English

• 1.   Introduction

  Chalcones, analogs of 1, 3-diaryl prop-2-ene-1-one containing two aromatic rings bound with vinyl ketone fragment form a wide class of compounds, represent an interesting group of natural compounds that are abundant in fruits, vegetables, spices, tea, and soy based foodstuff and possess multifarious pharmacological potentials, such as anti-fungal, ^[1] anti-hypertensive, ^[2] hypnotic, ^[3] antispasmodic, ^[4] immunosuppressant, ^[5] anti-platelet, ^[6] antidiabetic, ^[7] anti-tubercular, ^[8] anti-neoplastic, ^[9] antiangiogenic, ^[10] anti-oxidant, ^[11] hypolipidemic, ^[12] anti-filarial, ^[13] anti-retroviral, ^[14] anti-malarial, ^[15] antibacterial, ^[16] anti-ulcer, ^[17] anti-arrhythmic, ^[18] anti-invasive, ^[19] anti-histaminic, ^[20] etc. The potential anticancer activities of chalcone derivatives has been explored. Recently, the anticancer activity of chalcones have been observed on inhibiting various molecular targets, like ABCG2/P-gp/BCRP, 5α-reductase, aromatase, 17-β-hydroxysteroid dehydrogenase, HDAC/Situin-1, proteasome, VEGF, VEGFR-2 kinase, MMP-2/9, JAK/STAT signaling pathways, CDC- 25B, tubulin, cathepsin-K, topoisomerase-II, Wnt, NF-κB, B-Raf and mTOR.^[9] Heterocyclic nitrogen- containing substrates are common constituents of natural products, agrochemicals, and pharmaceuticals. Recently, the synthesis of hybrid compounds of chalcone and heterocycles, such as chalcone substituted piperazine, and their anticancer activity have been reported, but few chalcone substituted other heterocycles, for example piperidine, morpholine, have been documented in the literature.^[21] Based on the above observations, we have synthesized chalcone derivatives containing heterocyclic nitrogen. The synthesized compounds act as potential anticancer agents.

  2.   Results and discussion

  2.1   Synthesis

  The synthetic route of the proposed compounds 4a~4s is shown in Scheme 1. First, the acetophenones derivatives 3a~3c were obtained by the reaction of 4-fluorophenyle- thanone with piperidine, morpholine, and 1-methylpipera- zine with stirring at reflux according to literature procedures. In the present investigation, substituted chalcones were prepared by the Claisen-Schmidt condensation of substituted 1-phenylethanone and substituted benzaldehyde with NaOH (aq.) as base in high yield by a known literature method. All chalcones were prepared from the corresponding reactants in 38%~87% yields. Comparative data for novel derivatives with respective to structures, melting point and yield are provided in Table 1. A range of benzaldehydes, with electronrich or electron-poor substituents on the aryl rings at different positions, were well-tolerated for the condensation reaction, giving the corresponding products. The heterocyclic aldehydes were also found to be suitable reaction partners for oxygen- and nitrogen-containing aromatics, and the corresponding products were obtained.

  Scheme 1

  

  Scheme 1.  Synthesis of chalcone derivatives 4a~4s

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  Table 1

  

  Table 1.  Physical data of compounds 4a~4s

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  Compd.	X	Ar	Yield/%	m.p./℃
  4a	CH2	3, 4-(OCH2O)C6H3	76	170~173
  4b	CH2	3-CH3O-4-HOCH2CH2OC6H3	65	167~170
  4c	CH2	3-CH3OC6H4	44	160~163
  4d	CH2	4-(CH3)2NC6H4	58	214~218
  4e	CH2	2-Furyl	69	179~180
  4f	CH2	2-Pyridyl	72	167~170
  4g	O	3, 4-(OCH2O)C6H3	76	167~171
  4h	O	3-CH3O-4-HOCH2CH2OC6H3	41	165~168
  4i	O	3-CH3OC6H4	87	130~133
  4j	O	4-(CH3)2NC6H4	77	226~226
  4k	O	4-BrC6H4	79	213~216
  4l	O	2, 4-Cl2C6H3	40	147~148
  4m	O	2-Furyl	38	195~197
  4n	O	2-Pyridyl	52	150~153
  4o	CH3N	3, 4-(OCH2O)C6H3	52	155~158
  4p	CH3N	3-CH3O-4-HOCH2CH2OC6H3	54	185~188
  4q	CH3N	3-CH3OC6H4	46	147~149
  4r	CH3N	4-(CH3)2NC6H4	57	198~201
  4s	CH3N	2-Furyl	39	179~182
  Reaction conditions: 3 (1.0 mmol), aldehyde (1.0 mmol), 50% KOH (aq.) (1.0 mL), MeOH (3 mL), isolated yields.

  2.2   Spectra

  The structures of the obtained compounds 4a~4s were confirmed by ¹H NMR, ¹³C NMR and HRMS spectral data. In the ¹H NMR spectra of the compounds, the CH protons of the olefin resonated as a doublet at δ 7.58~8.17 and 7.41~8.09, respectively. The large coupling constant of the olefinic protons confirms the trans configuration. In general, IR spectra of these compounds exhibited the presence of absorption bands for C＝O between 1639~1649 cm^－1.

