CN108358879A - 灯盏乙素苷元醚类衍生物及其制备方法与应用 - Google Patents
灯盏乙素苷元醚类衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一类灯盏乙素苷元醚类衍生物(I)及其制备方法与在抗肿瘤药物中的应用。该类化合物的特征在于灯盏乙素苷元的7位羟基与大于一个碳的脂肪烃基成醚,6位羟基与4’位羟基被乙酰氧基修饰。该类化合物的制备以灯盏乙素为原料,经过两步反应而成,制备简便。与灯盏乙素和灯盏乙素苷元相比,该类化合物具有更好的抗肿瘤活性,并且更为稳定,本发明提供的灯盏乙素苷元醚类衍生物(I)可用于抗肿瘤。
Description
技术领域
本发明属于药物化学合成领域,具体涉及一类新型的灯盏乙素苷元醚类衍生物(I)及其制备方法与在抗肿瘤药物中的应用。
背景技术
肿瘤严重地威胁着人类的健康乃至生命,抗肿瘤药物的研究一直是人们关注的热点。发展安全而有效的抗肿瘤药物是研究的重中之重。灯盏细辛是云南省特有的天然药物之一,为菊科紫菀族飞蓬属植物短葶飞蓬[Erigeron breviscapus (Vant.) Hand.-mazz],其制剂广泛安全的应用于临床。灯盏乙素是灯盏细辛的主要有效成分,又名野黄芩苷,体内的主要活性代谢产物为灯盏乙素苷元。研究发现,灯盏乙素及其苷元具有抗氧化等作用。越来越多研究发现,灯盏乙素及其衍生物在抗肿瘤领域中展现出较好的应用前景。
灯盏乙素和灯盏乙素苷元溶解性比较低,药代动力学性质差,性质不稳定,抗肿瘤活性较低。为此,药物化学研究人员将灯盏乙素及其苷元作为先导化合物进行了系列结构改造,得到了一系列具有潜在应用价值的灯盏乙素衍生物。发明人在云南省教育厅科学研究基金项目“灯盏乙素苷元-L-精氨酸衍生物的合成”(项目编号:2015Y314)的支持下,以灯盏乙素为原料,经过两步反应制备得到新型的灯盏乙素苷元醚类衍生物,具有良好的抗肿瘤活性。
发明内容
本发明的目的在于提供一类新型的灯盏乙素苷元醚类衍生物(I)及其制备方法与在抗肿瘤药物中的应用。
本发明的目的是这样实现的:
灯盏乙素苷元醚类衍生物,其特征在于:其结构通式如(I)所示,式中R1为C>1的脂肪烃基,R2为氢或者乙酰基。
R1为乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基、正辛基、正癸基、正十二基、正十四基、正十六基、正十八基、油烯基。
通过如下的步骤获得:
A、以灯盏乙素为起始原料,与乙酸酐、吡啶一起反应,其中灯盏乙素:乙酸酐的摩尔比为1:5~1:20,乙酸酐:吡啶的体积比为1:1~2:1;反应结束后反应液浓缩经硅胶柱层析得到5,6,7,4’-O-四乙酰灯盏乙素苷元(a)和6,7,4’-O-三乙酰灯盏乙素苷元(b);
B、将5,6,7,4’-O-四乙酰灯盏乙素苷元(a)或6,7,4’-O-三乙酰灯盏乙素苷元(b)溶于DMF中,加入碳酸钾与溴代物,室温搅拌;反应结束后,将产物倾入水中,用乙酸乙酯萃取,有机层浓缩后经硅胶柱层析得到灯盏乙素苷元醚类衍生物。
灯盏乙素苷元醚类衍生物(I)在制备治疗癌症的药物中的应用。
所述癌症包括:肝癌、肺癌、胰腺癌、乳腺癌、宫颈癌、子宫内膜癌、大肠癌、胃癌、肾癌、鼻咽癌、卵巢癌、前列腺癌症、慢性或急性白血病、脑瘤、食道癌、口腔癌、贲门癌、结肠癌、胆囊癌、喉癌、牙龈癌、尿道癌、皮肤癌、直肠癌、中耳癌、骨癌、睾丸癌、淋巴细胞性淋巴瘤、脊柱轴肿瘤垂体腺瘤。
癌症是慢性或急性白血病或者是乳腺癌或者是结肠癌。
本发明优点:
1、本发明提供的灯盏乙素苷元醚类衍生物(I)的抗肿瘤活性明显强于灯盏乙素及其苷元。
2、本发明提供的灯盏乙素苷元醚类衍生物(I)由两步制备而来,简便。
3、本发明提供的灯盏乙素苷元醚类衍生物(I)的6位羟基与4’位羟基被乙酰基保护,提高了化合物的稳定性,易于保存。
附图说明
图1为本发明所述的灯盏乙素苷元醚类衍生物(I)的结构示意图。
图2为本发明所述的灯盏乙素苷元醚类衍生物(I)制备方法的反应流程图。
具体实施方式
下面对本发明作进一步的说明,但不以任何方式对本发明加以限制,基于本发明所作的任何变换,均属于本发明的保护范围。
