苯基哌嗪衍生物的合成及抗肿瘤活性

doi:10.7503/cjcu20150397

摘要/Abstract

摘要：

合成了一系列结构全新的苯基哌嗪类衍生物, 采用溴化噻唑蓝四氮唑(MTT)法进行了初步体外抗肿瘤细胞增殖活性研究. 结果表明, 当哌嗪环4位连有苯磺酰胺结构时, 其1位引入苯并呋喃结构的目标化合物4t的活性最好. 化合物4t对多种瘤株具有明显抑制作用, 特别是对人乳腺癌细胞MDA-MB-231的增殖抑制强度与阳性对照药棉酚相近.

关键词: 苯基哌嗪衍生物, 体外抗肿瘤活性, 构效关系

Abstract:

The structure of phenylpiperazine as an important pharmacophore could generate wide pharmacological activities. In this work, a series of novel phenylpiperazine derivatives was designed, synthesized and their preliminary antiproliferative activities against tumor cell lines were evaluated using MTT assay. Results indicated that the most active target compound 4t had the substitution of benzenesulfonamides and benzofuran on N1 and N4 position of piperazine respectively. Furthermore, IC₅₀ values of compound 4t against five tumor cell lines in vitro were determined. Compound 4t could inhibit the growth of some tumor cell lines and showed similar inhibitory activities against MDA-MB-231 tumor cell line(IC₅₀=3.50 μmol/L) compared with Gossypol(IC₅₀=1.40 μmol/L). These results provided useful information for designing new phenylpiperazine derivatives with higher antitumor activity.

Key words: Phenylpiperazine derivatives, Antitumor activity in vitro, Structure-activity relationship

中图分类号:

O625

TrendMD:

王刚, 韩雷强, 方浩. 苯基哌嗪衍生物的合成及抗肿瘤活性. 高等学校化学学报, 2015, 36(12): 2435.

WANG Gang, HAN Leiqiang, FANG Hao. Syntheses and Antitumor Activities of Phenylpiperazine Derivatives^†. Chem. J. Chinese Universities, 2015, 36(12): 2435.

图/表 5

参考文献 20

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Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd.), m/z [M+H]⁺
4a	Yellow solid	72	>250	530.0977(530.0976)
4b	Yellow solid	72	248—250	530.0979(530.0976)
4c	Yellow solid	88	220—221	519.0736(519.0736)
4d	Slightly yellow solid	74	>250	515.1231(515.1231)
4e	Yellow solid	69	164—166	485.1125(485.1125)
4f	Yellow solid	83	214—216	485.1125(485.1125)
4g	Yellow solid	78	174—176	474.0884(474.0885)
4h	Slightly yellow solid	95	182—184	470.1384(470.1380)
4i	Yellow solid	43	238—240	536.1234(536.1234)
4j	Yellow solid	67	202—204	536.1237(536.1234)
4k	Slightly yellow solid	89	212—214	525.0994(525.0994)
4l	Off-white solid	90	224—226	521.1486(521.1489)
4m	Yellow solid	72	242—244	530.0974(530.0976)
4n	Yellow solid	98	164—166	485.1121(485.1125)
4o	Slightly yellow solid	77	188—189	536.1236(536.1234)
4q	Slightly brown solid	73	64—66	470.1992(470.1994)
4r	Slightly brown solid	44	84—86	644.1536(644.1540)
4s	Slightly yellow solid	67	84—86	475.1786(475.1783)
4t	Off-white solid	56	202—204	449.0930(449.0932)

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd.), m/z [M+H]⁺
4a	Yellow solid	72	>250	530.0977(530.0976)
4b	Yellow solid	72	248—250	530.0979(530.0976)
4c	Yellow solid	88	220—221	519.0736(519.0736)
4d	Slightly yellow solid	74	>250	515.1231(515.1231)
4e	Yellow solid	69	164—166	485.1125(485.1125)
4f	Yellow solid	83	214—216	485.1125(485.1125)
4g	Yellow solid	78	174—176	474.0884(474.0885)
4h	Slightly yellow solid	95	182—184	470.1384(470.1380)
4i	Yellow solid	43	238—240	536.1234(536.1234)
4j	Yellow solid	67	202—204	536.1237(536.1234)
4k	Slightly yellow solid	89	212—214	525.0994(525.0994)
4l	Off-white solid	90	224—226	521.1486(521.1489)
4m	Yellow solid	72	242—244	530.0974(530.0976)
4n	Yellow solid	98	164—166	485.1121(485.1125)
4o	Slightly yellow solid	77	188—189	536.1236(536.1234)
4q	Slightly brown solid	73	64—66	470.1992(470.1994)
4r	Slightly brown solid	44	84—86	644.1536(644.1540)
4s	Slightly yellow solid	67	84—86	475.1786(475.1783)
4t	Off-white solid	56	202—204	449.0930(449.0932)