  2.3   Biological studies

  All the synthesized chalcone derivatives bearing a heterocyclic nitrogen moiety 4a~4s were evaluated for their anticancer activity in vitro against five cancer cell lines, MCF-7 (human breast adenocarcinoma cell line), A549 (human lung adenocarcinoma epithelial cell line), HL-60 (human leukemia cell line), Hela (human cervical cancer cell line), and Bewo (Human chorionic tumor cell line), using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetra- zolium bromide (MTT) assay method and compared with the well-known anticancer drug cisplatin. The anticancer activity results are shown in Table 2. The results showed that the structures of compounds had an obvious influence on anticancer activities. Among all compounds, there were three series of substituents of core benzene ring, including piperidino, morpholino, and 1-methylpiperazino. In generally, derivatives containing piperidino were more potent than compounds with other substituted groups. For example, compound 4a displayed the best anticancer activity against five cancer cell lines [for MCF-7 (IC₅₀＝8.70 μmol/L), A549 (IC₅₀＝9.72 μmol/L), HL-60 (IC₅₀＝7.15 μmol/L), Hela (IC₅₀＝12.88 μmol/L), and Bewo (IC₅₀＝18.81 μmol/L)]. Among all synthesized derivatives, compound 4j showed the highest anticancer activity against MCF-7 with an IC₅₀ value of 4.63 μmol/L, and better than cisplatin against MCF-7 cells. Compound 4j also displayed the best anticancer activity for HL-60 cells (IC₅₀＝6.00 μmol/L), compounds 4e, 4f, 4m, and 4o also showed selected anticancer activity against HL-60 cell lines. According to the result, it is found that most chalcone derivatives were non-sensitive to Hela cells. Compound 4a showed the most anticancer activity (IC₅₀＝12.88 μmol/L), and compounds 4c, 4d, 4h, 4j, and 4n had weak anticancer activity for Hela (IC₅₀ < 50 μmol/L). All compounds, except for 4a, showed anticancer activity against Bewo cells at an IC₅₀ level of > 50 μmol/L.

  Table 2

  

  Table 2.  In vitro anticancer activity of the title compounds 4a~4s against MCF-7, A549, HL-60, Hela, and Bewo cancer cell lines

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  Compd.	IC50a/(μmol·L－1)
  	MCF-7	A549	HL-60	Hela	Bewo
  4a	8.70	9.72	7.15	12.88	18.81
  4b	14.99	> 50	22.51	> 50	> 50
  4c	21.50	> 50	12.62	42.92	> 50
  4d	17.59	44.99	49.35	45.37	> 50
  4e	10.78	> 50	8.77	> 50	> 50
  4f	26.73	> 50	9.62	> 50	> 50
  4g	> 50	> 50	> 50	> 50	> 50
  4h	19.39	43.63	26.63	32.43	> 50
  4i	> 50	> 50	14.98	> 50	> 50
  4j	4.63	35.62	6.00	39.24	> 50
  4k	> 50	> 50	> 50	> 50	> 50
  4l	> 50	> 50	> 50	> 50	> 50
  4m	15.69	> 50	9.11	> 50	> 50
  4n	16.58	44.19	11.37	25.29	> 50
  4o	39.46	> 50	8.15	> 50	> 50
  4p	> 50	> 50	> 50	> 50	> 50
  4q	23.52	45.49	> 50	> 50	> 50
  4r	> 50	> 50	24.86	> 50	> 50
  4s	24.43	> 50	13.67	> 50	> 50
  Cisplatin	8.75	2.65	2.90	0.59	2.24
  a Anticancer activity was assayed by exposure for 48 h to the tested substances and expressed as the concentration required to inhibit tumour cell proliferation by 50% (IC50).

  The compounds 4a~4e containing piperidine group have significant potent anticancer activity (IC₅₀＝8.70~10.78 μmol/L) against MCF-7 as compared to the other compounds 4g~4i, 4m and 4o~4s containing morpholine or methylpiperazine groups as shown in Table 2. These data indicated that the activity of compounds 4a~4e was considerably attributed to the presence of piperidine group. The compound 4a with substituted C-3 phenyl ring [3, 4-(OCH₂O)] showed to have good activity (IC₅₀＝8.70 μmol/L). The change of 3, 4-(OCH₂O) group to 3-CH₃O4-HOCH₂CH₂O, 3-CH₃O, and 4-(CH₃)₂N did not show good activity. The activity of compound 4e which C-3 phenyl ring was changed to furanyl ring was similar to that of compound 4a. In the case of HL-60, investigation of structure-activity relationship (SAR) revealed that compounds 44, 4e, 4f, 4j, 4m and 4o (IC₅₀ < 10.0 μmol/L) have a significant potent activity against HL-60 as compared to the standard drug cisplatin (IC₅₀＝2.90 μmol/L) as shown in Table 2. This potency due to the presence of 3, 4-(OCH₂O) and 4-(CH₃)₂N group at C-3 phenyl ring in compounds 4a, 4j and 4o (IC₅₀＝7.15, 6.00 and 8.15 μmol/L), or furyl and pyridyl ring at C-3 in compounds 4e and 4f (IC₅₀＝8.77 and 9.62 μmol/L). In the case of A549, Hela, and Bewo, compound 4a also retained the activity (IC₅₀＝9.72, 12.88 and 18.81 μmol/L), and the other compounds showed lower or no anticancer activity in three cell lines. It indicated the importance of the type of piperidine group and 3, 4-(OCH₂O)-substituted group.

  3.   Conclusions

  In summary, a series of chalcone derivatives have been synthesized and the effects of all the compounds on anticancer activity of five cancer cell lines (MCF-7, A549, HL-60, Hela, and Bewo) were investigated. Compounds 4a, 4e, 4f, 4j, 4m, and 4o displayed the best anticancer activity for MCF-7 breast cancer cells, A549, lung cancer cells, and HL-60 leukemia cancer cells, respectively (IC₅₀ < 10 μmol/L). Moreover, compound 4a had inhibitory effects on the growth of five cancer cell lines.

  4.   Experimental

  4.1   Experimental details

  Under otherwise noted, materials were obtained from Aladdin Co., Ltd. and used without further purification. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and visualized using UV light. Column chromatography was performed with silica gel (mesh 300~400). NMR spectra were obtained on a Bruker Avance 500 spectrometer (¹H NMR at 500 Hz, ¹³C NMR at 125 Hz) in CDCl₃ or DMSO-d₆ using TMS as an internal standard. High-resolution mass spectra (HRMS) were measured on a high resolution mass spectrometer (GCT Premier). Infrared spectra (IR) were obtained on a 370 FT-IR spectrometer.

