Abstract
(E)-3-(3-Aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-ones 4a–i have been synthesized and evaluated for their in vitro cytotoxicity against a panel of three human cancer cell lines Caco-2, MIA PaCa-2, MCF-7 and a normal NIH-3T3 cell line. Compound 4g is cytotoxic with the IC50 value of 15.32±0.62 μm against the Caco-2 cell line.
Although there has been considerable progress in reducing cancer incidence in the United States, the number of cancer patients continues to increase [1]. Chemotherapy is one of the most effective approaches used for treating cancer patients. However, the lack of selectivity and development of drug-resistance reduces the efficacy of cancer chemotherapy [2]. Therefore development of effective and safe anticancer agents with high potency and less toxicity is a major focus for researchers across the world. The heterocyclic compounds containing a pyrazole ring have received considerable attention owing to their diverse chemotherapeutic potential [3], [4], [5]. Important pyrazole-based antitumor drugs available in the market include ruxolitinib and crizotinib [6]. Celecoxib is a typical model of pyrazole-based diaryl heterocyclic small molecule [7] with antitumor activity against prostate tumors in experimental models [8], [9], [10]. Chalcones show anti-cancer activity [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28] apparently due to their inhibition of tubulin [15], thioredoxin reductase [17], VEGF [18], mTOR [19] topoisomerase-I/II [20], 5α-reductase [21], sirtuin-1 [22], JAK/STAT signaling pathways [23], MMP-2 [24], cathepsin-K [25], Wnt [26], B-Raf [27] and NF-κB [28], among others.
On the basis of the interesting biological activity profiles of pyrazoles and chalcones, we were inspired to synthesize some pyrazolic chalcones as potential anticancer agents. Synthesis is outlined in Scheme 1. Pyrazolic chalcones were prepared from the corresponding 3-aryl-1-phenylpyrazol-4-carboxaldehydes 3a–i [29], [30], [31], [32], [33] which, in turn, were synthesized from the heterocyclic substrates 2a–i [30] (see Supplementary Material). The Claisen-Schmidt condensation of compounds 3a–i with 3-acetylpyridine in methanolic NaOH afforded the desired (E)-3-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-pyridin-3-yl)prop-2-en-1-ones 4a–i. Compounds 3a–i and 4a–i were characterized by spectral methods and elemental analysis.
Conditions: (i) EtOH, H2SO4, reflux; (ii) POCl3/DMF, 80°C, then NaHCO3/H2O; (iii) 3-acetylpyridine, MeOH, NaOH, r.t.
In vitro cytotoxicity of compounds 4a–i was measured by an MTT [(3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide)] assay against a panel of three different human cancer cell lines, namely Caco-2 (human intestinal), MIA PaCa-2 (human pancreatic) and MCF-7 (human breast) and one normal cell line (mouse embryo fibroblasts NIH-3T3) [34]. Etoposide was taken as the reference drug and the results are summarized in terms of IC50 values (Table 1). Most of the compounds show moderate to good cytotoxicity against intestinal, pancreatic and breast cancer cell lines and very weak toxicity towards NIH-3T3 normal cell line. Analogs 4f–h show significant cytotoxicity as compared to standard drug etoposide. Out of 9 pyrazolic chalcones synthesized, compound 4g displays the most potent cytotoxicity against Caco-2 cell line. SAR analysis of these pyrazolic chalcones indicate that compounds with a para substituted NO2 group in the benzene ring are more cytotoxic. Compounds with F, Cl, Br, CH3 or OCH3 substituent show more moderate effects, which is clearly seen from Table 1. The cytotoxic activity against all tested cancer cell lines shows that the strength order is NO2>F>Br>Cl for compounds with a para substituted electron-withdrawing group present in the benzene ring. Among compounds with meta substituted electron-withdrawing group, the cytotoxic activity order is NO2>Br. Finally, cytotoxic activity against Caco-2 and MIA PaCa-2 shows that the strength order is CH3>OCH3 for compounds with electron-donating substituent present in para position of the benzene ring. Furthermore, cytotoxic activity against MCF-7 shows the strength order is OCH3>CH3 for compounds with para electron-donating substituent.