Compd.	¹H NMR(300 MHz), δ
4a	8.57(d, J=8.8 Hz, 1H, ArH), 8.39(s, 1H, ArH), 8.20—8.24(m, 3H, ArH), 8.10(d, J=9.2 Hz, 1H, ArH), 7.96(t, J=8.4 Hz, 1H, ArH), 7.07(d, J=9.2 Hz, 2H, ArH), 6.96(dd, J=2.4, 9.6 Hz, 1H, ArH), 6.87(d, J=2.4 Hz, 1H, ArH), 3.60(t, J=4.4 Hz, 4H, piperazine), 3.11(t, J=4.4 Hz, 4H, piperazine)
4b	8.44(d, J=5.6 Hz, 2H, ArH), 8.22(d, J=5.6 Hz, 2H, ArH), 8.10(d, J=6.4 Hz, 1H, ArH), 8.04(d, J=5.6 Hz, 2H, ArH), 7.07(d, J=5.6 Hz, 2H, ArH), 6.96(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.87(d, J=1.6 Hz, 1H, ArH), 3.59(d, J=2.8 Hz, 4H, piperazine), 3.10(d, J=2.8 Hz, 4H, piperazine)
4c	8.22(d, J=6.0 Hz, 2H, ArH), 8.10(d, J=6.4 Hz, 1H, ArH), 7.75(dd, J=6.0, 17.6 Hz, 4H, ArH), 7.08(d, J=6.0 Hz, 2H, ArH), 6.97(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.87(d, J=1.6 Hz, 1H, ArH), 3.58(s, 4H, piperazine), 3.07(s, 4H, piperazine)
4d	8.23(d, J=9.2 Hz, 2H, ArH), 8.10(d, J=9.6 Hz, 1H, ArH), 7.69(d, J=8.8 Hz, 2H, ArH), 7.17(d, J=8.8 Hz, 2H, ArH), 7.08(d, J=9.2 Hz, 2H, ArH), 6.96(dd, J=2.8, 9.6 Hz, 1H, ArH), 6.87(d, J=2.8 Hz, 1H, ArH), 3.85(s, 3H, OCH₃), 3.58(t, J=4.8 Hz, 4H, piperazine), 2.95(t, J=4.8 Hz, 4H, piperazine)
4e	8.55(dd, J=0.8, 5.6 Hz, 1H, ArH), 8.37(s, 1H, ArH), 8.19(d, J=6.0 Hz, 1H, ArH), 8.02(d, J=6.4 Hz, 1H, ArH), 7.95(t, J=5.2 Hz, 1H, ArH), 7.34(t, J=5.2 Hz, 2H, ArH), 7.10(t, J=5.2 Hz, 1H, ArH), 6.90(d, J=5.2 Hz, 2H, ArH), 6.84(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.57(d, J=1.6 Hz, 1H, ArH), 3.50(t, J=3.2 Hz, 4H, piperazine), 3.08(t, J=3.2 Hz, 4H, piperazine)
4f	8.43(d, J=5.6 Hz, 2H, ArH), 8.02(dd, J=1.2, 6.0 Hz, 3H, ArH), 7.34(t, J=5.6 Hz, 2H, ArH), 7.10(t, J=4.8 Hz, 1H, ArH), 6.90(d, J=4.8 Hz, 2H, ArH), 6.85(dd, J=2.0, 6.4 Hz, 1H, ArH), 6.58(d, J=1.6 Hz, 1H, ArH), 3.49(t, J=3.2 Hz, 4H, piperazine), 3.08(t, J=3.2 Hz, 4H, piperazine)
4g	8.03(d, J=6.4 Hz, 1H, ArH), 7.75(dd, J=5.6, 14.8 Hz, 4H, ArH), 7.35(t, J=5.6 Hz, 2H, ArH), 7.10(t, J=5.2 Hz, 1H, ArH), 6.91(d, J=5.2 Hz, 2H, ArH), 6.85(dd, J=2.0, 6.0 Hz, 1H, ArH), 6.59(d, J=2.0 Hz, 1H, ArH), 3.48(t, J=3.2 Hz, 4H, piperazine), 3.00(t, J=3.2 Hz, 4H, piperazine)