  4.2   4-Subtitued acetophenone 3a~3c

  These were synthesized as described in previous work.^[22]

  4.3   General procedure for synthesis of (E)-chal- cones (4)

  To a mixture of acetophenone (1.0 mmol) and aldehyde (1.0 mmol) in methanol (10 mL) was added 50% KOH (aq.) (1 mL). The resulting mixture was stirred for 10 h at reflux. The reaction mixture was cooled to room temperature. After evaporation of methanol and added water, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na₂SO₄. The crude residue was obtained after evaporation of the solvent in vacuum, and the residue was purified by flash chromatography with petroleum and EtOAc as the eluent to give the pure product.

  (E)-3-(1, 3-Benzodioxol-5-yl)-1-(4-piperidinyl)phenyl-2-propen-1-one (4a): 1-(4-(Piperidin-1-yl)phenyl)ethan-1- one (204.1 mg, 1.0 mmol) and benzo[d]^{[1, 3]}dioxole-5- carbaldehyde (149.9 mg, 1.0 mmol) in methanol (10 mL) was reacted according to the general procedure for compounds 4 to give the product 4a (253.2 mg, 76% yield).R_f＝0.45 [V(petroleum ether):V(ethyl acetate)＝3:1]. Yellow solid, m.p. 170~173 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 7.98 (d, J＝9.0 Hz, 2H), 7.72 (d, J＝15.5 Hz, 1H), 7.42 (d, J＝15.5 Hz, 1H), 7.18 (d, J＝1.3 Hz, 1H), 7.12 (dd, J＝8.0, 1.3 Hz, 1H), 6.91 (d, J＝9.0 Hz, 2H), 6.85 (d, J＝8.0 Hz, 1H), 6.03 (s, 2H), 3.39 (t, J＝4.9 Hz, 2H), 1.68~1.70 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 187.4, 154.0, 149.2, 148.1, 142.4, 130.5, 129.7, 127.3, 124.6, 120.0, 113.3, 108.5, 106.5, 101.4, 48.6, 25.5, 24.5; IR (KBr) ν: 2935, 1651, 1600, 1499, 1360, 1196, 1124, 1034 cm^－1. HRMS (ESI) calcd for C₂₁H₂₂NO₃ [M+H]⁺: 226.1600, found 226.1603.

  (E)-3-[(3-Methoxyphenyl-4-(2-hydroxyethoxy)]-1-(4-piperidinyl)phenyl-2-propen-1-one (4b): R_f＝0.2 [V(petro-leum ether):V(ethyl acetate)＝1:1]. Yellow solid, m.p. 167~170 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 7.99 (d, J＝8.9 Hz, 2H), 7.73 (d, J＝15.5 Hz, 1H), 7.45 (d, J＝15.5 Hz, 1H), 7.21 (dd, J＝8.3, 1.4 Hz, 1H), 7.16 (d, J＝1.4 Hz, 1H), 6.93 (d, J＝8.3 Hz, 1H), 6.90 (d, J＝8.9 Hz, 2H), 4.18 (t, J＝4.4 Hz, 2H), 4.00~3.99 (m, 2H), 3.93 (s, 3H), 3.39 (t, J＝5.4 Hz, 4H), 2.79 (s, 1H), 1.69~1.67 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.9, 150.1, 149.9, 142.8, 130.8, 129.4, 122.5, 120.6, 114.2, 113.5, 110.9, 71.1, 61.3, 56.0, 48.7, 25.4, 24.4; IR (KBr) ν: 3537, 2939, 1643, 1609, 1511, 1268, 1207, 1033 cm^－1. HRMS (ESI) calcd for C₂₃H₂₈NO₄ [M+H]⁺: 382.2018; found 382.2014.

  (E)-3-(3-Methoxyphenyl)-1-(4-piperidinyl)phenyl-2-propen-1-one (4c): R_f＝0.25 [V(petroleum ether):V(ethyl acetate)＝10:1). Yellow solid, m.p. 160~163 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.00 (d, J＝8.9 Hz, 2H), 7.76 (d, J＝15.6 Hz, 1H), 7.56 (d, J＝15.6 Hz, 1H), 7.34 (t, J＝7.8 Hz, 1H), 7.25 (d, J＝7.8 Hz, 1H), 7.17 (d, J＝2.1 Hz, 1H), 6.96~6.92 (m, 3H), 3.87 (s, 3H), 3.41 (t, J＝4.9 Hz, 4H), 1.66~1.72 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.9, 159.9, 142.8, 136.9, 130.9, 129.9, 122.6, 120.9, 115.8, 113.5, 113.4, 55.4, 48.7, 25.4, 24.4; IR (KBr) ν: 3420, 2945, 2849, 1649, 1592, 1384, 1251, 1127, 1040 cm^－1. HRMS (ESI) calcd for C₂₁H₂₄NO₂ [M+H]⁺: 322.1807, found 322.1809.

  (E)-3-[(4-Dimethylamino)phenyl]-1-(4-piperidinyl)-phenyl-2-propen-1-one (4d): R_f＝0.23 [V(petroleum ether):V(ethyl acetate)＝1:1]. Yellow solid, m.p. 214~218 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.00 (d, J＝8.8 Hz, 2H), 7.79 (d, J＝15.4 Hz, 1H), 7.56 (d, J＝8.8 Hz, 2H), 7.41 (d, J＝15.4 Hz, 1H), 6.91 (d, J＝8.8 Hz, 2H), 6.71 (d, J＝8.8 Hz, 2H), 3.38 (t, J＝5.1 Hz, 4H), 3.04 (s, 6H), 1.74~1.62 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 188.2, 151.7, 143.8, 130.4, 130.0, 123.3, 117.1, 113.6, 111.9, 48.8, 40.2, 25.4, 24.3; IR (KBr) ν: 3408, 2933, 2854, 1732, 1641, 1599, 1228, 1029 cm^－1. HRMS (ESI) calcd for C₂₂H₂₇N₂O [M+H]⁺: 335.2123, found 335.2118.

