Syntheses and Bioactivities of Myricetin Derivatives Containing Piperazine Acidamide Moiety†

doi:10.7503/cjcu20170740

Abstract

Abstract:

Thirteen novel derivates of piperazine acidamide myricetin were synthesized with the raw materials of myricetin, piperazine and aromatic acids. First, the myricetin of high selectivity was obtained through methylation protection hydroxyl and deglucoside. Then, the intermediate underwent three-steps substitution reaction with the piperazine and various aromatic acids to form target compounds. Inhibitory activities of compounds on proliferation of human breast cancer cell line(MDA-MB-231) were tested by methyl thiazolyl tetrazolium(MTT) colorimetric assay in vitro. The experimental results demonstrated that most of the myricetin derivatives exhibited good inhibitory activity. Inhibitory activities of compounds 4a and 4i with the concentration of 1 μmol/L were higher than epirubicin hydrochloride as positive control drug, and the corresponding inhibitory activities were up to 86.7% and 83.6% at 10 μmol/L, respectively.

Key words: Myricetin, Piperazine amide, Bioactivity

CLC Number:

O625.42

TrendMD:

RUAN Xianghui, ZHAO Hongju, ZHANG Cheng, CHEN Lijuan, LI Pu, WANG Yihui, HE Ming, XUE Wei. Syntheses and Bioactivities of Myricetin Derivatives Containing Piperazine Acidamide Moiety^†[J]. Chem. J. Chinese Universities, 2018, 39(6): 1197.

Figures/Tables 5

References 27

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Compd.	Appearance	Yield(%)	m. p./℃	ESI-MS(calcd.), m/z [M+H]⁺
1	Yellow solid	78.0	227—229	—
2	White solid	64.6	154—156	—
3	Yellow solid	64.2	107—109	529.3(529.3)
4a	Yellow solid	60.5	124—126	651.4(651.3)
4b	Yellow solid	64.3	102—104	667.5(667.3)
4c	Yellow solid	58.7	149—151	678.5(678.3)
4d	Yellow solid	65.7	90—92	701.5(701.3)
4e	Yellow solid	48.7	105—107	685.5(685.2)
4f	Yellow solid	46.6	89—91	669.5(669.3)
4g	Yellow solid	68.4	76—78	633.5(633.3)
4h	Yellow solid	48.5	94—96	712.4(712.2)
4i	Yellow solid	82.0	123—125	723.5(724.3)
4j	Yellow solid	65.5	81—83	634.4(634.3)
4k	Yellow solid	51.2	117—119	651.4(651.3)
4l	Yellow solid	52.1	96—98	669.4(669.3)
4m	Yellow solid	54.3	141—143	678.5(678.3)

Compd.	Appearance	Yield(%)	m. p./℃	ESI-MS(calcd.), m/z [M+H]⁺
1	Yellow solid	78.0	227—229	—
2	White solid	64.6	154—156	—
3	Yellow solid	64.2	107—109	529.3(529.3)
4a	Yellow solid	60.5	124—126	651.4(651.3)
4b	Yellow solid	64.3	102—104	667.5(667.3)
4c	Yellow solid	58.7	149—151	678.5(678.3)
4d	Yellow solid	65.7	90—92	701.5(701.3)
4e	Yellow solid	48.7	105—107	685.5(685.2)
4f	Yellow solid	46.6	89—91	669.5(669.3)
4g	Yellow solid	68.4	76—78	633.5(633.3)
4h	Yellow solid	48.5	94—96	712.4(712.2)
4i	Yellow solid	82.0	123—125	723.5(724.3)
4j	Yellow solid	65.5	81—83	634.4(634.3)
4k	Yellow solid	51.2	117—119	651.4(651.3)
4l	Yellow solid	52.1	96—98	669.4(669.3)
4m	Yellow solid	54.3	141—143	678.5(678.3)

Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
2	7.35(s, 2H), 6.50(s, 1H), 6.35(s, 1H), 4.04(t, J=5.2 Hz, 2H), 3.96(s, 9H), 3.95(s, 3H), 3.92(s, 3H), 3.50(t, J=5.6 Hz, 2H, CH₂), 2.10—2.03(m, 2H), 1.92—1.84(m, 2H)	174.06, 164.06, 161.03, 158.84, 153.04, 152.76, 140.55, 139.91, 126.09, 109.42, 105.82, 95.89, 92.48, 71.18, 61.11, 56.51, 56.42, 55.93, 34.12, 29.42, 28.79
3	7.37(s, 2H), 6.50(d, J=2.2 Hz, 1H), 6.36(d, J=2.2 Hz, 1H), 4.05(t, J=6.6 Hz, 2H), 3.97(s, 3H), 3.94(s, 6H), 3.93(s, 3H), 3.91(s, 3H), 2.88(t, J=4.8 Hz, 4H), 2.34—2.30(m, 2H, CH₂), 1.89(s, 4H), 1.78—1.71(m, 2H), 1.62—1.56(m, 2H)	174.06, 163.92, 161.01, 158.76, 152.91, 152.45, 140.72, 139.79, 126.15, 105.84, 95.77, 92.36, 72.36, 61.01, 58.82, 56.42, 56.31, 55.81, 54.20 , 45.82 , 28.33 , 23.00
4a	7.41(dd, J=8.6, 5.5 Hz, 2H), 7.36(s, 2H), 7.10(t, J=8.6 Hz, 2H), 6.50(d, J=2.2 Hz, 1H), 6.35(d, J=2.2 Hz, 1H), 4.05(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.77(dd, J=13.9, 7.1 Hz, 2H), 3.41(s, 2H) 2.46(s, 1H), 2.40—2.33(m, 4H), 1.82—1.71(m, 2H), 1.62(dt, J=14.9, 7.5 Hz, 2H)	174.10, 169.38, 164.39, 164.05, 162.41, 161.04, 158.82, 152.99, 152.57, 140.72, 139.95, 131.90, 131.87, 129.48, 129.41, 126.18, 115.69, 115.67, 115.49, 109.44, 105.99, 95.87, 92.49, 72.24, 61.04, 58.07, 56.46, 56.38, 55.89, 28.24, 23.22
4b	7.41—7.33(m, 6H), 6.50(s, 1H), 6.36(s, 1H), 4.04(t, J=6.3 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.82—3.65(m, 2H), 3.39(s, 2H), 2.47(s, 2H), 2.36(dd, J=17.2, 10.1 Hz, 4H), 1.80—1.69(m, 2H), 1.66—1.55(m, 2H)	174.13, 169.24, 164.07, 161.10, 158.86, 153.03, 152.61, 140.75, 139.98, 135.79, 134.24, 128.82, 128.72, 126.21, 109.50, 106.02, 95.90, 92.50, 72.24, 61.07, 58.09, 56.51, 56.41, 55.90, 47.83, 28.26, 23.22
4c	8.31—8.26(m, 2H), 7.61—7.56(m, 2H), 7.35(s, 2H), 6.51(d, J=2.2 Hz, 1H), 6.36(d, J=2.2 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.97(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.92(s, 3H), 3.77(s, 2H), 3.34(s, 2H), 2.50(s, 2H), 2.41—2.32(m, 4H), 1.82—1.70(m, 2H), 1.68—1.56(m, 2H)	174.13, 167.92, 164.08, 161.07, 158.86, 153.02, 152.63, 148.38, 142.10, 140.72, 139.95, 128.19, 126.20, 123.95, 109.47, 106.00, 95.90, 92.51, 72.20, 61.06, 58.00,56.51, 56.40, 55.91, 47.66, 42.27, 28.20, 23.20
Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
