本发明涉及一种具有α,β-不饱和酮结构片段的孕烯醇酮衍生物及其在制备预防和/或治疗乳腺癌的用途。
背景技术：
肿瘤是机体在各种致瘤因素作用下，局部组织的细胞在基因水平上失去对其生长的正常调控导致异常增生与分化而形成的新生物。恶性肿瘤的病因尚未完全了解，其中乳腺癌是由于癌细胞亲润并破坏正常乳房组织形成的一种恶性肿瘤，是全世界女性最常见的癌症。据资料统计，乳腺癌发病率占全身各种恶性肿瘤的7-10％，在妇女仅次于子宫癌，严重影响妇女身心健康甚至危及生命。与发达国家相比，中国虽属乳腺癌的低发区，但近年来乳腺癌发病率增长趋势明显，目前约有47万名乳腺癌患者。针对乳腺癌药物这一市场，近年来制药公司的研发投入明显增强，尽管抗乳腺癌的化疗药物已不在少数，但是乳腺癌对于化疗药物的低敏感性及化疗药物造成的副作用均已引起了医学界的关注。
甾体类化合物广泛存在于动植物体内，是一类具有显著生理活性的物质，它们对细胞具有高度的渗透能力和对细胞核及细胞膜的结合能力，在医药化学中被广泛的应用。近年来，药物化学家一直致力通过不同的方式对甾体化合物进行结构改造，进而发现潜在药用价值的抗肿瘤药物先导物，然后进一步探索它们在临床上的应用，希望寻找到更好的高效低毒抗肿瘤药物。
本发明公开了一种具有α,β-不饱和酮结构片段的孕烯醇酮衍生物，可用于制备抗乳腺癌药物。
技术实现要素：
本发明人经过对大量实验室合成化合物及其结构衍生物的筛选，发现了一类结构相对简单、对乳腺癌mcf-7细胞具有一定的抑制活性的通式i所示的新化合物，由此可能具有预防和/或治疗乳腺癌的作用，从而在制药领域具有潜在的用途。迄今为止，未见关于式i所示化合物的结构、制备方法及用途的报道。
本发明采用以下技术方案：
一种具有α,β-不饱和酮结构片段的孕烯醇酮衍生物，其特征在于，它具有如下通式i所示的结构：
其中，r1、r2和r3为芳环上邻位、间位及对位取代基团，r1、r2或r3可分别或同时为氢、甲基、甲氧基、乙氧基、羟基、硝基、二甲胺基、二乙胺基、异丙基、氟、氯、溴、腈基。
本发明还提供了一种上述的衍生物在制备抗乳腺癌药物中的应用。
本发明还提供了一种用于预防和/或治疗乳腺癌的药物，它是由上述通式i所示的衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料制成。
本发明所涉及衍生物的制备方法，包括以下步骤：
a)孕烯醇酮(式1)和对硝基氯甲酸苯酯反应得到式2化合物。其中，所用缚酸剂为吡啶、三乙胺、二异丙基乙胺、碳酸钠和碳酸钾中至少一种；反应溶剂为n,n-二甲基甲酰胺、三乙胺、二异丙胺、二异丙基乙胺、四氢呋喃、二氯甲烷、1,4-二氧六环及甲苯中至少一种；该反应温度为0℃～100℃，反应时间为1～36小时。
b)式2化合物与n-boc-乙二胺反应得到式3化合物。其中，所用催化剂为三乙胺、二异丙基乙胺、二氮杂二环辛烷、吡啶、4-二甲氨基吡啶、碳酸钠、碳酸铯或碳酸钾；该反应所用溶剂为二氯甲烷、四氢呋喃、n,n-二甲基甲酰胺、四氢呋喃、1,4-二氧六环或水，该反应温度为0℃～100℃，反应时间为1～24小时。
c)式3化合物经脱boc保护基后得到在式4化合物。其中，去保护基试剂为盐酸、三氟乙酸、苯磺酸、硫酸、三氟化硼或乙酸；所用溶剂为二氯甲烷、乙酸乙酯、甲醇、四氢呋喃、三氯甲烷及水中至少一种；该反应温度为0℃～100℃，反应时间为1～48小时。
d)式4化合物与氰乙酸在缩合剂作用下，得到式5化合物。其中，所用的缩合剂为n,n'-二环己基碳二亚胺、n,n'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、1-羟基-7-偶氮苯并三氮唑、1-羟基苯并三氮唑、o-(7-氮苯并三氮唑)-n,n,n',n'-四甲基脲六氟磷酸酯和苯并三氮唑-n,n,n',n'-四甲基脲六氟磷酸酯中的一种或两种以上的组合；所用溶剂为甲醇、乙醇、丙醇、异丙醇、乙腈、1,4-二氧六环、二氯乙烷、n,n-二异丙基乙胺和水中的一种或一种以上；反应温度为0℃～100℃；反应时间为6～36小时；
e)式5化合物与式6化合物在碱催化作用下反应，得到通式i化合物。其中，所述碱可为三乙胺、n,n-二异丙基乙胺、哌啶、吡啶、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或1-4个碳的醇钾及醇钠；所用溶剂为甲醇、乙醇、丙醇、异丙醇、水和四氢呋喃中的一种或一种以上；反应温度为0℃～100℃；反应时间为6～24小时。
所述式6化合物结构如下：
其中，r1、r2和r3为芳环上邻位、间位及对位取代基团，r1、r2或r3可分别或同时为氢、甲基、甲氧基、乙氧基、羟基、硝基、二甲胺基、二乙胺基、异丙基、氟、氯、溴、腈基。
本发明提供了上述衍生物化合物在制备抗乳腺癌药物中的应用。
本发明还提供了一种用于预防和/或治疗乳腺癌的药物组合物，其特征在于，以上述通式i所示的衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料。
本发明的有益效果是：本发明的化合物为首次合成的一类具有α,β-不饱和酮结构片段的孕烯醇酮衍生物，在对合成化合物细胞测试实验中，首次发现该类化合物对mcf-7细胞具有较强的抑制活性，因而它们在制备预防和/或治疗乳腺癌的药物中具有潜在的应用前景。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1：式2化合物的制备
将3.16g式1化合物溶于30ml二氯甲烷中，随后加入1.82g吡啶和3.015g对硝基氯甲酸苯酯，氮气保护，室温下搅拌24小时。之后将反应液浓缩，二氯甲烷/水萃取有机相。有机相依次用饱和碳酸钠溶液、水和饱和食盐水洗涤，浓缩。残余物经柱层析纯化后得到3.80g无色油状化合物式2，产率79％。1hnmr(400mhz,cdcl3)δ8.29(s,1h),8.27(s,1h),7.40(s,1h),7.37(s,1h),5.43(d,j＝5.2hz,1h),4.68–4.55(m,1h),2.54(t,j＝8.9hz,3h),2.19(dd,j＝9.5,7.7hz,1h),2.13(s,3h),2.09–1.98(m,3h),1.94(dt,j＝13.4,3.5hz,1h),1.78–1.72(m,1h),1.69(d,j＝5.9hz,2h),1.68–1.59(m,1h),1.60(s,2h),1.51(d,j＝4.0hz,1h),1.49–1.44(m,2h),1.31–1.08(m,3h),1.05(s,3h),0.64(s,3h).13cnmr(151mhz,cdcl3)δ209.53,155.61,151.79,145.29,138.84,125.29,123.22,121.80,79.59,63.64,56.80,49.82,43.97,38.74,37.80,36.79,36.56,31.78,31.76,31.57,27.54,24.48,22.83,21.05,19.27,13.24.esi-msm/z:482[m+h]+.
