含哌嗪酰胺类杨梅素衍生物的合成及生物活性

doi:10.7503/cjcu20170740

摘要/Abstract

摘要：

以杨梅苷、哌嗪和各种芳香酸为原料, 通过甲基化保护羟基和脱苷形成选择性单一的杨梅素中间体, 然后以三步取代反应连接哌嗪和芳香酸, 合成了13个新型含哌嗪酰胺类杨梅素衍生物. 采用四甲基偶氮唑盐(MTT)比色法测试了化合物对人类乳腺癌细胞(MDA-MB-231)体外增殖的抑制活性. 结果表明, 大多数含哌嗪酰胺的杨梅素衍生物对MDA-MB-231细胞表现出较好的抑制活性. 当浓度为1 μmol/L时, 化合物4a和4i的抑制活性均高于阳性对照药盐酸表阿霉素; 当浓度为10 μmol/L时, 化合物4h和4i的抑制活性高达86.7%和83.6%.

关键词: 杨梅素, 哌嗪酰胺, 生物活性

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

中图分类号:

O625.42

TrendMD:

阮祥辉, 赵洪菊, 张橙, 陈丽娟, 李普, 王一会, 贺鸣, 薛伟. 含哌嗪酰胺类杨梅素衍生物的合成及生物活性. 高等学校化学学报, 2018, 39(6): 1197.

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^†. Chem. J. Chinese Universities, 2018, 39(6): 1197.

图/表 5

参考文献 27

[1]	Zhang Y. N., Yin H. M., Zhang Y., Zhang D. J., Su X., Kuang H. X., J. Mol. Struct., 2017, 1130, 199—207
[2]	Xiao W., Ruan X. H., Li Q., Zhang J. P., Zhong X. M., Xie Y., Wang X. B., Huang M. G., Xue W.,Chem. J. Chinese Universities, 2017, 38(1), 35—40
	(肖维, 阮祥辉, 李琴, 张菊平, 钟新敏, 谢艳, 王晓斌, 黄民国, 薛伟. 高等学校化学学报, 2017, 38(1), 35—40)
[3]	Pasetto S., Pardi V., Murata R.M., Plos One, 2014, 9(12), 1—18
[4]	Kang K. A., Wang Z. H., Zhang R., Piao M. J., Kim K. C., Kang S. S., Hyun J. W., Int. J. Mol. Sci., 2010, 11(11), 4348—4360
[5]	Medeiros K. C. P., Figueiredo C. A. V., Figueredo T. B., Freire K. R. L., Santos F. A. R., Alcântara-Neves N. M., Piuvezam M. R., J. Ethnopharmacol., 2008, 119(1), 41—46
[6]	Liu I. M., Tzeng T. F., Liou S. S., Lan T. W., Planta Med., 2007, 73(10), 1054—1060
[7]	Wang S. J., Tong Y., Lu S., Yang R., Liao X., Xu Y. F., Li X., Planta Med., 2010, 76(14), 1492—1496
[8]	Ma Z. G., Wang J., Jiang H., Liu T. W., Xie J. X., Neuroreport, 2007, 18(11), 1181—1185
[9]	Ong K. C., Khoo H. E., Gen. Pharmac., 1997, 29(2), 121—126
[10]	Lin G. B., Xie Y., Li G. W., Journal of International Pharmaceutical Research, 2012, 39(6), 483—487
	(林国钡, 谢燕, 李国文. 国际药学研究杂志, 2012, 39(6), 483—487)
[11]	Li C., Lim S. C., Jin K., Choi J. S., Eur. J. Drug Metab. Ph., 2011, 36(3), 175—182
[12]	Sun F., Zheng X. Y., Ye J., Wu T. T., Wang J., Chen W., Nutr. Cancer, 2012, 64(4), 599—606
[13]	Kim M. E., Ha T. K., Yoon J. H., Lee J. S., Anticancer Res., 2014, 34(2), 701—706
[14]	Xue W., Song B. A., Zhao H. J., Qi X. B., Huang Y. J., Liu X. H., Eur. J. Med. Chem., 2015, 97, 155—163
[15]	Feng J. F., Chen X. N., Wang Y. Y., Du Y. W., Sun Q. Q., Zang W. Q., Zhao G. Q., Mol. Cell Biochem., 2015, 408(1/2), 163—170
[16]	Zhang L. J., Liu Z. G., Meng D. L., Xia M. Y., Journal of Shenyang Pharmaceutical University, 2009, 26(4), 307—311
	(张莉静, 刘志国, 孟大利, 夏明钰. 沈阳药科大学学报, 2009, 26(4), 307—311)
[17]	Zhang X. H., Zou Z. Q., Xu C. W., Shen Y. Z., Li D., Mol. Med. Report, 2011, 4(2), 273—277
[18]	Wang Y. H., Xuan Z. H., Tian S., J. Funct. Foods, 2013, 5(1), 337—345
[19]	Zang W. Q., Wang T., Wang Y. Y., Li M., Xuan X. Y., Ma Y. Y., Du Y. W., Liu K. D., Dong Z. M., Zhao G. Q., Tumor Bio., 2014, 35(12), 12583—12592
[20]	Feng J. F., Chen X. N., Wang Y. Y., Du Y. W., Sun Q. Q., Zang W. Q., Zhao G. Q., Mol. Cell Biochem., 2015, 408(1/2), 163—170
[21]	Huang H. Z., Effects of Chinese Bayberry Phenolic Compounds on Antioxidant and Anticance., Zhejiang Universit., Hangzhou, 2015
	(黄海智. 杨梅酚类化合物抗氧化和抗癌功能及机理研究, 杭州: 浙江大学, 2015)
[22]	Maggioni D., Nicolini G., Rigolio R., Biffi L., Pignataro L., Gaini R., Garavello W., Nutr. Cancer, 2014, 66(7), 1257—1267
[23]	Li D., Fang W. J., LiuL., Wu Q., Zhang H. Y., Sun X. R., Chem. J. Chinese Universities, 2013, 34(8), 1924—1928
	(李丹, 方文军, 刘莉, 吴倩, 张洪艳, 孙晓日. 高等学校化学学报, 2013, 34(8), 1924—1928)
[24]	Lee Y. B., Gong Y. D., Yoon H., Ahn C. H., Jeon M. K., Kong J. Y., Bioorg. Med. Chem., 2010, 18(22), 7966—7974
[25]	Lin Y. P., Hu C.Y., Zheng X., Wang X. ., Wan C. P., Mao Z. W., Chinese J. Org. Chem., 2017, 37(1), 237
	(林玉萍, 虎春艳, 郑喜, 王秀丽, 万春平, 毛泽伟. 有机化学, 2017, 37(1), 237—241)
[26]	Bai L. F., Wang R. L., Zou Y., Xu G. H., Chem. Res. Chinese Universities, 2015, 31(6), 964—969
[27]	Li H. S., Wu X. M., Zhang R. Z., Hao L. Q., Duan G.Y., Xiao Y. ., Xia C. C., Li F. R., You G. R., Han J. F., Chem. Res. Chinese Universities, 2017, 33(2), 187—193

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^*