4h	8.03(d, J=9.2 Hz, 1H, ArH), 7.68(d, J=8.8 Hz, 2H, ArH), 7.35(t, J=7.6 Hz, 2H, ArH), 7.17(d, J=8.8 Hz, 2H, ArH), 7.10(t, J=7.2 Hz, 1H, ArH), 6.91(d, J=8.4 Hz, 2H, ArH), 6.86(dd, J=2.4, 9.2 Hz, 1H, ArH), 6.59(d, J=2.4 Hz, 1H, ArH), 3.85(s, 3H, OCH₃), 3.48(t, J=4.8 Hz, 4H, piperazine), 2.94(t, J=4.8 Hz, 4H, piperazine)
4i	8.85(dd, J=1.6, 4.4 Hz, 1H, ArH), 8.55(td, J=0.8, 8.4 Hz, 1H, ArH), 8.44(dd, J=1.2, 8.4 Hz, 1H, ArH), 8.34(d, J=1.2 Hz, 1H, ArH), 8.16(d, J=7.6 Hz, 1H, ArH), 8.06(d, J=9.6 Hz, 1H, ArH), 7.94(t, J=8.0 Hz, 1H, ArH), 7.79(d, J=8.0 Hz, 1H, ArH), 7.60(dd, J=4.0, 8.0 Hz, 1H, ArH), 7.54(t, J=8.0 Hz, 1H, ArH), 7.17(d, J=8.0 Hz, 1H, ArH), 6.81(dd, J=2.4, 9.2 Hz, 1H, ArH), 6.36(d, J=2.4 Hz, 1H, ArH), 3.38(t, J=4.8 Hz, 4H, piperazine), 3.02(t, J=4.8 Hz, 4H, piperazine)
4j	8.84(dd, J=0.8, 2.4 Hz, 1H, ArH), 8.41—8.44(m, 3H, ArH), 8.05(d, J=6.4 Hz, 1H, ArH), 7.98(d, J=5.6 Hz, 2H, ArH), 7.78(d, J=5.6 Hz, 1H, ArH), 7.60(dd, J=2.8, 5.6 Hz, 1H, ArH), 7.53(t, J=5.2 Hz, 1H, ArH), 7.16(d, J=4.8 Hz, 1H, ArH), 6.80(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.37(d, J=1.6 Hz, 1H, ArH), 3.37(t, J=3.2 Hz, 4H, piperazine), 3.00(t, J=3.2 Hz, 4H, piperazine)
4k	8.85(dd, J=0.8, 2.4 Hz, 1H, ArH), 8.44(dd, J=0.8, 5.2 Hz, 1H, ArH), 8.06(d, J=6.0 Hz, 1H, ArH), 7.79(d, J=5.2 Hz, 2H, ArH), 7.72(d, J=0.8 Hz, 4H, ArH), 7.60(dd, J=2.8, 5.6 Hz, 1H, ArH), 7.54(t, J=5.2 Hz, 1H, ArH), 7.16(d, J=5.2 Hz, 1H, ArH), 6.81(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.38(d, J=1.6 Hz, 1H, ArH), 2.93(t, J=3.2 Hz, 8H, piperazine)
4l	8.84(dd, J=0.8, 2.4 Hz, 1H, ArH), 8.43(dd, J=1.2, 5.6 Hz, 1H, ArH), 8.06(d, J=6.4 Hz, 1H, ArH), 7.79(d, J=5.2 Hz, 1H, ArH), 7.64(d, J=6.0 Hz, 2H, ArH), 7.60(dd, J=2.8, 5.6 Hz, 1H, ArH), 7.53(t, J=5.2 Hz, 1H, ArH), 7.13—7.17(m, 3H, ArH), 6.81(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.37(d, J=2.0 Hz, 1H, ArH), 3.84(s, 3H, OCH₃), 3.34(t, J=3.2 Hz, 4H, piperazine), 2.86(t, J=3.2 Hz, 4H, piperazine)
