), a number of cytokines,
including IL-6, IL-8, G-CSF (Granulocyte colony stimu-
lating factor), IFN-c (interferon-c), and MIP-1b (Macro-
phage inflammatory protein-1 b) were found to be more
abundant in breast carcinoma than in normal breast tissue .
Given its myriad pro-tumor effects, inflammation has
become a target for cancer prevention and therapy. More
than two decades ago, it was demonstrated that NSAIDs
(non-steroidal anti-inflammatory drugs) have anti-colon
cancer effects (Waddell and Loughry, 1983). Other clinical
trials have indicated that long-term use of aspirin or other
NSAIDs decreases the incidence of colorectal, esophageal,
breast, lung, and bladder cancers (Wang and Dubois,
2006). By inhibiting cyclooxygenase-2, nonsteroidal anti-
inflammatory drugs (NSAIDs) decrease aromatase activity
and might reduce breast cancer risk by suppressing estro-
gen synthesis (Gierach et al., 2008). Given that their tox-
icity is modest compared to conventional chemotherapeutic
agents, various anti-inflammatory agents are being inves-
tigated for cancer therapy and prevention.
Keywords Difluorinated 1,3-propanediones ꢀ
Sulforhodamine B assay ꢀ Breast cancer ꢀ Cytotoxicity
Introduction
Worldwide, breast cancer is the most common cancer
among women after skin cancer, and it is also the second
leading cause of cancer death (after lung cancer) in women
(Hsu et al. 2006). In 2007, breast cancer caused 40,460
deaths worldwide and in 2008, an estimated 182,480 new
cases of invasive breast cancer were diagnosed among
women, as well as an estimated 67,770 additional cases of
in situ breast cancer (Jemal et al., 2008; Kaur et al., 2010).
Breast cancer is currently controlled through surgery
and/or radiotherapy, and is frequently supported by adju-
vant chemo- or hormonotherapies. Unfortunately these
classical treatments are hampered by unwanted side-effects
T. Pathan ꢀ S. Ingale ꢀ A. Sharma ꢀ R. Mohan ꢀ
C. S. Ramaa (&)
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s
College of Pharmacy, Sector-8, C. B. D. Belapur, Navi Mumbai
400 614, Maharashtra, India
e-mail: sinharamaa@yahoo.in
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Med Chem Res (2012) 21:584–589
585
Our laboratory has been actively involved in synthesis
and evaluation of difluorinated chalcones and their prop-
anedione derivatives as anti-inflammatory agents (Jadhav
and Ramaa, 2007; More and Ramaa, 2010). The anticancer
effects of the synthesized difluorinated chalcones has pre-
viously been reported (Ingale et al., 2010). As a continu-
ation of the efforts in developing newer antitumor agents,
the authors report herein the results of preliminary cyto-
toxicity testing of difluorinated propanediones in a panel of
four cancer cell lines viz., MCF7 (breast cancer), HOP62
(lung cancer), A498 (renal cancer), and MIAPACA2
(pancreatic cancer).
with previously standardized and reported procedure (More
and Ramaa, 2010). Difluorinated chalcones 3a–3j were
prepared using the Claisen Schimdt condensation proce-
dure by condensing 2,4-difluoroacetophenone 1 with vari-
ously substituted benzaldehydes 2a–2j. These compounds
were converted to dibromo derivatives 4a–4j, which on
treatment with methanolic KOH gave the difluorinated
propanediones 5a–5j.
1
All the synthesized compounds were identified by H
nuclear magnetic resonance (NMR) and infrared (FTIR)
spectroscopy.