  (E)-3-(3-Furan-2-yl)-1-(4-piperidinyl)phenyl-2-propen-1-one (4e): R_f＝0.32 [V(petroleum ether):V(ethyl aceta-te)＝5:1];]. Yyellow solid, m.p. 179~180 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.01 (d, J＝8.9 Hz, 2H), 7.58 (d, J＝15.5 Hz, 1H), 7.52~7.48 (m, 2H), 6.98~6.84 (m, 2H), 6.68 (d, J＝3.4 Hz, 1H), 6.52~6.50 (m, 1H), 3.41 (t, J＝4.1 Hz, 4H), 1.69~1.62 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.3, 152.1, 144.4, 130.7, 129.1, 119.6, 115.1, 113.5, 112.5, 48.7, 25.4, 24.3; IR (KBr) ν: 3429, 2940, 2922, 2854, 1647, 1603, 1387, 1234, 1194, 1123, 1020 cm^－1. HRMS (ESI) calcd for C₁₈H₂₀NO₂ [M+H]⁺: 282.1494; found 282.1490.

  (E)-3-(Pyridin-2-yl)-1-(4-piperidinyl)phenyl-2-propen-1-one (4f): R_f＝0.25 [V(petroleum ether):V(ethyl aceta-te)＝3:1]. Yellow solid, m.p. 167~170 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.70 (d, J＝4.0 Hz, 1H), 8.17 (d, J＝15.2 Hz, 1H), 8.07 (d, J＝9.0 Hz, 2H), 7.76 (d, J＝15.2 Hz, 1H), 7.76~7.72 (m, 1H), 7.47 (d, J＝7.8 Hz, 1H), 7.29~7.27 (m, 1H), 6.90 (d, J＝9.0 Hz, 2H), 3.41 (t, J＝4.8 Hz, 4H), 1.70~1.68 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.6, 154.4, 153.7, 150.0, 140.8, 136.8, 131.1, 126.9, 125.8, 125.1, 123.9, 113.2, 48.4, 25.3, 24.3; IR (KBr) ν: 3421, 2934, 1647, 1588, 1392, 1192, 1126, 994 cm^－1. HRMS (ESI) calcd for C₁₉H₂₁N₂O [M+H]⁺: 293.1654; found 293.1655.

  (E)-3-(1, 3-Benzodioxol-5-yl)-1-[4-(4-morpholinyl)phen-yl]-2-propen-1-one (4g) (CAS: 305859-40-9): R_f＝0.19 [V(petroleum ether):V(ethyl acetate)＝3:1]. Yellow solid, m.p. 167~171 ℃ (CAS:305859-40-9); ¹H NMR (500 MHz, CDCl₃) δ: 8.01 (d, J＝9.0 Hz, 2H), 7.74 (d, J＝15.5 Hz, 1H), 7.42 (d, J＝15.5 Hz, 1H), 7.19 (d, J＝1.5 Hz, 1H), 7.13 (dd, J＝8.0, 1.5 Hz, 1H), 6.93 (d, J＝9.0 Hz, 2H), 6.86 (d, J＝8.0 Hz, 1H), 6.04 (s, 2H), 3.89 (t, J＝4.9 Hz, 4H), 3.35 (t, J＝4.9 Hz, 4H).

  (E)-3-[(3-Methoxyphenyl-4-(2-hydroxyethoxy)]-1-[4-(4-morpholinyl)phenyl]-2-propen-1-one (4h): R_f＝0.13 [V(petroleum ether):V(ethyl acetate)＝1:1]. Yellow solid, m.p. 165~168 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.02 (d, J＝8.8 Hz, 2H), 7.75 (d, J＝15.6 Hz, 1H), 7.44 (d, J＝15.6 Hz, 1H), 7.23 (dd, J＝8.2, 1.6 Hz, 1H), 7.17 (d, J＝1.6 Hz, 1H), 6.96~6.92 (m, 3H), 4.19 (t, J＝4.4 Hz, 2H), 4.01~3.99 (m, 2H), 3.95 (s, 3H), 3.88 (t, J＝4.8 Hz, 4H), 3.35 (t, J＝4.8 Hz, 4H), 2.54 (t, J＝6.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 188.2, 154.0, 150.2, 149.9, 143.3, 130.6, 129.2, 122.5, 120.4, 114.1, 113.6, 110.9, 71.1, 66.6, 61.2, 56.0, 47.7; IR (KBr) ν: 3539, 2966, 2858, 1641, 1607, 1508, 1266, 1032 cm^－1. HRMS (ESI) calcd for C₂₂H₂₆NO₅ [M+H]⁺: 384.1811; found 384.1808.

  (E)-3-(3-Methoxyphenyl)-1-[4-(4-morpholinyl)phenyl]-2-propen-1-one (4i) (CAS: 850351-83-6): R_f＝0.2 [V(petroleum ethe):V(ethyl acetate)＝3:1]. Yellow solid, m.p. 130~133 ℃ (CAS:850351-83-6); ¹H NMR (500 MHz, CDCl₃) δ: 8.03 (d, J＝8.9 Hz, 2H), 7.77 (d, J＝15.6 Hz, 1H), 7.55 (d, J＝15.6 Hz, 1H), 7.34 (t, J＝7.8 Hz, 1H), 7.26 (d, J＝7.8 Hz, 1H), 7.17 (s, 1H), 6.97~6.94 (m, 1H), 6.93 (d, J＝8.9 Hz, 2H), 3.89~3.88 (m, 4H), 3.87 (s, 3H), 3.35 (t, J＝5.0 Hz, 4H).

