b Faculty of Applied Science, UiTM Shah Alam, 40450 Shah Alam, Selangor D. E., Malaysia;
c Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia;
d Department of Biochemistry, Abdul Wali Khan University, Mardan 23200, Pakistan;
e Department of Chemistry, Hazara University, Mansehra 21300, Pakistan
Cancer is one of the foremost diseases accountable for the worldwide mortality [1, 2]. Cancer is a broad term to describe a disease that characterized by the uncontrolled proliferation of cells resulting from the disruption or dysfunction of regulatory signaling pathways that are normally under tight control [3-5]. In modern life, cancer is one of the big health killers. According to American Association for Cancer Research (AACR) cancer progress report 2013, it expected that 580, 350 Americans would die from various type of cancer in the same year. Luckily, ultimate evolution has made against cancer. Approximately, from 1990 to 2012 almost 1, 024, 400 lives saved . Breast cancer is also one of the mostly happening epithelial malignancies in women, with almost 1 million new cases and more than 400, 000 deaths annually throughout the world . Many women eventually develop metastatic breast carcinoma, which is basically an incurable ailment, and the diagnosis has altered little compare to the past decade . Currently chemotherapy is an ultimate clinic treatment to repel cancer . Cisplatin drug has been commonly used in cancer treatment for decades [10, 11]. However, its clinical value tends to be inadequate by the abrupt increase of drug resistance or new side effects . Consequently, the exploration for unusual chemotherapeutic agents has sparked great attention of scientists from varied disciplines.
The morpholine scaffold had found to be an outstanding pharmacophore in medicinal chemistry and a number of molecules having morpholine skeleton are the clinically approved drugs . N-substituted morpholines used in the treatment of inflammatory diseases, like migraine and asthma . Morpholines derivatives have reported to possess activity like platelet aggregation inhibitors, anti-emetics, and bronchodilators . Morpholine analogs establish a new antifungal chemical entity not allied with other presently available medications with antifungal potential [16, 17]. The benefit in synthesizing morpholine analogs resides in the fact that these molecules offer chlorohydrates that are water soluble for pharmacological assays .
In this study, we report synthesis, characterization, anticancer activity and molecular docking studies of morpholine derivatives.2. Results and discussion 2.1. Chemistry
In the continuation of our effort to develop lead molecules [19-24], novel derivatives of morpholine (1-17) were synthesized by different arylhydrazides and 5-morpholinothiophene-2-carbaldehyde (Scheme 1). The crude product was purified by recrystallization. The products were characterized by different spectroscopic method (Table 1).
2.2. In vitro anticancer activity
All synthesized compounds (1-17) screened against two human cancer cell lines, human breast carcinoma (MCF-7) and human livercarcinoma (HepG2).The potentialsof these analogscalculated in IC50 value shown in Table 2. Among the series ten compounds showed potential against HepG2 and six compounds showed potential against MCF-7.
Compound 8 was found to be the excellent inhibitor among the series against MCF-7 with IC50 value 1.26±0.34 μmol/L which is many folds better than the standard inhibitor Tamoxifen (IC50=11.00±0.40 μmol/L). Compound 5 got second position among the series with IC50 value 7.08±0.42 μmol/L almost two fold better than the standard. The analogs like 2, 7, 9, and 11 also showed potent inhibition for this cell line, while remaining analogs found to be completely inactive.
Compound 13 showed potent inhibition against HepG2 with IC50 value 6.31±1.03 μmol/L when compared with the standard Doxorubicin (IC50 value 6.00±0.80 μmol/L). Compounds 4 and 6 were found second and third most active analogs among the series with IC50 value 7.94±7.94 and 12.59±1.22 mol/L respectively. Other analogs like 5, 7, 9, 11, 12, 14 and 15 also showed good to moderate potential.
Molecular docking studies were performed to investigate the binding mode of the active compounds.2.3. Molecular docking analysis
Thedockingisa computationalmethod of searching for suitable ligand conformation that fits both geometrically and energetically the protein's binding pocket . Molecular docking studies predicted the proper orientation of the compound 5 inside the binding pocket of topoisomerase Ⅱ enzyme. From the docking conformation of this active compound, we have observed a docking score of (-11.4975) which correlates well to the biological activities (IC50=19.95±0.63 μmol/L in HepG2 and 7.08±0.42 μmol/L in MCF-7 cell lines). The compound was observed making two interactions with activeresidues of the activesitepocket of the enzyme. The oxygen atom of the morpholine moiety of the compound formed side chain acceptor interaction with the Lys 990 residue of the binding pocket. Arg 929 was observed making hydrogen bond with the -NH group of the hydrazine moiety of the ligand as shown in Fig. 1. The electronegative nature of Cl, O and S of the substituent moiety may increase the polarizability of the ligand by electrons withdrawing inductive effect resulting in the enhance potency and interactions.
