Antitumoral effect of 1, 2, 4-Triazole derivatives on prostate carcinoma... ), Human Liver carcinoma (HEPG2), and Human Breast Cancer (MCF

Antitumoral effect of 1, 2, 4-Triazole derivatives on prostate carcinoma... ), Human Liver carcinoma (HEPG2), and Human Breast Cancer (MCF

Australian Journal of Basic and Applied Sciences, 7(2): 133-140, 2013
ISSN 1991-8178
Antitumoral effect of 1, 2, 4-Triazole derivatives on prostate carcinoma (DU145), Human
Liver carcinoma (HEPG2), and Human Breast Cancer (MCF7) cell Lines.
1
Firas Abdullah Hassan, 2Khalid Waleed Younus and 3Alaa Hussain AL-Qaisi
1, 2, 3
Al-Nahrain University, college of science, Chemistry department, Al- Jadrya, Baghdad, Iraq
Abstract: 3-(3-bromo-5-chloro-4-methoxy phenyl)-2-[3-(furan-2-yl)-5-oxo-1H-1, 2, 4-triazole-4(5H)yl]isothiazolidin-4-one (C) was obtained from refluxed of compound (B) with acetonethioglycollic
acid. They were characterized by IR and 1H-NMR spectra. Compounds (B and C) is tested in Vitro for
their ability to inhibit growth of three different human cell lines [Breast Cancer (MCF7), Liver
carcinoma (HEPG2), and Prostate carcinoma (DU145) ]. 3-(3-bromo-5-chloro-4-methoxy phenyl)-2-[3(furan-2-yl)-5-oxo-1H-1, 2, 4-triazole-4(5H)-yl]isothiazolidin-4-one (C) compound is much more
active than standard drug of 5-flurouracil (5-fu) against prostate carcinoma cell line (DU145), because
their (log10GI50) values of derivative (C) were lower than those of (5-fu). Effect of combination with
retinoic acid on proliferation of (DU145) cell lines were examined using MTT assay. When (DU145)
cells were incubated with a combination of retinoic acid and compound C, the anti-proliferative effect
of retinoic acid was clearly enhanced. A combination of 0.005M retinoic acid and 0.020M compound
(C) resulted in a greater antiproliferative effect than that obtained with 0.010M retinoic acid alone. In
combination of compound (C with tamoxifen, the inhibition of cell growth of breast cancer (McF7) cell
line was lower effective than tamoxifen alone.
Key words: cancer, 1,2,4-Triazole, synthesis, In vitro cytotoxicity screening, MTT assay, retinoic
acid, Tamoxifen.
INTRODUCTION
Cancer is a disease of striking significance in the world today. It is the second leading cause of death in the
world after cardiovascular diseases and it is projected to beginning the primary cause of death there within the
coming year (Nikhil, D., et al., 2010; Hoaglad, H.C., 1982). The identification of novel structure that can be
potentially useful in designing new, potent selective and less toxic anticancer agent is still a major challenge to
medicinal chemistry researchers (Galal, S.A., et al., 2009; Asmaa, A., et al., 2010). Heterocyclic compounds are
widely distributed in nature and occupy prominent place in medicinal chemistry as pharmaceuticals and drug
intermediates (Amega, A., R. Nandini, 2007). They play a significant role in the metabolism of living cells and
many are clinically use in the treatment of various disease. The therapeutic importance of heterocycles has
generated much interest in the synthesis of new classes of heterocyclic system in order to explore their
biodynamic of condensed sulphare and nitrogen containing heterocyclic (Pattan, S.R., et al., 2008). Wide
ranging pharmacological activity of 1,2,4-triazole derivatives have been reported in the scientific literature
(Hasan, M., et al., 2010). Some bi-heterocyclic compounds incorporating a 1, 3, 4- Thiazole and 1, 2, 4Triazole ring having been produced as antimicrobial agent (Kumar, P., et al., 1999). 1,2,4-triazole derivatives
templates is a privileged structure fragments in modern medicinal chemistry considering its broad
pharmacological spectrum and affinity for various bio targets of these class heterocyclic compounds. It is among
the usually occur heterocyclic nuclei in many marine as well as natural plant products possessing the wide range
of biological applications (Yasemin, U.,). Some of 1,2,4-triazole derivative, possessed diuretic (Rastogi, N., et
al., 2006), antimicrobial (Hussain, S., J. Sharma, M. Amir, 2008), antihistamine (Kumar, P.S., et al., 2003),
anticonvulsant (Cansiz, A., et al., 2004), and anti-inflammatory (Wasfy, A.A.F., 2003; Xin-Ping, H., et al.,
2002), effects. The first enzymatic reaction in the biodegradation of retinoic acid is its conversion to the less
active 4-hydroxy metabolite. This reaction is catalyzed by the cytochrome P450 dependent 4-hydroxylase
(Napoli, J.L., A.N. Mecormick, 1981; Swanson, B.N., et al., 1981). This has been shown to be present mainly in
the Liver.