  (E)-3-[(4-Dimethylamino)phenyl]-1-[4-(4-morpholinyl)-phenyl]-2-propen-1-one (4j) (CAS: 1004038-07-6): R_f＝0.35 [V(petroleum ether):V(ethyl acetate)＝2:1]; yellow solid, m.p. 226~228 ℃ (CAS: 1004038-07-6); ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J＝8.9 Hz, 2H), 7.80 (d, J＝15.4 Hz, 1H), 7.56 (d, J＝8.8 Hz, 2H), 7.39 (d, J＝15.4 Hz, 1H), 6.93 (d, J＝8.9 Hz, 2H), 6.71 (d, J＝8.8 Hz, 2H), 3.88 (t, J＝4.9 Hz, 4H), 3.35 (t, J＝4.9 Hz, 4H), 3.05 (s, 6H).

  (E)-3-(4-Bromophenyl)-1-[4-(4-morpholinyl)phenyl]-2-propen-1-one (4k)^[23]: R_f＝0.26 [V(petroleum ether):V(ethyl acetate)＝3:1];]. Yyellow solid, m.p. 213~216 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.02 (d, J＝9.0 Hz, 2H), 7.73 (d, J＝15.6 Hz, 1H), 7.57~7.50 (m, 5H), 6.93 (d, J＝9.0 Hz, 2H), 3.88 (t, J＝4.9 Hz, 4H), 3.55 (t, J＝4.9 Hz, 4H).

  (E)-3-(2, 4-Dichlorophenyl)-1-[4-(4-morpholinyl)phen-yl]-2-propen-1-one (4l) (CAS: 796989-79-2): R_f＝0.33 [V(petroleum ether):V(ethyl acetate)＝3:1]. Yellow solid, m.p. 147~148 ℃ (CAS: 796989-79-2); ¹H NMR (500 MHz, CDCl₃) δ: 8.09 (d, J＝15.7 Hz, 1H), 8.01 (d, J＝8.9 Hz, 2H), 7.69 (d, J＝8.5 Hz, 1H), 7.51 (d, J＝15.7 Hz, 1H), 7.48 (d, J＝2.0 Hz, 1H), 7.31 (dd, J＝8.5, 2.0 Hz, 1H), 6.93 (d, J＝8.9 Hz, 2H), 3.89 (t, J＝5.0 Hz, 4H), 3.36 (t, J＝5.0 Hz, 4H).

  (E)-3-(3-Furan-2-yl)-1-[4-(4-morpholinyl)phenyl]-2-propen-1-one (4m): R_f＝0.3 [V(petroleum ether):V(ethyl acetate)＝3:1]. Yellow solid, m.p. 195~197 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.03 (d, J＝9.0 Hz, 2H), 7.59 (d, J＝15.3 Hz, 1H), 7.53 (d, J＝1.7 Hz, 1H), 7.50 (d, J＝15.3 Hz, 1H), 6.94 (d, J＝9.0 Hz, 2H), 6.70 (d, J＝3.4 Hz, 1H), 6.52 (dd, J＝3.4, 1.7 Hz, 1H), 3.89 (t, J＝4.9 Hz, 4H), 3.35 (t, J＝4.9 Hz, 4H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.6, 154.1, 152.0, 144.5, 130.6, 129.5, 128.9, 119.4, 115.4, 113.5, 112.5, 66.6, 47.6; IR (KBr) ν: 3457, 2974, 2850, 1647, 1604, 1384, 1231, 1193, 1130, 1025 cm^－1. HRMS (ESI) calcd for C₁₇H₁₈NO₃ [M+H]⁺: 284.1287; found 284.1287.

  (E)-3-(Pyridin-2-yl)-1-[4-(4-morpholinyl)phenyl]-2-propen-1-one (4n): R_f＝0.41 [V(petroleum ether):V(ethyl acetate)＝3:1]. Yellow solid, m.p. 150~153 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.69 (d, J＝3.9 Hz, 1H), 8.15 (d, J＝15.2 Hz, 1H), 8.09 (d, J＝9.0 Hz, 2H), 7.76 (d, J＝15.2 Hz, 1H), 7.75~7.72 (m, 1H), 7.47 (d, J＝7.7 Hz, 1H), 7.30~7.28 (m, 1H), 6.91 (d, J＝9.0 Hz, 2H), 3.87 (t, J＝4.9 Hz, 4H), 3.35 (t, J＝4.9 Hz, 4H); ¹³C NMR (125 MHz, CDCl₃) δ: 188.0, 154.3, 153.6, 150.1, 141.3, 136.9, 130.9, 128.6, 125.7, 125.3, 124.1, 113.3, 66.6, 47.4; IR (KBr) ν: 3463, 2960, 1656, 1591, 1382, 1193, 1117, 1049 cm^－1. HRMS (ESI) calcd for C₁₈H₁₉N₂O₂ [M+H]⁺: 295.1447; found 295.1448.

  (E)-3-(1, 3-Benzodioxol-5-yl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-2-propen-1-one (4o): R_f＝0.45 (ethyl acetate). Yellow solid, m.p. 155~158 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.00 (d, J＝8.9 Hz, 2H), 7.73 (d, J＝15.5 Hz, 1H), 7.41 (d, J＝15.5 Hz, 1H), 7.18 (d, J＝1.6 Hz, 1H), 7.13 (dd, J＝8.0, 1.6 Hz, 1H), 6.93 (d, J＝8.9 Hz, 2H), 6.85 (d, J＝8.0 Hz, 1H), 6.03 (s, 2H), 3.42 (t, J＝4.9 Hz, 4H), 2.60 (t, J＝4.9 Hz, 4H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 153.7, 149.3, 148.1, 142.8, 130.4, 129.7, 128.3, 124.7, 119.9, 113.5, 108.5, 106.5, 101.4, 54.7, 47.3, 46.1; IR (KBr) ν: 3418, 2904, 1647, 1609, 1384, 1250, 1198, 1037, 810 cm^－1. HRMS (ESI) calcd for C₂₁H₂₃N₂O₃ [M+H]⁺: 351.1709; found 351.1711.

