CN106866686B - 异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物及其制备方法及应用 - Google Patents

异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物及其制备方法及应用 Download PDF

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CN106866686B
CN106866686B CN201710204317.0A CN201710204317A CN106866686B CN 106866686 B CN106866686 B CN 106866686B CN 201710204317 A CN201710204317 A CN 201710204317A CN 106866686 B CN106866686 B CN 106866686B
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isoxazole
pyrroles
compound
loop coil
double loop
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CN106866686A (zh
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刘雄利
张文会
陈智勇
刘欢欢
周英
俸婷婷
王关炼
林冰
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Guizhou University
Sichuan University of Science and Engineering
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Sichuan University of Science and Engineering
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract

本发明公开了一种异恶唑拼接3,3'‑吡咯双螺环氧化吲哚化合物，本发明以各种取代的靛红、硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸，在有机溶剂中回流，进行1,3‑偶极子3+2环加成反应，获得异恶唑拼接3,3'‑吡咯双螺环氧化吲哚化合物，该类骨架包含潜在的生物活性异恶唑基团，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。且该化合物对三种肿瘤细胞株如人前列腺,人肺癌细胞以及人白血病细胞所进行的肿瘤生长抑制活性筛选。

Description

异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物及其制备方法 及应用
技术领域
本发明涉及化学技术领域，尤其是一种异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物及其制备方法及应用。
背景技术
根据药物设计中药效团和骨架迁越原理,把具有生物活性基团拼接到具有活性分子骨架中在有机化学和医药化学中是极其重要的研究领域。(1)多官能团氧化吲哚广泛存在天然产物和合成药物分子中，其中，尤其3,3′-吡咯双螺环氧化吲哚因为具有广泛的生物活性，吸引了许多化学工作者及医药化学团队的广泛关注，例如，化合物I是具有抗细菌活性；化合物II具有抗真菌活性，化合物III具有抗肿瘤活性。(2)异恶唑基团也普遍存在天然产物和药物分子中。例如:异噁唑基团也普遍存在天然产物和药物分子中。如:许多天然产物和药物(Cloxacillin,muscimol,Isoxicam,leflunomide,等)共享一个异恶唑分子单元，这些化合物在解除病痛、经济发展中起着重大作用。因此,根据药物设计中药效团和骨架迁越原理,鉴于3,3′-吡咯双螺环氧化吲哚骨架化合物具有潜在的生物活性，异恶唑基团属于潜在的生物活性官能团。因此，把异恶唑基团拼接到3,3′-吡咯双螺环氧化吲哚骨架，合成一系列新的潜在多活性官能团的氧化吲哚衍生物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。
发明内容
本发明的目的是：提供一种异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的：异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物，该化合物具有如下通式(Ⅰ)的结构：
式中，R1为苯基、甲基、H或苄基；R2为甲基、H或卤素；R3为甲基、H或卤素；R4为为苯基、甲基、H或苄基；R5为甲基、H或卤素；R6为甲基、H或卤素；X为C或S。
异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物的制备方法，由各种取代的靛红、硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物；
合成路线如下：
其中各种取代的靛红1以及硝基异恶唑烯烃化合物2的结构式，其取代基满足R1为苯基、甲基、H或苄基；R2为甲基、H或卤素；R3为甲基、H或卤素；R4为为苯基、甲基、H或苄基；R5为甲基、H或卤素；R6为甲基、H或卤素；X为C或S。
所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
各种取代的靛红、硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸，在有机溶剂中反应温度为50-100℃，反应时间为5-20小时。
异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
通过采用上述技术方案，以各种取代的靛红、硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物，该类骨架包含潜在的生物活性异恶唑基团，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该化合物对三种肿瘤细胞株如人前列腺(PC-3)，人肺癌细胞(A549)以及人白血病细胞(K562)具有抑制活性的作用。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
附图说明
图1及附图2为本发明的实施例1的化合物3aa谱图数据；
图3及附图4为本发明的实施例2的化合物3ab谱图数据；
图5及附图6为本发明的实施例3的化合物3ac谱图数据；
图7为本发明的实施例化合物3ed,3fd和3fe单晶图。
具体实施方式
本发明的实施例：在反应管中依次加入89.2mg N-甲基靛红1a(0.4mmol)，171.0mg硝基异恶唑烯烃化合物2a(0.6mmol)，92.0mg脯氨酸(0.8mmol)和10mL乙醇溶液，回流反应5h，TLC检测基本反应完全，直接上样经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯)＝4:1)纯化得187.6mg化合物3aa，黄色固体，熔点：219.8-221.2℃，dr：18:1；产率81％。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.50(s,3H),3.11(s,3H),3.17-3.20(m,1H),3.31-3.32(m,1H),3.85(d,J＝4.0Hz,1H),4.11(d,J＝4.0Hz,1H),4.83(d,J＝7.2Hz,1H),5.95-6.00(m,1H),6.51(d,J＝6.4Hz,1H),6.66(d,J＝6.4Hz,1H),6.74-6.81(m,2H),6.95(d,J＝6.0Hz,2H),7.15-7.18(m,1H),7.24-7.28(m,2H),7.46-7.52(m,3H),7.78-7.80(m,1H)；13C NMR(CDCl3,100MHz)δ:11.3,26.4,32.5,45.1,46.2,66.3,69.0,73.7,108.0,109.1,121.6,123.0,126.1,126.6,126.7,128.4,129.5,129.7,130.3,144.3,144.4,155.5,171.5,173.4,177.2；HRMS(ESI-TOF)m/z:Calcd.for C31H25N5NaO5S[M+Na]+:602.1474；Found:602.1475.