MATERIALS AND METHODS
2.1. Chemistry:
Melting points were determined with a Gallen Kamp melting point apparatus and are uncorrected. 1H-NMR
spectra were recorded on Varian-Mercury 200MHz spectrometer. The IR spectra were measured as Potassium
Bromide pellets using a Perkin-Elmer 1600 series FTIR spectrophotometer.
2.2.1. Method for the synthesis of 4-amino-3-(furan-2-yl)-1H-1,2,4-Triazole- 5(4H)-one (A):
Corresponding Author: Firas Abdullah Hassan, Al-Nahrain University, college of science, Chemistry department, AlJadrya, Baghdad, Iraq
E-mail: firas_fz@yahoo.com; Tel. 00964- 7709774448; Box No. 64020 Al-Nahrain university
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Aust. J. Basic & Appl. Sci., 7(2): 133-140, 2013
Hydrazine hydrate (99%) (0.04mol) was gradually added to ethyl-2-[ethoxy(furan-2-yl)methylene]
hydrazine carboxylate (0.02mole) dissolved in water (15ml) with stirring and the mixture was refluxed gently
for 3h.
2.1.2. Method for the synthesis of (E)-4-(3-bromo-5-chloro-4-methoxybenzylideneamino)3-(furan-2-yl)-1H1. 2, 4- triazole-5(4H)-one (B):
The corresponding 4-amino-3-(furan-2-yl) -1H-1,2,4-triazole-5(4H)-one (A) (0.03mole) and 3-bromo-5chloro-4-methoxy benzyaldehyde (0.01 mole) were heated at 160 ºC in oil bath for 2h. After cooling to room
temperature, a solid appear and recrystallized from an appropriate solvent to afford the desired compound.
2.1.3. Method for the synthesis of 3-(3-bromo-5-chloro-4-methoxy phenyl)-2-[3-(furan-2-yl)-5-oxo-1H-1, 2,
4-triazole-4(5H)-yl]isothiazolidin-4-one (C):
To a solution of compound (B) (0.06mole) acetonethioglycollic acid (0.06mole) was added the reaction
mixture was refluxed for 3. A solid product was obtained after cooling to give the adducts compound (C) which
were crystallized from ethanol
Table 1: Spectral data of the compounds 1,2,4-Triazole derivatives B and C.
Compound no.
IR (KBr) ( , cm-1)
(E)-4-(3-bromo-5-chloro-43150(NH),1710(triazole-C=O),
1598
methoxybenzylideneamino)3-(furan-2-yl)(C=N).
1H- 1. 2, 4- triazole-5(4H)-one (B)
3-(3-bromo-5-chloro-4-methoxy phenyl)3220(NH),1688(triazole-C=O), 3060 (C2-[3-(furan-2-yl)-5-oxo-1H-1,
2,
4- N).