实施例1:
将灯盏乙素10克(21.6mmol),与乙酸酐30毫升(158.7mmol)、吡啶20毫升一起回流4小时,冷却后浓缩经硅胶柱层析得到5,6,7,4’-O-四乙酰灯盏乙素苷元(a)(5.3 g, 54%)和6,7,4’-O-三乙酰灯盏乙素苷元(b)(2.1 g, 23%)。
5,6,7,4’-O-四乙酰灯盏乙素苷元(a),黄色固体。1H-NMR (CDCl3, 400 MHz) δ:7.88 (d, 2H, J =8.4 Hz, Ar'-H-2,6), 7.49 (s, 1H, Ar-H-8), 7.27 (d, 2H, J =6.0 Hz, Ar'-H-3,5); 6.62 (s, 1H, Ar-H-3); 2.44 (s, 3H, COCH3), 2.35 (s, 9H,COCH3×3).
6,7,4’-O-三乙酰灯盏乙素苷元(b),黄色固体。1H-NMR (CDCl3, 400 MHz) δ: 12.90(s, 1H, OH), 7.91 (d, 2H, J = 7.8 Hz, Ar'-H-2,6), 7.29 (d, 2H, J = 7.9 Hz,2H, Ar'-H-3,5), 6.96 (s, 1H, Ar-H-3), 6.70 (s, 1H, Ar-H-8), 2.37 (s, 3H,COCH3), 2.35 (s, 6H, COCH3×2).
实施例2:
将灯盏乙素5.9克(12.7mmol),与乙酸酐6毫升(63.5mmol)、吡啶6毫升一起回流4小时,冷却后浓缩经硅胶柱层析得到5,6,7,4’-O-四乙酰灯盏乙素苷元(a)(3.42 g, 59%)和6,7,4’-O-三乙酰灯盏乙素苷元(b)(1.03 g, 20%)。
实施例3:
将灯盏乙素5.9克(12.7mmol),与乙酸酐24毫升(254mmol)、吡啶12毫升一起回流4小时,冷却后浓缩经硅胶柱层析得到5,6,7,4’-O-四乙酰灯盏乙素苷元(a)(4.63g,80%)和6,7,4’-O-三乙酰灯盏乙素苷元(b)(0.57 g, 11%)。
实施例4:
5,6,7,4’-O-四乙酰灯盏乙素苷元(a)或6,7,4’-O-三乙酰灯盏乙素苷元(b) (1 mmol)溶于干燥DMF(10 mL),加入K2CO3 (691 mg, 5 mmol) and 溴代物 (1.5 mmol),室温搅拌过夜。将混合物倾入水(50 mL)中,用乙酸乙酯进行萃取(50 mL×3),合并乙酸乙酯层,用饱和食盐水(100 mL)洗,无水硫酸钠干燥,减压浓缩,用硅胶柱分离得到化合物c或d。
7-O-正己基-5,6,4’-O-三乙酰基灯盏乙素苷元(c1) ; 黄色固体; 产率 72%; 1HNMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.8 Hz, 2H, Ar'-H-2,6), 7.26 (d, J = 8.8Hz, 2H, Ar'-H-3,5), 6.92 (s, 1H, Ar-H-3), 6.57 (s, 1H, Ar-H-8), 4.09 (t, J =6.5 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.34 (s, 3H, COCH3), 2.33 (s, 3H,COCH3), 1.88 – 1.76 (m, 2H, CH2), 1.49 – 1.42 (m, 2H, CH2), 1.39 – 1.31 (m,4H, CH2×2), 0.92 (t, J = 6.7 Hz, 3H, CH3).13C NMR (100 MHz, CDCl3) δ 176.23,168.90, 168.73, 167.83, 161.23, 155.79, 155.69, 153.17, 141.77, 130.86,128.94, 127.47, 122.32, 111.09, 108.26, 98.70, 69.63, 31.36, 28.69, 25.44,22.52, 21.12, 20.85, 20.10, 13.94.