4m	8.58(d, J=5.6 Hz, 1H, ArH), 8.41(s, 1H, ArH), 8.29(d, J=6.0 Hz, 2H, ArH), 8.23(d, J=5.2 Hz, 1H, ArH), 7.96—8.01(m, 2H), 7.30(d, J=5.6 Hz, 2H, ArH), 7.09(d, J=0.8 Hz, 1H, ArH), 6.84(dd, J=0.8, 6.0 Hz, 1H, ArH), 3.12(s, 8H, piperazine)
4n	8.58(d, J=5.6 Hz, 1H, ArH), 8.41(s, 1H, ArH), 8.23(d, J=4.8 Hz, 1H, ArH), 8.00(t, J=5.6 Hz, 1H, ArH), 7.92(d, J=6.0 Hz, 1H, ArH), 7.47(t, J=5.6 Hz, 2H, ArH), 7.28(t, J=5.2 Hz, 1H, ArH), 7.15(d, J=5.6 Hz, 2H, ArH), 6.89(d, J=1.6 Hz, 1H, ArH), 6.54(dd, J=1.6, 6.0 Hz, 1H, ArH), 3.11(d, J=6.4 Hz, 8H, piperazine)
4o	8.84(d, J=2.4 Hz, 1H, ArH), 8.59(d, J=5.2 Hz, 1H, ArH), 8.48(d, J=5.2 Hz, 1H, ArH), 8.42(s, 1H, ArH), 8.23(d, J=5.2 Hz, 1H, ArH), 8.00(t, J=5.2 Hz, 1H, ArH), 7.97(d, J=5.6 Hz, 1H, ArH), 7.82(d, J=6.4 Hz, 1H, ArH), 7.68(t, J=5.6 Hz, 1H, ArH), 7.60—7.62(m, 2H, ArH), 6.94(d, J=1.2 Hz, 1H, ArH), 6.27(dd, J=1.6, 6.0 Hz, 1H, ArH), 3.11(d, J=2.4 Hz, 8H, piperazine)
4q	7.46—7.50(m, 5H, ArH), 7.28—7.36(m, 4H, ArH), 7.22(dd, J=0.8, 4.8 Hz, 1H, ArH), 7.01(t, J=4.8 Hz, 1H, ArH), 6.86(d, J=5.2 Hz, 2H, ArH), 6.73(d, J=5.6 Hz, 1H, ArH), 6.59(dd, J=1.6, 5.6 Hz, 1H, ArH), 6.42(d, J=1.6 Hz, 1H, ArH), 4.39(s, 2H, NH₂), 3.35(s, 2H, CH₂), 2.84(s, 4H, piperazine), 2.36(s, 4H, piperazine)
4r	7.57(dd, J=2.4, 8.8 Hz, 3H, ArH), 7.33—7.36(m, 6H, ArH), 7.22—7.30(m, 5H, ArH), 7.09(t, J=6.4 Hz, 1H, ArH), 6.63—6.66(m, 2H, ArH), 6.50(d, J=8.0 Hz, 2H, ArH), 6.20(d, J=2.0 Hz, 1H, ArH), 3.39(s, 2H, CH₂), 3.00(s, 4H, piperazine), 2.45(s, 4H, piperazine)
4s	7.60(d, J=0.8 Hz, 1H, ArH), 7.55(d, J=6.4 Hz, 1H, ArH), 7.52(d, J=4.8 Hz, 1H, ArH), 7.49(s, 4H, ArH), 7.36—7.40(m, 2H, ArH), 7.22—7.26(m, 2H, ArH), 7.14(d, J=1.2 Hz, 1H, ArH), 4.34(q, J=4.8 Hz, 2H, OCH₂), 3.40(s, 2H, ArCH₂), 3.07(s, 4H, piperazine), 2.45(s, 4H, piperazine), 1.33(t, J=4.8 Hz, 3H, CH₃)
4t	7.78(dd, J=5.6, 18.0 Hz, 4H, ArH), 7.62(s, 1H, ArH), 7.58(d, J=6.4 Hz, 1H, ArH), 7.22(dd, J=1.2, 6.0 Hz, 1H, ArH), 7.18(d, J=1.2 Hz, 1H, ArH), 4.34(q, J=4.8 Hz, 2H, OCH₂), 3.19(s, 4H, piperazine), 3.07(s, 4H, piperazine), 1.33(t, J=4.8 Hz, 3H, CH₃)