triazole-4(5H)-yl]isothiazolidin-4-one
(C)
1
H-NMR (DMSO-d6) σ(ppm)
7.65 – 7.72 (m, 1H, arH)
11.35 (s, 1H, NH), 9.92(s, 1H, N= CH),
4.21(s,3H,OCH3),5.34(s, 1H, CH-ph)
3.82(s, 2H, CH2 of the ring), 10.76(s, 1H,
NH), 4.73(s,3H,OCH3), 3.95(s, 1H, NCH), 5.72(s, 1H, CH-ph)
2.2. In Vitro cytotoxicity screening [18, 19]:
The human tumor cell lines of the cancer screening panel were growth in PRMI 1640 medium containing
10% fetal bovine serum and 4mM glutamine. For a typical screening experiment. Cells were inoculated into 96well micro titer plates in 120µL at plating densities 4000 cells/ well depending on the doubling time of
individual cell lines. After cell incubation, the micro titer plates were incubated at 37ºC, 5% CO2, 95% air and
100% relative humidity for 24h. Prior to addition of experimental drugs. After 24h, two plates of each cell line
were fixed in situ with tri-chloro acetic acid (TCA), to represent a measurement of the cell population for each
cell line at time of drug addition (Tz). Experimental drugs were solubilized with dimethyl sulfoxide at 400-fold
the desired maximum test conc. and stored frozen prior to use. At the time of drug addition, aliquot of frozen
concentrate was thawed and diluted to twice the desired final maximum test concentration with complete
medium containing 50µg/ml gentamicin. Additional four, 10-fold or 1/2 –log serial dilutions were up to provide
a total of five drug concentrations plus control. Aliquots of 50µl of these different drug dilutions were added to
the appropriate micro-titer wells already containing 50µl of medium. Resulting in the required final drug conc.
Following drug addition, the plates were incubated for an additional 48h. At 37ºC, 5% CO2, 95% air, and 100%
relative humidity. For adherent cells, the assay was terminated by the addition of cold TCA. Cells were fixed in
situ by the gentle addition of 50µml cold 50% (w/v) TCA (final conc., 10% TCA) and incubated for 60 min at
5ºC. The supernatant was discarded, and the plates were washed five times with tap water and air dried
(Tayseer, A.A., et al., 2002).
2.2.1. MTT Assay (Carmichael, J., et al., 1987):
MTT (serva) was dissolved at 3mg/mL in phosphate buffer saline. At the end of the growth experiments,
25µL of this solution was added to each well without removing the medium, and the cells were further
incubated for 2.5 h at 37ºC. The medium was then carefully aspirated, and the blue MTT- formazan product was
solubilized by addition of 100µL dimethyl sulfoxide. The micro test plates were shaken for 10min on a micro
plate shaker, and the absorbance at 450nm was read using automatic plate reader. The MTT assay was validated
for use prostate carcinoma DU145 by comparing the MTT results obtained 4h after plating different numbers of
cell with those obtained by homo-cytometer counting.
2.2.3. Statistical analysis
Where appropriate, data were analyzed using the two-tailed students test. Significance was defined at the
level of P<0.05 (Crowder, M.J., D.J. Hand, 1990).
RESULTS AND DISCUSSION
Chemistry:
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Aust. J. Basic & Appl. Sci., 7(2): 133-140, 2013
(E)-4-(3-bromo-5-chloro-4-methoxybenzylideneamino)3-(furan-2-yl)-1H- 1. 2, 4- triazole-5(4H)-one (B)
were obtained from the reaction of compound (A) with substituted aldehydes. In the 1HNMR spectra of
compound (B) the proton signal due to –N=CH- were recorded at 9.92, integration for 1 proton. The NH proton
at position ring of triazole appeared at 11.35 ppm, and appeared signal for (-OCH3) at 4.21, integration for 3
proton.
3-(3-bromo-5-chloro-4-methoxy
phenyl)-2-[3-(furan-2-yl)-5-oxo-1H-1,
2,
4-triazole-4(5H)yl]isothiazolidin-4-one (C) were obtained from the reaction of acetone thioglycollic acid with compound (B) at
the reflux temperature. In IR appeared the signal of (C-N) at 3060 cm-1 and disappeared of (C=N) signal that
binding to (3-methoxy-4-substitutedphenyl). In the 1HNMR the (-N=CH) proton signal of compound (B) was
recorded at 9.92 ppm, that binding between 1,2,4-triazole and phenyl ring. This signal disappeared when
compound (C) formed. Instead, new signals at 5.52 ppm and 4.65 ppm belonging to (N-CH) and (CH2-S)
protons in isothiazolidien ring, respectively, as shown in scheme 1.
Scheme 1: Synthetic Pathways for the Preparation of 1, 2, 4-Triazole Derivatives.
In Vitro Cytotoxicity Screening:
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Aust. J. Basic & Appl. Sci., 7(2): 133-140, 2013
(E)-4-(3-bromo-5-chloro-4-methoxybenzylideneamino)3-(furan-2-yl)-1H- 1. 2, 4- triazole-5(4H)-one (B)
and -(3-bromo-5-chloro-4-methoxy phenyl)-2-[3-(furan-2-yl)-5-oxo-1H-1, 2, 4-triazole-4(5H)-yl]isothiazolidin4-one (C) were tested for their cytotoxic activity using tumor lines (Fathalla, O.A., et al., 2002; Maclead, R., A.