实施例2：式3化合物的制备
将3.80g式2化合物溶于50ml二氯甲烷中，加入2.4g三乙胺和3.79gn-boc-乙二胺，氮气保护，室温搅拌30小时。反应液减压浓缩后，加入100ml水，乙酸乙酯萃取三次。有机相依次用饱和碳酸钠溶液、饱和食盐水洗涤，用饱和碳酸钠溶液洗至溶液为中性，无水硫酸镁干燥。最后经过滤、有机相浓缩，柱层析得到2.667g淡黄色固体化合物式3，产率84％。1hnmr(400mhz,cdcl3)δ5.42–5.33(m,1h),4.91(d,j＝54.1hz,2h),4.49(t,j＝11.4hz,1h),3.26(s,4h),2.53(t,j＝8.9hz,1h),2.39–2.32(m,1h),2.31–2.24(m,1h),2.20–2.15(m,1h),2.12(s,3h),2.06–1.94(m,2h),1.92–1.82(m,2h),1.67(d,j＝7.8hz,1h),1.63(s,3h),1.60(d,j＝2.5hz,1h),1.55–1.51(m,1h),1.49(d,j＝3.9hz,1h),1.46(s,1h),1.44(s,9h),1.28–1.21(m,1h),1.17(dd,j＝9.8,5.8hz,2h),1.00(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.64,156.48,139.80,122.20,79.56,74.33,63.69,56.84,49.86,44.00,41.28,40.74,38.79,38.48,36.98,36.57,31.82,31.76,31.58,28.38,28.09,24.48,22.81,21.04,19.32,13.23.esi-msm/z:525[m+na]+.
实施例3：式4化合物的制备
将2.667g式3化合物溶于30ml二氯甲烷中，冰浴至0℃后加入10ml三氟乙酸，氮气保护，搅拌30小时。反应结束后，反应液并浓缩，得到2.19g油状的式4化合物，未纯化，直接用于下一步反应。
实施例4：式5化合物的制备
将924mg氰乙酸、1.597gedci、147mg的hobt溶于30ml二氯甲烷中，后加入2.103gn,n-二异丙基乙胺，氮气保护，搅拌半小时后，加入2.19g式4化合物后，室温搅拌36小时。反应液浓缩，残余物经柱层析纯化后得到1.98g的式5化合物，产率84％。1hnmr(400mhz,cdcl3)δ7.22(s,1h),5.36(d,j＝5.0hz,1h),5.23(t,j＝5.6hz,1h),4.51–4.41(m,1h),3.45–3.40(m,2h),3.39(s,3h),3.36–3.29(m,2h),2.53(t,j＝8.9hz,1h),2.36(d,j＝4.4hz,1h),2.28(d,j＝12.4hz,1h),2.20–2.13(m,1h),2.11(s,3h),2.05–1.94(m,3h),1.90–1.82(m,3h),1.66(d,j＝8.0hz,2h),1.62–1.51(m,3h),1.44(d,j＝8.9hz,3h),1.23(s,2h),1.17(d,j＝5.8hz,1h),1.13(d,j＝4.2hz,1h),0.99(s,3h),0.61(s,3h).13cnmr(151mhz,cdcl3)δ209.71,161.72,157.36,139.60,122.42,114.48,74.92,63.68,56.82,49.84,44.00,41.70,40.14,38.77,38.42,36.94,36.56,31.81,31.75,31.59,28.05,25.92,24.48,22.82,21.04,19.32,13.23.esi-msm/z:492[m+na]+.
实施例5：通式i化合物的制备
室温下，在3ml乙醇中加入155mg的式5化合物(1equiv)，加入相应式6化合物(1.1equiv)和200μl哌啶，氮气保护，室温搅拌16小时。浓缩反应液得残余物，经柱层析纯化后得到相应的通式i化合物。化合物编号、具体结构式以及原料如下表1所示。
表1化合物编号、具体结构式、所用原料以及活性结果
化合物i-1，淡黄色固体(147mg,76％).1hnmr(400mhz,cdcl3)δ8.22(s,1h),7.95(s,1h),7.92(s,1h),6.99(s,1h),6.96(s,1h),5.34(d,j＝5.0hz,1h),5.12(t,j＝5.6hz,1h),4.57–4.45(m,1h),3.88(s,3h),3.58–3.52(m,2h),3.48(s,2h),3.40(d,j＝5.4hz,2h),2.53(t,j＝8.8hz,1h),2.41–2.32(m,1h),2.27(d,j＝11.3hz,1h),2.17(s,1h),2.12(s,3h),2.03(d,j＝7.4hz,1h),1.66(d,j＝8.1hz,1h),1.59(s,1h),1.56(s,1h),1.52(s,1h),1.44(s,1h),1.42(s,1h),1.22–1.18(m,1h),1.17(d,j＝5.9hz,1h),1.13(s,1h),0.98(s,3h),0.61(s,3h).13cnmr(151mhz,cdcl3)δ209.69,163.39,161.77,156.82,152.43,139.73,133.18,124.62,122.27,117.44,114.72,100.36,74.65,63.70,56.84,55.61,49.84,44.01,41.27,40.60,38.80,38.43,36.96,36.55,31.82,31.76,31.59,28.06,24.49,22.82,21.04,19.32,13.24.esi-msm/z:610[m+na]+.