  (E)-3-[(3-Methoxyphenyl-4-(2-hydroxyethoxy)]-1-[4-(4-methylpiperazin-1-yl)phenyl]-2-propen-1-one (4p): R_f＝0.18 (ethyl acetate). Yellow solid, m.p. 185~188 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.01 (d, J＝8.9 Hz, 2H), 7.75 (d, J＝15.6 Hz, 1H), 7.44 (d, J＝15.6 Hz, 1H), 7.23 (dd, J＝8.3, 1.7 Hz, 1H), 7.17 (d, J＝1.7 Hz, 1H), 6.95~6.92 (m, 3H), 4.19 (t, J＝4.5 Hz, 2H), 4.00 (t, J＝4.5 Hz, 2H), 3.94 (s, 3H), 3.42 (t, J＝4.9 Hz, 4H), 2.59 (t, J＝4.9 Hz, 4H), 2.38 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 188.2, 154.1, 150.2, 149.9, 143.2, 130.7, 129.3, 128.6, 122.5, 120.5, 114.1, 113.7, 110.9, 71.1, 61.3, 56.0, 54.8, 47.3, 46.1; IR (KBr) ν: 3414, 2939, 2844, 1644, 1599, 1511, 1269, 1141, 1032 cm^－1. HRMS (ESI) calcd for C₂₃H₂₉N₂O₄ [M+H]⁺: 397.2127; found 397.2123.

  (E)-3-(3-Methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-2-propen-1-one (4q): R_f＝0.21 (ethyl acetate). Yellow solid, m.p. 147~149 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J＝8.9 Hz, 2H), 7.73 (d, J＝15.6 Hz, 1H), 7.52 (d, J＝15.6 Hz, 1H), 7.31 (t, J＝7.7 Hz, 1H), 7.22 (d, J＝7.7 Hz, 1H), 7.13 (t, J＝1.9 Hz, 1H), 6.93~6.92 (m, 1H), 6.90 (d, J＝8.9 Hz, 2H), 3.85 (s, 3H), 3.39 (t, J＝4.9 Hz, 4H), 2.56 (t, J＝4.9 Hz, 4H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.7, 159.7, 153.8, 142.8, 136.5, 130.5, 129.7, 128.1, 122.2, 120.8, 115.6, 113.4, 113.2, 55.4, 54.7, 47.3, 46.2; IR (KBr) ν: 3473, 2936, 1660, 1603, 1382, 1250, 1203, 1053 cm^－1. HRMS (ESI) calcd for C₂₁H₂₅N₂O₂ [M+H]⁺: 337.1916; found 337.1919.

  (E)-3-[(4-Dimethylamino)phenyl]-1-[4-(4-methylpipe-razin-1-yl)phenyl]-2-propen-1-one (4r): R_f＝0.19 (ethyl acetate). Yellow solid, m.p. 198~201 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.01 (d, J＝8.9 Hz, 2H), 7.79 (d, J＝15.4 Hz, 1H), 7.56 (d, J＝8.8 Hz, 2H), 7.39 (d, J＝15.4 Hz, 1H), 6.93 (d, J＝8.9 Hz, 2H), 6.71 (d, J＝8.8 Hz, 2H), 3.40 (t, J＝5.0 Hz, 4H), 3.04 (s, 6H), 2.58 (t, J＝5.0 Hz, 4H), 2.37 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 188.0, 153.5, 151.5, 143.9, 130.2, 129.9, 129.0, 122.9, 116.8, 113.5, 111.7, 54.8, 47.4, 46.2, 40.2; IR (KBr) ν: 3455, 2936, 2795, 1636, 1598, 1518, 1231, 1180, 1033 cm^－1. HRMS (ESI) calcd for C₂₂H₂₈N₃O [M+H]⁺: 350.2232; found 350.2231.

  (E)-3-(3-Furan-2-yl)-1-[4-(4-methylpiperazin-1-yl)-phenyl]-2-propen-1-one (4s): R_f＝0.15 (ethyl acetate). Yellow solid, m.p. 179~182 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (d, J＝8.9 Hz, 2H), 7.55 (d, J＝15.3 Hz, 1H), 7.49~7.44 (m, 2H), 6.89 (d, J＝8.9 Hz, 2H), 6.65 (d, J＝3.3 Hz, 1H), 6.48 (dd, J＝3.3, 1.7 Hz, 1H), 3.39 (t, J＝4.9 Hz, 4H), 2.56 (t, J＝4.9 Hz, 4H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 187.4, 154.0, 152.1, 144.4, 130.6, 129.3, 128.3, 119.5, 115.2, 113.5, 112.5, 54.7, 47.2, 46.1; IR (KBr) ν: 3416, 2845, 1647, 1602, 1383, 1233, 1187, 1019, 923 cm^－1. HRMS (ESI) calcd for C₁₈H₂₁N₂O₂ [M+H]⁺: 297.1603; found 297.1606.

  4.4   Cytotoxic activity

  For observing the anticancer activity of the target compounds in vitro, MTT assay was used. MCF-7, A549, HL-60, Hela, and Bewo cells were harvested in the logarithmic growth phase and seeded in 96-well plates, and cultured at 37 ℃ in humidified atmosphere containing 5% CO₂ in Dulbecco's Modified Eagle Medium (DMEM) with 10% FBS for 24 h before any treatments. Tested compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted in the culture fluid to get various concentrations. The cells were treated with target compounds subsequently and incubated 24 h. Then 20 μL of MTT (5 mg/mL) was added in a 37 ℃, 5% CO₂ incubator for 4 h, the medium was removed immediately and MTT formazan was solubilized in 150 μL of DMSO. Cell survival was assayed by enzyme-labeled instrument. Inhibitory effects were determined as IC₅₀ value.^[23]

  Supporting Information The electronic supplementary information (ESI) available free of charge via the Internet at http://sioc-journal.cn/.

