CN109705130A - 二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物及其制备方法及应用 - Google Patents

二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物及其制备方法及应用 Download PDF

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CN109705130A
CN109705130A CN201811409157.4A CN201811409157A CN109705130A CN 109705130 A CN109705130 A CN 109705130A CN 201811409157 A CN201811409157 A CN 201811409157A CN 109705130 A CN109705130 A CN 109705130A
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CN109705130B (zh
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刘雄利
岳静
陈爽
汪军鑫
徐圣文
周英
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Guizhou University
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Abstract

本发明公开了一种二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物，本发明以3‑羧酸取代的色酮、各种取代的靛红、脯氨酸或硫代脯氨酸按摩尔比为1:2:3的比例在有机溶剂中，进行1,3‑偶极子3+2环加成反应，获得二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物，该类化合物包含潜在的生物活性二氢色原酮和吡咯螺环氧化吲哚骨架，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。且该化合物对人白血病细胞(K562)所进行的肿瘤生长抑制活性筛选。

Description

二氢色原酮骨架拼接多环吡咯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，尤其是一种二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物及其制备方法及应用。
背景技术
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-吡咯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，天然产物3-吡咯螺环氧化吲哚类化合物pteropodine和alstonisine表现明显的生物活性。(2)二氢色原酮骨架也普遍存在天然产物和药物分子中。例如:天然产物分子elaeocarpine，diaportheone B 和tephrosin和12a-hydroxy-a-toxicarol共享一个二氢色原酮分子单元，这些化合物在解除病痛、经济发展中起着重大作用。鉴于3-吡咯螺环氧化吲哚骨架具有潜在的生物活性，多取代二氢色原酮骨架属于潜在的生物活性骨架。因此，把多取代二氢色原酮骨架拼接到3-吡咯螺环氧化吲哚骨架，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(如附图8所示)。
发明内容
本发明的目的是：提供一种二氢色原酮骨架拼接多环吡咯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：二氢色原酮骨架拼接多环吡咯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为甲基或乙基或苯基或苄基；R2为氢或卤素或甲基；R3为卤素或甲基或氢；X为亚甲基或硫。
二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物的制备方法，将3-羧酸取代的色酮、各种取代的靛红、脯氨酸或硫代脯氨酸按摩尔比为2:3:5的比例在有机溶剂中，进行1,3-偶极子3+2环加成反应，获得二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物。
合成路线如下：
其中合成路线中的化合物，其取代基满足R1为甲基或乙基或苯基或苄基； R2为氢或卤素或甲基；R3为卤素或甲基或氢；X为亚甲基或硫。
所述的有机溶剂为乙腈、甲苯、乙醇、或甲醇。
3-羧酸取代的色酮、各种取代的靛红、脯氨酸或硫代脯氨酸，在有机溶剂中的反应温度为80℃(油浴)，反应时间为1-5小时。
二氢色原酮骨架拼接多环吡咯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3-羧酸取代的色酮、各种取代的靛红、脯氨酸或硫代脯氨酸按摩尔比为2:3:5的比例在有机溶剂中，进行1,3-偶极子3+2环加成反应，获得二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物，该类化合物包含潜在的生物活性二氢色原酮和吡咯螺环氧化吲哚骨架，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
附图1及附图2为本发明的实施例的化合物3aa谱图数据；
附图3及附图4为本发明的实施例的化合物3ab谱图数据；
附图5及附图6为本发明的实施例的化合物3ac谱图数据。
附图7为本发明的实施例的化合物3ak单晶图。
附图8为本发明的所合成化合物的设计及其创造性
具体实施方式
本发明的实施例：在反应管中依次加入38.1mg 3-羧酸色酮1a(0.2mmol)，66.9mgN-苯基靛红2a(0.3mmol)，57.5mg脯氨酸(0.50mmol)和4.0mL EtOH溶液，油浴80℃中反应3小时，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71.7mg化合物3aa，淡黄色固体，熔点：228.0-229.3℃，dr：12:1；产率85％。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.94-1.96(m,1H), 2.07-2.10(m,2H),2.18-2.20(m,1H),2.75-2.78(m,1H),2.84-2.87(m,1H),3.84-3.87(m,1H), 4.07-4.10(m,1H),5.00-5.03(m,1H),6.83(d,J＝7.5Hz,1H),7.00-7.06(m,2H),7.23-7.26(m,1H),7.28-7.31(m,1H),7.38-7.44(m,3H),7.47-7.53(m,4H),7.83(d,J＝5.2Hz,1H),7.92(d,J ＝4.8Hz,1H)；13C NMR(CDCl3,125MHz)δ:28.7,31.4,48.8,53.8,68.0,87.4,109.3,118.1, 121.9,123.4,126.5,127.1,128.4,128.7,129.7,143.3,160.0,175.5,191.5；HRMS(ESI-TOF)m/z: Calcd.for C27H22N2NaO3[M+Na]+:445.1523；Found:445.1527.