4d	7.70(d, J=7.9 Hz, 1H), 7.56(dt, J=41.5, 7.6 Hz, 2H), 7.36(s, 2H), 7.33(d, J=7.6 Hz, 1H), 6.50(d, J=2.2 Hz, 1H), 6.35(d, J=2.0 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.79(s, 2H), 3.15(t, J=5.0 Hz, 2H), 2.53—2.43(m, 2H), 2.39—2.24(m, 4H), 1.78—1.70(m, 2H), 1.66—1.55(m, 2H)	174.11, 167.33, 164.06, 161.08, 158.84, 153.01, 152.58, 140.74, 139.95, 134.97, 132.23, 129.15, 127.37, 126.77, 126.73, 126.69, 126.19, 124.79, 122.62, 109.48, 105.99, 95.88, 92.49, 72.25, 61.05, 58.05, 56.39,56.43, 55.89, 52.74, 52.62, 47.18, 41.75, 28.24, 23.28
4e	7.36(s, 2H), 7.33—7.29(m, 1H), 7.22(d, J=8.1 Hz, 1H), 7.05(t, J=8.2 Hz, 1H), 6.50(d, J=2.2 Hz, 1H), 6.35(d, J=2.2 Hz, 1H), 4.04(t, J=6.5 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.84—3.79(m, 2H), 3.26(dd, J=7.5, 5.1 Hz, 2H), 2.49(t, J=5.1 Hz, 2H), 2.41—2.33(m, 4H) 1.80—1.70(m, 2H), 1.66—1.56(m, 2H)	174.13, 164.07, 161.85, 161.07, 159.71, 158.84, 157.72, 153.01, 152.62, 140.73, 139.96, 131.92, 131.88, 130.81, 130.74, 126.18, 125.57, 125.54, 124.59, 124.41, 114.54, 114.37, 109.46, 106.00, 95.89, 92.50, 72.25, 61.06, 58.01, 56.40, 55.90, 53.25, 52.66, 46.59, 41.78, 28.22, 23.29
4f	7.39(dd, J=14.7, 7.8 Hz, 1H), 7.36(s, 2H), 6.95(td, J=8.3, 2.1 Hz, 1H), 6.85(td, J=9.2, 2.1 Hz, 1H), 6.50(d, J=1.8 Hz, 1H), 6.36(d, J=1.9 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 3.97(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.80(s, 2H), 3.33(s, 2H), 2.51(s, 2H), 2.40(s, 4H), 1.79—1.73(m, 2H), 1.65(s, 2H)	174.05, 164.65, 164.25, 164.00, 162.55, 161.02, 159.49, 158.79, 152.96, 152.56, 140.65, 139.92, 130.55, 126.10, 112.18, 109.41, 105.93, 104.40, 104.19, 103.99, 95.82, 92.43, 72.08, 60.99, 57.92, 56.34, 55.82, 53.13, 52.62, 28.12, 23.07
4g	7.41(s, 5H), 7.35(s, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.0 Hz, 1H), 4.03(t, J=6.1 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.83(s, 2H), 3.48(s, 2H), 2.58(s, 2H), 2.50(s, 4H), 1.76(dd, J=12.9, 6.3 Hz, 2H), 1.70(s, 2H)	174.13, 170.33, 164.10, 161.07, 158.87, 153.05, 152.69, 140.68, 140.03, 135.69, 129.83, 128.58, 127.15, 126.13, 109.47, 105.99, 95.92, 92.53, 72.05, 61.07, 58.00, 56.43, 55.91, 52.86, 47.29, 28.14, 22.94
4h	8.15(s, 1H), 7.53(dd, J=9.0, 2.2 Hz, 1H), 7.37(d, J=2.2 Hz, 1H), 7.35(s, 2H), 6.50(d, J=2.2 Hz, 1H), 6.36(d, J=2.2 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.91(s, 6H), 3.79(d, J=38.4 Hz, 2H), 3.20(s, 2H), 2.52(d, J=47.7 Hz, 2H), 2.41—2.28(m, 4H), 1.78—1.69(m, 2H), 1.66—1.56(m, 2H)	174.13, 164.89, 164.07, 161.09, 158.86, 153.02, 152.65, 143.61, 141.32, 140.73, 139.96, 134.52, 129.95, 128.27, 126.36, 126.20, 109.49, 106.02, 95.90, 92.51, 72.24, 61.06, 58.01, 56.41, 55.90, 52.60, 52.28, 46.91, 41.99, 28.20, 23.28