Compd.	¹H NMR(300 MHz), δ
4a	8.57(d, J=8.8 Hz, 1H, ArH), 8.39(s, 1H, ArH), 8.20—8.24(m, 3H, ArH), 8.10(d, J=9.2 Hz, 1H, ArH), 7.96(t, J=8.4 Hz, 1H, ArH), 7.07(d, J=9.2 Hz, 2H, ArH), 6.96(dd, J=2.4, 9.6 Hz, 1H, ArH), 6.87(d, J=2.4 Hz, 1H, ArH), 3.60(t, J=4.4 Hz, 4H, piperazine), 3.11(t, J=4.4 Hz, 4H, piperazine)
4b	8.44(d, J=5.6 Hz, 2H, ArH), 8.22(d, J=5.6 Hz, 2H, ArH), 8.10(d, J=6.4 Hz, 1H, ArH), 8.04(d, J=5.6 Hz, 2H, ArH), 7.07(d, J=5.6 Hz, 2H, ArH), 6.96(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.87(d, J=1.6 Hz, 1H, ArH), 3.59(d, J=2.8 Hz, 4H, piperazine), 3.10(d, J=2.8 Hz, 4H, piperazine)
4c	8.22(d, J=6.0 Hz, 2H, ArH), 8.10(d, J=6.4 Hz, 1H, ArH), 7.75(dd, J=6.0, 17.6 Hz, 4H, ArH), 7.08(d, J=6.0 Hz, 2H, ArH), 6.97(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.87(d, J=1.6 Hz, 1H, ArH), 3.58(s, 4H, piperazine), 3.07(s, 4H, piperazine)
4d	8.23(d, J=9.2 Hz, 2H, ArH), 8.10(d, J=9.6 Hz, 1H, ArH), 7.69(d, J=8.8 Hz, 2H, ArH), 7.17(d, J=8.8 Hz, 2H, ArH), 7.08(d, J=9.2 Hz, 2H, ArH), 6.96(dd, J=2.8, 9.6 Hz, 1H, ArH), 6.87(d, J=2.8 Hz, 1H, ArH), 3.85(s, 3H, OCH₃), 3.58(t, J=4.8 Hz, 4H, piperazine), 2.95(t, J=4.8 Hz, 4H, piperazine)
4e	8.55(dd, J=0.8, 5.6 Hz, 1H, ArH), 8.37(s, 1H, ArH), 8.19(d, J=6.0 Hz, 1H, ArH), 8.02(d, J=6.4 Hz, 1H, ArH), 7.95(t, J=5.2 Hz, 1H, ArH), 7.34(t, J=5.2 Hz, 2H, ArH), 7.10(t, J=5.2 Hz, 1H, ArH), 6.90(d, J=5.2 Hz, 2H, ArH), 6.84(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.57(d, J=1.6 Hz, 1H, ArH), 3.50(t, J=3.2 Hz, 4H, piperazine), 3.08(t, J=3.2 Hz, 4H, piperazine)
4f	8.43(d, J=5.6 Hz, 2H, ArH), 8.02(dd, J=1.2, 6.0 Hz, 3H, ArH), 7.34(t, J=5.6 Hz, 2H, ArH), 7.10(t, J=4.8 Hz, 1H, ArH), 6.90(d, J=4.8 Hz, 2H, ArH), 6.85(dd, J=2.0, 6.4 Hz, 1H, ArH), 6.58(d, J=1.6 Hz, 1H, ArH), 3.49(t, J=3.2 Hz, 4H, piperazine), 3.08(t, J=3.2 Hz, 4H, piperazine)
4g	8.03(d, J=6.4 Hz, 1H, ArH), 7.75(dd, J=5.6, 14.8 Hz, 4H, ArH), 7.35(t, J=5.6 Hz, 2H, ArH), 7.10(t, J=5.2 Hz, 1H, ArH), 6.91(d, J=5.2 Hz, 2H, ArH), 6.85(dd, J=2.0, 6.0 Hz, 1H, ArH), 6.59(d, J=2.0 Hz, 1H, ArH), 3.48(t, J=3.2 Hz, 4H, piperazine), 3.00(t, J=3.2 Hz, 4H, piperazine)