化合物3ab至3db-1的制备方法同化合物3aa，投料比与化合物3aa相同，可得到化合物化合物3ab至3db-1，反应产率和dr值见表1和表2，但需强调的是本发明的化合物不限于表1所表示的内容。
表1为一种二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物的化学结构
表2为一种二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物的化学结构
表3为一种二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物的化学结构
本实施例制备化合物3ab：淡黄色固体；熔点：208.7-209.8℃；产率：84％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.92-1.95(m,1H),2.08-2.18(m,3H),2.45(s,3H),2.57-2.60(m,1H),2.75-2.78(m,1H),3.23(s,3H),3.86-3.87(m, 1H),4.04-4.06(m,1H),4.82(s,1H),6.78(d,J＝6.0Hz,1H),6.99(d,J＝6.4Hz,1H),7.03-7.06 (m,1H),7.20(d,J＝5.6Hz,1H),7.48-7.51(m,1H),7.61(s,1H),7.92(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.1,26.2,28.5,31.3,48.8,53.6,67.9,87.3,107.6,118.0,119.2, 121.7,126.9,128.9,129.6,132.5,136.1,140.8,159.9,175.4,191.5；HRMS(ESI-TOF)m/z: Calcd.for C23H22N2NaO3[M+Na]+:397.1523；Found:397.1521.
本实施例制备化合物3ac：淡黄色固体；熔点：215.2-217.0℃；产率：85％,18:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.82-1.84(m,1H),1.96-1.98(m,2H),2.06-2.08(m,1H),2.46-2.48(m,1H),2.65-2.67(m,1H),3.13(s,3H),3.69-3.71(m,1H),3.93-3.95(m,1H),4.72-4.74(m,1H),6.66(d,J＝8.0Hz,1H),6.91(d,J＝8.0 Hz,1H),6.95-6.98(m,1H),7.42(d,J＝7.0Hz,2H),7.78-7.83(m,2H)；13C NMR(CDCl3,125 MHz)δ:26.3,28.6,31.3,48.8,53.7,68.0,87.2,109.4,115.9,118.0,119.3,122.0,127.0,129.2, 131.4,132.2,136.4,142.3,159.8,175.2,191.2；HRMS(ESI-TOF)m/z:Calcd.for C22H19BrN2NaO3[M+Na]+:461.0471；Found:461.0478.
本实施例制备化合物3ad：淡黄色固体；熔点：217.0-218.8℃；产率：Yield 86％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.87-1.95(m,1H), 2.03-2.08(m,2H),2.10-2.18(m,1H),2.51-2.57(m,1H),2.71-2.76(m,1H),3.21(s,3H), 3.76-3.80(m,1H),3.99-4.05(m,1H),4.80(d,J＝4.0Hz,1H),6.78(d,J＝8.4Hz,1H),6.97-7.06 (m,2H),7.33-7.36(m,1H),7.47-7.51(m,1H),7.71(d,J＝7.0Hz,1H),7.88-7.90(m,1H)；13C NMR(CDCl3,100MHz)δ:26.4,28.7,31.4,48.8,53.8,67.9,87.2,108.9,118.1,119.3,122.0, 127.0,128.6,129.3,136.4,141.8,159.8,175.3,191.3；HRMS(ESI-TOF)m/z:Calcd.for C22H19ClN2NaO3[M+Na]+:417.0976；Found:417.0984.
本实施例制备化合物3ae：淡黄色固体；熔点：99.3-100.4℃；产率：Yield 78％,5:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.80-1.82(m,1H),1.96-2.07(m,3H),2.45-2.50(m,1H),2.63-2.65(m,1H),3.50(s,3H),3.70-3.73(m,1H),3.92-3.95(m,1H),4.70-4.72(m,1H),6.85(d,J＝6.4Hz,1H),6.93-6.96(m,1H),6.98-7.02(m, 1H),7.20(d,J＝6.4Hz,1H),7.36-7.39(m,1H),7.55(d,J＝6.0Hz,1H),7.81(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:28.7,29.8,31.4,48.8,53.8,67.9,76.5,87.3,115.3,118.0,119.5, 122.0,123.6,127.0,127.1,130.1,131.6,136.3,139.1,159.9,176.1,191.3；HRMS(ESI-TOF)m/z: Calcd.for C22H19ClN2NaO3[M+Na]+:417.0976；Found:417.0981.