化合物i-2，淡黄色固体(139mg,70％).1hnmr(600mhz,cdcl3)δ8.20(s,1h),7.70(s,1h),7.41(s,1h),7.00(s,1h),6.90(s,1h),6.32(s,1h),5.35(s,1h),5.09(s,1h),4.53(s,1h),3.97(s,3h),3.57(s,2h),3.42(s,2h),2.54(s,1h),2.37(s,1h),2.27(s,1h),2.18(d,j＝9.7hz,1h),2.13(s,3h),2.05(s,1h),1.98(d,j＝15.3hz,1h),1.90(s,1h),1.85(d,j＝12.5hz,1h),1.69(s,3h),1.63–1.52(m,3h),1.46(s,2h),1.26(s,2h),1.15(d,j＝10.2hz,2h),1.00(s,3h),0.63(s,3h).13cnmr(151mhz,cdcl3)δ209.74,161.78,156.86,152.89,150.43,146.82,139.72,127.92,124.47,122.28,117.62,115.02,111.20,100.02,74.64,63.70,56.84,56.11,49.85,44.01,41.29,40.62,38.79,38.43,36.95,36.55,31.82,31.76,31.59,28.07,24.49,22.82,21.04,19.32,13.24.esi-msm/z:604[m+h]+.
化合物i-3，淡黄色固体(79mg,38％).1hnmr(600mhz,dmso)δ9.65(s,1h),8.24(t,j＝5.6hz,1h),8.04(s,1h),7.35(s,2h),7.13(t,j＝5.6hz,1h),5.29–5.25(m,1h),4.30(ddd,j＝15.9,11.4,4.5hz,1h),3.79(s,6h),3.27–3.23(m,2h),3.13–3.08(m,2h),2.54(t,j＝9.0hz,1h),2.30–2.25(m,1h),2.18(t,j＝11.3hz,1h),2.04(s,3h),1.97(d,j＝11.3hz,1h),1.92–1.85(m,1h),1.79(dd,j＝21.7,9.6hz,2h),1.56–1.50(m,3h),1.47(d,j＝13.7hz,1h),1.40–1.36(m,2h),1.22(dq,j＝13.3,7.1hz,2h),1.14–1.10(m,2h),1.06–1.00(m,1h),0.93(s,3h),0.84(dd,j＝11.5,4.4hz,1h),0.80(t,j＝7.3hz,1h),0.50(s,3h).13cnmr(151mhz,dmso)δ208.99,162.06,156.35,151.57,148.34,141.09,140.21,122.43,122.21,117.85,108.86,101.87,73.48,63.47,63.02,56.47,49.78,43.72,41.96,38.76,38.34,37.04,36.55,31.77,31.68,30.25,29.11,28.33,24.48,22.68,21.03,19.45,13.40.esi-msm/z:656[m+na]+.
化合物i-4，淡黄色固体(79mg,38％).1hnmr(600mhz,dmso)δ9.70(s,1h),8.33(t,j＝5.6hz,1h),7.96(s,1h),7.15(d,j＝1.9hz,1h),7.12(t,j＝5.8hz,1h),7.09(d,j＝1.8hz,1h),5.27–5.24(m,1h),4.28(ddd,j＝16.1,11.4,4.7hz,1h),3.77(s,3h),3.72(s,3h),3.22(dt,j＝7.7,6.3hz,2h),3.11–3.06(m,2h),2.53(t,j＝9.0hz,1h),2.27–2.23(m,1h),2.17(d,j＝11.1hz,1h),2.03(s,3h),2.01–1.95(m,2h),1.88(ddd,j＝12.3,5.1,2.5hz,1h),1.77(dd,j＝7.6,3.0hz,1h),1.74(s,1h),1.55–1.50(m,3h),1.49–1.44(m,1h),1.39–1.35(m,2h),1.10(d,j＝3.3hz,2h),1.05–0.99(m,1h),0.92(s,3h),0.49(s,3h).13cnmr(151mhz,dmso)δ207.94,160.73,155.29,152.52,150.26,149.94,139.46,139.12,126.43,121.14,115.98,110.60,105.77,103.74,72.41,61.95,59.48,55.39,55.21,48.71,42.65,37.69,37.26,35.96,35.48,30.70,30.61,27.25,23.40,21.60,19.95,18.38,12.32.esi-msm/z:656[m+na]+.
化合物i-5，褐色固体(37mg,19％).1hnmr(600mhz,cdcl3)δ8.31(s,1h),8.00(s,2h),7.78(s,2h),7.22(s,1h),5.35(s,1h),5.01(s,1h),4.53(s,1h),3.58(s,2h),3.44(s,2h),2.53(s,1h),2.37(s,1h),2.27(s,1h),2.17(d,j＝9.5hz,1h),2.12(s,3h),2.04(s,1h),1.98(d,j＝17.1hz,1h),1.90(s,1h),1.85(d,j＝12.9hz,1h),1.67(s,1h),1.61(s,4h),1.57(s,1h),1.46(s,3h),1.23(dd,j＝14.2,8.9hz,2h),1.16(d,j＝10.9hz,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.65,159.98,157.18,150.17,139.61,135.71,132.84,130.68,122.38,117.81,115.75,115.52,107.84,99.99,74.89,63.67,56.81,49.83,43.99,42.08,40.19,38.77,38.39,36.92,36.54,31.80,31.75,31.58,28.04,24.48,22.81,21.03,19.31,13.23.esi-msm/z:612[m+na]+.