4i	9.09(t, J=1.9 Hz), 8.59(d, J=2.1 Hz, 2H), 7.34(s, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.0 Hz), 4.05(t, J=6.3 Hz, 2H), 3.97(s, 3H), 3.93(s, 6H), 3.92(s, 3H), 3.89(s, 3H), 3.80(s, 2H), 3.35(s, 2H), 2.50(s, 2H), 2.42—2.38(m, 2H), 2.36(s, 2H), 1.78—1.71(m, 2H), 1.67—1.59(m,2H)	174.11, 165.16, 164.09, 161.09, 158.86, 153.03, 152.63, 148.57, 140.73, 139.93, 139.34, 127.59, 126.23, 119.68, 109.48, 106.02, 95.91, 92.51, 72.19, 61.04, 57.89, 56.40, 55.91, 53.10, 47.96, 28.16, 23.23
4j	8.70(dd, J=4.5, 1.4 Hz, 2H), 7.36(s, 2H), 7.31(dd, J=4.5, 1.4 Hz, 2H), 6.51(d, J=2.1 Hz, 1H), 6.35(d, J=2.1 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.93(s, 3H), 3.91(s, 3H), 3.77(s, 2H), 3.35(s, 2H), 2.50(s, 2H), 2.42—2.38(m, 2H), 2.36(s, 2H), 1.79—1.72(m, 2H), 1.67—1.59(m, 2H)	174.06, 167.54, 164.02, 160.91, 158.75, 152.92, 152.57, 150.23, 143.50, 140.62, 139.82, 126.10, 121.31, 109.31, 105.87, 95.84, 92.46, 72.13, 60.99, 57.92, 56.41, 56.32, 55.87, 53.18, 52.63, 47.40, 41.97, 28.11, 23.11
4k	7.42—7.37(m, 1H), 7.36(s, 2H), 7.17(d, J=7.7 Hz, 1H), 7.14—7.09(m, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.1 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.78(s, 2H), 3.41(s, 2H), 2.51(s, 2H), 2.42(s, 2H), 2.37(s, 2H), 1.80—1.72(m, 2H), 1.67—1.62(m, 2H)	174.11, 168.78, 164.07, 163.57, 161.60, 161.07, 158.85, 153.02, 152.62, 140.71, 139.97, 130.41, 130.35, 126.17, 122.77, 116.85, 116.68, 114.52, 114.34, 109.47, 105.99, 95.90, 92.50, 72.16, 61.05, 58.03, 56.50, 56.40, 55.90, 52.78, 42.08, 28.19, 23.13
Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
4l	7.37—7.32(m, 3H), 6.94(t, J=7.9 Hz, 2H), 6.49(d, J=2.1 Hz, 1H), 6.35(d, J=2.2 Hz, 1H), 4.03(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.91(s, 3H), 3.91(s, 3H), 3.81(s, 2H), 3.31(s, 2H), 2.49(s, 2H), 2.37(s, 4H), 1.79—1.69(m, 2H), 1.66—1.58(m, 2H)	174.13, 164.07, 161.10, 160.03, 158.86, 157.96, 153.03, 152.61, 140.74, 139.98, 131.08, 126.19, 111.95, 111.77, 109.50, 106.01, 95.89, 92.50, 72.23, 61.07, 58.00, 56.50, 56.41, 55.90, 53.26, 52.70, 46.84, 41.90, 28.23, 23.25
4m	8.21(d, J=2.6 Hz, 1H), 8.19(s, 2H), 7.60(d, J=8.4 Hz, 1H), 7.35(s, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.0 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.97(s, 3H), 3.93(s, 6H), 3.91(s, 6H), 3.82(s, 2H), 3.23(d, J=18.2 Hz, 2H), 2.52(d, J=13.2 Hz, 2H), 2.40(s, 2H), 2.32(s, 2H), 1.78—1.72(m, 2H), 1.67—1.61(m, 2H)	174.13, 164.38, 164.08, 161.10, 158.87, 153.03, 152.64, 146.73, 140.73, 139.97, 137.48, 137.27, 130.91, 126.20, 124.94, 123.34, 109.49, 106.01, 95.91, 92.51, 72.18, 61.07, 57.97, 56.52, 56.41, 55.91, 53.12, 52.58, 46.81, 41.91, 28.20, 23.24

Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
2	7.35(s, 2H), 6.50(s, 1H), 6.35(s, 1H), 4.04(t, J=5.2 Hz, 2H), 3.96(s, 9H), 3.95(s, 3H), 3.92(s, 3H), 3.50(t, J=5.6 Hz, 2H, CH₂), 2.10—2.03(m, 2H), 1.92—1.84(m, 2H)	174.06, 164.06, 161.03, 158.84, 153.04, 152.76, 140.55, 139.91, 126.09, 109.42, 105.82, 95.89, 92.48, 71.18, 61.11, 56.51, 56.42, 55.93, 34.12, 29.42, 28.79
3	7.37(s, 2H), 6.50(d, J=2.2 Hz, 1H), 6.36(d, J=2.2 Hz, 1H), 4.05(t, J=6.6 Hz, 2H), 3.97(s, 3H), 3.94(s, 6H), 3.93(s, 3H), 3.91(s, 3H), 2.88(t, J=4.8 Hz, 4H), 2.34—2.30(m, 2H, CH₂), 1.89(s, 4H), 1.78—1.71(m, 2H), 1.62—1.56(m, 2H)	174.06, 163.92, 161.01, 158.76, 152.91, 152.45, 140.72, 139.79, 126.15, 105.84, 95.77, 92.36, 72.36, 61.01, 58.82, 56.42, 56.31, 55.81, 54.20 , 45.82 , 28.33 , 23.00
4a	7.41(dd, J=8.6, 5.5 Hz, 2H), 7.36(s, 2H), 7.10(t, J=8.6 Hz, 2H), 6.50(d, J=2.2 Hz, 1H), 6.35(d, J=2.2 Hz, 1H), 4.05(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.77(dd, J=13.9, 7.1 Hz, 2H), 3.41(s, 2H) 2.46(s, 1H), 2.40—2.33(m, 4H), 1.82—1.71(m, 2H), 1.62(dt, J=14.9, 7.5 Hz, 2H)	174.10, 169.38, 164.39, 164.05, 162.41, 161.04, 158.82, 152.99, 152.57, 140.72, 139.95, 131.90, 131.87, 129.48, 129.41, 126.18, 115.69, 115.67, 115.49, 109.44, 105.99, 95.87, 92.49, 72.24, 61.04, 58.07, 56.46, 56.38, 55.89, 28.24, 23.22
4b	7.41—7.33(m, 6H), 6.50(s, 1H), 6.36(s, 1H), 4.04(t, J=6.3 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.82—3.65(m, 2H), 3.39(s, 2H), 2.47(s, 2H), 2.36(dd, J=17.2, 10.1 Hz, 4H), 1.80—1.69(m, 2H), 1.66—1.55(m, 2H)	174.13, 169.24, 164.07, 161.10, 158.86, 153.03, 152.61, 140.75, 139.98, 135.79, 134.24, 128.82, 128.72, 126.21, 109.50, 106.02, 95.90, 92.50, 72.24, 61.07, 58.09, 56.51, 56.41, 55.90, 47.83, 28.26, 23.22
4c	8.31—8.26(m, 2H), 7.61—7.56(m, 2H), 7.35(s, 2H), 6.51(d, J=2.2 Hz, 1H), 6.36(d, J=2.2 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.97(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.92(s, 3H), 3.77(s, 2H), 3.34(s, 2H), 2.50(s, 2H), 2.41—2.32(m, 4H), 1.82—1.70(m, 2H), 1.68—1.56(m, 2H)	174.13, 167.92, 164.08, 161.07, 158.86, 153.02, 152.63, 148.38, 142.10, 140.72, 139.95, 128.19, 126.20, 123.95, 109.47, 106.00, 95.90, 92.51, 72.20, 61.06, 58.00,56.51, 56.40, 55.91, 47.66, 42.27, 28.20, 23.20
Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
4d	7.70(d, J=7.9 Hz, 1H), 7.56(dt, J=41.5, 7.6 Hz, 2H), 7.36(s, 2H), 7.33(d, J=7.6 Hz, 1H), 6.50(d, J=2.2 Hz, 1H), 6.35(d, J=2.0 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.79(s, 2H), 3.15(t, J=5.0 Hz, 2H), 2.53—2.43(m, 2H), 2.39—2.24(m, 4H), 1.78—1.70(m, 2H), 1.66—1.55(m, 2H)	174.11, 167.33, 164.06, 161.08, 158.84, 153.01, 152.58, 140.74, 139.95, 134.97, 132.23, 129.15, 127.37, 126.77, 126.73, 126.69, 126.19, 124.79, 122.62, 109.48, 105.99, 95.88, 92.49, 72.25, 61.05, 58.05, 56.39,56.43, 55.89, 52.74, 52.62, 47.18, 41.75, 28.24, 23.28