本实施例制备化合物3af：淡黄色固体；熔点：171.0-172.3℃；产率：Yield 83％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.24-1.28(m,3H), 1.86-1.94(m,1H),2.03-2.09(m,1H),2.12-2.17(m,1H),2.53-2.59(m,1H),2.70-2.75(m,1H), 3.71-3.81(m,3H),3.99-4.04(m,1H),4.81(d,J＝3.6Hz,1H),6.78-6.81(m,1H),6.96-7.09(m, 3H),7.45-7.50(m,2H),7.88-7.90(m,1H)；13C NMR(CDCl3,100MHz)δ:12.8,28.6,31.4,34.9, 48.6,53.8,67.9,87.3,108.5(d,JCF＝8.4Hz),115.6(d,JCF＝24.6Hz),116.4(d,JCF＝25.1Hz), 118.0,122.0,127.0,129.3(d,JCF＝8.1Hz),136.3,138.1,；138.2,159.4(d,JCF＝239.6Hz),159.8, 175.0,191.3；HRMS(ESI-TOF)m/z:Calcd.for C23H21FN2NaO3[M+Na]+:415.1428；Found: 415.1435.
本实施例制备化合物3ag：淡黄色固体；熔点：237.0-246.9℃；产率：Yield 84％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.25-1.28(m,3H), 1.88-1.96(m,1H),2.05-2.10(m,2H),2.11-2.19(m,1H),2.53-2.59(m,1H),2.72-2.77(m,1H), 3.70-3.81(m,3H),4.00-4.06(m,1H),4.83(d,J＝3.6Hz,1H),6.80(d,J＝8.4Hz,1H),6.99-7.07 (m,2H),7.33-7.36(m,1H),7.48-7.52(m,1H),7.74(d,J＝2.4Hz,1H),7.89-7.92(m,1H)；13C NMR(CDCl3,100MHz)δ:12.8,28.7,31.4,34.9,48.6,53.8,67.9,87.2,109.0,118.1,119.4, 122.0,127.0,128.4,128.8,129.2,136.4,140.8,159.8,174.9,191.3；HRMS(ESI-TOF)m/z: Calcd.for C23H21ClN2NaO3[M+Na]+:431.1133；Found:431.1135.
本实施例制备化合物3ah：淡黄色固体；熔点：151.0-152.3℃；产率：Yield 81％,8:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.30-1.32(m,3H), 1.89-1.90(m,1H),2.05-2.07(m,2H),2.15-2.17(m,1H),2.55-2.58(m,1H),2.71-2.73(m,1H), 3.79-3.82(m,1H),4.01-4.04(m,1H),4.16-4.18(m,2H),4.79-4.80(m,1H),6.94(d,J＝6.4Hz, 1H),7.02-7.05(m,1H),7.08-7.11(m,1H),7.28-7.31(m,1H),7.45-7.48(m,1H),7.64(d,J＝5.6 Hz,1H),7.90(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:15.0,28.6,31.4,36.7,48.6, 53.8,67.9,76.1,87.2,114.8,117.9,119.4,121.9,123.4,127.0,130.4,131.7,136.2,138.4,159.8, 175.9,191.3；HRMS(ESI-TOF)m/z:Calcd.forC23H21ClN2NaO3[M+Na]+:431.1133；Found: 431.1137.
本实施例制备化合物3ai：淡黄色固体；熔点：224.5-225.0℃；产率：Yield 90％,7:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.25-1.28(m,3H), 1.91-1.93(m,1H),2.07-2.22(m,3H),2.43(s,3H),2.56-2.59(m,1H),2.74-2.76(m,1H), 3.71-3.80(m,2H),3.85-3.87(m,1H),4.02-4.06(m,1H),4.83(d,J＝2.4Hz,1H),6.78(d,J＝6.0 Hz,1H),6.98(d,J＝6.4Hz,1H),7.02-7.04(m,1H),7.18(d,J＝5.6Hz,1H),7.46-7.49(m,1H), 7.61(s,1H),7.90(d,J＝5.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:12.8,21.1,28.6,31.4,34.7, 48.7,53.8,67.9,87.3,107.8,118.0,119.4,121.8,127.0,127.2,129.2,129.6,132.3,136.2,139.9, 160.0,175.1,191.6；HRMS(ESI-TOF)m/z:Calcd.forC24H24N2NaO3[M+Na]+:411.1679；Found: 411.1687.
本实施例制备化合物3aj：淡黄色固体；熔点：172.3-173.5℃；产率：Yield 87％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.27-1.29(m,3H), 1.90-1.92(m,1H),2.04-2.18(m,3H),2.56(s,4H),2.71-2.73(m,1H),3.82-3.85(m,1H), 3.95-4.02(m,3H),4.77(d,J＝2.8Hz,1H),6.94(d,J＝6.8Hz,1H),6.99-7.03(m,1H),7.06-7.13 (m,2H),7.43-7.46(m,1H),7.61(d,J＝5.2Hz,1H),7.89(d,J＝5.2Hz,1H)；13CNMR(CDCl3, 125MHz)δ:14.9,18.9,28.6,31.4,36.6,48.6,53.8,67.8,75.9,87.3,118.0,118.9,119.4,121.7, 122.5,126.4,126.9,128.1,133.3,136.1,140.2,160.0,176.3,191.6；HRMS(ESI-TOF)m/z: Calcd.for C24H24N2NaO3[M+Na]+:411.1679；Found:411.1683.