化合物3ab至3ea-1的制备方法同化合物3aa，投料比与化合物3aa相同，可得到化合物3ab至3ea-1，反应产率和非对映选择性见表1和表2，但需强调的是本发明的化合物不限于表1和表2所表示的内容。
表1为一种异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物的化学结构
表2为一种异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物的化学结构
本实施例制备化合物3ab：黄色固体；熔点：154.9-156.1℃；产率：78％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.37(s,3H),3.04-3.08(m,1H),3.19-3.22(m,1H),3.76(d,J＝4.0Hz,1H),3.98(d,J＝4.0Hz,1H),4.32(d,J＝12.8Hz,1H),4.77(d,J＝7.2Hz,1H),5.24(d,J＝13.2Hz,1H),5.86-5.91(m,1H),6.31(d,J＝6.4Hz,1H),6.47(d,J＝6.4Hz,1H),6.64-6.73(m,4H),6.82(d,J＝5.6Hz,2H),6.95-7.01(m,2H),7.11-7.22(m,4H),7.33-7.39(m,3H),7.69(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.3,32.5,44.6,45.0,47.0,66.4,69.1,73.6,109.2,109.3,126.6,126.7,127.2,127.3,128.5,128.6,129.5,129.7,130.2,144.0,144.6,155.6,171.3,173.7,177.4；HRMS(ESI-TOF)m/z:Calcd.for C37H29N5NaO5S[M+Na]+:678.1787；Found:678.1785.
本实施例制备化合物3ac：黄色固体；熔点：228.5-229.4℃；产率：71％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.98(s,3H),2.39(s,3H),2.96(s,3H),3.04-3.09(m,1H),3.19-3.22(m,1H),3.74(d,J＝5.2Hz,1H),4.02(d,J＝4.8Hz,1H),4.70(d,J＝8.4Hz,1H),5.83-5.88(m,1H),6.37-6.43(m,3H),6.80(d,J＝7.2Hz,2H),6.93(d,J＝8.0Hz,1H),7.02-7.06(m,1H),7.12-7.16(m,1H),7.34-7.41(m,3H),7.65-7.67(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,20.7,26.3,32.6,45.2,46.1,66.3,69.1,73.7,107.6,109.1,122.9,126.5,126.6,126.7,128.3,129.4,129.8,130.2,131.1,141.9,144.2,155.4,171.6,173.4,177.0；HRMS(ESI-TOF)m/z:Calcd.for C32H27N5NaO5S[M+Na]+:616.1631；Found:616.1635.
本实施例制备化合物3ad：黄色固体；熔点：203.8-204.3℃；产率：75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.43(s,3H),2.99(s,3H),3.04-3.08(m,1H),3.19-3.23(m,1H),3.72(d,J＝5.2Hz,1H),4.01(d,J＝5.2Hz,1H),4.69(d,J＝8.4Hz,1H),5.81-5.86(m,1H),6.44-6.48(m,2H),6.33(s,1H),6.88-6.91(m,2H),7.03-7.07(m,1H),7.12-7.19(m,2H),7.35-7.46(m,3H),7.63-7.65(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,26.5,32.6,45.2,46.3,66.2,68.7,73.6,108.9,109.4,123.1,126.3,126.5,127.1,128.5,129.6,129.7,130.5,142.9,144.3,155.6,171.1,173.2,176.7；HRMS(ESI-TOF)m/z:Calcd.for C31H24ClN5NaO5S[M+Na]+:636.1084；Found:636.1085.
本实施例制备化合物3ag：黄色固体；熔点：212.8-214.9℃；产率：73％,13:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.44(s,3H),3.04-3.08(m,1H),3.19-3.23(m,1H),3.74(d,J＝5.2Hz,1H),4.00(d,J＝4.8Hz,1H),4.33(d,J＝16.4Hz,1H),4.73(d,J＝8.8Hz,1H),5.22(d,J＝16.4Hz,1H),5.84-5.89(m,1H),6.17(d,J＝8.4Hz,1H),6.54(d,J＝8.0Hz,1H),6.65(d,J＝7.2Hz,2H),6.83-6.84(m,1H),6.90-6.92(m,2H),6.96-7.00(m,1H),7.11-7.15(m,3H),7.16-7.19(m,1H),7.23-7.26(m,1H),7.37-7.46(m,3H),7.66(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.2,32.5,44.6,45.1,47.0,66.2,68.8,73.4,109.5,110.8,114.4,126.5,126.6,127.2,127.3,128.6,129.7,143.0,144.4,155.6,170.9,173.5,176.8；HRMS(ESI-TOF)m/z:Calcd.for C37H28BrN5NaO5S[M+Na]+:756.0892；Found:756.0895.
本实施例制备化合物3bc：黄色固体；熔点：221.4-223.3℃；产率：71％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.08(s,3H),2.41(s,3H),2.83(s,3H),2.94(s,3H),3.01-3.06(m,1H),3.18-3.21(m,1H),3.58(d,J＝5.2Hz,1H),3.91(d,J＝4.8Hz,1H),4.66(d,J＝8.4Hz,1H),5.79-5.85(m,1H),6.34(d,J＝7.6Hz,1H),6.45(s,1H),6.53(d,J＝8.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.99-7.03(m,1H),7.21-7.25(m,1H),7.60(d,7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.2,20.8,25.2,26.3,32.5,45.4,46.5,66.1,68.5,73.6,107.4,107.8,122.2,122.6,122.8,126.3,126.4,129.7,130.2,130.9,141.8,144.1,155.4,171.6,173.9,177.1；HRMS(ESI-TOF)m/z:Calcd.forC27H25N5NaO5S[M+Na]+:554.1474；Found:554.1475.