4e	7.36(s, 2H), 7.33—7.29(m, 1H), 7.22(d, J=8.1 Hz, 1H), 7.05(t, J=8.2 Hz, 1H), 6.50(d, J=2.2 Hz, 1H), 6.35(d, J=2.2 Hz, 1H), 4.04(t, J=6.5 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.84—3.79(m, 2H), 3.26(dd, J=7.5, 5.1 Hz, 2H), 2.49(t, J=5.1 Hz, 2H), 2.41—2.33(m, 4H) 1.80—1.70(m, 2H), 1.66—1.56(m, 2H)	174.13, 164.07, 161.85, 161.07, 159.71, 158.84, 157.72, 153.01, 152.62, 140.73, 139.96, 131.92, 131.88, 130.81, 130.74, 126.18, 125.57, 125.54, 124.59, 124.41, 114.54, 114.37, 109.46, 106.00, 95.89, 92.50, 72.25, 61.06, 58.01, 56.40, 55.90, 53.25, 52.66, 46.59, 41.78, 28.22, 23.29
4f	7.39(dd, J=14.7, 7.8 Hz, 1H), 7.36(s, 2H), 6.95(td, J=8.3, 2.1 Hz, 1H), 6.85(td, J=9.2, 2.1 Hz, 1H), 6.50(d, J=1.8 Hz, 1H), 6.36(d, J=1.9 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 3.97(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.80(s, 2H), 3.33(s, 2H), 2.51(s, 2H), 2.40(s, 4H), 1.79—1.73(m, 2H), 1.65(s, 2H)	174.05, 164.65, 164.25, 164.00, 162.55, 161.02, 159.49, 158.79, 152.96, 152.56, 140.65, 139.92, 130.55, 126.10, 112.18, 109.41, 105.93, 104.40, 104.19, 103.99, 95.82, 92.43, 72.08, 60.99, 57.92, 56.34, 55.82, 53.13, 52.62, 28.12, 23.07
4g	7.41(s, 5H), 7.35(s, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.0 Hz, 1H), 4.03(t, J=6.1 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.83(s, 2H), 3.48(s, 2H), 2.58(s, 2H), 2.50(s, 4H), 1.76(dd, J=12.9, 6.3 Hz, 2H), 1.70(s, 2H)	174.13, 170.33, 164.10, 161.07, 158.87, 153.05, 152.69, 140.68, 140.03, 135.69, 129.83, 128.58, 127.15, 126.13, 109.47, 105.99, 95.92, 92.53, 72.05, 61.07, 58.00, 56.43, 55.91, 52.86, 47.29, 28.14, 22.94
4h	8.15(s, 1H), 7.53(dd, J=9.0, 2.2 Hz, 1H), 7.37(d, J=2.2 Hz, 1H), 7.35(s, 2H), 6.50(d, J=2.2 Hz, 1H), 6.36(d, J=2.2 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.91(s, 6H), 3.79(d, J=38.4 Hz, 2H), 3.20(s, 2H), 2.52(d, J=47.7 Hz, 2H), 2.41—2.28(m, 4H), 1.78—1.69(m, 2H), 1.66—1.56(m, 2H)	174.13, 164.89, 164.07, 161.09, 158.86, 153.02, 152.65, 143.61, 141.32, 140.73, 139.96, 134.52, 129.95, 128.27, 126.36, 126.20, 109.49, 106.02, 95.90, 92.51, 72.24, 61.06, 58.01, 56.41, 55.90, 52.60, 52.28, 46.91, 41.99, 28.20, 23.28
4i	9.09(t, J=1.9 Hz), 8.59(d, J=2.1 Hz, 2H), 7.34(s, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.0 Hz), 4.05(t, J=6.3 Hz, 2H), 3.97(s, 3H), 3.93(s, 6H), 3.92(s, 3H), 3.89(s, 3H), 3.80(s, 2H), 3.35(s, 2H), 2.50(s, 2H), 2.42—2.38(m, 2H), 2.36(s, 2H), 1.78—1.71(m, 2H), 1.67—1.59(m,2H)	174.11, 165.16, 164.09, 161.09, 158.86, 153.03, 152.63, 148.57, 140.73, 139.93, 139.34, 127.59, 126.23, 119.68, 109.48, 106.02, 95.91, 92.51, 72.19, 61.04, 57.89, 56.40, 55.91, 53.10, 47.96, 28.16, 23.23