本实施例制备化合物3ak：淡黄色固体；熔点：250.1-251.2℃；产率：Yield 80％,18:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.83-1.95(m,1H), 2.07-2.10(m,2H),2.20-2.22(m,1H),2.65-2.69(m,1H),2.78-7.80(m,1H),3.84-3.87(m,1H), 4.04-4.09(m,1H),4.87-4.91(m,3H),6.64-6.67(m,1H),6.94-6.99(m,2H),7.03-7.06(m,1H), 7.25-7.28(m,3H),7.30-7.33(m,2H),7.47-7.50(m,2H),7.91(d,J＝5.2Hz,1H)；13C NMR (CDCl3,125MHz)δ:28.7,31.4,43.9,48.8,53.8,67.9,87.4,109.4,115.6(d,JCF＝23.8Hz), 116.3(d,JCF＝25.2Hz),118.0,119.4,122.0,127.0,127.1,127.9,128.9,129.0,129.1,135.3, 136.3,138.2,159.5(d,JCF＝240.7Hz),159.8,175.6,191.2；HRMS(ESI-TOF)m/z:Calcd.for C28H23FN2NaO3[M+Na]+:477.1585；Found:477.1579.
本实施例制备化合物3al：淡黄色固体；熔点：216.7-217.6℃；产率：83％,8:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.98-1.99(m,1H),2.13-2.15 (m,2H),2.24-2.26(m,1H),2.68-2.71(m,1H),2.83-2.85(m,1H),3.88-3.90(m,1H),4.09-4.12 (m,1H),4.92-4.95(m,3H),6.70(d,J＝6.8Hz,1H),7.05(d,J＝6.8Hz,1H),7.09-7.12(m,1H), 7.27-7.37(m,6H),7.53-7.56(m,1H),7.77(s,1H),7.97(d,J＝5.6Hz,1H)；13C NMR(CDCl3, 100MHz)δ:28.8,31.4,44.0,48.8,53.9,68.0,87.4,109.9,118.1,119.4,122.1,127.1,127.2, 128.0,128.7,128.8,129.0,129.2,135.2,136.4,140.9,159.8,175.5,191.3；HRMS(ESI-TOF)m/z: Calcd.for C28H23ClN2NaO3[M+Na]+:493.1289；Found:493.1288.
本实施例制备化合物3am：黄色固体；熔点：201.2-202.1℃；产率：Yield 85％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.94-1.98(m,1H),2.11-2.15(m,2H),2.21-2.24(m,1H),2.67-2.72(m,1H),2.82-2.84(m,1H),3.86-3.90(m,1H), 4.09-4.14(m,1H),4.90(d,J＝2.8Hz,1H),5.38-5.46(m,2H),7.00(d,J＝6.4Hz,1H),7.07-7.10 (m,1H),7.14-7.18(m,1H),7.27-7.31(m,4H),7.33-7.35(m,2H),7.51-7.54(m,1H),7.74(d,J＝ 5.6Hz,1H),7.97(d,J＝5.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:28.8,31.5,45.0,48.9,53.9, 68.0,87.5,115.2,118.0,119.5,122.1,123.8,126.4,127.1,127.2,127.3,128.7,130.2,131.9, 136.4,137.4,138.5,159.9,176.6,191.3,222.7；HRMS(ESI-TOF)m/z:Calcd.for C28H23ClN2NaO3[M+Na]+:493.1289；Found:493.1293.
本实施例制备化合物3an：黄色固体；熔点：200.0-201.0℃；产率：Yield 88％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.94-1.96(m,1H),2.08-2.13(m,2H),2.18-2.22(m,1H),2.40(s,3H),2.65-2.70(m,1H),2.78-2.81(m,1H),3.88-3.92(m,1H),4.05-4.10(m,1H),4.88-4.90(m,3H),6.65(d,J＝6.4Hz,1H),6.97(d,J＝6.4 Hz,1H),7.02-7.08(m,2H),7.26-7.32(m,5H),7.46-7.49(m,1H),7.60(s,1H),7.90-7.92(m,1H)；13C NMR(CDCl3,125MHz)δ:21.2,28.7,31.5,43.8,48.9,53.8,68.0,87.5,108.7,118.1,121.9, 127.0,127.2,127.7,128.9,129.1,129.6,132.6,135.7,136.2,160.0,175.7,191.5,222.7；HRMS (ESI-TOF)m/z:Calcd.for C29H26N2NaO3[M+Na]+:473.1836；Found:473.1837.