In vitro cytotoxicity evaluation of the synthesized compounds against a panel of human cancer cell lines and a normal cell line in terms of IC50 value in μm.
| Compounds | R | Caco-2 | MIA PaCa-2 | MCF-7 | NIH-3T3 |
|---|---|---|---|---|---|
| 4a | H | 32.30±0.65 | 38.52±2.31 | 56.65±2.75 | >100 |
| 4b | 4-F | 23.09±0.93 | 28.28±2.17 | 34.38±3.83 | 91.46±2.99 |
| 4c | 4-Cl | 38.93±2.49 | 46.57±2.30 | 54.53±1.10 | 92.58±2.52 |
| 4d | 3-Br | 30.28±2.01 | 24.80±1.46 | 46.67±2.01 | 96.56±1.55 |
| 4e | 4-Br | 27.95±0.29 | 30.40±0.84 | 39.79±1.07 | 96.13±2.09 |
| 4f | 3-NO2 | 19.62±0.76 | 19.70±0.32 | 29.78±0.84 | 87.58±1.96 |
| 4g | 4-NO2 | 15.32±0.62 | 18.89±0.44 | 29.59±2.18 | 87.39±0.44 |
| 4h | 4-CH3 | 37.83±2.85 | 21.94±5.10 | 68.78±1.16 | >100 |
| 4i | 4-OCH3 | 49.12±8.37 | 32.05±1.23 | 44.36±1.08 | >100 |
| Etoposide | – | 17.51±0.24 | 23.66±0.33 | 32.31±1.48 | 90.53±4.6 |
Experimental
All starting materials and solvents were purchased from commercial sources and used without further purification. Melting points were determined in open capillaries using an electro-thermal melting point apparatus and are uncorrected. The progress of the reactions was monitored by TLC using precoated aluminum sheets (Silica gel 60 F254, Merck) and spots were visualized under UV light. IR spectra were recorded on an Agilent Cary 630 FT-IR spectrometer. The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker Avance 400 spectrometer using CDCl3 or DMSO-d6 as a solvent and TMS as an internal standard. Elemental analysis were performed on an Elementar Vario analyzer. Mass spectra (ESI-MS) were recorded on an AB-Sciex 2000 spectrometer.
General synthesis of compounds 4a–i
A mixture of 3-aryl-1-phenylpyrazol-4-carboxaldehyde 3a–i (10 mmol) and 3-acetylpyridine (10 mmol) in methanolic solution of sodium hydroxide was stirred for 24 h at room temperature. The resultant precipitate of 4a–i was filtered off, washed with water, dried, and crystallized from ethanol (4a–e and 4h,i) or N,N-dimethylformamide (4f,g).
(E)-3-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4a)
Yellow solid; yield 64%; mp 168–170°C; IR (neat, νmax): 3132, 1665, 1585, 1415 cm-1; 1H NMR (CDCl3): δ 9.13 (s, 1H), 8.73–8.75 (m, 1H), 8.37(s, 1H), 8.21 (m, 1H), 7.91 (d, J = 15.6 Hz, 1H), 7.26–7.78 (m, 12H); 13C NMR (CDCl3): δ 188.5, 154.0, 153.0, 149.6, 139.3, 136.5, 135.7, 133.5, 132.1, 129.6, 128.9, 128.8, 128.8, 127.3, 127.2, 123.6, 120.5, 119.3, 117.9. ESI-MS. Calcd for C23H17N3O, [M + H]+: m/z 352.1. Found: m/z 352.2. Anal. Calcd for C23H17N3O: C, 78.61; H, 4.55; N, 11.96. Found: C, 78.33; H, 4.84; N, 11.94.
(E)-3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4b)
Yellow solid; yield: 70%; mp 170–172°C; IR (neat, νmax): 3119, 1667, 1596, 1525, 1419 cm-1; 1H NMR (CDCl3): δ 9.20 (s, 1H), 8.80 (d, J = 3.6 Hz, 1H), 8.40 (s, 1H), 8.28 (d, J = 8 Hz, 1H), 7.91 (d, J = 15.6 Hz, 1H), 7.80 (d, J = 8 Hz, 2H), 7.33–7.70 (m, 7H), 7.20 (t, J = 8.4 Hz, 2H); 13C NMR (CDCl3): δ 188.4, 164.4, 162.0, 153.1, 149.6, 139.2, 136.2, 135.8, 133.4, 130.6, 130.5, 129.6, 128.2, 127.5, 127.1, 123.7, 120.6, 119.4, 117.9, 116.0, 115.8. ESI-MS. Calcd for C23H16FN3O, [M + H]+: m/z 370.1. Found: m/z 370.5. Anal. Calcd for C23H16FN3O: 74.78; H, 4.37; N, 11.38. Found: C, 74.73; H, 4.39; N, 11.41.