Biological evaluation
Results and discussion
Anticancer evaluation
Chemistry
After successful synthesis of the derivatives of 2,4-difluo-
rinated propanediones, their anticancer activity was eval-
uated in vitro on the 4-cell line panel consisting of MCF7
(breast cancer), HOP62 (lung cancer), A498 (renal cancer)
Compounds 5a–5j (Table 1) were synthesized according to
the synthetic pathway depicted in Scheme 1 in accordance
Table 1 Physical and spectral data for compounds 5a–5j
Compound
name
R
M.P(8C) Yield 1H NMR (d) (CDCl3)
(%)
5a
3-NO2 144
88.42 3.89 (s, 2H, CH2), 6.45 (dd, J = 12.6 Hz, 2.4 Hz, 1H, aromatic proton); 6.83 (dd, J = 9 Hz, 2.7 Hz,
1H, aromatic proton), 6.98 (s, 1H, aromatic proton), 7.68 (t, J = 8.1 Hz, 1H, aromatic proton),
7.99–8.07 (m, 1H, aromatic proton), 8.27–8.41 (m, 1H, aromatic proton), 8.79 (s, 1H, aromatic
proton)
5b
5c
4-Cl
4-F
102
93
72.30 3.88 (s, 2H, CH2), 6.67 (dd, J = 10.8 Hz, 2.4 Hz, 1H, aromatic proton), 6.81 (dd, 1H, J = 9 Hz,
2.4 Hz, aromatic proton), 6.90 (s, 1H, aromatic proton), 7.45 (d, J = 8.1 Hz, 2H, aromatic protons),
7.89 (d, J = 8.7 Hz, 1H, aromatic proton), 8.01 (t, 1H, J = 8.7 Hz, aromatic proton)
78.13 3.88 (s, 2H, CH2), 6.69 (dd, J = 13.6 Hz, 2.1 Hz, 1H, aromatic proton); 6.82 (dd, J = 8.8 Hz, 2.7 Hz,
1H, aromatic proton), 6.89 (s, 1H, aromatic proton),7.36 (t, J = 7.5 Hz, 1H, aromatic proton),7.67
(d, J = 6.9 Hz, 1H aromatic proton), 7.93 (d, J = 7.8 Hz, 1H, aromatic proton).7.98–8.10 (m, 1H,
aromatic proton)
5d
5e
5f
3-Br
105
88.57 3.87 (s, 2H, CH2), 6.65 (dd, J = 13.4 Hz, 2.1 Hz, 1H, aromatic proton); 6.80 (dd, J = 8.8 Hz, 2.1 Hz,
1H, aromatic proton), 6.86 (s, 1H, aromatic proton), 7.11–7.20 (m, 2H, aromatic protons), 7.94–8.07
(m, 2H, aromatic protons)
4-OCH3 153
76.13 3.88 (s, 2H, CH2), 3.98 (s, 3H, OCH3), 6.67 (dd, J = 13.8 Hz, 2.4 Hz, 1H, aromatic proton), 6.81 (dd,
J = 9 Hz, 2.7 Hz, 1H, aromatic proton), 6.85 (s, 1H, aromatic proton), 6.97 (d, J = 8.7 Hz, 1H,
aromatic proton), 7.92–8.02 (m, 2H, aromatic protons), 8.18 (s, 1H, aromatic proton)
2-Cl
4-Br
89
58.00 3.90 (s, 2H, CH2), 6.66 (dd, J = 13.8 Hz, 2.4 Hz, 1H, aromatic proton); 6.8 (d, J = 8.4 Hz, 2H,
aromatic protons), 7.4 (m, 2H, aromatic protons), 7.68 (dd, J = 7.8 Hz, 2.4 Hz, 1H, aromatic
proton), 8.0 (t, J = 8.7 Hz, 1H, aromatic proton)
5g
5h
114
80.00 3.90 (s, 2H, CH2), 6.68 (dd, J = 13.5 Hz, 2.1 Hz, 1H, aromatic proton), 6.82 (dd, J = 9 Hz, 2.4 Hz,
1H, aromatic proton), 6.9 (s, 1H, aromatic proton), 7.6 (d, J = 8.7 Hz, 1H, aromatic proton), 7.82
(d, J = 9 Hz, 2H, aromatic protons), 8.0 (t, 1H, aromatic proton)
4-CH3 100
2-NO2 114
52.00 2.4 (s, 3H, CH3); 3.90 (s, 2H, CH2), 6.7 (dd, J = 13.5 Hz, 2.4 Hz, 1H, aromatic proton), 6.8 (dd,
J = 9 Hz, 2.4 Hz, 1H, aromatic proton), 6.9 (s, 1H, aromatic proton), 7.3 (s, 1H, aromatic proton),
7.9 (d, J = 9.3 Hz, 2H, aromatic protons), 8.0 (t, J = 8.7 Hz, 1H, aromatic proton)
5i
5j
52.00 3.90 (s, 2H, CH2), 6.60 (s, 1H, aromatic proton), 6.64 (dd, J = 13.8 Hz, 2.4 Hz, 1H, aromatic proton),
6.8 (m, 1H, aromatic proton), 7.7 (m, 3H, aromatic protons), 8.0 (m, 1H, aromatic proton)
3,4,5-
OCH3
116