本实施例制备化合物3ao：黄色固体；熔点：203.0-204.0℃；产率：Yield 80％,18:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.85-1.90(m,1H),1.99-2.04(m,2H),2.09-2.12(m,1H),2.22(s,3H),2.59-2.64(m,1H),2.73-2.75(m,1H),3.78-3.81(m,1H),3.98-4.01(m,1H),4.80-4.82(m,1H),5.11-5.13(m,2H),6.89-7.07(m,6H), 7.15-7.18(m,1H),7.21-7.24(m,2H),7.37-7.41(m,1H),7.58(d,J＝5.2Hz,1H),7.82-7.84(m, 1H)；13C NMR(CDCl3,125MHz)δ:18.8,28.8,31.5,45.1,48.9,53.9,68.0,76.2,87.6,118.1, 119.5,121.8,122.9,125.5,126.5,127.0,127.3,127.8,129.0,133.4,136.2,137.3,140.5,160.0, 176.8,191.6,222.7；HRMS(ESI-TOF)m/z:Calcd.forC29H26N2NaO3[M+Na]+:473.1836；Found: 473.1838.
本实施例制备化合物3bb：黄色固体；熔点：193.3-194.4℃；产率：Yield 90％,16:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.91-1.93(m,3H),2.06-2.16(m,3H),2.30(s,3H),2.43(s,3H),2.55-2.59(m,1H),2.73-2.76(m,1H),3.20(s,3H), 3.81-3.83(m,1H),4.01-4.04(m,1H),4.77-4.79(m,1H),6.75(d,J＝7.5Hz,1H),6.87(d,J＝8.0 Hz,1H),7.18(d,J＝7.5Hz,1H),7.28(d,J＝9.0Hz,1H),7.59(s,1H),7.69(s,1H)；13C NMR (CDCl3,125MHz)δ:20.4,21.2,26.2,28.6,31.4,48.9,53.7,67.9,87.3,107.7,117.9,119.0, 126.5,127.0,129.0,129.6,131.2,132.6,137.3,140.9,158.1,175.5,191.8；HRMS(ESI-TOF)m/z: Calcd.for C24H24N2NaO3[M+Na]+:411.1679；Found:411.1674.
本实施例制备化合物3bf：黄色固体；熔点：226.0-227.2℃；产率：Yield 81％,13:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.18-1.19(m,3H),1.81-1.83(m,1H),1.95-1.98(m,2H),2.06-2.08(m,1H),2.22(s,3H),2.48-2.50(m,1H),2.64-2.66(m,1H),3.64-3.70(m,3H),3.92-3.94(m,1H),4.69-4.71(m,1H),6.70-6.72(m,1H), 6.79-6.81(m,1H),6.96-7.00(m,1H),7.20-7.22(m,1H),7.40-7.42(m,1H),7.59-7.61(m,1H)；13C NMR(CDCl3,125MHz)δ:12.7,20.4,28.6,31.3,34.9,48.6,53.8,67.9,87.2,108.4,115.5(d, JCF＝23.8Hz),116.4(d,JCF＝23.8Hz),117.8,119.0,126.5,131.4,137.4,138.1,157.9,159.3(d, JCF＝238.8Hz),175.0,191.5；HRMS(ESI-TOF)m/z:Calcd.for C24H23FN2NaO3[M+Na]+: 429.1585；Found:429.1589.
本实施例制备化合物3bk：黄色固体；熔点：188.0-189.2℃；产率：77％,5:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.92-1.94(m,1H),2.07-2.09(m, 2H),2.18-2.21(m,1H),2.30(s,3H),2.66-2.68(m,1H),2.78-2.79(m,1H),3.82-3.84(m,1H), 4.04-4.06(m,1H),4.84-4.94(m,3H),6.64-6.66(m,1H),6.87-6.89(m,1H),6.93-6.96(m,1H), 7.26-7.32(m,6H),7.48-7.51(m,1H),7.70(s,1H)；13C NMR(CDCl3,125MHz)δ:20.5,28.8, 31.4,44.0,48.9,53.9,68.0,87.5,109.5,115.6(d,JCF＝23.8Hz),116.3(d,JCF＝25.1Hz),117.9, 119.1,126.6,127.2,127.9,129.0,131.5,135.4,137.5,138.2,157.9,159.6(d,JCF＝240.4Hz), 175.7,191.5；HRMS(ESI-TOF)m/z:Calcd.forC29H25FN2NaO3[M+Na]+:491.1741；Found: 491.1747.