Skehan, 1999), [ HEPG2 (human liver carcinoma), McF7 (human breast carcinoma), and D145 (prostate
carcinoma)] table(1) at ten-fold dilution of five concentrations ranging from 0.025M to 0.0025M. Primary
anticancer assay was performed in accordance with protocol of Groopman (Groopman, Jerome E., 2007). The
48h continues drug exposure was used, and a sulforhudamine B (SBR) protein assay was used to estimate cell
viability or growth. The percentage growth was obtained spectrophotometrically. For all three lines, the 50%
growth inhibition (GI50) and total growth inhibition (TGI) were determined and expressed as the logarithmic
form (log10 GI50 and log10 TGI). The means of these values (MG-MID) were calculated and deviations of
individual values from the means were found. Negative values from the mean indicate more sensitive cell lines.
The compounds having the individual values which were equal or smaller than -4, were declared to be active
(Najar, V.C., 2002), and compared this negative value with the standard drug (5-flurouracil) (5-Fu), using the
method of Skehan et al. (1988).
Table 2: In Vitro tumor cell growth inhibition of compounds B and C.
Compounds no.
Panel /cell line
B
log10 GI50
log10 TGI
HEPG2
MCF7
Du145
Mean
midpoint
MG-MID
C
log10 GI50
log10 TGI
(5-Fu)
log10 GI50
log10 TGI
- 3.41
- 3.81
- 4.18
- 3.48
- 4.33
- 4.32
- 5.23
-2.60
-3.36
- 4.78
- 4.73
-5.85
- 4.21
-5.22
-4.68
- 4.81
-2.34
-2.89
- 3.83
- 3.87
- 4.97
- 4.25
- 4.90
- 2.61
graph
When the compounds are compared with 5-Flurouracil (5-Fu), the log10 GI50 values for B (- 4.18) and C (5.85) where found to be lower than that of (5-Fu) (- 4.81) on prostate carcinoma cell line DU145, but log10 GI50
values of B (-3.41) and C (- 4.33) were found to be higher than that of (5-Fu) (-5.23) on liver carcinoma cell line
(HEPG2). In view of this evidence, the cytotoxicity of compound B and C on the above two cell lines was
compared to those (5-Fu). For breast cancer, these values of B (- 3.81) and C (- 4.73) were also comparable of
those of (5-Fu) (-4.68). The log10 GI50 values of the compounds B and C on cell lines (HEPG2) was higher than
those of (5-Fu), but in prostate carcinoma cell lines and breast cancer were lower than those of (5-Fu), as
shown in table (2). Therefore, compound C is much more active than standard drug (5-Fu) against prostate cell
lines (DU145) and breast cancer (MCF7), because their log10 GI50 values were lower than those of (5-Fu), and
may be considered promising for the development of new anticancer agents.
3.2.1. Antitumoral effect of compound C alone or combination with retinoic acid:
Retinoic acid is known to play a key role in cell growth and differentiation of epithelial tissues and has been
shown to have antitumoral properties (Farennec, I., M.J. Cals, 1988; Miller, J.R., 1998). The effect of all-transretinoic acid alone or combination with compound (C) on inhibition of cell growth of prostate carcinoma
(DU145) is shown in fig. 1. When DU145 cells were incubated with a combination of retinoic acid (RA) and
compound E(3), the cell growth effect of compound E(3) was clearly enhanced. This enhancement was
depending of the compound E(3) concentration. The enhancement by 1,2,4-triazole-5-one derivative E(3) of the
antiproliferative effect on (DU145) prostate carcinoma cells is probably due to inhibition of retinoic acid
metabolism. Retinoic acid itself had low effect in the growth of Du145 cells but significantly potintionated the
antiproliferative effects of compound E(3) greater than approximately five-fold. This potentiating was clearly a
synergistic interaction since concentration of retinoic compound (C) shows increase antiproliferative effect
when use this derivative alone. Continues exposure of the cells to compound (C) for 7 days lead to
concentration-dependent inhibition of cell growth with more than 80% inhibition at the highest compound (C)
concentration 0.025M, as shown in fig. 1.