7-O-正十二烷基-5,6,4’-O-三乙酰基灯盏乙素苷元(c2) 黄色固体; 产率 72%; 1HNMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H, Ar'-H-2,6), 7.25 (d, J = 8.4Hz, 2H, Ar'-H-3,5), 6.92 (s, 1H, Ar-H-3), 6.56 (s, 1H, Ar-H-8), 4.08 (t, J =6.4 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.34 (s, 3H, COCH3), 2.33 (s, 3H,COCH3), 1.91 – 1.71 (m, 2H, CH2), 1.49 – 1.40 (m, 2H, CH2), 1.38 – 1.23 (m,16H, CH2×8), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 176.20,168.89, 168.72, 167.82, 161.21, 155.77, 155.68, 153.16, 141.75, 130.85,128.91, 127.46, 122.31, 111.06, 108.22, 98.71, 69.62, 31.91, 29.69, 29.65,29.63, 29.56, 29.53, 29.33, 29.23, 28.74, 25.78, 22.67, 21.12, 20.86, 20.11,14.10.
7-O-正十八烷基-5,6,4’-O-三乙酰基灯盏乙素苷元(c3) 黄色固体; 产率 57%;1HNMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 2H, Ar'-H-2,6), 7.25 (d, J = 8.4Hz, 2H, Ar'-H-3,5), 6.92 (s, 1H, Ar-H-3), 6.57 (s, 1H, Ar-H-8), 4.09 (t, J =6.5 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.34 (s, 3H, COCH3), 2.33 (s, 3H,COCH3), 1.91 – 1.74 (m, 2H, CH2), 1.51 – 1.39 (m, 2H, CH2), 1.26 (s, 28H, CH2×14), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 176.22,168.90, 168.73, 167.84, 161.24, 155.79, 155.70, 153.17, 141.78, 130.87,128.96, 127.47, 122.33, 111.09, 108.28, 98.69, 69.63, 31.91, 29.69, 29.65,29.57, 29.53, 29.34, 29.32, 29.23, 28.75, 25.79, 22.67, 21.13, 20.85, 20.11,14.08.
7-O-油烯基-5,6,4’-O-三乙酰基灯盏乙素苷元(c4) 黄色固体; 产率 70%; 1H NMR(400 MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 2H, Ar'-H-2,6), 7.24 (d, J = 8.8 Hz,2H, Ar'-H-3,5), 6.91 (s, 1H, Ar-H-3), 6.56 (s, 1H, Ar-H-8), 5.43 – 5.30 (m,2H, =CH×2), 4.08 (t, J = 6.4 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.33 (s, 3H,COCH3), 2.33 (s, 3H, COCH3), 2.08 – 1.95 (m, 4H, CH2×2), 1.88 – 1.77 (m, 2H,CH2), 1.50 – 1.40 (m, 2H, CH2), 1.39 – 1.18 (m, 20H, CH2×10), 0.87 (t, J =6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 176.18, 168.88, 168.71, 167.80,161.21, 155.76, 155.68, 153.17, 141.76, 130.86, 130.02, 129.74, 128.92,127.45, 122.31, 111.08, 108.24, 98.70, 69.60, 31.89, 29.75, 29.68, 29.52,29.44, 29.31, 29.21, 28.75, 27.23, 27.20, 25.79, 22.67, 21.11, 20.85, 20.10,14.09.