本实施例制备化合物3bd：黄色固体；熔点：210.2-210.9℃；产率：72％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.88(s,3H),2.96(s,3H),3.01-3.05(m,1H),3.18-3.21(m,1H),3.57(d,J＝4.4Hz,1H),3.91(d,J＝4.0Hz,1H),4.64(d,J＝7.2Hz,1H),5.78-5.83(m,1H),6.40(d,J＝6.4Hz,1H),6.56(d,J＝6.0Hz,1H),6.64-6.65(m,1H),7.02-7.07(m,2H),7.23-7.27(m,1H),7.57-7.59(m,1H)；13CNMR(CDCl3,100MHz)δ:11.3,25.4,26.5,32.6,45.4,46.7,66.1,68.2,73.7,108.1,108.7,121.9,122.8,124.5,126.0,126.4,126.9,129.5,130.5,142.8,144.2,155.6,171.2,173.7,176.9；HRMS(ESI-TOF)m/z:Calcd.for C26H22ClN5NaO5S[M+Na]+:574.0928；Found:574.0929.
本实施例制备化合物3be：黄色固体；熔点：169.6-175.8℃；产率：73％,7:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.88(s,3H),2.96(s,3H),3.03-3.09(m,2H),3.18-3.22(m,1H),3.57(d,J＝5.2Hz,1H),3.91(d,J＝4.8Hz,1H),4.63(d,J＝8.4Hz,1H),5.77-5.83(m,1H),6.35(d,J＝8.0Hz,1H),6.56(d,J＝7.6Hz,1H),6.76(d,J＝2.0Hz,1H),7.00-7.04(m,1H),7.19-7.23(m,2H),7.57(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.3,25.4,26.4,32.6,45.4,46.7,66.1,68.2,73.6,108.1,108.6,109.2,113.9,121.8,122.8,124.8,126.3,128.8,130.5,132.4,143.3,144.1,155.6,171.1,173.7,176.7；HRMS(ESI-TOF)m/z:Calcd.for C26H22BrN5NaO5S[M+Na]+:618.0423；Found:618.0423.
本实施例制备化合物3bf：黄色固体；熔点：152.1-152.7℃；产率：78％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.44(s,3H),2.89(s,3H),2.97(s,3H),2.97-3.05(m,1H),3.18-3.21(m,1H),3.57(d,J＝5.2Hz,1H),3.91(d,J＝5.2Hz,1H),4.67(d,J＝8.8Hz,1H),5.78-5.84(m,1H),6.39-6.42(m,1H),6.50-6.53(m,1H),6.56(d,J＝8.0Hz,1H),6.77-6.82(m,1H),7.01-7.05(m,1H),7.23-7.27(m,1H),7.60(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.3,25.4,26.5,32.5,45.5,46.7,66.1,68.3,73.7,108.0,108.2,108.3,108.6,113.8(d,JCF＝26.0Hz),115.9(d,JCF＝23.0Hz),122.0,122.8,124.4,126.5,130.5,140.2,144.1,155.6,157.9(d,JCF＝239.0Hz),171.1,173.6,177.0；HRMS(ESI-TOF)m/z:Calcd.for C26H22FN5NaO5S[M+Na]+:558.1223；Found:558.1225.
本实施例制备化合物3bg：黄色固体；熔点：210.8-211.4℃；产率：81％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.91(s,3H),3.01-3.07(m,1H),3.19-3.22(m,1H),3.61(d,J＝4.0Hz,1H),3.89(d,J＝4.4Hz,1H),4.26(d,J＝12.8Hz,1H),4.69(d,J＝7.2Hz,1H),5.21(d,J＝12.8Hz,1H),5.81-5.86(m,1H),6.11(d,J＝7.2Hz,1H),6.61(d,J＝5.6Hz,2H),6.65(d,J＝6.4Hz,1H),6.85(s,1H),6.94-6.97(m,1H),7.05-7.07(m,1H),7.10-7.13(m,2H),7.16-7.19(m,1H),7.30-7.34(m,1H),7.60-7.62(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,25.5,32.5,44.5,45.2,47.3,66.2,68.4,73.5,108.2,110.5,114.2,126.5,127.1,127.3,128.6,129.1,130.4,132.5,142.8,144.3,155.6,171.0,174.0,176.8；HRMS(ESI-TOF)m/z:Calcd.for C32H26BrN5NaO5S[M+Na]+:694.0736；Found:694.0739.
本实施例制备化合物3cd：黄色固体；熔点：231.4-232.5℃；产率：67％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.44(s,3H),2.99(s,3H),3.00-3.03(m,1H),3.16-3.19(m,1H),3.61(d,J＝4.0Hz,1H),3.87(d,J＝4.4Hz,1H),4.64(d,J＝7.2Hz,1H),5.69-5.74(m,1H),6.43(d,J＝6.4Hz,1H),6.61(d,J＝1.6Hz,1H),6.66(d,J＝6.0Hz,1H),7.00-7.03(m,1H),7.06-7.08(m,1H),7.20-7.23(m,1H),7.58(d,J＝6.0Hz,1H),7.78(br s,1H)；13C NMR(CDCl3,100MHz)δ:11.3,26.6,32.5,45.2,46.6,65.9,68.1,73.6,108.9,110.0,122.4,122.9,124.5,126.3,127.0,127.1,129.6,130.6,141.3,142.9,155.7,171.1,175.4,176.8；HRMS(ESI-TOF)m/z:Calcd.for C25H20ClN5NaO5S[M+Na]+:560.0771；Found:560.0774.