• 1. [1]

     Lahtchev, K. L.; Batovska, D. I.; Parushev, S. P.; Ubiyvovk, V. M.; Sibirny, A. A. Eur. J. Med. Chem. 2008, 43, 2220. doi: 10.1016/j.ejmech.2007.12.027

  2. [2]

     (a) Kantevari, S.; Addla, D.; Bagul, P. K.; Sridhar, B.; Banerjee, S. K. Bioorg. Med. Chem. 2011, 19, 4772.
     (b) Yan, Y. K.; Xu, Q.; Gao, Y.; Liu, H.; Tang, X. R. Chin. J. Org. Chem. 2018, 38, 1763(in Chinese).
     (严映坤, 徐侨, 高扬, 刘辉, 唐孝荣, 有机化学, 2018, 38, 1763.) http://sioc-journal.cn/Jwk_yjhx/CN/abstract/abstract346500.shtml

  3. [3]

     (a) Cho, S.; Kim, S.; Jin, Z.; Yang, H.; Han, D.; Baek, N. I.; Jo, J.; Cho, C. W.; Park, J. H.; Shimizu, M.; Jin, Y. H. Res. Commun. 2011, 413, 637.
     (b) Zhang, E.; Wang, M. M.; Xu, S. M.; Wang, S.; Zhao, D.; Bai, P. Y.; Cui, D. Y.; Hua, Y. G.; Wang, Y. N.; Qin, S. S; Liu, H. M. Chin. J. Org. Chem. 2017, 37, 959(in Chinese).
     (张恩, 王铭铭, 徐帅民, 王上, 赵娣, 白鹏燕, 崔得运, 化永刚, 王亚娜, 秦上尚, 刘宏民, 有机化学, 2017, 37, 959.) http://sioc-journal.cn/Jwk_yjhx/CN/Y2017/V37/I4/959

  4. [4]

     Sato, Y.; He, J.; Nagai, H.; Tani, T.; Akao, T. Biol. Pharm. Bull. 2007, 30, 145. doi: 10.1248/bpb.30.145

  5. [5]

     Luo, Y.; Song, R.; Li, Y.; Zhang, S.; Liu, Z. J.; Fu, J.; Zhu, H. L. Bioorg. Med. Chem. Lett. 2012, 22, 3039. doi: 10.1016/j.bmcl.2012.03.080

  6. [6]

     Zhao, L.; Jin, H.; Sun, L.; Piao, H.; Quan, Z. Bioorg. Med. Chem. Lett. 2005, 15, 5027. doi: 10.1016/j.bmcl.2005.08.039

  7. [7]

     Mahapatra, D. K.; Asati, V.; Bharti, S. K. Eur. J. Med. Chem. 2015, 92, 839. doi: 10.1016/j.ejmech.2015.01.051

  8. [8]

     Mascarello, A.; Chiaradia, L. D.; Vernal, J.; Villarino, A.; Guido, R. V.; Perizzolo, P.; Poirier, V.; Wong, D.; Martins, P. G.; Nunes, R. J.; Yunes, R. A.; Andricopulo, A. D.; Av-Gay, Y.; Terenzi, H. Bioorg. Med. Chem. 2010, 18, 3783. doi: 10.1016/j.bmc.2010.04.051

  9. [9]

     Mahapatra, D. K.; Bharti, S. K.; Asati, V. Eur. J. Med. Chem. 2015, 98, 69. doi: 10.1016/j.ejmech.2015.05.004

  10. [10]

      Lee, Y. S.; Lim, S. S.; Shin, K. H.; Kim, Y. S.; Ohuchi, K.; Jung, S. H. Biol. Pharm. Bull. 2006, 29, 1028. doi: 10.1248/bpb.29.1028

  11. [11]

      Aoki, N.; Muko, M.; Ohta, E.; Ohta, S. J. Nat. Prod. 2008, 71, 1308. doi: 10.1021/np800187f

  12. [12]

      Sashidhara, K. V.; Palnati, G. R.; Sonkar, R.; Avula, S. R.; Awasthi, C.; Bhatia, G. Eur. J. Med. Chem. 2013, 64, 422. doi: 10.1016/j.ejmech.2013.04.026

  13. [13]

      Sashidhara, K. V.; Rao, K. B.; Kushwaha, V.; Modukuri, R. K.; Verma, R.; Murthy, P. K. Eur. J. Med. Chem. 2014, 81, 473. doi: 10.1016/j.ejmech.2014.05.029

  14. [14]

      Rizvi, S. U. F.; Siddiqui, H. L.; Johns, M.; Detorio, M.; Schinazi, R. F. Med. Chem. Res. 2012, 21, 3741. doi: 10.1007/s00044-011-9912-x

  15. [15]

      Tomar, V.; Bhattacharjee, G.; Kamaluddin; Rajakumar, S.; Srivastava, K.; Puri, S. K. Eur. J. Med. Chem. 2010, 45, 745. doi: 10.1016/j.ejmech.2009.11.022

  16. [16]

      Abdullah, M. I.; Mahmood, A.; Madni, M.; Masood, S.; Kashif, M. Bioorg. Chem. 2014, 54, 31. doi: 10.1016/j.bioorg.2014.03.006

  17. [17]

      Sashidhara, K. V.; Avula, S. R.; Mishra, V.; Palnati, G. R.; Singh, L. R.; Singh, N.; Chhonker, Y. S.; Swamy, P.; Bhatta, R. S.; Palit, G. Eur. J. Med. Chem. 2015, 89, 638. doi: 10.1016/j.ejmech.2014.10.068