53.00 3.90 (s, 2H, CH2), 3.98 (s, 9H, O-CH3), 6.7 (dd, J = 13.8 Hz, 2.4 Hz, 1H, aromatic proton), 6.82 (dd,
J = 9 Hz, 2.7 Hz, 1H, aromatic proton), 6.89 (s, 1H, aromatic proton), 7.67 (s, 1H, aromatic
proton), 8.0 (t, J = 8.7 Hz, 1H, aromatic proton)
123

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Med Chem Res (2012) 21:584–589
F
O
F
O
Aqueous
NaOH
CH3
R
R
Ethanol
O
F
F
H
2,4-difluoroacetophenone
Substituted Aromatic Benzaldehyde
2,4-difluorinated chalcones
1
2a-2j
3a-3j
CHCl3 Br2
F
O
O
F
O
Br
Reflux
R
R
Br
Methanolic KOH
F
F
2,4-difluorinated propanediones
2,4-(difluorophenyl) dibromostyryl ketones
5a-5j
4a-4j
Scheme 1 Synthetic route for difluorinated propanedione derivatives
and MIAPACA2 (pancreatic cancer). Primary anticancer
assay was performed in accordance with the US NCI
protocol (Momose et al., 1991; Monks et al., 1991; Boyd
and Paull, 1995).
cell line A498. Compounds 5b (log10GI50 allvalue -4.42),
5d (log10GI50 value -4.49), 5f (log10GI50 value -4.49), 5h
(log10GI50 value -4.47) were moderately active in the in
vitro screen on renal cancer cell line (A498).
The cytotoxic effects of synthesized compounds were
tested in vitro against the panel of cell lines at ten-fold
dilutions of four concentrations ranging from 10-4 to
10-7 M. The percentage growth was evaluated spectro-
photometrically versus negative control not treated with
test agents and positive control, treated with doxorubicin, a
proven anticancer agent. A 48 h continuous drug exposure
protocol was followed and an SRB protein assay was used
to estimate cell viability or growth. For the compounds, the
50% growth inhibition (GI50) and total growth inhibition
(TGI) were obtained for each cell line. The log10 GI50 and
log10 TGI were then determined, defined as the mean of the
log10’s of the individual GI50 and TGI values. Negative
values indicated the most sensitive cell lines. Compounds
having log10 GI50 value -4.0 and \-4.0 were declared to
be active. The results obtained for anticancer evaluation
have been tabulated in Table 2.
Compound 5c (log10GI50 value -5.54) yielded good
anti-proliferative activity against pancreatic cancer cell line
MIAPACA2 and compounds 5d (log10GI50 value -4.45),
5e (log10GI50 value -4.50), 5f (log10GI50 value -4.52) and
5h (log10GI50 value -4.44) were found to have moderate
cytotoxicity in the same cell line.
Compound 5a with a 3-nitro substitution was found to
be inactive in all the tested cell lines with log10GI50 values
greater than -4.0.
In one of our earlier articles, we have reported the anti-
proliferative prowess of difluorinated chalcones (Ingale
et al., 2010). A striking observation made was that both
chalcones and their b diketone derivatives proved to be more
cytotoxic in MCF7 breast cancer cell line than in other tested
cell lines. A comparative profile of anti-proliferative evalu-
ation of difluorinated chalcones and their corresponding
propanediones have been described in Table 3 and Fig. 1.
Amongst the various cell lines in which compounds
were tested, MCF7 breast cancer cell line afforded maxi-
mum cytotoxicity, wherein nine of the ten synthesized
propanediones showed good anti-proliferative activity.
