双-β-咔啉衍生物的设计、合成及抗肿瘤活性

doi:10.7503/cjcu20160103

摘要/Abstract

摘要：

以去氢骆驼蓬碱为原料, 经过脱甲基、烷基化等步骤, 合成了一系列双-β-咔啉衍生物. 目标化合物均经核磁共振谱(NMR)和质谱(MS)进行结构确证. 以顺铂为阳性对照药, 采用四甲基偶氮唑盐(MTT)法考察了目标化合物体外抗肿瘤(Bel-7402, 786-0, BGC-823, A375, 769-P和MCF7等6株细胞)活性. 结果表明, 化合物4g和4o与阳性对照药相比具有良好的抗肿瘤活性, 其半抑制浓度(IC₅₀)值均小于10 μmol/L. 初步构效关系研究表明, 当桥链亚甲基数目为8~10, β-咔啉环上9-丁基或9-异丁基取代时, 化合物的抗肿瘤活性较强.

关键词: 去氢骆驼蓬碱, β-咔啉, 抗肿瘤活性, 构效关系

Abstract:

A series of novel bivalent β-carbolines with a spacer of three to ten methylene units between the 7-oxygen was synthesized and characterized by nuclear magnetic resonance(NMR) and mass spectrometry(MS). The antitumor activities against Bel-7402, 786-0, BGC-823, A375, 769-P and MCF7 cell lines in vitro were investigated by MTT method. The results demonstrated that compounds 4c, 4k and 4r were almost inactive against all tumor cell lines, compounds 4g and 4o displayed significant cytotoxic activities with IC₅₀ value of lower than 10 μmol/L against all tumor cell lines. Most compounds displayed good and selective cytotoxic activities against HT-29 and Blu-87 cell lines. Primary structure-activity relationships(SARs) analysis indicated that the length of the spacer affected cytotoxic activities in vitro, and 8—10 methylene units were more favorable. Moreover, n-butyl or i-butyl substituents in position-9 of β-carboline facilitated the antitumor potencies.

Key words: Harmine, β-Carboline, Antitumor activity, Structure-activity relationship

中图分类号:

O626

TrendMD:

郭亮, 曹日晖, 范文玺, 甘紫云, 马芹. 双-β-咔啉衍生物的设计、合成及抗肿瘤活性. 高等学校化学学报, 2016, 37(6): 1093.

GUO Liang, CAO Rihui, FAN Wenxi, GAN Ziyun, MA Qin. Design, Synthesis and in vitro Antitumor Activities of Novel Bivalent β-Carbolines^†. Chem. J. Chinese Universities, 2016, 37(6): 1093.

图/表 7

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Compd.	m.p./℃	Compd.	m.p./℃
2a	121.3—121.9(121—123^[6])	3a	>270
2b	98.7—99.2(99—101^[6])	3b	257.1—258.9(258—260^[23])
2c	104.2—104.8(104—105^[6])	3c	205.3—206.7(205—206^[23])
2d	80.3—80.6	3d	230.9—231.6
2e	65.4—65.7	3e	214.2—216.4
2f	111.7—112.6(112—113^[23])	3f	246.2—247.9(247—248^[23])
2g	117.5—118.6(117—118^[6])	3g	258.3—259.6(258—259^[23])

Compd.	m.p./℃	Compd.	m.p./℃
2a	121.3—121.9(121—123^[6])	3a	>270
2b	98.7—99.2(99—101^[6])	3b	257.1—258.9(258—260^[23])
2c	104.2—104.8(104—105^[6])	3c	205.3—206.7(205—206^[23])
2d	80.3—80.6	3d	230.9—231.6
2e	65.4—65.7	3e	214.2—216.4
2f	111.7—112.6(112—113^[23])	3f	246.2—247.9(247—248^[23])
2g	117.5—118.6(117—118^[6])	3g	258.3—259.6(258—259^[23])