本实施例制备化合物3bm：黄色固体；熔点：227.1-228.1℃；产率：Yield 81％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.84-1.87(m,1H),1.96-2.01(m,2H),2.08-2.11(m,1H),2.23(s,3H),2.54-2.59(m,1H),2.69-2.72(m,1H),3.70-3.73(m,1H),3.96-3.99(m,1H),4.73-4.75(m,1H),5.27-5.30(m,2H),6.78(d,J＝8.0Hz, 1H),7.01-7.04(m,1H),7.13-7.18(m,4H),7.20-7.24(m,3H),7.58-7.62(m,2H)；13CNMR (CDCl3,125MHz)δ:20.4,28.7,31.4,45.0,48.8,53.9,68.0,76.3,87.4,115.2,117.8,119.1,123.8, 126.3,126.6,127.2,127.3,128.7,130.3,131.5,131.8,137.3,137.4,138.5,157.9,176.6,191.5； HRMS(ESI-TOF)m/z:Calcd.for C29H25ClN2NaO3[M+Na]+:507.1446；Found:507.1447.
本实施例制备化合物3bn：黄色固体；熔点：223.0-224.0℃；产率：Yield 84％,10:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.90-1.99(m,1H),2.03-2.14(m,2H),2.14-2.22(m,1H),2.30(s,3H),2.38(s,3H),2.63-2.69(m,1H),2.76-2.82(m, 1H),3.85-3.88(m,1H),4.02-4.08(m,1H),4.84(d,J＝4.5Hz,1H),4.89(s,2H),6.63(d,J＝10.0 Hz,1H),6.87(d,J＝10.4Hz,1H),7.04-7.06(m,1H),7.22-7.31(m,6H),7.59(s,1H),7.69(d,J ＝2.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:20.6,21.3,28.8,31.6,43.9,49.1,53.9,68.1,87.6, 108.8,118.0,119.2,126.7,127.3,127.8,129.0,129.2,129.7,131.4,135.8,137.4,140.1,158.2, 175.8,191.9；HRMS(ESI-TOF)m/z:Calcd.forC30H28N2NaO3[M+Na]+:487.1992；Found: 487.1997.
本实施例制备化合物3cd：黄色固体；熔点：81.0-82.3℃；产率：Yield 80％,14:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.80-1.82(m,1H),1.96-1.98(m,2H),2.05-2.07(m,1H),2.27(s,3H),2.45-2.47(m,1H),2.63-2.65(m,1H),3.13(s, 3H),3.64-3.66(m,1H),3.90-3.92(m,1H),4.66-4.68(m,1H),6.69-6.71(m,2H),6.76-6.78(m, 1H),7.25-7.27(m,1H),7.62(s,1H),7.68-7.70(m,1H)；13C NMR(CDCl3,125MHz)δ:21.9, 26.4,28.7,31.4,48.8,53.7,68.0,87.3,108.9,117.1,118.0,123.4,126.9,128.6,129.3,141.8, 148.1,159.8,175.4,190.9,222.8；HRMS(ESI-TOF)m/z:Calcd.for C23H21ClN2NaO3[M+Na]+: 431.1133；Found:431.1135.
本实施例制备化合物3ci：黄色固体；熔点：98.2-99.7℃；产率：Yield 73％,15:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.21-1.27(m,3H),1.89-1.92(m,1H),2.04-2.11(m,2H),2.13-2.16(m,1H),2.34(s,3H),2.44(s,3H),2.54-2.59(m, 1H),2.72-2.74(m,1H),3.69-3.76(m,2H),3.79-3.82(m,1H),4.78-4.79(m,1H),6.75-6.77(m, 2H),6.84(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.59(s,1H),7.78(d,J＝8.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:12.8,21.2,21.9,28.6,31.4,34.8,48.8,53.8,68.0,87.4,107.8,117.2, 118.0,123.2,126.8,127.4,129.2,129.6,132.3,139.9,147.8,160.1,175.2,191.3,197.0,222.9； HRMS(ESI-TOF)m/z:Calcd.for C25H26N2NaO3[M+Na]+:425.1836；Found:425.1836.
本实施例制备化合物3cn：黄色固体；熔点：77.2-78.7℃；产率：Yield 74％,17:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.85-1.87(m,1H),2.01-2.06(m,2H),2.10-2.13(m,1H),2.27(s,3H),2.33(s,3H),2.56-2.61(m,1H),2.70-2.72(m, 1H),3.76-3.79(m,1H),3.96-3.98(m,1H),4.77-4.78(m,1H),4.81-4.83(m,2H),6.56(d,J＝7.5 Hz,1H),6.69(s,1H),6.77(d,J＝7.5Hz,1H),6.99(d,J＝8.0Hz,1H),7.18-7.24(m,5H),7.51 (s,1H),7.72(d,J＝8.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:21.2,21.9,28.7,31.5,43.8,48.9, 53.8,68.1,87.6,108.7,118.0,123.3,126.9,127.2,127.7,128.9,129.1,129.6,135.7,140.0,147.8, 160.1,175.8,191.2；HRMS(ESI-TOF)m/z:Calcd.for C30H28N2NaO3[M+Na]+:487.1992；Found: 487.1997.