7-O-正己基-6,4’-O-二乙酰基灯盏乙素苷元(d1) 黄色固体; 产率 72%; 1H NMR(400 MHz, CDCl3) δ 12.72 (s, 1H, OH), 7.89 (d, J = 8.8 Hz, 1H), 7.26 (d, J =8.8 Hz, 2H), 6.63 (s, 1H), 6.54 (s, 1H), 4.06 (t, J = 6.5 Hz, 2H), 2.35 (s,3H), 2.34 (s, 3H), 1.96 – 1.73 (m, 2H), 1.51 – 1.40 (m, 2H), 1.39 – 1.30 (m,4H), 1.29 – 1.19 (m, 3H), 0.97 – 0.87 (m, 3H). 13C NMR (100 MHz, CDCl3) δ182.42, 168.84, 168.43, 163.30, 157.30, 154.91, 153.48, 152.60, 128.74,127.66, 123.55, 122.41, 105.85, 105.72, 91.29, 69.44, 31.39, 29.68, 28.76,25.44, 22.53, 21.11, 20.21, 13.95.
7-O-正十二烷基-6,4’-O-二乙酰基灯盏乙素苷元(d2) 黄色固体; 产率 68%; 1H NMR(400 MHz, CDCl3) δ 12.72 (s, 1H, OH), 7.90 (d, J = 8.8 Hz, 2H, Ar'-H-2,6),7.27 (d, J = 8.1 Hz, 2H, Ar'-H-3,5), 6.64 (s, 1H, Ar-H-3), 6.56 (s, 1H, Ar-H-8), 4.07 (t, J = 6.5 Hz, 2H, OCH2), 2.36 (s, 3H, COCH3), 2.35 (s, 3H, COCH3),1.96 – 1.70 (m, 2H, CH2), 1.51 – 1.39 (m, 2H, CH2), 1.39 – 1.14 (m, 16H, CH2×8), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 182.44, 168.84,168.44, 163.31, 157.31, 154.93, 153.47, 152.63, 128.78, 127.67, 123.58,122.42, 105.88, 105.77, 91.29, 69.45, 31.91, 29.69, 29.65, 29.63, 29.57,29.54, 29.34, 29.25, 28.81, 25.78, 22.67, 21.12, 20.23, 14.08.
7-O-正十八烷基-6,4’-O-二乙酰基灯盏乙素苷元(d3) 黄色固体; 产率 53%; 1H NMR(400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H, Ar'-H-2,6), 7.20 (d, J = 8.5 Hz,2H, Ar'-H-3,5), 6.57 (s, 1H, Ar-H-3), 6.49 (s, 1H, Ar-H-8), 3.99 (t, J = 6.5Hz, 2H, OCH2), 2.29 (s, 3H, COCH3), 2.27 (s, 3H, COCH3), 1.80 – 1.71 (m, 2H,CH2), 1.42 – 1.33 (m, 2H, CH2), 1.32 – 1.12 (m, 28H, CH2×14), 0.81 (t, J =6.7 Hz, 6H, CH3). 13C NMR (100 MHz, CDCl3) δ 182.43, 168.83, 168.42, 163.31,157.30, 154.92, 153.48, 152.63, 130.02, 129.74, 128.77, 127.67, 122.41,105.88, 105.76, 91.28, 69.43, 31.89, 29.77, 29.74, 29.69, 29.65, 29.52,29.44, 29.32, 29.30, 29.22, 28.82, 27.23, 27.20, 25.79, 22.67, 21.12, 20.23,14.08.