本实施例制备化合物3da：黄色固体；熔点：220.7-221.6℃；产率：82％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.23(s,3H),2.41(s,3H),2.52-2.55(m,1H),2.91(s,3H),3.04(s,3H),3.56-3.60(m,1H),3.68(d,J＝5.2Hz,1H),4.86(d,J＝4.8Hz,1H),5.17-5.22(m,1H),6.01(d,J＝7.2Hz,1H),6.40(d,J＝6.4Hz,1H),6.48(d,J＝6.0Hz,1H),6.78-6.81(m,1H),6.94-6.98(m,1H),7.02-7.07(m,1H),7.24(d,J＝6.0Hz,1H),7.31(s,1H)；13C NMR(CDCl3,100MHz)δ:11.5,21.1,25.7,25.9,31.7,45.6,52.0,61.6,68.1,75.0,108.0,108.1,120.7,122.5,123.5,123.8,128.1,129.4,130.8,131.9,142.3,144.1,155.9,171.0,175.3,175.6；HRMS(ESI-TOF)m/z:Calcd.forC27H25N5NaO5S[M+Na]+:554.1474；Found:554.1474.
本实施例制备化合物3dd：黄色固体；熔点：228.7-229.4℃；产率：82％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.32(s,3H),2.45(s,3H),2.86(s,3H),2.97(s,3H),3.01-3.04(m,1H),3.18-3.20(m,1H),3.56(d,J＝4.4Hz,1H),3.88(d,J＝4.4Hz,1H),4.64(d,J＝7.2Hz,1H),5.77-5.81(m,1H),6.39(d,J＝6.4Hz,1H),6.44(d,J＝6.4Hz,1H),6.63(s,1H),7.03-7.06(m,2H),7.40(s,1H)；13C NMR(CDCl3,100MHz)δ:11.3,21.0,25.4,26.4,32.6,45.3,46.5,66.1,68.2,73.6,107.7,108.7,121.8,124.5,126.0,126.9,129.4,130.7,132.5,141.7,142.8,155.6,171.2,173.5,176.9；HRMS(ESI-TOF)m/z:Calcd.for C27H24ClN5NaO5S[M+Na]+:588.1084；Found:588.1081.
本实施例制备化合物3dg：黄色固体；熔点：219.5-221.6℃；产率：76％,7:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.13(s,3H),2.45(s,3H),2.90(s,3H),3.01-3.06(m,1H),3.18-3.21(m,1H),3.60(d,J＝4.4Hz,1H),3.88(d,J＝4.0Hz,1H),4.23(d,J＝13.2Hz,1H),4.68(d,J＝7.2Hz,1H),5.32(d,J＝13.2Hz,1H),5.81-5.86(m,1H),6.11(d,J＝6.8Hz,1H),6.54-6.59(m,3H),6.84(s,1H),7.05-7.07(m,1H),7.09-7.12(m,3H),7.17-7.20(m,1H),7.43(s,1H)；13C NMR(CDCl3,100MHz)δ:11.2,20.9,25.5,32.5,44.4,45.1,47.2,66.1,68.5,73.5,108.0,110.5,114.2,126.1,127.3,127.7,128.6,129.0,130.7,132.5,141.9,143.0,155.6,171.1,173.9,177.0；HRMS(ESI-TOF)m/z:Calcd.for C33H28BrN5NaO5S[M+Na]+:708.0892；Found:708.0895.
本实施例制备化合物3ea：黄色固体；熔点：206.7-207.9℃；产率：78％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.33(s,3H),2.75(s,3H),2.92-2.96(m,4H),3.08-3.11(m,1H),3.48(d,J＝4.0Hz,1H),3.75(d,J＝4.0Hz,1H),4.58(d,J＝7.2Hz,1H),5.69-5.74(m,1H),6.38-6.44(m,2H),6.58-6.63(m,2H),6.86-6.90(m,1H),6.99-7.03(m,1H),7.35-7.37(m,1H)；13C NMR(CDCl3,125MHz)δ:11.3,25.5,26.5,32.3,45.0,46.4,66.3,68.5,73.3,108.0,108.3,108.4,114.6(d,JCF＝25.0Hz),116.7(d,JCF＝22.5Hz),121.6,122.6,124.1,124.2,125.9,129.7,140.2,144.2,155.6,159.1(d,JCF＝240.0Hz),171.3,173.7,177.0；HRMS(ESI-TOF)m/z:Calcd.for C26H22FN5NaO5S[M+Na]+:558.1223；Found:558.1225.
本实施例制备化合物3ec：黄色固体；熔点：198.1-198.5℃；产率：72％,11:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.08(s,3H),2.41(s,3H),2.83(s,3H),2.99(s,3H),3.02-3.04(m,1H),3.15-3.19(m,1H),3.56(d,J＝4.8Hz,1H),3.84(d,J＝4.8Hz,1H),4.64(d,J＝8.4Hz,1H),5.75-5.81(m,1H),6.37(d,J＝8.0Hz,1H),6.45-6.49(m,2H),6.88(d,J＝8.0Hz,1H),6.92-6.97(m,1H),7.41-7.44(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,20.8,25.4,26.4,32.3,45.0,46.3,66.2,68.2,73.3,107.6,107.9,108.2,108.3,114.5(d,JCF＝26.0Hz),116.5(d,JCF＝24.0Hz),122.6,123.1,124.5,126.4,129.9,131.1,132.2,140.1,141.6,141.7,155.4,155.8,159.1(d,JCF＝240.0Hz),170.8,171.4,173.6,176.9；HRMS(ESI-TOF)m/z:Calcd.for C27H24FN5NaO5S[M+Na]+:572.1380；Found:572.1382.