4j	8.70(dd, J=4.5, 1.4 Hz, 2H), 7.36(s, 2H), 7.31(dd, J=4.5, 1.4 Hz, 2H), 6.51(d, J=2.1 Hz, 1H), 6.35(d, J=2.1 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.93(s, 3H), 3.91(s, 3H), 3.77(s, 2H), 3.35(s, 2H), 2.50(s, 2H), 2.42—2.38(m, 2H), 2.36(s, 2H), 1.79—1.72(m, 2H), 1.67—1.59(m, 2H)	174.06, 167.54, 164.02, 160.91, 158.75, 152.92, 152.57, 150.23, 143.50, 140.62, 139.82, 126.10, 121.31, 109.31, 105.87, 95.84, 92.46, 72.13, 60.99, 57.92, 56.41, 56.32, 55.87, 53.18, 52.63, 47.40, 41.97, 28.11, 23.11
4k	7.42—7.37(m, 1H), 7.36(s, 2H), 7.17(d, J=7.7 Hz, 1H), 7.14—7.09(m, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.1 Hz, 1H), 4.04(t, J=6.3 Hz, 2H), 3.96(s, 3H), 3.94(s, 6H), 3.92(s, 3H), 3.91(s, 3H), 3.78(s, 2H), 3.41(s, 2H), 2.51(s, 2H), 2.42(s, 2H), 2.37(s, 2H), 1.80—1.72(m, 2H), 1.67—1.62(m, 2H)	174.11, 168.78, 164.07, 163.57, 161.60, 161.07, 158.85, 153.02, 152.62, 140.71, 139.97, 130.41, 130.35, 126.17, 122.77, 116.85, 116.68, 114.52, 114.34, 109.47, 105.99, 95.90, 92.50, 72.16, 61.05, 58.03, 56.50, 56.40, 55.90, 52.78, 42.08, 28.19, 23.13
Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
4l	7.37—7.32(m, 3H), 6.94(t, J=7.9 Hz, 2H), 6.49(d, J=2.1 Hz, 1H), 6.35(d, J=2.2 Hz, 1H), 4.03(t, J=6.4 Hz, 2H), 3.96(s, 3H), 3.93(s, 6H), 3.91(s, 3H), 3.91(s, 3H), 3.81(s, 2H), 3.31(s, 2H), 2.49(s, 2H), 2.37(s, 4H), 1.79—1.69(m, 2H), 1.66—1.58(m, 2H)	174.13, 164.07, 161.10, 160.03, 158.86, 157.96, 153.03, 152.61, 140.74, 139.98, 131.08, 126.19, 111.95, 111.77, 109.50, 106.01, 95.89, 92.50, 72.23, 61.07, 58.00, 56.50, 56.41, 55.90, 53.26, 52.70, 46.84, 41.90, 28.23, 23.25
4m	8.21(d, J=2.6 Hz, 1H), 8.19(s, 2H), 7.60(d, J=8.4 Hz, 1H), 7.35(s, 2H), 6.50(d, J=2.1 Hz, 1H), 6.36(d, J=2.0 Hz, 1H), 4.04(t, J=6.4 Hz, 2H), 3.97(s, 3H), 3.93(s, 6H), 3.91(s, 6H), 3.82(s, 2H), 3.23(d, J=18.2 Hz, 2H), 2.52(d, J=13.2 Hz, 2H), 2.40(s, 2H), 2.32(s, 2H), 1.78—1.72(m, 2H), 1.67—1.61(m, 2H)	174.13, 164.38, 164.08, 161.10, 158.87, 153.03, 152.64, 146.73, 140.73, 139.97, 137.48, 137.27, 130.91, 126.20, 124.94, 123.34, 109.49, 106.01, 95.91, 92.51, 72.18, 61.07, 57.97, 56.52, 56.41, 55.91, 53.12, 52.58, 46.81, 41.91, 28.20, 23.24

Compd.	R	Inhibition rate(%)
Compd.	R	1 μmol/L	10 μmol/L
3	—	17.3±7.6^*	67.4±4.8^*
4a	4-FPh	36.9±4.4^*	71.3±1.0^*
4b	4-ClPh	0^*	54.2±6.2^*
4c	4-NO₂Ph	5.3±9.8	60.3±3.6^*
4d	4-CF₃Ph	22.1±5.8^*	58.4±4.7^*
4e	2-F-6-ClPh	20.4±9.0^*	55.6±7.9^*
4f	2,4-di-FPh	3.4±5.1^*	53.6±4.5^*
4g	Ph	23.7±6.3^*	51.8±3.6^*
4h	2-NO₂-5-ClPh	16.0±5.8^*	86.7±2.7^*
4i	3,5-di-NO₂Ph	31.1±6.4^*	83.6±3.2^*
4j	Pyridin-4-yl	12.1±7.2	47.7±7.2^*
4k	3-FPh	0^*	4.9±8.3
4l	2,6-di-NO₂Ph	0^*	0^*
4m	2-NO₂Ph	0^*	0^*
Gefitinib	—	9.7±8.0^*	67.5±4.1^*
Epirubicin	—	25.9±3.5^*	94.6±1.7^*