(E)-3-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4c)
Yellow solid; yield 64%; mp 162–164°C; IR (neat, νmax): 3134, 1665, 1583, 1501, 1404 cm-1; 1H NMR (CDCl3): δ 9.16 (s, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.37 (s, 1H), 8.21 (d, J = 8 Hz, 1H), 7.85 (d, J = 15.2 Hz, 1H), 7.76 (d, J = 8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.29–7.50 (m, 7H); 13C NMR (CDCl3): δ 188.8, 153.1, 152.8, 149.6, 139.2, 136.0, 135.7, 134.9, 133.4, 130.6, 130.0, 129.6, 129.0, 127.5, 127.1, 123.7, 120.8, 119.4, 117.9. ESI-MS. Calcd for C23H16ClN3O, [M + H]+: m/z 386.1. Found: m/z 386.4. Anal. Calcd for C23H16ClN3O: C, 71.59; H, 4.18; N, 10.89. Found: C, 71.65; H, 4.16; N, 10.85.
(E)-3-(3-(3-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4d)
Yellow solid; yield 82%; mp 172–174°C; IR (neat, νmax): 3136, 1663, 1596, 1493, 1404 cm-1; 1H NMR (CDCl3): δ 9.17 (s, 1H), 8.80 (d, J = 3.2 Hz, 1H), 8.39 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 15.2 Hz, 2H), 7.80 (d, J = 8 Hz, 2H), 7.36–7.62 (m, 8H); 13C NMR (CDCl3): δ 188.5, 153.1, 152.3, 149.6, 139.1, 135.8, 135.8, 134.2, 133.4, 131.8, 131.6, 130.3, 129.6, 127.6, 127.4, 127.3, 123.6, 122.9, 121.0, 119.4, 118.0. ESI-MS. Calcd. for C23H16BrN3O, [M + H]+: m/z 430.05. Found: m/z 430.04. Anal. Calcd for C23H16BrN3O: C, 64.20; H, 3.75; N, 9.77. Found: C, 64.26; H, 3.71; N, 9.75.
(E)-3-(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4e)
Yellow solid; yield 75%; mp 158–160°C; IR (neat, νmax ): 3136, 1663, 1596, 1501, 1400 cm-1; 1H NMR (CDCl3): δ 9.20 (s, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.40 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 15.6 Hz, 1H), 7.80 (d, J = 8 Hz, 2H), 7.64 (d, J = 8 Hz, 2H), 7.58 (d, J = 8 Hz, 2H), 7.33–7.53 (m, 5H); 13C NMR (CDCl3): δ 188.3, 153.1, 152.8, 149.6, 139.1, 136.0, 135.8, 133.4, 132.0, 131.0, 130.2, 129.6, 127.5, 127.1, 123.7, 123.2, 120.8, 119.3, 117.9. ESI-MS. Calcd for C23H16BrN3O, [M + H]+: m/z 430.05. Found: 430.04. Anal. Calcd for C23H16BrN3O: C, 64.20; H, 3.75; N, 9.75. Found: C, 64.14; H, 3.77; N, 9.79.
(E)-3-(3-(3-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4f)
Yellow solid; yield 69%; mp 206–208°C; IR (neat, νmax): 3136, 1665, 1596, 1533, 1423, 1344 cm-1; 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 9.24 (d, J = 1.6 Hz, 1H), 8.78–8.80 (m, 1H), 8.40 (s, 1H), 8.32 (d, J = 8 Hz, 1H), 8.27 (d, J = 8 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.77–7.89 (m, 4H), 7.65 (d, J = 15.2 Hz, 1H), 7.37–7.58 (m, 4H); 13C NMR (DMSO-d6): δ 188.1, 153.7, 150.8, 149.9, 148.5, 139.1, 136.0, 134.9, 134.3, 133.8, 133.1, 131.0, 130.1, 129.9, 127.9, 124.4, 123.8, 122.9, 122.2, 119.2, 118.4. ESI-MS. Calcd. for C23H16N4O3, [M + H]+: m/z 397.2. Found: m/z 397.2. Anal. Calcd for C23H16N4O3: C, 69.69; H, 4.07; N, 14.13. Found: C, 69.65; H, 4.08; N, 14.16.