本实施例制备化合物3ed：黄色固体；熔点：211.1-211.9℃；产率：78％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.89(s,3H),2.99-3.03(m,4H),3.16-3.19(m,1H),3.56(d,J＝4.0Hz,1H),3.83(d,J＝4.0Hz,1H),4.63(d,J＝6.8Hz,1H),5.74-5.79(m,1H),6.44(d,J＝6.8Hz,1H),6.50-6.53(m,1H),6.65(s,1H),6.95-6.99(m,1H),7.08-7.10(m,1H),7.38-7.41(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,25.6,26.6,32.4,45.0,46.5,66.1,68.2,73.3,108.6,108.8,114.5(d,JCF＝21.0Hz),116.9(d,JCF＝19.0Hz),123.6,124.2,126.1,127.0,129.7,140.1,142.8,155.6,159.1(d,JCF＝192.0Hz),170.9,173.4,176.5；HRMS(ESI-TOF)m/z:Calcd.for C26H21ClFN5NaO5S[M+Na]+:592.0834；Found:592.0835.
本实施例制备化合物3eg：黄色固体；熔点：213.6-214.7℃；产率：75％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.90(s,3H),3.00-3.04(m,1H),3.17-3.20(m,1H),3.59(d,J＝4.0Hz,1H),3.83(d,J＝4.0Hz,1H),4.29(d,J＝12.8Hz,1H),4.68(d,J＝7.2Hz,1H),5.24(d,J＝12.8Hz,1H),5.78-5.82(m,1H),6.21(d,J＝6.8Hz,1H),6.55-6.58(m,1H),6.74(d,J＝5.6Hz,2H),6.84(s,1H),6.99-7.03(m,1H),7.09-7.11(m,1H),7.15-7.20(m,3H),7.41-7.43(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,25.6,32.3,44.6,44.9,47.1,66.2,68.4,73.2,108.7,108.8,110.6,114.3,115.4(d,JCF＝21.0Hz),116.8(d,JCF＝19.0Hz),123.9,124.6,126.6,127.5,128.7,129.1,132.7,134.7,140.2,142.9,155.7,159.3(d,JCF＝194.0Hz),170.7,173.7,176.6；HRMS(ESI-TOF)m/z:Calcd.for C32H25BrFN5NaO5S[M+Na]+:712.0642；Found:712.0645.
本实施例制备化合物3fa：黄色固体；熔点：143.5-144.6℃；产率：76％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.40(s,3H),2.80(s,3H),2.99-3.05(m,4H),3.15-3.19(m,1H),3.55(d,J＝4.8Hz,1H),3.83(d,J＝5.2Hz,1H),4.66(d,J＝8.4Hz,1H),5.75-5.81(m,1H),6.41(d,J＝8.4Hz,1H),6.49(d,J＝8.0Hz,1H),6.60(d,J＝7.6Hz,1H),6.66-6.69(m,1H),7.06-7.10(m,1H),7.35-7.39(m,1H),7.75(s,1H)；13CNMR(CDCl3,100MHz)δ:11.3,25.4,26.4,32.3,45.0,46.1,66.3,68.5,73.2,108.0,109.3,115.5,121.5,122.4,124.2,125.6,129.3,129.8,133.2,143.2,144.1,155.6,171.3,173.3,176.9；HRMS(ESI-TOF)m/z:Calcd.for C26H22BrN5NaO5S[M+Na]+:618.0423；Found:618.0425.
本实施例制备化合物3fd：黄色固体；熔点：223.2-224.9℃；产率：79％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.87(s,3H),3.00-3.05(m,4H),3.15-3.19(m,1H),3.55(d,J＝4.0Hz,1H),3.84(d,J＝4.0Hz,1H),4.63(d,J＝6.8Hz,1H),5.73-5.77(m,1H),6.43-6.46(m,2H),6.59(s,1H),7.07-7.09(m,1H),7.38-7.40(m,1H),7.72(s,1H)；13C NMR(CDCl3,100MHz)δ:11.3,25.5,26.5,32.4,45.1,46.2,66.2,68.3,73.2,108.9,109.5,115.7,123.9,124.1,125.9,127.0,129.3,129.7,133.4,142.8,143.1,155.6,170.9,173.1,176.5；HRMS(ESI-TOF)m/z:Calcd.forC26H21BrClN5NaO5S[M+Na]+:652.0033；Found:652.0037.
本实施例制备化合物3fe：黄色固体；熔点：234.1-234.7℃；产率：81％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.46(s,3H),2.88(s,3H),3.00-3.05(m,4H),3.15-3.19(m,1H),3.56(d,J＝4.0Hz,1H),3.84(d,J＝4.0Hz,1H),4.63(d,J＝7.2Hz,1H),5.72-5.77(m,1H),6.39(d,J＝7.2Hz,1H),6.46(d,J＝7.2Hz,1H),6.69(s,1H),7.22-7.24(m,1H),7.38-7.40(m,1H),7.71(s,1H)；13C NMR(CDCl3,100MHz)δ:11.2,25.5,26.5,32.4,45.0,46.2,66.1,68.3,73.1,109.4,109.5,114.0,115.6,123.8,124.4,128.7,129.3,132.6,133.4,143.1,143.2,155.6,170.9,173.1,176.4；HRMS(ESI-TOF)m/z:Calcd.for C26H21Br2N5NaO5S[M+Na]+:695.9528；Found:695.9529.