化合物i-6，黄色固体(90mg,47％).1hnmr(600mhz,cdcl3)δ8.30(s,1h),8.00(d,j＝7.7hz,2h),7.78(d,j＝7.7hz,2h),5.35(d,j＝2.5hz,1h),5.02(s,1h),4.53(t,j＝11.1hz,1h),3.57(d,j＝5.0hz,2h),3.43(d,j＝4.2hz,2h),2.53(t,j＝8.7hz,1h),2.38(d,j＝9.4hz,1h),2.27(t,j＝12.0hz,1h),2.18(t,j＝10.3hz,1h),2.12(s,3h),2.04(s,1h),1.98(d,j＝17.5hz,1h),1.90(d,j＝11.4hz,1h),1.85(d,j＝13.4hz,1h),1.67(s,1h),1.64(s,3h),1.59(s,1h),1.57(s,1h),1.54(s,1h),1.45(d,j＝8.9hz,2h),1.26–1.20(m,2h),1.15(d,j＝12.3hz,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ207.81,158.14,155.33,148.33,137.77,133.87,131.00,128.84,120.54,115.97,113.91,113.67,106.00,73.04,61.83,54.97,47.99,42.15,40.23,38.35,36.93,36.55,35.08,34.70,29.96,29.91,29.74,26.20,22.64,20.97,19.19,17.47,11.39.esi-msm/z:605[m+na]+.
化合物i-7，白色固体(82mg,42％).1hnmr(600mhz,cdcl3)δ8.26(s,1h),7.87(s,2h),7.46(s,2h),7.05(s,1h),5.34(s,1h),5.03(s,1h),4.52(s,1h),3.56(s,2h),3.42(s,2h),2.53(d,j＝6.7hz,1h),2.36(s,1h),2.26(s,1h),2.17(d,j＝8.9hz,1h),2.12(s,3h),2.04(s,1h),1.97(d,j＝16.9hz,1h),1.90(s,1h),1.84(d,j＝12.9hz,1h),1.65(s,3h),1.62–1.52(m,3h),1.45(s,3h),1.15(d,j＝10.5hz,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.66,160.78,156.98,151.37,139.64,139.01,131.84,130.21,129.63,122.32,116.45,104.48,74.75,63.68,56.82,49.82,43.99,41.65,40.36,38.78,38.41,36.93,36.54,31.80,31.75,31.58,28.04,24.48,22.81,21.03,19.31,13.23.esi-msm/z:614[m+na]+.
化合物i-8，白色固体(53mg,28％).1hnmr(600mhz,cdcl3)δ8.28(s,1h),8.18(s,1h),8.13(s,1h),7.80(s,1h),7.64(d,j＝6.6hz,1h),7.20(s,1h),5.36(s,1h),5.00(s,1h),4.53(s,1h),3.58(s,2h),3.44(s,2h),2.53(s,1h),2.37(s,1h),2.28(s,1h),2.17(d,j＝8.9hz,1h),2.12(s,3h),2.04(s,1h),1.98(d,j＝17.2hz,1h),1.90(s,1h),1.86(d,j＝12.6hz,1h),1.67(s,1h),1.59(s,5h),1.46(s,2h),1.25(s,1h),1.22(d,j＝5.0hz,1h),1.16(d,j＝11.7hz,2h),1.00(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.67,160.03,157.19,149.88,139.61,135.28,133.83,133.74,133.01,130.24,122.40,117.56,115.75,113.92,107.27,74.90,63.68,56.82,49.82,43.99,42.06,40.20,38.78,38.40,36.93,36.55,31.81,31.75,31.58,28.04,24.48,22.81,21.03,19.31,13.23.esi-msm/z:605[m+na]+.
化合物i-9，淡黄色固体(81mg,40％).1hnmr(600mhz,cdcl3)δ8.22(s,1h),7.70(d,j＝1.3hz,1h),7.46(dd,j＝8.5,2.0hz,1h),6.96–6.92(m,1h),6.87(s,1h),5.37–5.33(m,1h),5.02(s,1h),4.56–4.49(m,1h),3.96(s,3h),3.95(s,3h),3.59–3.54(m,2h),3.42(d,j＝5.2hz,2h),2.53(dd,j＝11.3,6.7hz,1h),2.38(dd,j＝12.7,2.8hz,1h),2.27(t,j＝11.6hz,1h),2.21–2.15(m,1h),2.12(s,3h),2.04(dd,j＝7.9,2.8hz,1h),1.97(dtd,j＝17.4,5.2,2.8hz,1h),1.90(d,j＝11.7hz,1h),1.87–1.82(m,1h),1.68–1.66(m,1h),1.57(dd,j＝9.7,2.7hz,2h),1.45(d,j＝9.7hz,2h),1.32–1.26(m,1h),1.24–1.19(m,1h),1.18–1.15(m,1h),1.13(dd,j＝13.2,4.3hz,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.62,161.68,156.83,156.79,153.23,152.71,149.22,139.71,127.22,124.83,122.26,117.55,111.45,110.98,100.40,74.61,63.68,56.83,56.14,56.01,49.84,43.99,41.32,40.61,38.79,38.42,36.94,36.55,31.81,31.75,31.58,28.05,24.48,22.81,21.03,19.31,13.23.esi-msm/z:640[m+na]+.
化合物i-10，白色固体(66mg,31％).1hnmr(600mhz,cdcl3)δ8.24(s,1h),7.80(s,2h),7.63(s,2h),7.05(s,1h),5.34(s,1h),5.02(s,1h),4.52(s,1h),3.56(s,2h),3.42(s,2h),2.53(d,j＝7.0hz,1h),2.36(s,1h),2.27(s,1h),2.17(d,j＝6.9hz,1h),2.12(s,3h),2.04(s,1h),1.97(d,j＝16.7hz,1h),1.90(s,1h),1.84(d,j＝12.3hz,1h),1.67(s,1h),1.63(s,3h),1.56(s,1h),1.45(s,3h),1.27–1.23(m,1h),1.14(s,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.66,160.77,156.99,151.47,139.64,132.62,131.90,130.61,127.63,122.33,116.44,104.64,74.77,63.69,56.83,49.83,44.00,41.68,40.35,38.79,38.41,36.93,36.54,31.81,31.75,31.59,28.04,24.49,22.82,21.04,19.31,13.23.esi-msm/z:658[m+na]+.