(E)-3-(3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4g)
Yellow solid; yield 76%; mp 220–222°C; IR (neat, νmax): 3131, 1669, 1596, 1542, 1512, 1421, 1346 cm-1; 1H NMR (DMSO-d6): δ 9.38 (s, 1H), 9.23 (s, 1H), 8.78 (d, J = 3.6 Hz, 1H), 7.80–8.32 (m, 8H), 7.63 (d, J = 15.2 Hz, 1H), 7.34–7.57 (m, 4H, 1H); 13C NMR (DMSO-d6): δ 187.9, 153.7, 150.8, 149.9, 147.6, 139.0, 138.6, 136.0, 134.3, 133.1, 130.1, 129.9, 129.6, 127.9, 124.4, 124.4, 122.2, 119.2, 118.7. ESI-MS. Calcd for C23H16N4O3, [M + H]+: m/z 397.2. Found: m/z 397.2. Anal. Calcd for C23H16N4O3: C, 69.69; H, 4.07; N, 14.13. Found: C, 69.67; H, 4.08; N, 14.14.
(E)-3-(1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4h)
Yellow Solid; yield 61%; mp 146–148°C; IR (neat, νmax): 3119, 1667, 1596, 1538, 1499, 1419 cm-1; 1H NMR (CDCl3): δ 9.15 (s, 1H), 8.76 (d, J = 3.2 Hz, 1H), 8.36 (s, 1H), 8.21 (d, J = 8Hz, 1H), 7.91 (d, J = 15.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8Hz, 2H), 7.26–7.49 (m, 7H), 2.41 (s, 3H); 13C NMR (CDCl3): δ 188.5, 154.1, 152.9, 149.6, 139.3, 138.8, 136.7, 135.8, 133.6, 129.5, 129.5, 129.2, 128.6, 127.3, 127.1, 123.6, 120.4, 119.3, 117.9, 21.3. ESI-MS. Calcd for C24H19N3O, [M + H]+: m/z 366.1. Found: m/z 366.2. Anal. Calcd for C24H19N3O: C, 78.88; H, 5.24; N, 11.50. Found: C, 78.85; H, 5.25; N, 11.52.
(E)-3-(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-one (4i)
Yellow solid; yield 61%; mp 158–160°C; IR (neat, νmax): 3119, 1665, 1596, 1525, 1503, 1419 cm-1; 1H NMR (CDCl3): δ 9.15 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J = 8Hz, 1H), 7.89 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.26–7.47 (m, 5H), 6.99 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H); 13C NMR (CDCl3): δ 188.5, 160.2, 153.9, 153.0, 149.6, 139.3, 136.7, 135.7, 133.5, 130.0, 129.5, 127.2, 127.0, 124.5, 123.6, 120.2, 119.3, 117.8, 114.3, 55.3. ESI-MS. Calcd for C24H19N3O2, [M + H]+: m/z 382.1. Found: m/z 382.2. Anal. Calcd for C24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C, 75.54; H, 5.03; N, 11.04.
In vitro cytotoxic activity
The MTT [(3-(4, 5-dimethyl-2-thiazolyl) 2,5-diphenyl-2H-tetrazolium bromide)] assay is based on conversion of yellow, water soluble tetrazolium dye to a water-insoluble purple formazan by living cells. The amount of formazan crystals generated is directly proportional to the number of viable cells. The Caco-2, MIA PaCa-2, MCF-7 and NIH-3T3 cells were grown (37°C, 5% CO2 in water jacketed incubator shell) using DMEM media with 10% FBS (fotal bovine serum), seeded on a single 96 well plate and allowed to adhere for MTT assays. The plate was treated with increasing concentrations of 1, 12.5, 25, 50 and 100 μm of the compounds. These concentrations were used in triplicate to the single 96 well tissue culture plate. After 24 h of treatment, the MTT assay was performed to check cell viability. For the MTT assay, the media were removed from all the wells, 10 μL of MTT reagent per well from a working stock (5 mg/mL) was added and the plates were incubated (37°C and 5% CO2) for 2–3 h, and then the reagent was removed and the crystals were dissolved in dimethyl sulfoxide. The absorbance was measured at a test wavelength of 570 nm using an ELISA plate reader, LMR-340 M with a microplate reader. The percentage inhibition was calculated by the formulae:
Each assay was repeated three times. The IC50 values were calculated from the dose effect curve (Figure S1) and expressed as concentration (μm) of drug [34].
Acknowledgments
The authors thank the Head, Department of Chemistry, JMI, New Delhi, for providing research facilities, Prof. Vibha Tandon and Dr. Mohammad Abid for helpful discussions, and UGC, New Delhi, for research fellowship for Raquib Alam.
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