本实施例制备化合物3ga：黄色固体；熔点：200.8-201.8℃；产率：81％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.40(s,3H),2.81(s,3H),2.99-3.04(m,4H),3.15-3.19(m,1H),3.56(d,J＝4.8Hz,1H),3.83(d,J＝4.8Hz,1H),4.66(d,J＝8.4Hz,1H),5.75-5.81(m,1H),6.45-6.51(m,2H),6.61(d,J＝6.8Hz,1H),6.66-6.70(m,1H),7.06-7.11(m,1H),7.20-7.23(m,1H),7.63(s,1H)；13C NMR(CDCl3,100MHz)δ:11.3,25.4,26.4,32.3,45.0,46.2,66.3,68.5,73.2,108.0,108.8,121.5,122.5,124.0,125.7,126.6,128.4,129.7,130.3,142.7,144.1,155.6,171.3,173.5,176.9；HRMS(ESI-TOF)m/z:Calcd.for C26H22ClN5NaO5S[M+Na]+:574.0928；Found:574.0929.
本实施例制备化合物3gg：黄色固体；熔点：206.2-207.1℃；产率：80％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),2.90(s,3H),3.01-3.04(m,1H),3.16-3.20(m,1H),3.59(d,J＝4.0Hz,1H),3.84(d,J＝4.0Hz,1H),4.28(d,J＝12.8Hz,1H),4.68(d,J＝7.2Hz,1H),5.28(d,J＝12.8Hz,1H),5.77-5.81(m,1H),6.20(d,J＝6.4Hz,1H),6.57(d,J＝6.4Hz,1H),6.76(d,J＝5.2Hz,2H),6.81(s,1H),7.08-7.10(m,1H),7.17-7.21(m,3H),7.29-7.31(m,1H)；13C NMR(CDCl3,100MHz)δ:11.2,25.6,32.4,44.7,44.9,47.1,66.2,68.4,73.1,109.3,110.7,114.3,126.5,127.4,127.5,128.7,129.0,130.5,132.7,142.8,143.0,155.7,170.7,173.5,176.6；HRMS(ESI-TOF)m/z:Calcd.for C32H25BrClN5NaO5S[M+Na]+:728.0346；Found:728.0347.
本实施例制备化合物3hg：黄色固体；熔点：207.2-207.9℃；产率：75％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),3.02-3.06(m,1H),3.21-3.24(m,1H),3.63(d,J＝5.2Hz,1H),3.87(d,J＝5.2Hz,1H),4.26-4.38(m,2H),4.73(d,J＝8.8Hz,1H),4.98(d,J＝16.0Hz,1H),5.24(d,J＝16.4Hz,1H),5.82-5.88(m,1H),6.14(d,J＝8.0Hz,1H),6.48(d,J＝8.0Hz,1H),6.55(d,J＝7.2Hz,2H),6.66(d,J＝7.2Hz,2H),6.86-6.94(m,2H),7.02-7.19(m,8H),7.65(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.2,32.4,43.3,44.4,45.1,47.2,66.1,68.6,73.5,109.4,110.7,114.6,126.4,126.5,127.2,127.4,128.6,128.7,132.5,143.0,143.8,155.7,170.9,173.8,176.8；HRMS(ESI-TOF)m/z:Calcd.for C38H30BrN5NaO5S[M+Na]+:770.1049；Found:770.1048.
本实施例制备化合物3ig：黄色固体；熔点：216.6-217.2℃；产率：73％,>20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.45(s,3H),3.02-3.05(m,1H),3.19-3.22(m,1H),3.61(d,J＝4.0Hz,1H),3.82(d,J＝4.0Hz,1H),4.29-4.38(m,2H),4.72(d,J＝7.2Hz,1H),4.93(d,J＝12.8Hz,1H),5.27(d,J＝12.8Hz,1H),5.77-5.82(m,1H),6.23(d,J＝7.2Hz,1H),6.34(d,J＝6.4Hz,1H),6.66(d,J＝5.6Hz,2H),6.71(d,J＝6.0Hz,2H),6.84(s,1H),7.08-7.19(m,7H),7.29-7.31(m,1H),7.82(s,1H)；13C NMR(CDCl3,100MHz)δ:11.2,32.2,43.4,44.7,44.8,47.0,66.1,68.6,73.0,110.8,110.9,114.7,116.5,126.4,126.5,127.5,127.6,128.8,128.9,142.7,143.1,155.7,170.7,173.2,176.6；HRMS(ESI-TOF)m/z:Calcd.for C38H29Br2N5NaO5S[M+Na]+:848.0154；Found:848.0155.
本实施例制备化合物3jg：黄色固体；熔点：183.0-184.4℃；产率：64％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.11(s,3H),2.44(s,3H),2.99-3.02(m,1H),3.15-3.18(m,1H),3.64(d,J＝4.4Hz,1H),3.86(d,J＝4.0Hz,1H),4.19(d,J＝13.2Hz,1H),4.68(d,J＝7.2Hz,1H),5.39(d,J＝9.2Hz,1H),5.71-5.76(m,1H),6.12(d,J＝7.2Hz,1H),6.53(d,J＝6.0Hz,2H),6.76(d,J＝6.4Hz,2H),6.91-6.93(m,1H),7.05-7.17(m,4H),7.44(s,1H),9.15(br s,1H)；13C NMR(CDCl3,100MHz)δ:11.2,26.8,32.3,44.2,44.9,47.0,65.8,68.4,73.7,110.6,110.9,114.3,122.7,124.9,126.1,127.2,128.5,130.9,132.4,133.3,134.6,139.3,142.9,155.7,171.0,176.8,176.9；HRMS(ESI-TOF)m/z:Calcd.for C32H26BrN5NaO5S[M+Na]+:694.0736；Found:694.0738.