本实施例制备化合物3cl：黄色固体；熔点：91.0-92.3℃；产率：Yield 79％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.86-1.88(m,1H),2.01-2.02(m,2H),2.12-2.13(m,1H),2.29(s,3H),2.56-2.58(m,1H),2.70-2.72(m,1H),3.71-3.74(m,1H),3.96-3.98(m,1H),4.77-4.78(m,1H),4.82-4.84(m,2H),6.57-6.59(m,1H), 6.72(s,1H),6.78-6.80(s,1H),7.14-7.21(m,4H),7.23-7.26(m,2H),7.65(s,1H),7.73(d,J＝8.0 Hz,1H)；13C NMR(CDCl3,125MHz)δ:21.9,28.8,31.5,44.0,48.8,53.8,68.1,87.5,109.9, 117.2,118.0,123.5,127.0,127.2,127.9,128.8,129.0,129.2,135.2,140.9,148.1,159.9,175.5, 190.9,202.5,222.9；HRMS(ESI-TOF)m/z:Calcd.forC29H25ClN2NaO3[M+Na]+:507.1446； Found:507.1448.
本实施例制备化合物3db：黄色固体；熔点：222.0-222.1℃；产率：83％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.83-1.85(m,1H),1.98-2.00 (m,2H),2.07-2.09(m,1H),2.35(s,3H),2.48-2.51(m,1H),2.66-2.68(m,1H),3.13(s,3H), 3.77-3.79(m,1H),3.93-3.95(m,1H),4.72-4.74(m,1H),6.67-6.69(m,1H),6.88-6.89(m,1H), 7.10-7.12(m,2H),7.46-7.49(m,2H)；13C NMR(CDCl3,125MHz)δ:21.2,26.3,28.6,31.4,48.9, 53.4,67.8,87.7,107.8,111.9(d,JCF＝22.5Hz),119.8,119.9,123.7(d,JCF＝241.3Hz),126.8, 128.9,129.8,132.7,140.9,156.2,156.5,158.4,175.4,190.9,222.7；HRMS(ESI-TOF)m/z: Calcd.for C23H21FN2NaO3[M+Na]+:415.1428；Found:415.1422.
本实施例制备化合物3dk：黄色固体；熔点：198.0-199.2℃；产率：83％,6:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.92-1.94(m,1H),2.07-2.10(m, 2H),2.19-2.21(m,1H),2.65-2.68(m,1H),2.78-7.80(m,1H),3.85-3.89(m,1H),4.04-4.06(m, 1H),4.87-4.91(m,3H),6.65-6.68(m,1H),6.94-7.00(m,2H),7.20-7.32(m,6H),7.46-7.49(m, 1H),7.54-7.56(m,1H)；13C NMR(CDCl3,125MHz)δ:28.7,31.3,43.9,48.8,53.5,67.8,87.7, 109.4,109.5,112.0(d,JCF＝22.5Hz),115.7(d,JCF＝23.8Hz),116.2(d,JCF＝25.0Hz),119.8, 123.8(d,JCF＝25.3Hz),127.1,127.9,128.7,128.9,135.2,138.2,156.0,156.5,159.5(d,JCF＝ 240.4Hz),175.5,190.5；HRMS(ESI-TOF)m/z:Calcd.for C28H22F2N2NaO3[M+Na]+:495.1491； Found:495.1497.
本实施例制备化合物3eb：黄色固体；熔点：87.0-88.9℃；产率：82％,19:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.82-1.85(m,1H),1.96-1.99(m, 2H),2.07-2.09(m,1H),2.36(s,3H),2.46-2.49(m,1H),2.65-2.67(m,1H),3.13(s,3H), 3.76-3.78(m,1H),3.91-3.93(m,1H),4.73-4.75(m,1H),6.68(d,J＝7.5Hz,1H),6.92-6.95(m, 2H),7.11(d,J＝7.5Hz,1H),7.46(s,1H),7.77(d,J＝8.0Hz,1H)；13C NMR(CDCl3,125MHz) δ:21.3,26.3,28.7,31.4,48.9,53.6,67.9,88.0,107.8,118.0,118.2,122.7,128.4,128.9,129.8, 132.7,140.9,142.1,160.4,175.5,190.6,222.9；HRMS(ESI-TOF)m/z:Calcd.for C23H21ClN2NaO3[M+Na]+:431.1133；Found:431.1130.
本实施例制备化合物3ed：黄色固体；熔点：112.0-113.7℃；产率：84％,20:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.79-1.87(m,1H),1.96-1.98(m, 2H),2.06-2.09(m,1H),2.44-2.49(m,1H),2.65-2.67(m,1H),3.13(s,3H),3.70-3.73(m,1H), 3.90-3.93(m,1H),4.74-4.75(m,1H),6.71(d,J＝8.5Hz,1H),6.95(s,2H),7.26-7.29(m,1H), 7.60(s,1H),7.75-7.77(m,1H)；13C NMR(CDCl3,125MHz)δ:26.4,28.7,31.3,48.7,53.6,67.9, 87.8,108.9,117.9,118.1,122.9,128.3,128.5,128.7,129.4,141.8,142.3,160.1,175.2,190.2； HRMS(ESI-TOF)m/z:Calcd.for C22H18Cl2N2NaO3[M+Na]+:451.0587；Found:451.0586.