|Figure 1. Docking conformation of compound 5 in the active site of topoisomerase Ⅱ enzyme|
In conclusion, in this study a series of morpholine derivatives (1-17) havebeensynthesized, evaluatedfor their in vitro anticancer potential against two human cell lines like HepG2 and MCF-7. The results showed morpholine derivatives showed strong growth inhibitory effect on MCF-7 cell by encouraging cancer cell apoptosis. Compounds 5 and 8 were found to be outstanding inhibitors for MCF-7 cell. Compound 13 showed potent inhibition against HepG2 cell. The molecular docking studies were performed to understand the binding interaction of the active compounds.4. Experimental 4.1. Synthetic protocol for hydrazide 4.2. Synthetic protocol for morpholinothiophene hydrazones
derivatives Equimolar quantities (1 mmol) of 5-morpholinothiophene-2-carbaldehyde and appropriate substituted arylhydrazides in methanol (25 mL) were refluxed for 3h in the presence of catalytic amount of glacial acetic acid. The resulting solid was filtered and crystallized in methanol in good yields. (Please see the Supporting information for characterization of compounds 1-3, 9, 10, 12, 14, 16, 17).
(E)-4-Methoxy-N'-((5-morpholinothiophen-2-yl) methylene) benzohydrazide (4): Greenish; Yield: 81%; MP: 280-282 ℃; 1H NMR (500MHz, DMSO-d6): δ 3.18 (t, 4H, J=5.0Hz, 2xCH2); 3.75 (t, 4H, J=5.0nHz, 2xCH2); 3.83 (s, CH3, 3H); 6.18 (d, 2H, J=4.0Hz, CH2); 7.15 (d, 2H, J=4.0Hz, CH2) 7.86 (dd, 2H, J=2.0Hz, CH2); 8.45 (s, 1H); 11.41 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 164.0, 163.2, 144.6, 139.3, 139.3, 128.5, 128.5, 127.4, 125.0, 114.4, 114.4, 66.3, 66.3, =.8, 53.2, 53.2; Anal. Calcd. for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.17; Found: C, 59.9; H, 5.52; N, 12.16; MS: m/z 346.21 [M+1].
(E)-3-Chloro-N'-((5-morpholinothiophen-2-yl) methylene) thiophene-2-carbohydrazide (5): Green; Yield: 82%; MP: 246-248 ℃; 1H NMR (500 MHz, DMSO-d6): δ 3.18 (t, 4H, J=4.5 Hz, 2xCH2); 3.74 (t, 4H, J=5.0 Hz, 2xCH2); 6.18 (d, 1H, J=3.0 Hz); 7.71 (d, 1H, J=4.0 Hz); 7.86 (d, 1H, J=4.0 Hz); 7.97 (d, 1H, J=4.0 Hz); 8.36 (s, 1H); 11.44 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 169.3, 144.6, 140.8, 139.3, 139.3, 137.7, 135.0, 129.0, 127.4, 125.0, 66.3, 66.3, 53.2, 53.2; Anal. Calcd. for C14H14ClN3O2S2: C, 47.25; H, 3.97; N, 11.81; Found C, 47.24; H, 3.96; N, 11.80; MS: m/z 356.03 [M+1].
(E)-3, 4-Dimethoxy-N'-((5-morpholinothiophen-2-yl) methylene) benzohydrazide (6): Greenish; Yield: 91%; MP: 278-280 ℃; 1H NMR (500 MHz, DMSO-d6): δ 3.18 (t, 4H, J=5.0 Hz, 2xCH2); 3.60 (t, 4H, J=5.0 Hz, 2xCH2); 3.90 (s, 6H, 2xOCH3); 6.18 (d, 1H, J=4.0 Hz); 7.03 (d, 1H, J=8.5 Hz); 7.15 (d, 1H, J=4.0 Hz) 7.86 (m, 1H); 8.67 (s, 1H); 11.31 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 163.2, 153.2, 149.9, 144.6, 139.3, 139.3, 127.5, 127.4, 125.0, 120.8, 114.3, 111.9, 66.3, 66.3, 56.1, 56.1, 53.2, 53.2; Anal. Calcd. for C18H21N3O4S: C, 57.58; H, 5.64; N, 11.19; Found C, 57.56; H, 5.63; N, 11.17; MS: m/z 376.09 [M+1].