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•
■
Fig. 1: Effect of retinoic acid (■) and 1,2,4 –Triazole derivative (C) (●) on proliferation of prostate carcinoma
(DU145) cells. Cells were incubated with the compound (C) for 7 days with medium changes on 2, 5, and
7 days.
Cells were continuously cultured with the test derivative (C), and the growth was assessed on days 2, 5 and
7. Under controlled conditions, cells growth exponentially until day 7, and incubation with 0.020M of triazole
derivative (C) or 0.005M retinoic acid did not alter the growth curve. Effect of 0.010M retinoic acid alone or of
a combination of 0.005M retinoic acid with 0.020M of triazole derivative (C) were apparent on day 7 only. The
0.020M of antiproliferative effect of 0.015M retinoic acid alone or combination of 0.010M retinoic acid with
0.020M compound (C) was already visible on day 5. Evaluation of the data on day 7 revealed that the
combination of 0.005M retinoic acid with 0.020M compound (C) was more effective than 0.010M retinoic acid
alone, as shown in fig. 2. Similarly, a combination of 0.010M retinoic acid with 0.020M compound (C) was
more effective than 0.015M retinoic acid alone. Thus, triazole derivative (C) enhanced the retinoic effect about
approximately ten-fold. This resulting in an enhancement of the antiproliferative effect that was depends on the
compound (C) concentration.
■
Fig. 2: Effect of 0.005M [A] and 0.010M [B] retinoic acid alone or combined with derivative (C) on cell
growth of (DU145) cells. (■), effect of compound (C) alone.
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3.2.2. Antitumoral effect of compound ( C) alone or combination with Tamoxifen:
Tamoxifen is widely used as a single agent for the treatment of both pre- and postmenopausal estrogen
receptor (RE) positive breast cancer (Anzano, M.A., et al., 1994). The effect of Tamoxifen alone or combination
with triazole derivative (C) on inhibition cell proliferative of breast cancer cell line (McF7) are shown in fig. 3.
Fig. 3: Effect of Thiazole derivative (C) alone or combined with Tamoxifen (T) as (Standard drug) on cell
growth of human breast cancer (MCF7) cells (C+T). Results are expressed as percentages of control
incubation with solvent and are means ± SD of three independent experiments with eight replicates for
each experiment condition.
Triazole derivative (C) had low effect on inhibition of cell proliferative of McF7 cells, but significantly
potentiated the inhibition effect of these derivative less than value when use this derivative combination with
Tamoxifen of 0.020M derivative (C) and 0.010M Tamoxifen. In comparison with retinoic acid, a combination
of 0.010M retinoic acid with 0.020M derivative (C) was more effective than 0.015M retinoic acid alone, while
combination of this derivative with tamoxifen (C+T), in the same concentration above, will be obtained less
effective than tamoxifen alone, this agreement with activity of tamoxifen as described by Jacolot et al., (1991).
Both triazole derivative (C) and tamoxifen when given alone demonstrated anti-tumor effects. However,
tamoxifen lead to tumor shrinkage, while compound (C) was only able to stop tumor growth. When given in
combination, derivative (C) plus tamoxifen was more effective inhibition of cell proliferation of breast cancer
(McF7) cells derivative (C) alone, in comparison of this derivative with all trance-retinoic acid.
Conclusion:
3-(3-bromo-5-chloro-4-methoxy
phenyl)-2-[3-(furan-2-yl)-5-oxo-1H-1,
2,
4-triazole-4(5H)yl]isothiazolidin-4-one (C) was more active than (5-Flurouracil), as standard drug, against prostate carcinoma
cell line (DU145) and breast cancer cells(MCF7), comparing with the values of ( log10 GI50) of this derivatives
with derivative (B) and (5-Flurouracil). Combination of retinoic acid with derivative (C) was more effective
than retinoic acid alone, this derivative enhanced the retinoic acid effect about ten-fold, due to inhibition of alltrance-retinoic acid metabolism, in prostate carcinoma (DU145) cells. Further research into these effects in
(DU145) cells as well as in other cancer cell lines will provide more information concerning the exact mechanism
of action of 1,2,4-triazole derivative (C) and the use of inhibitors of retinoic metabolism in cancer treatment.
Combination of tamoxifen with compound (C) was less effective than tamoxifen alone, in breast cancer (MCF7)
cell line.
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