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Synthesis and Evaluation of Certain Symmetrical Schiff Bases as Inhibitors of MDA-MB-241 Human Breast Cancer Cell Proliferation Smaail Radi1,*, Said Tighadouini1, Olivier Feron2, Olivier Riant3 and Yahia N. Mabkhot4 1
LCAE, Département de Chimie, Faculté des Sciences, Université Mohammed Premier, BP 524, 60000-Oujda, Morocco 2
Angiogenesis and Cancer Research Lab, Pole of Pharmacology and Therapeutics - FATH5349, Institute of Experimental and Clinical Research, UCL, Brussels, Belgium 3
Molecules, Solids and Reactivity (MOST), Institute of Condensed Mater and Nanosciences (IMCN), UCLouvain, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium 4
Department of Chemistry, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
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Abstract: A series of symmetrical Schiff base derivatives (L1-L7) were designed by a one-pot condensation reaction of various aldehyde/ketone compounds with hydrazine under mild conditions (room temperature, 3 days), using ether as solvent and acetic acid as catalyst. The target products were characterized and analysed by 1H and 13C NMR, FT-IR and liquid chromatography mass spectrometry (LC/MS). Our research focuses on the identification of synthetically chemotherapeutic substances able to inhibit, delay, or reverse the process of carcinogenesis in several stages. The target compounds presenting two regions for SAR evaluation were screened for their activity toward MDA-MB-241 breast cancer cell proliferation for the first time. Compound (1E, 2E)-1,2-bis(1-(3-nitrophenyl)ethylidene) hydrazine (L6) showed significant inhibitory activity (IC50 = 7.08 μg/mL).
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It is well known that the breast cancer repersents the most common kind of cancer diagnosed in women, accounting for nearly a third of all diagnosed cancers. This disease strikes one in eight women and there are about 200,000 annual events in the US only. More than twenty-five percent of women affected will eventually die of this disease. The current treatment for breast cancer are: chemotherapy, surgery, radiation and hormone treatment [1]. However, The negative results of currently available treatment modalities can be attributed to the development of resistance against the existing drugs. Therefore, the research of new treatment and drug candidates which can be potentially useful in the design of new potent, less toxic and selective agents is still a major challenge for researchers in medicinal chemistry.
On the other hand, heterocyclic derivatives are well established in the literatures as important biologically effective compounds. Their versatile utility in the world of medicinal chemistry is firmly established. Most of the natural compounds used as drugs possess at least one heterocyclic unit viz. pyridine, furan, thiophene, pyrole, imidazole, etc. These derivatives represent now more than two thirds of the drugs used in the pharmaceutical industry and are the subject of very active research worldwide. Their roles in biological processes are of paramount importance [13].
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1. INTRODUCTION
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Keywords: Schiff bases, heterocycles, nitro, antitumor activity, breast cancer, cell proliferation
In terms of this trend, Schiff base derivatives, bearing azomethine functional group –C=N–, are considered as welldesigned and privileged drugs [2]. Their interest is based on (i) their easy preparation by a simple condensation of aldehyde or ketone synthons and primary amines, and (ii) their wide variety of biological and pharmacological properties [3]. Indeed, a number of Schiff bases are well known for their properties as anticancer [4], anti-inflammatory [5], an tibacterial [6], antifungal [7], anticonvulsant [8, 9], antituberculosis [10, 11], and analgesic [12]. *Address correspondence to this author at the LCAE, Département de Chimie, Faculté des Sciences, Université Mohammed Premier, BP 524, 60000-Oujda, Morocco; E-mail:
[email protected]
17-8;/16 $58.00+.00
Keeping in mind the bioactivity of Schiff bases and heterocyclic compounds, seven symmetrical Schiff bases bearing pyridine, furan, thiophene, pyrole and ortho-, meta- or para-nitrophenyl groups has been synthesized in a modified known method based on replacing of the heating under reflux of ethanol by mild conditions (room temperature, 3 days). The target products, obtained in a higher yield, were evaluated for the first time for their anticancer activity toward breast human cell lines cancer (MDA-MB241). Significant activity was observed especially for the compound (L6). 2. MATERIALS AND METHODS 2.1. General All commercial reagents were analytical grade (Aldrich, purity > 99%). Melting points were measured using a BUCHÏ 510 m.p. apparatus. 1H and 13C NMR spectra were
©2016 Bentham Science Publishers
206 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 3
Radi et al.