化合物i-11，淡黄色固体(61mg,31％).1hnmr(600mhz,cdcl3)δ8.36(s,1h),8.34(s,1h),8.33(s,1h),8.08(s,1h),8.06(s,1h),5.35(d,j＝3.1hz,1h),5.05(d,j＝6.9hz,1h),4.52(dd,j＝13.5,8.8hz,1h),3.60–3.56(m,2h),3.48(d,j＝4.5hz,1h),3.44(d,j＝4.5hz,2h),2.53(t,j＝8.9hz,1h),2.41–2.35(m,1h),2.26(t,j＝11.8hz,1h),2.17(s,1h),2.12(s,3h),2.06–2.02(m,1h),1.97(dd,j＝17.5,2.3hz,1h),1.90(d,j＝10.3hz,1h),1.87–1.83(m,1h),1.68(s,1h),1.65(s,1h),1.62–1.53(m,3h),1.44(d,j＝9.8hz,3h),1.27–1.18(m,2h),1.15(dt,j＝17.1,9.1hz,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.68,159.87,157.22,149.68,149.44,139.60,137.43,131.15,124.32,122.39,115.66,108.48,74.90,63.67,56.81,49.82,43.99,42.12,40.17,38.76,38.40,36.92,36.55,31.80,31.75,31.58,28.04,24.47,22.81,21.03,19.31,13.23.esi-msm/z:610[m+na]+.
化合物i-b12，淡黄色固体(70mg,38％).1hnmr(600mhz,cdcl3)δ8.31(s,1h),7.93(d,j＝7.3hz,2h),7.53(dd,j＝8.6,6.0hz,1h),7.49(dd,j＝10.1,4.6hz,2h),7.00(s,1h),5.36–5.34(m,1h),5.05(s,1h),4.53(td,j＝11.2,5.5hz,1h),3.59–3.54(m,2h),3.45–3.40(m,2h),2.53(dd,j＝11.2,6.7hz,1h),2.38(dd,j＝12.7,2.9hz,1h),2.27(t,j＝11.6hz,1h),2.20–2.15(m,1h),2.12(s,3h),2.04(dd,j＝8.2,2.4hz,1h),1.97(dtd,j＝17.4,5.2,2.8hz,1h),1.91(d,j＝12.1hz,1h),1.84(dt,j＝13.3,3.4hz,1h),1.68–1.65(m,1h),1.64(d,j＝3.2hz,1h),1.64–1.61(m,1h),1.61–1.57(m,1h),1.56(d,j＝2.6hz,1h),1.54(d,j＝2.2hz,1h),1.48(dd,j＝10.6,4.8hz,1h),1.44(d,j＝9.4hz,2h),1.24–1.19(m,1h),1.18–1.15(m,1h),1.14(d,j＝4.0hz,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.63,161.06,156.89,152.99,139.68,132.81,131.78,130.69,129.24,122.28,116.71,103.96,74.69,63.68,56.82,49.82,43.99,41.49,40.45,38.78,38.41,36.94,36.53,31.80,31.74,31.58,28.05,24.48,22.80,21.03,19.30,13.22.esi-msm/z:580[m+na]+.
化合物i-13，白色固体(70mg,38％).1hnmr(600mhz,cdcl3)δ8.28(s,1h),7.53–7.46(m,2h),7.39(t,j＝7.9hz,1h),7.08(d,j＝8.1hz,1h),7.01(s,1h),5.35(d,j＝3.5hz,1h),5.06(s,1h),4.52(dd,j＝13.5,9.0hz,1h),3.86(s,3h),3.57(d,j＝4.4hz,2h),3.42(d,j＝5.1hz,2h),2.53(t,j＝8.9hz,1h),2.37(d,j＝9.1hz,1h),2.27(t,j＝12.0hz,1h),2.20–2.15(m,1h),2.12(s,3h),2.04(s,1h),1.97(d,j＝17.5hz,1h),1.90(d,j＝11.2hz,1h),1.84(d,j＝13.4hz,1h),1.70–1.65(m,2h),1.60(dd,j＝11.8,6.2hz,2h),1.56(s,1h),1.48–1.41(m,3h),1.24–1.19(m,1h),1.18–1.11(m,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.70,161.07,159.93,156.91,153.01,139.67,132.96,130.22,123.68,122.29,119.41,116.74,114.48,104.11,74.70,63.69,56.82,55.43,49.83,44.00,41.47,40.45,38.78,38.41,36.93,36.54,31.80,31.75,31.58,28.05,24.48,22.81,21.03,19.31,13.23.esi-msm/z:610[m+na]+.
化合物i-14，白色固体(50mg,26％).1hnmr(600mhz,cdcl3)δ8.23(s,1h),7.89–7.80(m,2h),7.49(d,j＝7.5hz,1h),7.43(d,j＝7.7hz,1h),7.13(s,1h),5.34(s,1h),5.11(s,1h),4.51(s,1h),3.56(s,2h),3.42(s,2h),2.52(t,j＝8.5hz,1h),2.36(d,j＝9.0hz,1h),2.25(s,1h),2.18–2.14(m,1h),2.11(s,3h),2.03(d,j＝6.0hz,1h),1.96(d,j＝16.8hz,1h),1.89(d,j＝8.8hz,1h),1.83(d,j＝13.2hz,1h),1.66(s,2h),1.61–1.51(m,3h),1.44(t,j＝8.5hz,3h),1.24(s,2h),1.14(d,j＝11.5hz,2h),0.98(s,3h),0.61(s,3h).13cnmr(151mhz,cdcl3)δ209.71,160.58,157.03,151.16,139.65,135.30,133.44,132.56,130.50,130.40,128.38,122.34,116.14,105.72,74.75,63.69,56.82,49.82,44.00,41.67,40.34,38.78,38.43,36.94,36.55,31.81,31.75,31.59,28.06,24.49,22.82,21.04,19.31,13.24.esi-msm/z:614[m+na]+.