Compounds 5c, with 4-fluoro substitution, and 5f, with
2-chloro substitution, showed favorable anti-proliferative
activity in all of the four tested cancer cell lines.
Experimental section
Melting points were determined with a Veego melting
point apparatus in open capillaries and are uncorrected. IR
spectra were recorded as KBr discs, using Shimadzu 8400S
1
Compounds 5c (log10GI50 value -5.56), 5g (log10GI50
value -5.58) exhibited good cytotoxicity on renal cancer
FTIR spectrophotometer. H NMR spectra were recorded
on Varian Mercury Plus spectrometer at 300 MHz, with
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Med Chem Res (2012) 21:584–589
587
Table 2 In vitro anticancer activity in four human tumor cell lines for 5a–5j
Compound
Disease
Cancer cell line
Log10GI50 (lM)
Log10TG1 (lM)
5a
Renal cancer
A498
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
[-4
-5.63
-6.70
-5.68
-6.77
Breast cancer
MCF7
[-4
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
[-4
[-4
5b
-4.42
-4.46
[-4
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
[-4
5c
-5.56
-4.52
-4.44
-5.54
-4.49
-5.65
[-4
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
5d
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
-4.45
[-4
5e
Breast cancer
MCF7
-4.51
[-4
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
-4.50
-4.49
-5.60
-5.69
-4.52
-5.58
-5.6
5f
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
5g
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
[-4
[-4
5h
-4.47
-4.52
[-4
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
-4.44
[-4
5i
Breast cancer
MCF7
-5.60
[-4
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
[-4
5j
[-4
Breast cancer
MCF7
-5.64
[-4
NSC lung cancer
Pancreatic cancer
Renal cancer
HOP62
MIACAPA2
A498
[-4
Doxorubicin
-6.91
-6.92
-6.88
-6.95
Breast cancer
MCF7
NSC lung cancer
Pancreatic cancer
HOP62
MIACAPA2
CDCl3 as a solvent and TMS as an internal standard. All
reactions as well as column chromatography were followed
by TLC using Merck pre-coated silica gel 60 F254 plates
and spots were visualized by observing in UV cabinet
under short UV. All reagents were used as received unless
otherwise stated.
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Med Chem Res (2012) 21:584–589
measurement of the cell population for each cell line at the
time of drug addition (Tz). Test compounds were solubi-
lized in DMSO solvent at 400-fold the desired final max-
imum test concentration and stored frozen prior to use. At
the time of compound addition, an aliquot of frozen con-
centrate was thawed and diluted to ten times the desired
final maximum test concentration with complete medium
containing 1% gentamicin. Additional three, ten-fold serial
dilutions were made to provide a total of four concentra-
tions plus control. Aliquots of 10 ll of these different
dilutions were added to the appropriate micro-titer wells
already containing 90 ll of medium, resulting in the
required final concentrations.
Table 3 Comparison of anti-proliferative potential of chalcones with
propanediones in MCF7 (breast cancer cell line)
R
Chalcones
Propanediones
3-nitro
-5.56
-4.48
-5.51
-5.55
-4.42
-5.60
-5.55
[-4
[-4
4-chloro
4-fluoro
-4.46
-4.52
-5.65
-4.51
-5.60
-5.60
-4.52
-5.60
-5.64
3-bromo
4-methoxy
2-chloro
4-bromo
4-methyl
2-nitro
-5.62
-5.61
3,4,5-trimethoxy
After compound addition, plates were incubated at
standard conditions for 48 h at 37° C, 5% CO2, 95% air,
and 100% relative humidity and assay was terminated by
the addition of cold TCA. Cells were fixed in situ by the
gentle addition of 50 ll of cold 30% (w/v) TCA (final
concentration, 10% TCA) and incubated for 60 min at 4°C.
The supernatant was discarded; the plates were washed five
times with tap water and air dried. Sulforhodamine B
(SRB) solution (50 ll) at 0.4% (w/v) in 1% acetic acid was
added to each of the wells, and plates were incubated for
20 min at room temperature. After staining, unbound dye
was recovered and the residual dye was removed by
washing five times with 1% acetic acid. The plates were air
dried. Bound stain was subsequently eluted with 10 mM
trizma base, and the absorbance was read on an Elisa plate
reader at a wavelength of 540 with 690 nm reference
wavelength.