4h	8.03(d, J=9.2 Hz, 1H, ArH), 7.68(d, J=8.8 Hz, 2H, ArH), 7.35(t, J=7.6 Hz, 2H, ArH), 7.17(d, J=8.8 Hz, 2H, ArH), 7.10(t, J=7.2 Hz, 1H, ArH), 6.91(d, J=8.4 Hz, 2H, ArH), 6.86(dd, J=2.4, 9.2 Hz, 1H, ArH), 6.59(d, J=2.4 Hz, 1H, ArH), 3.85(s, 3H, OCH₃), 3.48(t, J=4.8 Hz, 4H, piperazine), 2.94(t, J=4.8 Hz, 4H, piperazine)
4i	8.85(dd, J=1.6, 4.4 Hz, 1H, ArH), 8.55(td, J=0.8, 8.4 Hz, 1H, ArH), 8.44(dd, J=1.2, 8.4 Hz, 1H, ArH), 8.34(d, J=1.2 Hz, 1H, ArH), 8.16(d, J=7.6 Hz, 1H, ArH), 8.06(d, J=9.6 Hz, 1H, ArH), 7.94(t, J=8.0 Hz, 1H, ArH), 7.79(d, J=8.0 Hz, 1H, ArH), 7.60(dd, J=4.0, 8.0 Hz, 1H, ArH), 7.54(t, J=8.0 Hz, 1H, ArH), 7.17(d, J=8.0 Hz, 1H, ArH), 6.81(dd, J=2.4, 9.2 Hz, 1H, ArH), 6.36(d, J=2.4 Hz, 1H, ArH), 3.38(t, J=4.8 Hz, 4H, piperazine), 3.02(t, J=4.8 Hz, 4H, piperazine)
4j	8.84(dd, J=0.8, 2.4 Hz, 1H, ArH), 8.41—8.44(m, 3H, ArH), 8.05(d, J=6.4 Hz, 1H, ArH), 7.98(d, J=5.6 Hz, 2H, ArH), 7.78(d, J=5.6 Hz, 1H, ArH), 7.60(dd, J=2.8, 5.6 Hz, 1H, ArH), 7.53(t, J=5.2 Hz, 1H, ArH), 7.16(d, J=4.8 Hz, 1H, ArH), 6.80(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.37(d, J=1.6 Hz, 1H, ArH), 3.37(t, J=3.2 Hz, 4H, piperazine), 3.00(t, J=3.2 Hz, 4H, piperazine)
4k	8.85(dd, J=0.8, 2.4 Hz, 1H, ArH), 8.44(dd, J=0.8, 5.2 Hz, 1H, ArH), 8.06(d, J=6.0 Hz, 1H, ArH), 7.79(d, J=5.2 Hz, 2H, ArH), 7.72(d, J=0.8 Hz, 4H, ArH), 7.60(dd, J=2.8, 5.6 Hz, 1H, ArH), 7.54(t, J=5.2 Hz, 1H, ArH), 7.16(d, J=5.2 Hz, 1H, ArH), 6.81(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.38(d, J=1.6 Hz, 1H, ArH), 2.93(t, J=3.2 Hz, 8H, piperazine)
4l	8.84(dd, J=0.8, 2.4 Hz, 1H, ArH), 8.43(dd, J=1.2, 5.6 Hz, 1H, ArH), 8.06(d, J=6.4 Hz, 1H, ArH), 7.79(d, J=5.2 Hz, 1H, ArH), 7.64(d, J=6.0 Hz, 2H, ArH), 7.60(dd, J=2.8, 5.6 Hz, 1H, ArH), 7.53(t, J=5.2 Hz, 1H, ArH), 7.13—7.17(m, 3H, ArH), 6.81(dd, J=1.6, 6.4 Hz, 1H, ArH), 6.37(d, J=2.0 Hz, 1H, ArH), 3.84(s, 3H, OCH₃), 3.34(t, J=3.2 Hz, 4H, piperazine), 2.86(t, J=3.2 Hz, 4H, piperazine)
4m	8.58(d, J=5.6 Hz, 1H, ArH), 8.41(s, 1H, ArH), 8.29(d, J=6.0 Hz, 2H, ArH), 8.23(d, J=5.2 Hz, 1H, ArH), 7.96—8.01(m, 2H), 7.30(d, J=5.6 Hz, 2H, ArH), 7.09(d, J=0.8 Hz, 1H, ArH), 6.84(dd, J=0.8, 6.0 Hz, 1H, ArH), 3.12(s, 8H, piperazine)