(E)-2, 3-Dihydroxy-N'-((5-morpholinothiophen-2-yl) methylene) benzohydrazide (7): Green; Yield: 87%; MP: 278-280 ℃; 1H NMR (500 MHz, DMSO-d6): δ 3.20 (t, 4H, J=5.0 Hz, 2xCH2); 3.75 (t, 4H, J=5.0 Hz, 2xCH2); 6.20 (d, 1H, J=4.0 Hz); 6.68 (t, 1H, J=7.5 Hz); 6.92 (d, 1H, J=7.5 Hz) 7.21 (d, 3H, J=4.5 Hz, CH, 2xOH); 7.29 (dd, 1H, J=1.0 Hz, CH); 8.45 (s, 1H); 11.86 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 163.2, 148.3, 146.1, 144.6, 139.3, 139.3, 127.4, 125.0, 121.5, 121.2, 120.7, 119.3, 66.3, 66.3, 53.2, 53.2; Anal. Calcd. for C16H17N3O4S: C, =.32; H, 4.93; N, 12.10; Found: C, =.31; H, 4.92; N, 12.10; MS: m/z 348.05 [M+1].
(E)-2, 4-Dimethoxy-N'-((5-morpholinothiophen-2-yl) methylene) benzohydrazide (8): Russet; Yield: 88%; MP: 276-278 ℃; 1H NMR (500 MHz, DMSO-d6): δ 3.18 (t, 4H, J=5.0 Hz, 2xCH2); 3.83 (t, 4H, J=8.0 Hz, 2xCH2); 3.93 (s, 6H 2xOCH3); 6.18 (d, 1H, J=4.0 Hz, =CH); 6.66 (m, 2H); 7.11 (d, 1H, J=3.5 Hz); 7.77 (d, 1H, J=8.5 Hz); 9.01 (s, 1H); 10.94 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 165.0, 163.2, 144.6, 139.3, 139.3, 136.4, 129.5, 127.4, 125.0, 110.5, 110.4, 98.3, 66.3, 66.3, 55.8, 53.2, 53.2; Anal. Calcd. for C18H21N3O4S: C, 57.58; H, 5.64; N, 11.19; Found C, 57.56; H, 5.63; N, 11.17; MS: m/z 376.11 [M+1].
(E)-3, 5-Dimethoxy-N'-((5-morpholinothiophen-2-yl)-methylene) benzohydrazide (11): Golden green; Yield: 80%; MP: 278-280 ℃; 1H NMR (500 MHz, DMSO-d6): δ 3.19 (t, 4H, J=5.0 Hz, 2xCH2); 3.75 (t, 4H, J=5.0 Hz, 2xCH2); 3.81 (s, 6H, 2xOCH3); 6.19 (d, 1H, J=4.0 Hz); 6.69 (d, 1H, J=2.5 Hz); 7.01 (d, 2H, J=2.5 Hz); 7.17 (d, 1H, J=4.0 Hz); 8.46 (s, 1H); 11.45 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 163.2, 161.7, 161.7, 144.6, 139.3, 139.3, 163.2, 127.4, 125.0, 105.5, 105.5, 103.8, 66.3, 66.3, =.8, 53.2, 53.2; Anal. Calcd. for C18H21N3O4S; C, 57.58; H, 5.64; N, 11.19; Found; C, 57.57; H, 5.62; N, 11.18; MS: m/z 376.05 [M+1].
(E)-4-(tert-Butyl)-N'-((5-morpholinothiophen-2-yl) methylene) benzohydrazide (13): Brown; Yield: 92%; MP: 270-272 ℃; 1H NMR (500 MHz, DMSO-d6): δ 2.30 (d, 9H, J=1.0 Hz, 3xCH3); 3.18 (t, 4H, J=5.0 Hz, 2xCH2); 3.76 (t, 4H, J=5.0 Hz, 2xCH2); 6.17 (d, 1H, J=4.0 Hz); 7.12 (d, 1H, J=2.5 Hz); 7.57 (d, 2H, J=4.0 Hz); 7.70 (d, 2H, J=4.0 Hz); 8.46 (s, 1H); 11.45 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 163.2, 154.7, 144.6, 139.3, 139.3, 129.7, 127.4, 127.1, 127.1, 125.1, 125.1, 125.0, 66.3, 66.3, 53.2, 53.2, 31.3, 31.3, 31.3; Anal. Calcd. for C20H25N3O2S; C, 64.66; H, 6.78; N, 11.31; Found; C, 64.65; H, 6.76; N, 11.30; MS: m/z 372.25 [M+1].