本实施例制备化合物3kg：黄色固体；熔点：190.5-193.2℃；产率：62％,6:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.44(s,3H),2.99-3.03(m,1H),3.15-3.18(m,1H),3.64(d,J＝4.0Hz,1H),3.82(d,J＝4.0Hz,1H),4.25(d,J＝12.8Hz,1H),4.68(d,J＝7.2Hz,1H),5.33(d,J＝12.8Hz,1H),5.68-5.72(m,1H),6.21(d,J＝7.2Hz,1H),6.64(d,J＝6.4Hz,1H),6.71-6.74(m,3H),7.04-7.06(m,1H),7.14-7.21(m,3H),7.42-7.44(m,1H),7.81(s,1H),7.98(br s,1H)；13C NMR(CDCl3,100MHz)δ:11.2,26.9,32.2,44.7,46.9,66.1,68.5,73.1,110.9,111.8,114.5,116.5,124.6,126.5,127.0,127.6,128.8,129.0,129.2,130.7,132.8,133.5,134.6,155.8,170.6,175.4,176.4；HRMS(ESI-TOF)m/z:Calcd.for C31H23Br2N5NaO5S[M+Na]+:757.9684；Found:757.9684.
本实施例制备化合物3lg：黄色固体；熔点：196.6-198.5℃；产率：65％,4:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.43(s,3H),2.99-3.03(m,1H),3.15-3.18(m,1H),3.64(d,J＝4.0Hz,1H),3.83(d,J＝4.0Hz,1H),4.24(d,J＝12.8Hz,1H),4.68(d,J＝7.2Hz,1H),5.33(d,J＝12.8Hz,1H),6.22(d,J＝6.8Hz,1H),6.70-6.75(m,4H),7.01-7.03(m,1H),7.12-7.20(m,3H),7.27-7.29(m,1H),7.67(s,1H),8.32(br s,1H)；13C NMR(CDCl3,100MHz)δ:11.2,26.9,34.7,44.7,46.9,66.1,68.4,73.3,111.0,111.5,114.5,124.6,124.7,126.5,127.5,128.0,128.7,129.2,129.3,130.6,132.7,134.6,155.8,170.6,175.8,176.4；HRMS(ESI-TOF)m/z:Calcd.for C31H23BrClN5NaO5S[M+Na]+:714.0189；Found:714.0185.
本实施例制备化合物3bb-1：黄色固体；熔点：129.8-131.2℃；产率：82％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.66(s,1H),2.02-2.06(m,1H),2.09-2.14(m,1H),2.31-2.38(m,4H),2.49-2.56(m,1H),2.64-2.69(m,1H),2.80-2.83(m,1H),3.22(s,3H),4.29(d,J＝12.8Hz,1H),4.67-4.72(m,1H),4.88(d,J＝12.8Hz,1H),6.20(d,J＝7.2Hz,1H),6.36-6.42(m,2H),6.56(d,J＝5.6Hz,1H),6.61-6.64(m,1H),6.68(d,J＝6.0Hz,1H),7.00-7.03(m,2H),7.08-7.11(m,1H),7.15-7.22(m,3H),8.08-8.10(m,1H)；13C NMR(CDCl3,100MHz)δ:11.5,26.3,30.5,30.8,43.3,44.5,47.3,68.3,68.4,107.7,109.1,121.8,122.2,126.0,126.2,127.0,128.2,128.5,129.5,129.6,142.2,144.4,155.4,169.4,170.8,176.4；HRMS(ESI-TOF)m/z:Calcd.for C33H29N5NaO5[M+Na]+:598.2066；Found:598.2067.
本实施例制备化合物3bc-1：黄色固体；熔点：189.9-191.0℃；产率：85％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.68-1.75(m,1H),1.80-1.90(m,1H),2.01-2.06(m,3H),2.23(s,3H),2.25(s,3H),2.71-2.75(m,1H),3.24(m,3H),3.36(s,3H),3.81-3.87(m,1H),4.99-5.02(m,1H),6.60(d,J＝8.0Hz,1H),6.86(d,J＝7.6Hz,1H),6.98(d,J＝7.6Hz,1H),7.05-7.08(m,1H),7.33-7.37(m,1H),7.57(s,1H),7.63(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.2,21.2,24.7,26.5,26.6,26.8,49.5,54.7,64.5,73.0,75.4,107.4,108.5,122.4,125.3,125.6,126.8,128.3,128.8,130.4,132.6,141.1,144.6,155.2,169.5,176.1,179.2；HRMS(ESI-TOF)m/z:Calcd.forC28H27N5NaO5[M+Na]+:536.1910；Found:536.1912.
本实施例制备化合物3ca-1：黄色固体；熔点：169.2-171.1℃；产率：72％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.70-1.76(m,1H),1.78-1.90(m,1H),1.97-2.06(m,3H),2.23(s,3H),2.74-2.78(m,1H),3.27(s,3H),3.76-3.82(m,1H),4.96-5.00(m,1H),6.72(d,J＝7.6Hz,1H),6.88-6.95(m,2H),7.02-7.06(m,1H),7.16-7.20(m,1H),7.26-7.30(m,1H),7.61(d,J＝7.6Hz,1H),7.71(d,J＝6.8Hz,1H),7.96(br s,1H)；13C NMR(CDCl3,100MHz)δ:11.3,24.8,26.5,26.8,49.2,54.6,64.2,73.2,75.2,107.8,110.1,122.4,123.0,125.8,126.0,126.1,128.3,128.6,130.4,141.7,143.5,155.3,169.4,177.4,179.3；HRMS(ESI-TOF)m/z:Calcd.for C26H23N5NaO5[M+Na]+:508.1597；Found:508.1599.