7-O-油烯基-6,4’-O-二乙酰基灯盏乙素苷元(d4) 黄色固体; 产率 59%; 1H NMR(400 MHz, CDCl3) δ 12.72 (s, 1H, OH), 7.90 (d, J = 8.8 Hz, 2H, Ar'-H-2,6),7.27 (d, J = 8.8 Hz, 2H, Ar'-H-3,5), 6.64 (s, 1H, Ar-H-3), 6.55 (s, 1H, Ar-H-8), 5.47 – 5.16 (m, 2H, =CH×2), 4.06 (t, J = 6.5 Hz, 2H, OCH2), 2.36 (s, 3H,COCH3), 2.34 (s, 3H, COCH3), 2.09 – 1.92 (m, 4H, CH2×2), 1.87 – 1.76 (m, 2H,CH2), 1.51 – 1.40 (m, 2H, CH2), 1.40 – 1.21 (m, 20H, CH2×10), 0.88 (t, J =6.7 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 182.43, 168.83, 168.42, 163.31,157.30, 154.92, 153.48, 152.63, 130.02, 129.74, 128.77, 127.67, 122.41,105.88, 105.76, 91.28, 69.43, 31.89, 29.77, 29.74, 29.69, 29.65, 29.52,29.44, 29.32, 29.30, 29.22, 28.82, 27.23, 27.20, 25.79, 22.67, 21.12, 20.23,14.08.
实施例5:
利用CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS)方法进行抗肿瘤活性试验。将肿瘤细胞Jukart、HCT-116或MDA-MB-231接种于96孔板(1000-5000细胞/孔,每孔200 μL),37°C孵育24小时,加入受试样品(浓度为2.5-40 μM),继续37°C孵育72小时,每孔加入加入CellTiter 96® AQueous One Solution Cell ProliferationAssay (MTS) solution (Promega),37°C孵育1小时,利用Bio-Rad 680 MicroplateReader (Bio-Rad, USA)490nm测吸收光。最后测算出IC50值,各受试物的IC50值见下表。
Claims (7)
1.灯盏乙素苷元醚类衍生物,其特征在于:其结构通式如(I)所示,式中R1为C>1的脂肪烃基,R2为氢或者乙酰基。
2.根据权利要求1所述的灯盏乙素苷元醚类衍生物,其特征在于R1为乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基、正辛基、正癸基、正十二基、正十四基、正十六基、正十八基、油烯基。
3.一种药物组合物,该药物组合物包含治疗有效量的游离形式或可药用盐形式的权利要求1或2中任意一项所定义的化合物作为活性成分;一种或多种药用载体物质和/或稀释剂。
4.灯盏乙素苷元醚类衍生物的制备方法,其特征是:是通过如下的步骤获得:
A、以灯盏乙素为起始原料,与乙酸酐、吡啶一起反应,其中灯盏乙素:乙酸酐的摩尔比为1:5~1:20,乙酸酐:吡啶的体积比为1:1~2:1;反应结束后反应液浓缩经硅胶柱层析得到5,6,7,4’-O-四乙酰灯盏乙素苷元(a)和6,7,4’-O-三乙酰灯盏乙素苷元(b);
B、将5,6,7,4’-O-四乙酰灯盏乙素苷元(a)或6,7,4’-O-三乙酰灯盏乙素苷元(b)溶于DMF中,加入碳酸钾与溴代物,室温搅拌;反应结束后,将产物倾入水中,用乙酸乙酯萃取,有机层浓缩后经硅胶柱层析得到灯盏乙素苷元醚类衍生物。
5.权利要求1~4任一项的所述的灯盏乙素苷元醚类衍生物在制备治疗癌症的药物中的应用。
6.根据权利要求5所述的应用,其中所述癌症包括:肝癌、肺癌、胰腺癌、乳腺癌、宫颈癌、子宫内膜癌、大肠癌、胃癌、肾癌、鼻咽癌、卵巢癌、前列腺癌症、慢性或急性白血病、脑瘤、食道癌、口腔癌、贲门癌、结肠癌、胆囊癌、喉癌、牙龈癌、尿道癌、皮肤癌、直肠癌、中耳癌、骨癌、睾丸癌、淋巴细胞性淋巴瘤、脊柱轴肿瘤垂体腺瘤。
7.根据权利要求6的应用,其中所述癌症是慢性或急性白血病或者是乳腺癌或者是结肠癌。
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