(E)-8-Fluoro-4-hydroxy-N'-((5-morpholinothiophen-2-yl) methylene) quinoline-3-carbohydrazide (15): Black; Yield: 86%; MP: 301-303 ℃; 1H NMR (500 MHz, DMSO-d6): δ 3.28 (t, 4H, J=5.0 Hz, 2xCH2); 3.74 (t, 4H, J=5.0 Hz, 2xCH2); 6.23 (d, 1H, J=4.5 Hz); 6.56 (d, 2H, J=6.0 Hz); 7.28 (s, 1H, OH); 7.32-7.34 (m, 1H); 7.47-7.57 (m, 1H); 8.02(dd, 1H, J=1.5 Hz); 8.71 (s, 1H); 11.88 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ 163.2, 161.2, 157.1, 146.3, 144.6, 139.3, 139.3, 138.0, 128.1, 127.4, 125.0, 121.7, 119.3, 116.2, 113.3, 66.3, 66.3, 53.2, 53.2; Anal. Calcd. for C19H17FN4O3S; C, 56.99; H, 4.28; N, 13.99; Fund; C, 56.97; H, 4.26; N, 13.98; MS: m/z 401.10 [M+1].4.3. In vitro cytotoxicity activity assay
All series of morpholines and coumarins derivatives were measured in vitro for cytotoxicity activity by using MTT assay. This assay is based on the reduction of MTT by mitochondrial succinate dehydrogenase. MTT enters the cells and passes into mitochondria where mitochondrial dehydrogenases of viable cells cleave the tetrazolium ring, yielding purple MTT formazan crystals which are insoluble in aqueous solutions. The crystals can be dissolved in dimethyl sulfoxide (DMSO) and produce the purple colour measured spectrophotometric. Reduction of MTT can only occur in metabolically active cells whereby the cells level of activity is a measure of the viability of the cells. MTT assay is a measurement of cell proliferation, when metabolic events lead to apoptosis and reduction in cell viability.
When the cells reach 80-90% confluences, the cells will be harvest by trypsinized with trypsin-EDTA. Cells counted by using cell counter machine and cells density seeded for each well were 2 × 104 cells/well. After incubated for 24 h, the cells treated with all series of morpholine and coumarin compounds ranging from 0.001 μmol/L to 100 μmol/L. Cells incubated for 72 h at 37 ℃ and 5% CO2. After 72 h, 20 mL of MTT solution added into each well and incubated for another 4 h in CO2 incubator. After 4 h, MTTcontaining media was aspirated off and 100 mL DMSO was added to each well. Plate was then shaken gently and read at 520 nm using a microplate reader (Tecan, Switzerland). Percentage of cell inhibition graph was plotted to determine the half maximal inhibitory concentration (IC50) of the test compounds.
All the synthesized candidates were evaluated for their in vitro antiproliferative activity against selected human cancer cell lines (MCF7 and HepG2) and toxic test towards normal cell lines (MCF10 and Chang) using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Doxorubicin, Tamoxifen and Cisplatin were used as reference standards.4.4. Molecular docking analysis
The molecular docking procedure was widely used to predict the binding interaction of the compound in the binding pocket of the enzyme. The 3D crystal structure of the topoisomerase Ⅱ enzyme (PDB id: 4FM9) was retrieved from the protein databank. All the ions and water molecules removed and the hydrogen atoms added to the enzyme by the 3D protonation using the MOE (Molecular Operating Environment) software. The target enzyme were then energy minimized by the default parameters of the MOE for the stability and further assessment of the enzyme. The structures of the analogs of the morpholinothiophene hydrazone compounds built in MOE and energy minimized using the MMFF94x forcefield and gradient: 0.05. The active site pocket of the enzyme found out by the site-finder implemented in the MOE software. The synthesized compounds docked into the active site of the target enzyme in MOE by the default parameters i.e., Placement: Triangle Matcher, Rescoring: London dG. For each ligand, ten conformations generated. The top-ranked conformation of each compound used for further analysis.Acknowledgments
Syed Adnan Ali Shah would like to acknowledge the Ministry of Higher Education (MOHE) for financial support under the Fundamental Research Grant Scheme (FRGS) with sponsorship reference numbers FRGS/1/2015/SG05/UiTM/02/6. The author would also like to acknowledge Universiti Teknologi MARA for the financial support under the reference number 600-RMI/FRGS 5/3 (135/2015).Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.10.020.
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