performed on a Bruker AC 300 spectrometer (CNRS) (300 MHz for 1H and 75.47 MHz for 13C spectra). JEOL JMS DX-300 Mass Spectrometer was used for the determination of molecular weights. Infrared (IR) spectra were recorded on a Shimadzu infrared spectrophotometer using the KBr disc technique. The amount of formazan obtained at the end of the experiment in MTT assays, was measured by means of a spectrophotometer (Plate Reader Victor X4 Microplate reader, Perkin Elmer). The known compounds have spectral data according to the literature data [14-17].
yrrole-Cᾳ); m/z (M+): 187.08; IR: ν(CH=N, imine) = 1616 cm-1. (1E, 2E)-1,2-bis(1-(2-nitrophenyl)ethylidene)hydrazine (L5) White powder; Yield 54%; Mp = 192°C; Rf = 0.34 (silica, CH2Cl2/MeOH, 9/1); 1H NMR (300MHz, DMSO) δ ppm: 8.07 (d, 2H, aromatic, C6-H), 7.80 (m, 2H, aromatic, C3-H), 7.60(t, 2H, aromatic, C5-H), 7.33(m, 2H, aromatic, C4-H), 2.11 (s, 6H, imine, CH3); 13C NMR (75 MHz, DMSO) δ ppm: 163.06 (2C, imine, C=N), 146.99 (2C, aromatic, C1), 134.51 (2C, aromatic, C2), 133.61(2C, aromatic, C4), 130.09 (2C, aromatic, C3), 128.58 (2C, aromatic, C5), 124.18 (2C, aromatic, C6), 24.38 (2C, aliphatic, CH3-C=N); m/z (M+): 327.04; IR: v(C=N)=1545cm-1.
2.2. General Procedure
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Orange powder; Yield 83%; Mp = 208 °C; Rf = 0.7 (silica/CH2Cl2); 1H NMR (300MHz, DMSO) δ ppm: 8.29 (d, 4H, aromatic, C3-H, C5-H), 8.15 (d, 4H, aromatic, C2-H, C6 H), 2.30 (s, 6H, imine, CH3); 13C NMR (75 MHz, DMSO) δ ppm: 156.55 (2C, aromatic, C1), 148.58 (2C, aromatic, C4), 143.90 (2C, imine, C=N), 128.35 (4C, aromatic, C2, C6), 124.12 (4C, aromatic, C3, C5), 15.54 (2C, aliphatic, CH3C=N); m/z (M+): 327.15; IR: v(C=N) =1552cm-1.
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Yellow powder; Yield 86%; Mp =113°C; Rf = 0.33 (silica/CH2Cl2) 1H NMR (300MHz, CDCl3) δ ppm: 8.59 (s, 2H, Himine), 7.62 (d, 2H, Hᾳ), 7.03 (d, 2H, Hγ), 6.63 (m, 2H, Hβ); 13 C NMR (75 MHz, CDCl3) δ ppm: 150.76 (2C, Cimine), 148.14 (2C, furan-Cδ), 146.56 (2C, furan-Cᾳ), 0118.20 (2C, furan-Cϒ), 112.58 (2C, furan-Cβ); m/z (M+): 189; IR: ν(CH=N, imine) = 1630 cm-1.
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(1E, 2E)-1,2-bis(1-(4-nitrophenyl)ethylidene)hydrazine (L7)
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Yellow powder; Yield 81%; Mp 151 °C; Rf = 0.73 (silica, CH2Cl2/MeOH, 9/1); 1H NMR (300MHz, CDCl3) δ ppm: 8.71 (d, 2H, Hᾳ), 8.70 (d, 2H, Hδ), 8.12 (s, 2H, Himine), 7.81 (t, 2H, Hγ), 7.36 (m, 2H, Hβ); 13C NMR (75 MHz, CDCl3) δ ppm: 161.75 (2C, imine), 152.59 (2C, pyridine-Cε), 149.64 (2C, pyridine-Cᾳ), 136.94 (2C, pyridine-Cϒ), 125.26 (2C, pyridine-Cβ), 122.62 (2C, pyridine-Cδ); m/z (M+): 211.10; IR: ν(CH=N, imine) = 1640cm-1. (1E, 2E)-1,2-bis(furan-2-ylmethylene)hydrazine (L2)
Yellow powder; Yield 89%; Mp = 202 °C; Rf = 0.7 (silica/CH2Cl2); 1H NMR (300MHz, DMSO) δ ppm: 8.65 (s, 2H, aromatic, C2-H), 8.31 (d, 2H, aromatic, C5-H), 8.28 (d, 2H, aromatic, C3-H), 11.64 (t, 2H, aromatic, C4-H), 2.34 (s, 6H, imine, CH3); 13C NMR (75 MHz, DMSO) δ ppm: 156.81 (2C, aromatic, C1), 148.53 (2C, aromatic, C6), 139.57 (2C, aromatic, C3), 133.40 (2C, aromatic, C2), 130.68 (2C, imine, CH3-C=N), 124.91 (2C, aromatic, C4), 121.96 (2C, aromatic, C5), 15.43 (2C, aliphatic, CH3-C=N); m/z (M+): 327.04; IR: v(C=N) = 1555cm-1.