化合物i-15，白色固体(100mg,53％).1hnmr(600mhz,cdcl3)δ8.27(s,1h),7.69(d,j＝7.7hz,1h),7.66(d,j＝9.3hz,1h),7.47(dd,j＝14.4,7.1hz,1h),7.23(d,j＝8.2hz,1h),7.07(s,1h),5.36(d,j＝2.7hz,1h),5.02(s,1h),4.53(t,j＝11.3hz,1h),3.57(d,j＝4.8hz,2h),3.43(d,j＝4.9hz,2h),2.53(t,j＝8.8hz,1h),2.38(d,j＝9.4hz,1h),2.27(t,j＝11.6hz,1h),2.17(d,j＝11.4hz,1h),2.12(s,3h),2.04(s,1h),1.98(d,j＝17.4hz,1h),1.91(d,j＝11.4hz,1h),1.85(d,j＝13.4hz,1h),1.67(d,j＝3.0hz,1h),1.62–1.59(m,2h),1.56(d,j＝15.0hz,2h),1.47–1.41(m,3h),1.25(s,1h),1.16(dd,j＝10.9,5.0hz,2h),0.99(s,3h),0.86(d,j＝7.6hz,1h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.67,163.59,161.94,160.59,151.38,139.64,130.90,130.85,126.66,126.64,122.35,116.89,116.74,116.19,105.55,74.79,63.69,56.82,49.83,44.00,41.72,40.33,38.78,38.40,36.93,36.54,31.81,31.75,31.58,28.05,24.48,22.81,21.03,19.31,13.23.esi-msm/z:598[m+na]+.
化合物i-16，白色固体(60mg,28％).1hnmr(600mhz,cdcl3)δ8.23(s,1h),8.01(s,1h),7.90(d,j＝7.6hz,1h),7.66(d,j＝7.9hz,1h),7.38(t,j＝7.8hz,1h),7.06(s,1h),5.36(s,1h),4.99(s,1h),4.53(s,1h),3.57(s,2h),3.43(d,j＝4.0hz,2h),2.54(t,j＝8.7hz,1h),2.38(d,j＝10.6hz,1h),2.27(t,j＝11.7hz,1h),2.19–2.14(m,1h),2.12(s,2h),2.05(s,1h),1.98(d,j＝17.2hz,1h),1.91(d,j＝10.7hz,1h),1.85(d,j＝13.1hz,1h),1.67(d,j＝2.8hz,1h),1.58(s,5h),1.45(dd,j＝21.2,12.4hz,3h),1.28–1.20(m,2h),1.15(t,j＝12.9hz,2h),1.00(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.65,160.5,160.49,157.04,156.99,151.08,151.04,139.63,135.48,133.72,133.67,133.39,130.71,128.70,123.27,122.36,116.15–116.10(m),105.71–105.66(m),74.79,63.69,56.83,49.83,44.00,41.75,40.33,38.79,38.41,36.93,36.55,31.81,31.76,31.58,28.05,24.48,22.81,21.04,19.31,13.23.esi-msm/z:658[m+na]+.
化合物i-17，白色固体(89mg,47％).1hnmr(600mhz,cdcl3)δ8.27(s,1h),7.97(dd,j＝8.6,5.3hz,2h),7.18(t,j＝8.5hz,2h),7.01(s,1h),5.37–5.34(m,1h),5.02(s,1h),4.55–4.50(m,1h),3.56(d,j＝5.2hz,2h),3.42(d,j＝5.3hz,2h),2.53(t,j＝8.9hz,1h),2.40–2.36(m,1h),2.28(d,j＝11.0hz,1h),2.17(dd,j＝9.3,2.5hz,1h),2.12(s,3h),2.04(dd,j＝7.6,2.8hz,1h),2.00–1.95(m,1h),1.91(d,j＝11.4hz,1h),1.87–1.83(m,1h),1.67(dd,j＝6.4,2.8hz,1h),1.61(s,3h),1.57(d,j＝3.4hz,1h),1.45(d,j＝9.7hz,2h),1.25(s,1h),1.23(d,j＝5.9hz,1h),1.20(s,1h),1.18–1.16(m,1h),1.15(s,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.66,164.26,160.95,156.95,151.49,139.67,133.17,133.11,128.14,122.32,116.72,116.64,116.57,103.6,103.53,74.75,63.69,56.83,49.84,44.00,41.61,40.41,38.79,38.41,36.94,36.55,31.81,31.76,31.59,28.05,24.48,22.81,21.04,19.31,13.23.esi-msm/z:598[m+na]+.
化合物i-18，黄色固体(80mg,40％).1hnmr(600mhz,cdcl3)δ8.18(s,1h),7.62(s,1h),7.47(d,j＝7.8hz,1h),6.93(d,j＝8.5hz,1h),5.96(s,1h),5.35(d,j＝5.0hz,1h),5.05(d,j＝5.1hz,1h),4.55–4.48(m,1h),3.97(s,2h),3.55(s,2h),3.41(d,j＝5.5hz,2h),2.53(t,j＝8.9hz,1h),2.37(d,j＝9.5hz,1h),2.30–2.23(m,1h),2.20–2.15(m,1h),2.12(s,3h),2.05–2.02(m,1h),1.99–1.95(m,1h),1.90(d,j＝11.9hz,1h),1.86–1.82(m,1h),1.63(s,3h),1.56(d,j＝2.7hz,1h),1.45(d,j＝9.5hz,2h),1.28(dd,j＝12.5,4.8hz,1h),1.22(ddd,j＝14.8,10.7,4.8hz,2h),1.18–1.13(m,2h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.70,161.68,156.81,152.64,150.67,145.99,139.69,125.54,125.36,122.27,117.26–117.21(m),115.84,110.70,100.95,74.66,63.69,56.83,56.15,49.83,44.00,41.97,40.57,38.79,38.42,36.94,36.54,31.81,31.75,31.58,28.06,24.48,22.81,21.03,19.31,13.23.esi-msm/z:626[m+na]+.