  18. [18]

      Yarishkin, O. V.; Ryu, H. W.; Park, J.; Yang, M. S.; Hong, S.; Park, K. H. Bioorg. Med. Chem. Lett. 2008, 18, 137. doi: 10.1016/j.bmcl.2007.10.114

  19. [19]

      Wang, L.; Chen, G.; Lu, X.; Wang, S.; Hans, S.; Li, Y.; Ping, G.; Jiang, X.; Li, H.; Yang, J.; Wu, C. Eur. J. Med. Chem. 2015, 89, 88. doi: 10.1016/j.ejmech.2014.10.036

  20. [20]

      Yamamoto, T.; Yoshimura, M.; Yamaguchi, F.; Kouchi, T.; Tsuji, R.; Saito, M.; Obata, A.; Kikuchi, M. Biosci. Biotechnol. Biochem. 2004, 68, 1706. doi: 10.1271/bbb.68.1706

  21. [21]

      高慧, 郑喜, 祁燕, 王斯, 万春平, 饶高雄, 毛泽伟, 有机化学, 2018, 38, 648. http://sioc-journal.cn/Jwk_yjhx/CN/abstract/abstract346358.shtmlGao, H.; Zheng, X.; Qi, Y.; Wang, S.; Wan, C. P.; Rao, G. X.; Mao, Z. W. Chin. J. Org. Chem. 2018, 38, 648(in Chinese). http://sioc-journal.cn/Jwk_yjhx/CN/abstract/abstract346358.shtml

  22. [22]

      Thanusu, J.; Kanagarajan, V.; Gopalakrishnan, M. J. Enzyme Inhib. Med. Chem. 2010, 25, 347. doi: 10.3109/14756360903179468

  23. [23]

      Ramya, V.; Vembu, S.; Ariharasivakumar, G.; Gopalakrishnan, M. Pharma Chem. 2017, 9, 46.

  24. [24]

      Arasakumar, T.; Mathusalini, S.; Ata, A.; Shankar, R.; Gopalan, S.; Lakshmi, K.; Sakthivel, P.; Mohan, P. S. Mol. Diversity 2017, 21, 37. doi: 10.1007/s11030-016-9695-6

  25. [25]

      张新刚, 史冠莹, 何利钦, 陶科, 侯太平, 农药, 2012, 51, 301. http://www.cnki.com.cn/Article/CJFDTotal-NYZZ201204024.htm

• 

  Scheme 1  Synthesis of chalcone derivatives 4a~4s

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  Table 1.  Physical data of compounds 4a~4s

  Compd.	X	Ar	Yield/%	m.p./℃
  4a	CH2	3, 4-(OCH2O)C6H3	76	170~173
  4b	CH2	3-CH3O-4-HOCH2CH2OC6H3	65	167~170
  4c	CH2	3-CH3OC6H4	44	160~163
  4d	CH2	4-(CH3)2NC6H4	58	214~218
  4e	CH2	2-Furyl	69	179~180
  4f	CH2	2-Pyridyl	72	167~170
  4g	O	3, 4-(OCH2O)C6H3	76	167~171
  4h	O	3-CH3O-4-HOCH2CH2OC6H3	41	165~168
  4i	O	3-CH3OC6H4	87	130~133
  4j	O	4-(CH3)2NC6H4	77	226~226
  4k	O	4-BrC6H4	79	213~216
  4l	O	2, 4-Cl2C6H3	40	147~148
  4m	O	2-Furyl	38	195~197
  4n	O	2-Pyridyl	52	150~153
  4o	CH3N	3, 4-(OCH2O)C6H3	52	155~158
  4p	CH3N	3-CH3O-4-HOCH2CH2OC6H3	54	185~188
  4q	CH3N	3-CH3OC6H4	46	147~149
  4r	CH3N	4-(CH3)2NC6H4	57	198~201
  4s	CH3N	2-Furyl	39	179~182
  Reaction conditions: 3 (1.0 mmol), aldehyde (1.0 mmol), 50% KOH (aq.) (1.0 mL), MeOH (3 mL), isolated yields.

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  Table 2.  In vitro anticancer activity of the title compounds 4a~4s against MCF-7, A549, HL-60, Hela, and Bewo cancer cell lines

  Compd.	IC50a/(μmol·L－1)
  	MCF-7	A549	HL-60	Hela	Bewo
  4a	8.70	9.72	7.15	12.88	18.81
  4b	14.99	> 50	22.51	> 50	> 50
  4c	21.50	> 50	12.62	42.92	> 50
  4d	17.59	44.99	49.35	45.37	> 50
  4e	10.78	> 50	8.77	> 50	> 50
  4f	26.73	> 50	9.62	> 50	> 50
  4g	> 50	> 50	> 50	> 50	> 50
  4h	19.39	43.63	26.63	32.43	> 50
  4i	> 50	> 50	14.98	> 50	> 50
  4j	4.63	35.62	6.00	39.24	> 50
  4k	> 50	> 50	> 50	> 50	> 50
  4l	> 50	> 50	> 50	> 50	> 50
  4m	15.69	> 50	9.11	> 50	> 50
  4n	16.58	44.19	11.37	25.29	> 50
  4o	39.46	> 50	8.15	> 50	> 50
  4p	> 50	> 50	> 50	> 50	> 50
  4q	23.52	45.49	> 50	> 50	> 50
  4r	> 50	> 50	24.86	> 50	> 50
  4s	24.43	> 50	13.67	> 50	> 50
  Cisplatin	8.75	2.65	2.90	0.59	2.24
  a Anticancer activity was assayed by exposure for 48 h to the tested substances and expressed as the concentration required to inhibit tumour cell proliferation by 50% (IC50).

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•