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(1E, 2E)-1,2-bis(pyridine-2-ylmethylene)hydrazine (L1)
(1E, 2E)-1,2-bis(1-(3-nitrophenyl)ethylidene)hydrazine (L6)
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To a solution of heterocycle-2-carbaldehyde (2 equiv., 31.24 mmol) in dry ether (20 mL) was added hydrazine (1 equiv., 15.62 mmol) using two drops of acetic acid as catalyst. The mixture was stirred at room temperature for 3 days. The crystallized material was filtrated and washed with dry ether to give the target products (L1), (L2), (L6) and (L7), while products (L3), (L4) and (L5) were obtained after purification on a silica column using dichloromethane as eluent.
2.3. Determination of the Anti-Cancer Activity: MTT Cell Viability Assay
(1E, 2E)-1,2-bis(1H-pyrol-2-ylmethylene)hydrazine (L4)
3. RESULTS AND DISCUSSION
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Yellow powder; Yield 64%; Mp = 147°C; Rf =0.76 (silica/CH2Cl2); 1H NMR (300MHz, DMSO) δ ppm: 8.82 (s, 2H, Himine), 7.76 (d, 2H, H ᾳ), 7.61 (d, 2H, Hγ), 7.18 (t, 2H, Hβ); 13C NMR (75 MHz, DMSO) δ ppm: 156.26 (2C, Cimine), 138.87 (2C, thiophen-Cδ), 134.25 (2C, thiophen-Cᾳ), 131.45 (2C, thiophen-Cβ), 128.75 (2C, thiophen-Cγ); m/z (M+): 121.02; IR: ν(CH=N, imine) = 1609cm-1
The drugs described in this work were evaluated for their activity against breast (MDA-MB241) human cancer cell lines using the standard MTT tests as given in our previous work [18, 19]. For each experimental condition, the mean optical density was calculated, allowing the determination of the percentage of living cells in comparison to the control. Tests were performed on Angiogenesis and Cancer Research Lab, Institute of Experimental and Clinical Research (UCL, Brussels, Belgium).
(1E, 2E)-1,2-bis(thiophen-2-ylmethylene)hydrazine (L3)
Yellow powder; Yield 62%; Mp = 186°C; Rf =0.32 (silica/CH2Cl2); 1H NMR (300MHz, DMSO) δ ppm: 11.52 (s, 1H, pyrrole-NH), 8.36 (s, 2H, Himine), 6.96 (d, 2H, Hᾳ), 6.59 (s, 2H, Hγ), 6.16 (m, 2H, Hβ); 13C NMR (75 MHz, DMSO) δ ppm: 151.03 (2C, Cimine), 127.81 (2C, pyrrole-Cδ), 123.71 (2C, pyrrole-Cγ), 115.25 (2C, pyrrole-Cβ), 110.14 (2C,
3.1. Linker Synthesis The result of our investigation is given below (schemes 1 and 2). The synthesis of the target drugs was developed using a modified known method based on replacing the heating
Synthesis and Evaluation of Certain Symmetrical Schiff Bases
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 3
NH2-NH2 2
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X = N, O, S, NH R = Pyridine R = Furan R = Thiophene R = Pyrole
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Scheme (1). Methodology of synthesized products (L1-L4). O2N CH3 NH2-NH2
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3.2. Biological Tests Against MDA-MB 241 (Breast Cancer)
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The products had been assigned using resonance frequency of protons on the basis of their integration and multiplicity pattern. For example, the aldehyde peak of started products, that usually appears at about 9.7 ppm, disappears in the spectra of formed Schiff bases indicating that the aldehyde group (-CH=O) was transformed to azomethine functional group (-C=N-).