Compd.	¹H NMR(400 MHz, CDCl₃), δ	FAB-MS,m/z [M+1]⁺
2d	8.30(d, J=5.2 Hz, 1H), 7.98(dd, J=8.8, 3.6 Hz, 1H), 7.74(d, J=5.2 Hz, 1H), 6.85—6.91(m, 2H), 4.44(t, J=8.0 Hz, 2H), 3.96(s, 3H), 3.03(s, 3H), 1.79—1.87(m, 2H), 1.40—1.49(m, 2H), 1.27—1.39(m, 4H), 0.91(t, J=7.2 Hz, 3H)	297
2e	8.30(d, J=5.2 Hz, 1H), 8.01(dd, J=8.8, 3.2 Hz, 1H), 7.77(d, J=5.2 Hz, 1H), 6.83—6.94(m, 2H), 4.46(t, J=8.0 Hz, 2H), 3.95(s, 3H), 3.06(s, 3H), 1.75—1.91(m, 2H), 1.18—1.48(m, 10H), 0.88(t, J=7.2 Hz, 3H)	325
3a	8.32(d, J=5.2 Hz, 1H); 8.07(d, J=8.8 Hz, 1H), 7.86(d, J=5.2 Hz, 1H), 7.03—7.12(m, 2H), 4.11(s, 3H), 2.96(s, 3H)	213
3d	8.30(d, J=5.2 Hz, 1H); 7.98(d, J=8.4 Hz, 1H), 7.82(d, J=5.2 Hz, 1H), 7.02—7.11(m, 2H), 4.44(t, J=8.0 Hz, 2H), 2.96(s, 3H), 1.74—1.79(m, 2H), 1.28—1.37(m, 6H), 0.90(t, J=7.2 Hz, 3H)	283
3e	8.29(d, J=6.0 Hz, 1H); 8.02(d, J=8.8 Hz, 1H), 7.90(d, J=5.2 Hz, 1H), 7.02(d, J=8.8 Hz, 1H), 6.86(s, 1H), 4.48(t, J=8.0 Hz, 2H), 2.96(s, 3H), 1.68—1.83(m, 2H), 1.12—1.43(m, 10H), 0.89(t, J=6.8 Hz, 3H)	311

Compd.	¹H NMR(400 MHz, CDCl₃), δ	FAB-MS,m/z [M+1]⁺
2d	8.30(d, J=5.2 Hz, 1H), 7.98(dd, J=8.8, 3.6 Hz, 1H), 7.74(d, J=5.2 Hz, 1H), 6.85—6.91(m, 2H), 4.44(t, J=8.0 Hz, 2H), 3.96(s, 3H), 3.03(s, 3H), 1.79—1.87(m, 2H), 1.40—1.49(m, 2H), 1.27—1.39(m, 4H), 0.91(t, J=7.2 Hz, 3H)	297
2e	8.30(d, J=5.2 Hz, 1H), 8.01(dd, J=8.8, 3.2 Hz, 1H), 7.77(d, J=5.2 Hz, 1H), 6.83—6.94(m, 2H), 4.46(t, J=8.0 Hz, 2H), 3.95(s, 3H), 3.06(s, 3H), 1.75—1.91(m, 2H), 1.18—1.48(m, 10H), 0.88(t, J=7.2 Hz, 3H)	325
3a	8.32(d, J=5.2 Hz, 1H); 8.07(d, J=8.8 Hz, 1H), 7.86(d, J=5.2 Hz, 1H), 7.03—7.12(m, 2H), 4.11(s, 3H), 2.96(s, 3H)	213
3d	8.30(d, J=5.2 Hz, 1H); 7.98(d, J=8.4 Hz, 1H), 7.82(d, J=5.2 Hz, 1H), 7.02—7.11(m, 2H), 4.44(t, J=8.0 Hz, 2H), 2.96(s, 3H), 1.74—1.79(m, 2H), 1.28—1.37(m, 6H), 0.90(t, J=7.2 Hz, 3H)	283
3e	8.29(d, J=6.0 Hz, 1H); 8.02(d, J=8.8 Hz, 1H), 7.90(d, J=5.2 Hz, 1H), 7.02(d, J=8.8 Hz, 1H), 6.86(s, 1H), 4.48(t, J=8.0 Hz, 2H), 2.96(s, 3H), 1.68—1.83(m, 2H), 1.12—1.43(m, 10H), 0.89(t, J=6.8 Hz, 3H)	311

Compd.	Appearance	Yield(%)	m. p./℃	FAB-MS, m/z [M+1]⁺
4a	White solid	45	>270	465
4b	White solid	45	131.3—132.3	507
4c	White solid	57	>270	507
4d	Slightly yellow solid	64	>270	549
4e	White solid	48	>270	577
4f	Yellow solid	55	135.6—137.1	591
4g	Slightly yellow solid	52	141.9—143.3	619
4h	Slightly yellow solid	54	108.1—109.5	633
4i	Yellow solid	42	137.6—138.9	675
4j	White solid	46	106.3—107.6	661
4k	White solid	44	107.0—108.1	704
4l	White solid	49	95.2—96.6	746
4m	Slightly yellow solid	56	187.9—188.1	563
4n	White solid	62	123.3—124.6	605
4o	White solid	48	115.8—116.9	647
4p	Yellow solid	47	190.0—191.7	687
4q	White solid	45	>270	715
4r	White solid	49	101.1—102.4	729
4s	White solid	56	122.8—124.5	772