本实施例制备化合物3en：黄色固体；熔点：80.0-81.6℃；产率：80％,11:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:1.86-1.89(m,1H),1.99-2.06(m, 2H),2.11-2.14(m,1H),2.33(s,3H),2.56-2.61(m,1H),2.71-2.73(m,1H),3.81-3.84(m,1H), 3.93-3.98(m,1H),4.81-4.83(m,3H),6.57(d,J＝8.0Hz,1H),6.92-6.95(m,2H),6.99(d,J＝8.0 Hz,1H),7.16-7.19(m,3H),7.21-7.25(m,2H),7.47(s,1H),7.78(d,J＝8.5Hz,1H)；13C NMR (CDCl3,125MHz)δ:21.2,28.7,31.5,43.9,48.9,53.6,68.0,88.1,108.8,118.1,118.2,122.7, 127.2,127.8,128.4,128.9,129.0,129.8,132.7,135.6,140.0,160.4,175.6,190.5,222.9；HRMS (ESI-TOF)m/z:Calcd.for C29H25ClN2NaO3[M+Na]+:507.1446；Found:507.1447.
本实施例制备化合物3db-1：黄色固体；熔点：104.0-105.2℃；产率：65％,12:1dr；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,500MHz)δ:2.37(s,3H),2.48-2.53(m, 1H),3.03(s,3H),3.36-3.40(m,1H),3.54-3.59(m,2H),4.18(d,J＝12.5Hz,1H),4.38-4.43(m, 1H),5.08(d,J＝7.5Hz,1H),6.71(d,J＝10.0Hz,1H),7.06-7.09(m,1H),7.12(s,1H),7.17-7.26 (m,2H),7.35-7.38(m,1H)；13C NMR(CDCl3,125MHz)δ:21.1,26.4,35.3,55.0,55.6,75.1, 75.9,80.7,108.2,111.7(d,JCF＝23.3Hz),119.9(d,JCF＝7.4Hz),124.0(d,JCF＝25.0Hz),125.2, 125.9,130.9,132.4,137.1,142.0,157.2,157.3(d,JCF＝237.3Hz),175.1,188.8；HRMS (ESI-TOF)m/z:Calcd.for C22H19FN2NaO3S[M+Na]+:433.0993；Found:433.0997.
本发明的式(1)化合物具有重要的生物活性，体外对人白血病细胞(K562) 的细胞毒性试验表明：此类式(1)所示的结构的二氢色原酮骨架拼接多环吡咯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白血病细胞(K562)表示的细胞毒性。
药理实施例：化合物3ad,3af,3db,3dk和3db-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。细胞经过24小时的孵育后，分别将新配的化合物3ad,3af,3db,3dk和3db-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6μmol/L,12μmol/L,25μmol/L,50μmol/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150 μL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3ad,3af,3db,3dk和3db-1对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3ad对K562肿瘤细胞的IC50为41.47μmol/L；化合物3af对K562肿瘤细胞的IC50为37.55μmol/L；化合物 3db对K562肿瘤细胞的IC50为41.84μmol/L；化合物3dk对K562肿瘤细胞的 IC50为50.79μmol/L；化合物3db-1对K562肿瘤细胞的IC50为37.40μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为29.57μmol/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)所示的二氢色原酮骨架拼接多环吡咯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人白血病细胞(K562)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)

1.一种二氢色原酮骨架拼接多环吡咯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为甲基或乙基或苯基或苄基；R2为氢或卤素或甲基；R3为卤素或甲基或氢；X为亚甲基或硫。
2.一种如权利要求1所述的二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物的制备方法，其特征在于：将3-羧酸取代的色酮、各种取代的靛红、脯氨酸或硫代脯氨酸按摩尔比为2:3:5的比例在有机溶剂中，进行1,3-偶极子3+2环加成反应，获得二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物。
3.根据权利要求2所述的二氢色原酮骨架拼接多环吡咯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、甲苯、乙醇、或甲醇。
4.根据权利要求2所述的二氢色原酮骨架拼接多环吡咯螺环氧化吲哚化合物的制备方法，其特征在于：3-羧酸取代的色酮、各种取代的靛红、脯氨酸或硫代脯氨酸，在有机溶剂中的反应温度为80℃油浴，反应时间为1-5小时。
5.一种如权利要求1所述的二氢色原酮骨架拼接多环吡咯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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