化合物i-19，白色固体(60mg,30％).1hnmr(600mhz,cdcl3)δ8.71(s,1h),8.37(s,2h),8.29(d,j＝7.8hz,1h),7.72(t,j＝8.0hz,1h),7.22(s,1h),5.38–5.34(m,1h),5.02(s,1h),4.53(td,j＝11.3,5.6hz,1h),3.59(d,j＝4.5hz,2h),3.45(d,j＝5.2hz,2h),2.54(t,j＝8.9hz,1h),2.42–2.36(m,1h),2.28(t,j＝11.6hz,1h),2.21–2.16(m,1h),2.13(s,3h),2.07–2.03(m,1h),2.01–1.95(m,1h),1.91(d,j＝11.6hz,1h),1.86(d,j＝13.4hz,1h),1.67(dd,j＝7.8,3.5hz,1h),1.61(s,3h),1.57(s,1h),1.55(d,j＝4.6hz,1h),1.45(d,j＝9.8hz,2h),1.27–1.20(m,2h),1.19–1.12(m,2h),1.00(s,3h),0.63(s,3h).13cnmr(151mhz,cdcl3)δ207.46,157.75,154.98,147.61,146.43,137.41,132.97,131.12,128.26,124.42,123.11,120.20,113.48,105.51,72.68,61.48,54.62,47.63,41.80,39.86,38.03,36.58,36.21,34.73,34.35,29.61,29.56,29.39,25.85,22.29,20.62,18.84,17.12,11.04.esi-msm/z:625[m+na]+.
化合物i-20，黄色固体(80mg,39％).1hnmr(600mhz,cdcl3)δ8.16(s,1h),7.53(d,j＝2.1hz,1h),7.48(dd,j＝8.5,2.0hz,1h),6.94(d,j＝8.5hz,1h),6.87(s,1h),5.36–5.34(m,1h),5.04(d,j＝5.3hz,1h),4.54–4.49(m,1h),4.35–4.33(m,2h),4.30–4.28(m,2h),3.54(d,j＝2.3hz,2h),3.40(d,j＝5.4hz,2h),2.53(t,j＝9.0hz,1h),2.39–2.35(m,1h),2.26(t,j＝11.6hz,1h),2.17(dd,j＝8.9,3.0hz,1h),2.12(s,3h),2.05–2.02(m,1h),2.00–1.95(m,1h),1.90(d,j＝11.6hz,1h),1.86–1.82(m,1h),1.68–1.66(m,1h),1.63(s,3h),1.61(d,j＝8.3hz,1h),1.57(dd,j＝6.5,3.0hz,1h),1.45(d,j＝9.5hz,2h),1.24–1.19(m,1h),1.18–1.15(m,1h),1.14(d,j＝4.0hz,1h),1.02(d,j＝5.5hz,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.70,161.62,156.80,152.34,147.98,143.76,139.71,125.49,125.38,122.27,119.70,118.06,117.19,101.08,74.65,64.80,64.05,63.70,56.84,49.84,44.01,41.27,40.58,38.80,38.42,36.95,36.55,31.82,31.76,31.59,28.06,24.49,22.81,21.04,19.31,13.24.esi-msm/z:638[m+na]+.
化合物i-21，黄色固体(80mg,39％).1hnmr(600mhz,cdcl3)δ8.11(s,1h),7.87(s,1h),7.85(s,1h),6.67(s,1h),6.66(s,1h),5.37–5.34(m,1h),5.07(d,j＝5.2hz,1h),4.55–4.48(m,1h),3.54(s,2h),3.44(q,j＝7.1hz,4h),3.41–3.37(m,2h),2.53(dd,j＝11.3,6.7hz,1h),2.40–2.34(m,1h),2.30–2.24(m,1h),2.19–2.15(m,1h),2.12(s,3h),2.04(s,1h),1.97(dtd,j＝17.4,5.2,2.9hz,1h),1.90(d,j＝12.4hz,1h),1.84(d,j＝13.4hz,1h),1.68–1.65(m,2h),1.61(s,4h),1.56(dd,j＝5.9,3.4hz,1h),1.45(d,j＝9.0hz,3h),1.23(s,2h),1.22(s,3h),1.21(s,2h),1.18–1.15(m,1h),1.14(d,j＝3.9hz,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.66,163.20,156.6,156.5,152.50,151.23,139.80,133.92,122.16,118.94,111.11,110.7,110.65,94.33,74.47,63.70,56.84,49.84,44.72,44.00,40.95,40.81,38.80,38.43,36.97,36.54,31.82,31.76,31.58,28.06,24.49,22.81,21.04,19.31,13.23,12.55.esi-msm/z:629[m+na]+.
化合物i-22，黄色固体(90mg,45％).1hnmr(600mhz,cdcl3)δ8.14(s,1h),7.89(s,1h),7.88(s,1h),6.70(s,1h),6.69(s,1h),5.38–5.34(m,1h),5.06(d,j＝5.3hz,1h),4.55–4.49(m,1h),3.54(s,2h),3.49(d,j＝5.4hz,1h),3.40(d,j＝5.4hz,2h),3.10(s,4h),2.54(dd,j＝11.3,6.6hz,1h),2.40–2.35(m,1h),2.27(t,j＝11.3hz,1h),2.19–2.16(m,1h),2.13(s,3h),2.06–2.03(m,1h),1.98(ddd,j＝12.2,5.0,2.6hz,1h),1.91(d,j＝12.2hz,1h),1.85(d,j＝13.4hz,1h),1.69–1.66(m,1h),1.64(dd,j＝9.1,5.7hz,1h),1.60(s,3h),1.57(dd,j＝5.7,3.4hz,1h),1.45(d,j＝9.6hz,2h),1.26–1.22(m,1h),1.19–1.16(m,1h),1.14(d,j＝3.8hz,1h),0.99(s,3h),0.63(s,3h).13cnmr(151mhz,cdcl3)δ209.67,162.99,156.62,153.26,152.67,139.78,133.55,122.18,119.53,118.74,111.49,95.17,74.50,63.70,56.84,49.84,44.01,40.91,40.03,38.80,38.43,36.97,36.55,31.82,31.76,31.59,28.06,24.49,22.81,21.04,19.31,13.23.esi-msm/z:601[m+na]+.