4n	8.58(d, J=5.6 Hz, 1H, ArH), 8.41(s, 1H, ArH), 8.23(d, J=4.8 Hz, 1H, ArH), 8.00(t, J=5.6 Hz, 1H, ArH), 7.92(d, J=6.0 Hz, 1H, ArH), 7.47(t, J=5.6 Hz, 2H, ArH), 7.28(t, J=5.2 Hz, 1H, ArH), 7.15(d, J=5.6 Hz, 2H, ArH), 6.89(d, J=1.6 Hz, 1H, ArH), 6.54(dd, J=1.6, 6.0 Hz, 1H, ArH), 3.11(d, J=6.4 Hz, 8H, piperazine)
4o	8.84(d, J=2.4 Hz, 1H, ArH), 8.59(d, J=5.2 Hz, 1H, ArH), 8.48(d, J=5.2 Hz, 1H, ArH), 8.42(s, 1H, ArH), 8.23(d, J=5.2 Hz, 1H, ArH), 8.00(t, J=5.2 Hz, 1H, ArH), 7.97(d, J=5.6 Hz, 1H, ArH), 7.82(d, J=6.4 Hz, 1H, ArH), 7.68(t, J=5.6 Hz, 1H, ArH), 7.60—7.62(m, 2H, ArH), 6.94(d, J=1.2 Hz, 1H, ArH), 6.27(dd, J=1.6, 6.0 Hz, 1H, ArH), 3.11(d, J=2.4 Hz, 8H, piperazine)
4q	7.46—7.50(m, 5H, ArH), 7.28—7.36(m, 4H, ArH), 7.22(dd, J=0.8, 4.8 Hz, 1H, ArH), 7.01(t, J=4.8 Hz, 1H, ArH), 6.86(d, J=5.2 Hz, 2H, ArH), 6.73(d, J=5.6 Hz, 1H, ArH), 6.59(dd, J=1.6, 5.6 Hz, 1H, ArH), 6.42(d, J=1.6 Hz, 1H, ArH), 4.39(s, 2H, NH₂), 3.35(s, 2H, CH₂), 2.84(s, 4H, piperazine), 2.36(s, 4H, piperazine)
4r	7.57(dd, J=2.4, 8.8 Hz, 3H, ArH), 7.33—7.36(m, 6H, ArH), 7.22—7.30(m, 5H, ArH), 7.09(t, J=6.4 Hz, 1H, ArH), 6.63—6.66(m, 2H, ArH), 6.50(d, J=8.0 Hz, 2H, ArH), 6.20(d, J=2.0 Hz, 1H, ArH), 3.39(s, 2H, CH₂), 3.00(s, 4H, piperazine), 2.45(s, 4H, piperazine)
4s	7.60(d, J=0.8 Hz, 1H, ArH), 7.55(d, J=6.4 Hz, 1H, ArH), 7.52(d, J=4.8 Hz, 1H, ArH), 7.49(s, 4H, ArH), 7.36—7.40(m, 2H, ArH), 7.22—7.26(m, 2H, ArH), 7.14(d, J=1.2 Hz, 1H, ArH), 4.34(q, J=4.8 Hz, 2H, OCH₂), 3.40(s, 2H, ArCH₂), 3.07(s, 4H, piperazine), 2.45(s, 4H, piperazine), 1.33(t, J=4.8 Hz, 3H, CH₃)
4t	7.78(dd, J=5.6, 18.0 Hz, 4H, ArH), 7.62(s, 1H, ArH), 7.58(d, J=6.4 Hz, 1H, ArH), 7.22(dd, J=1.2, 6.0 Hz, 1H, ArH), 7.18(d, J=1.2 Hz, 1H, ArH), 4.34(q, J=4.8 Hz, 2H, OCH₂), 3.19(s, 4H, piperazine), 3.07(s, 4H, piperazine), 1.33(t, J=4.8 Hz, 3H, CH₃)

Compd.	IC₅₀/(μmol·L^-1)
Compd.	MDA-MB-231	A549	MCF-7	Hela	KG1
4t	3.50±0.68	25.9±7.9	20.9±3.9	> 42	17.3±0.4
Gossypol	1.40±0.24	4.02±0.41	3.00±0.87	8.81±1.22	2.87±0.77