本实施例制备化合物3da-1：黄色固体；熔点：183.4-184.7℃；产率：82％,11:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.63-1.66(m,1H),1.75-1.80(m,1H),1.91-2.00(m,3H),2.14(s,3H),2.26(s,3H),2.66-2.69(m,1H),3.20(s,3H),3.26(s,3H),3.71-3.76(m,1H),4.94-4.96(m,1H),6.64-6.69(m,2H),6.85-6.88(m,1H),7.06-7.12(m,2H),7.37(s,1H),7.68(d,J＝4.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.2,21.0,24.7,26.4,26.5,26.8,49.4,54.8,64.3,73.1,75.4,107.7,108.3,123.1,125.3,126.1,126.3,128.3,128.5,130.2,130.6,132.1,142.2,143.5,155.2,169.6,176.1,179.4；HRMS(ESI-TOF)m/z:Calcd.for C28H27N5NaO5[M+Na]+:536.1910；Found:536.1910.
本实施例制备化合物3ea-1：黄色固体；熔点：181.8-182.1℃；产率：75％,9:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.69-1.75(m,1H),1.81-1.88(m,1H),1.96-2.08(m,3H),2.22(s,3H),2.73-2.77(m,1H),3.26(s,3H),3.34(s,3H),3.73-3.80(m,1H),4.99-5.01(m,1H),6.72(d,J＝7.6Hz,1H),6.78-6.81(m,1H),6.91-6.95(m,1H),7.04-7.09(m,1H),7.16-7.20(m,1H),7.38-7.40(m,1H),7.72(d,J＝7.2Hz,1H)；13CNMR(CDCl3,100MHz)δ:11.2,24.8,26.5,26.6,26.8,49.3,54.8,64.2,73.1,75.4,107.8,109.0,109.1,113.7(d,JCF＝26.0Hz),116.8(d,JCF＝23.0Hz),123.1,126.0,126.1,126.7,126.8,128.1,128.6,140.6,143.5,155.4,158.9(d,JCF＝240.0Hz),169.1,175.9,179.2；HRMS(ESI-TOF)m/z:Calcd.for C27H24FN5NaO5[M+Na]+:540.1659；Found:540.1657.
本发明的式(1)化合物具有重要的生物活性，体外对人前列腺(PC-3),人肺癌细胞(A549)以及人白血病细胞(K562)共三株肿瘤细胞的细胞毒性试验表明：此类式(1)所示的结构的异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人前列腺(PC-3),人肺癌细胞(A549)以及人白血病细胞(K562)表示的细胞毒性。
药理实施例1：化合物3ca-1和3ea-1对PC-3细胞的细胞毒性
PC-3(人前列腺癌)细胞用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL青霉素及100U/mL的链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配的3ca-1和3ea-1的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/L。48小时后，每孔加入10μLMTT(5mg/mL)的磷酸盐缓冲液，再继续在37℃培养4小时后，离心5分钟除去未转化的MTT，每孔中加入150μL二甲基亚砜。以溶解还原的MTT晶体甲臜(formazan)，用酶标仪在490nm波长测定OD值。其中化合物3ca-1和3ea-1对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3ca-1对PC-3肿瘤细胞的IC50为32.5μmol/L；化合物3ea-1对PC-3肿瘤细胞的IC50为31.2μmol/L；而阳性对照顺铂对PC-3肿瘤细胞的IC50为26.5μmol/L。
实验结论：PC-3细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例2：化合物3cd和3ca-1,3da-1,3ea-1对A549细胞的细胞毒性
A549(人非小细胞肺癌肺癌)用DMEM培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔4000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3cd对A549肿瘤细胞的IC50为65.9μmol/L；化合物3ca-1对A549肿瘤细胞的IC50为63.7μmol/L；化合物3da-1对A549肿瘤细胞的IC50为53.1μmol/L；化合物3ea-1对A549肿瘤细胞的IC50为32.8μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为22.4μmol/L。
实验结论：A549细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例3：化合物化合物3cd,3ga,3kg,3lg和3bb-1,3ca-1,3da-1,3ea-1对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3cd对K562肿瘤细胞的IC50为74.7μmol/L；化合物3ga对K562肿瘤细胞的IC50为62.7μmol/L；化合物3kg对K562肿瘤细胞的IC50为65.3μmol/L；化合物3lg对K562肿瘤细胞的IC50为33.5μmol/L；化合物3bb-1对K562肿瘤细胞的IC50为45.5μmol/L；化合物3ca-1对K562肿瘤细胞的IC50为34.5μmol/L；化合物3da-1对K562肿瘤细胞的IC50为39.0μmol/L；化合物3ea-1对K562肿瘤细胞的IC50为24.1μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为20.7μmol/L。
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的异恶唑拼接3,3′-吡咯双螺环氧化吲哚化合物对K562细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些化合物对这三株肿瘤细胞都显示有一定的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。

Claims (5)

1.异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
式中，R1为苯基、甲基、H或苄基；R2为甲基、H或卤素；R3为甲基、H或卤素；R4为为苯基、甲基、H或苄基；R5为甲基、H或卤素；R6为甲基、H或卤素；X为C或S。
2.一种如权利要求1所述的异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物的制备方法，其特征在于：将各种取代的靛红、硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸，按摩尔比为2:3:6的比例在有机溶剂中回流，进行1,3-偶极子3+2环加成反应，获得异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物
合成路线如下：
3.根据权利要求2所述的异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
4.根据权利要求2所述的异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物的制备方法，其特征在于：各种取代的靛红、硝基异恶唑烯烃化合物与脯氨酸或硫代脯氨酸，在有机溶剂中的反应温度为50-100℃，反应时间为5-20小时。
5.一种如权利要求1所述的异恶唑拼接3,3'-吡咯双螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
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