F
O
F
O
O
R
R
F
F
Chalcones
Propanediones
Fig. 1 General structure of chalcones and propanediones
General method for synthesis of difluorinated
propanediones 5a–5j
A series of 20,40-difluorinated chalcones 3a–3j were prepared
by condensing substituted benzaldehydes, 2a–2j and 2,4-
difluoroactophenone 1, using sodium hydroxide in ethanol at
RT. Their synthesis, physical constants and spectral char-
acterization have been reported by us in an earlier article
(Jadhav and Ramaa, 2007). 2,4-(difluorophenyl)dibromo-
styrylketones, 4a–4j, were synthesized by reacting difluori-
nated chalcones with bromine in chloroform. Difluorinated
propanediones (5a–5j) were synthesized by refluxing
2,4-(difluorophenyl) dibromostyrylketones with KOH in
methanol for 3 h followed by reflux with concentrated HCl
for further 2 h. Compounds 5a–5e have been reported by us
in an earlier article (More and Ramaa, 2010).
Percent growth was calculated on a plate-by-plate basis
for test wells relative to control wells. Percent growth was
expressed as the ratio of average absorbance of the test well
to the average absorbance of the control wells *100.
Using the six absorbance measurements [time zero (Tz),
control growth (C), and test growth in the presence of drug
at the four concentration levels (Ti)], the percentage
growth was calculated at each of the drug concentration
levels. Percentage growth inhibition was calculated as:
½ðTi ꢁ TzÞ=ðC ꢁ TzÞꢂ
Cell culture and drug treatment
ꢃ 100 for concentrations for which Ti [ =
¼ Tz ðTi ꢁ TzÞ positive or zero
½ðTi ꢁ TzÞ=Tzꢂ
The cell lines were grown in RPMI 1640 medium con-
taining 10% fetal bovine serum and 2 mM L-glutamine. For
present screening experiment, cells were inoculated into
96-well microtiter plates in 90 ll at plating densities of
5,000 cells/well. After cell inoculation, the microtiter
plates were incubated at 37°C, 5% CO2, 95% air, and 100%
relative humidity for 24 h prior to addition of experimental
drugs.
ꢃ 100 for concentrations for which Ti\Tz:
ðTi ꢁ TzÞ negative
The dose response parameters were calculated for each
test article. Growth inhibition of 50% (GI50) was calculated
from [(Ti–Tz)/(C–Tz)] 9 100 = 50, which is the drug
concentration resulting in a 50% reduction in the net
protein increase (as measured by SRB staining) in control
After 24 h, one plate of each cell line was fixed in
situ with trichloroacetic acid (TCA), to represent a
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589
Chopin V, Toillon RA, Jouy N, Le Bourhis X (2004) P21 (WAF1/
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cells during the drug incubation. The drug concentration
resulting in total growth inhibition (TGI) was calculated
from Ti = Tz.
Values were calculated for each of these parameters if
the level of activity was reached; however, if the effect was
not reached or was exceeded, the values for that parameter
were expressed as greater or less than the maximum or
minimum concentration tested.
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Conclusion
Ingale S, Pathan T, Mohan R, Ramaa CS (2010) Synthesis and
preliminary evaluation of a series of difluorinated chalcones as
potential antiproliferative agents in the treatment of breast
cancer. Int J Drug Design Discover 1(3):209–215
Jadhav DH, Ramaa CS (2007) Synthesis and anti-inflammatory
activity of fluorinated chalcone derivatives. Indian J Chem 46B:
2064–2067
The results obtained in this study strongly suggest that
difluorinated 1,3-propanediones have pronounced cytotoxic
activity in MCF7 breast cancer cell line as compared with
other tested cell lines. In an earlier study published by us,
toxicity studies on b diketones established their safety in
mice at doses up to 2,000 mg/kg (More and Ramaa, 2010).
These findings indicate that difluorinated 1,3-propanedi-
ones may be used as lead molecules for development of
agents in the treatment of breast cancer.
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Further extensive studies need to be carried to determine
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ascertain the cause for their greater specificity toward
breast cancer cell line.
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