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The data indicated and confirmed the Schiff bases formation.
The drugs described in this work L1-L7 were evaluated for their activity against MDA-MB-241(breast cancer cell) using normoxie conditions [21-23]. The results are shown in Table 1.
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Structures of resulting compounds were determined on the basis of the corresponding analytical and spectroscopic data. Indeed:
The crystal structure of a new drug (L7), synthesized here, was also characterized and confirmed by X-ray crystallography [20].
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under reflux of ethanol [14-17] by gentle conditions. The synthesis passes through the stirring mixture of each heterocycle-2-carbaldehydes or nitrophenyl ketones and hydrazine at room temperature and atmospheric pressure for 3 days, using anhydrous ether as solvent and acetic acid as catalyst. The reaction is relatively slow but selective and more yielding at room temperature.
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Scheme (2). Methodology of synthesized products (L5-L7).
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ortho-NO2 meta-NO2 para-NO2
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In 13C NMR spectra, we note the disappearance of carbaldehyde signal (at ~178 ppm) and appearance of signal at about 150 ppm characteristic of formed C=N- group. The IR spectra show the appearance of a signal characteristic of imine group at a region of 1550-1640 cm-1, whereas the C=O group of started products with a signal at ~1700 cm-1 disappeared after condensation indicating its reactivity and certifying the product formation. Moreover, two bands which appered arround 1555 cm-1 and 1455 cm-1 were attributed to the C=N and C=C vibration of heterocyclic moities respectively. The m/z spectra of the target product show dominant ions which are consistent with the expected molecular ions (M+). These m/z ions are singly charged, and so the m/z value is consistent with the molecular mass.
Table 1. IC50 values of compounds (L1–L7) against breast cancer cell lines as determined by MTT assay. N/A means non applicable because IC50 >100 µg/mL. (Standard errors were always below 5% of presented IC50 values). MDA-MB241 Compounds
IC50 (μg/mL)
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vitro test results against MDA-MB-241 human breast cancer cell proliferation show a significant antitumor activity, especially for product L6.
Cell Viability (%)
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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
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ACKNOWLEDGEMENTS
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The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for assistance and support through the research group project Number RGP-VPP-007-2015.
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Fig. (1). Curve of active compound (L6) against MDA-MB-231 proliferation in Normoxie conditions.
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It is depicted, that most of these products are cytotoxic against this cell line in dose dependent manner. The activity is strongly depending on both the structure and the nature of the heterocyclic compounds. The concentration required to induce activity (IC50) is more pronounced for compound L6 (with meta-nitro group).
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It is known that nitro group (with strong electronwithdrawing) has generally the strongest influence on antiproliferative activity [24]. Moreover, multi-step process can lead to activation of biological responses of these nitro compounds such as: (i) their penetration into the vessel walls and cell plasmatic membranes, (ii) their interaction with active site of the nitroreductase followed by a one-electron reduction, (iii) reaction of nitro derivatives with oxygen (in aerobic conditions) or with cell macromolecules (in hypoxic conditions) resulting in an oxidative steress, modulation of gene expression, and a complex immune response to haptenconjugate adducts [25-27]. The mechanism of the anti-tumor immune response activation by nitro compounds can be similar to the delay-type hypersensitivity reaction [28].
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However, compounds with nitro group in ortho- and para- positions did not exhibit significant activity. This is probably attributed to the C-H…N bonds and π -π interactions in case of meta- position while the spatial distance is not beneficial to the formation of hydrogen bond or π -π interaction in case of ortho- and para- positions. The curve of the active compound L6 against MDA-MB241 proliferation in normoxie conditions is shown in Fig. (1).
We also noted that all compounds present two regions for SAR evaluation: (i) symmetrical heterocyclic units and (ii) twice imine groups. In spite of the marked biological interest of heterocyclic compounds, herein these heterocyclic units (furan, thiophene, pyridine, pyrole) showed no significant activity.
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CONCLUSION In conclusion, seven symmetrical Schiff bases structures were prepared from easily accessible starting materials in a modified known method by replacing the heating under reflux of ethanol with gentle conditions. The preliminary in
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Synthesis and Evaluation of Certain Symmetrical Schiff Bases
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Revised: July 14, 2015
Accepted: July 26, 2015
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Received: April 25, 2015
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