化合物i-23，淡黄色固体(70mg,36％).1hnmr(600mhz,cdcl3)δ8.78(s,1h),8.15(d,j＝7.7hz,1h),7.53–7.47(m,1h),7.04(q,j＝7.7hz,1h),6.95(t,j＝7.5hz,1h),6.88(s,1h),5.37–5.33(m,1h),5.03(d,j＝5.2hz,1h),4.58–4.48(m,1h),3.89(s,3h),3.56(d,j＝4.6hz,2h),3.49(d,j＝4.3hz,1h),3.42(d,j＝5.3hz,2h),2.53(dd,j＝11.3,6.7hz,1h),2.38(dd,j＝12.7,3.2hz,1h),2.27(t,j＝11.3hz,1h),2.21–2.14(m,1h),2.12(s,3h),2.04(dd,j＝7.9,2.8hz,1h),2.01–1.95(m,1h),1.91(dd,j＝9.7,2.3hz,1h),1.87–1.82(m,1h),1.59(s,3h),1.58–1.53(m,2h),1.45(d,j＝9.7hz,2h),1.26–1.24(m,1h),1.24–1.20(m,1h),1.18–1.13(m,2h),1.00(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.66,161.50,159.15,156.78,148.03,139.73,134.44,129.07,122.25,121.05,120.84,117.2,117.1,111.17,103.5,103.4,74.63,63.69,56.84,55.67,49.84,44.00,41.27,40.59,38.79,38.41,36.96,36.55,31.82,31.76,31.58,28.06,24.49,22.81,21.04,19.31,13.23.esi-msm/z:610[m+na]+.
化合物i-24，白色固体(82mg,42％).1hnmr(600mhz,cdcl3)δ8.28(s,1h),7.89(s,1h),7.88(s,1h),7.35(s,1h),7.34(s,1h),6.91(s,1h),5.37–5.34(m,1h),5.01(d,j＝5.2hz,1h),4.56–4.49(m,1h),3.56(s,2h),3.42(d,j＝5.4hz,2h),2.97(dt,j＝13.8,6.9hz,1h),2.53(t,j＝9.0hz,1h),2.40–2.35(m,1h),2.27(t,j＝11.5hz,1h),2.17(s,1h),2.12(s,3h),2.04(dd,j＝8.2,2.5hz,1h),2.00–1.95(m,1h),1.91(d,j＝10.4hz,1h),1.87–1.82(m,1h),1.68–1.66(m,1h),1.66–1.62(m,1h),1.59(s,3h),1.58–1.53(m,2h),1.45(d,j＝9.2hz,2h),1.28(s,3h),1.27(s,3h),1.22(dd,j＝12.2,5.7hz,1h),1.17(dd,j＝6.5,4.0hz,1h),1.14(d,j＝4.2hz,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ209.65,161.40,156.84,154.74,152.98,139.69,131.04,129.47,127.41,122.27,117.04,102.54,74.67,63.69,56.83,49.84,44.00,41.39,40.52,38.79,38.41,36.94,36.54,34.37,31.81,31.76,31.58,28.05,24.48,23.60,22.81,21.04,19.31,13.23.esi-msm/z:622[m+na]+.
化合物i-25，白色固体(82mg,42％).1hnmr(600mhz,cdcl3)δ8.16(s,1h),7.85(s,1h),7.84(s,1h),6.94(s,1h),6.93(s,1h),5.35(s,1h),5.12(t,j＝5.5hz,1h),4.55–4.49(m,1h),3.57–3.54(m,2h),3.50(s,1h),3.42(d,j＝5.3hz,2h),2.54(t,j＝8.9hz,1h),2.38(d,j＝9.9hz,1h),2.27(t,j＝12.3hz,1h),2.18(s,1h),2.13(s,3h),2.03(dd,j＝8.1,2.5hz,1h),1.99–1.95(m,1h),1.91(d,j＝10.7hz,1h),1.84(d,j＝13.3hz,1h),1.69(d,j＝2.8hz,1h),1.68–1.66(m,2h),1.59(s,1h),1.56(d,j＝2.6hz,1h),1.46–1.42(m,3h),1.30–1.27(m,1h),1.26(dd,j＝5.9,2.3hz,1h),1.23–1.20(m,1h),1.15(dd,j＝6.5,1.9hz,1h),1.14–1.12(m,1h),0.99(s,3h),0.62(s,3h).13cnmr(151mhz,cdcl3)δ210.11,162.02,160.83,157.08,152.64,139.60,133.50,124.20,122.35,117.44,116.42,99.70,74.92,63.70,56.81,49.80,44.06,41.32,40.61,38.76,38.40,36.92,36.53,31.80,31.74,31.59,28.05,24.48,22.83,21.03,19.31,13.24.esi-msm/z:596[m+na]+.
实施例6：化合物对乳腺癌细胞mcf-7的抑制作用测定
mtt比色法：根据细胞生长速率，将处于对数生长期的mcf-7细胞以100μl/孔接种于96孔板中，贴壁生长24小时再加浓度梯度药物，设5个梯度(0,3.125,6.25,12.5,25,50,100μm/孔)，每个浓度设三个复孔。在37℃、5％co2条件下培养48h，然后弃去培养液，每孔加入100μl含10％mtt的培养液，继续培养4h后吸去培养液。最后每孔加入100μl的二甲基亚砜，在全自动多功能酶标仪检测od值为490nm波长下测定，计算细胞的存活率。
通过graphpadprism5软件计算存活率达50％时的药物浓度即ic50值。对乳腺癌细胞mcf-7的抑制活性测定，结果如表1所示。
表1说明：各化合物对乳腺癌细胞mcf-7具有不同程度的抑制作用。其中化合物i-7,i-8,i-10,i-12,i-14,i-15,i-16,i-17,i-19,i-20对乳腺癌细胞mcf-7的ic50值分别达到了6.21,8.81,6.27,6.64,6.02,6.12,6.10,6.03,6.52,6.50μm。结果表明，这些化合物对乳腺癌细胞mcf-7具有较强的抑制作用，是抗乳腺癌的潜在药物。