CN114315884B - 两个大黄素衍生物的合成及其在抗人宫颈癌药物中的应用 - Google Patents
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Abstract
本发明属于药物化学领域,具体是两个大黄素衍生物的制备及其抗肿瘤活性的评价。本发明首次合成出大黄素衍生物化合物1和化合物2,其结构如下图所示。随后用Hela细胞评价了化合物1和化合物2的抗肿瘤活性。结果表明,化合物1和化合物2对Hela细胞的IC50值为:0.50±0.16μM,3.87±0.71μM。
Description
技术领域
本发明属于药物化学领域,具体是两个大黄素衍生物的合成及其在制备抗宫颈癌药物中的应用。
背景技术
大黄素类化合物有多种生理和药理活性。如:抗肿瘤、修复损伤DNA、抗菌、保护大脑皮层神经元、抗病毒等。但是大黄素本身具有三环共平面结构,因此其脂溶性较差,此外其生物活性中等,因此如何通过化学修饰提高其脂溶性和活性是一个需要解决的问题。
氟原子或者含氟基团引入有机小分子中,能够显著性地改善分子的亲脂性,脂溶性,代谢稳定性,细胞通透性,同时能够提高其生物活性。硒元素作为抗癌元素之首,能够清除细胞内的自由基,帮助白细胞和巨噬细胞消灭癌细胞,还能缓解铂类药物引起的肾毒性和骨髓抑制的副作用。因此将硒元素和氟元素引入到大黄素中可以提高其脂溶性和抗肿瘤活性,为合成新型的大黄素衍生物作为抗肿瘤的药物提供新的思路。
发明内容
本发明的目的在于两个大黄素衍生物的制备及其抗肿瘤活性的评价。本发明合成出大黄素衍生物化合物1和化合物2的合成方法简单,并且具有较高的抗宫颈癌药物活性。
本发明所述的大黄素衍生物化合物1和化合物2可应用于制备抗宫颈癌药物。
本发明的目的通过以下技术方案实现的
1、大黄素衍生物化合物1和化合物2的结构式如下:
2、大黄素衍生物化合物1和化合物2的合成路线如下:
3、大黄素衍生物化合物1和化合物2的合成及其在抗人宫颈癌药物中的应用,其特征在于:所述化合物在细胞水平对Hela细胞的增殖有显著的抑制作用。
本发明的优点:
大黄素衍生物化合物1和化合物2在细胞水平对Hela细胞的增殖的抑制作用比其母体化合物大黄素强,化合物1和化合物2对Hela细胞的IC50值为:0.50±0.16μM,3.87±0.71μM。而母体化合物大黄素对Hela细胞的IC50值为:12.98±0.58μM。
具体实施方式:
为了理解本发明,下面结合实施例对本发明作进一步说明:下述实施例是说明性的,不是限定性的,不能以下述实施例来限定本发明的保护范围。
本发明基于大黄素类化合物有很好的生物活性,首次合成出大黄素衍生物化合物1和H 化合物2,这类衍生物具有较好的抗宫颈癌细胞活性。其中化合物1抗肿瘤活性测试IC50 达至0.50±0.16μM,具有较大的药物开发应用前景。
本发明提供大黄素衍生物化合物1和化合物2的结构式如下式所示:
本发明提供的供大黄素衍生物化合物1和化合物2合成路线如下式所示:
本发明提供的供大黄素衍生物化合物1和化合物2对人宫颈癌Hela细胞的增殖抑制活性。
测定方法如下:
1)铺板,收集对数生长期的Hela细胞,调整细胞悬液浓度至5*104cell/mL,接种在96孔板上,每孔加入100μL,并设有三个复孔,空白孔,对照孔,铺板培养24h。
2)加药,待细胞培养至细胞平铺满孔板,加入设置好的梯度浓度的药物0.5μL),培养48h。
3)加MTT溶液,每孔加入20μL MTT溶液,培养4h。(若MTT溶液与药物反应可将加药后的培养液离心后去除培养基,PBS冲洗后加MTT溶液)。
4)终止培养,吸出培养液,加入100μL DMSO,孵育10min,使用酶联免疫检测仪检测吸光度(OD)值。
5)计算细胞存活率,公式如下:
实施例1
大黄素衍生物化合物1的合成方法:
取250mL烧瓶,将40mL四氢呋喃(THF)和40mL的超纯水加入烧瓶中,磁力搅拌10min;冰浴下缓慢加入大黄素4.00g(14.81mmol),恢复至室温,反应0.5h;缓慢加入碘单质3.76g(14.81mmol),水浴搅拌0.5h;最后加入碳酸氢钠3.75g(44.73mmol),升至室温,继续反应0.5h。TLC检测反应完全,反应液由原来深黄棕色变为深紫黑色。将反应液倒入冰水中,搅拌,缓加稀盐酸至反应液不再产生气泡,且颜色由深紫黑色变为黄棕色悬浮液,过滤,滤饼真空干燥,得到化合物3(3.98g,产率:68%)。
向烧瓶中加入化合物32.7g(6.82mmol),用DMF溶解,冰浴下加入碳酸钾4.71g(34.1 mmol),搅拌0.5h;缓慢加入碘甲烷2.12mL(34.10mmol),40℃下反应8h;TLC监测反应完全,冷却至室温,稀盐酸调至中性,DCM/H2O萃取,饱和NaCl盐洗,无水NaSO4干燥,浓缩,柱层析纯化(PE∶EA=5∶1,V∶V),得到化合物4(1.11g,产率:37%)。
在无水无氧条件下进行反应。冰浴条件下取1.50g(3.42mmol)化合物4、CuI 65mg(0.34mmol)、三苯基磷二氯化钯120mg(0.17mmol)于除水冷却后的支口瓶中,换气除氧;加入四氢呋喃溶解;随后依次加入三乙胺0.95mL(6.84mmol)、三甲基乙炔基硅1.5mL(10.26mmol);缓慢升至室温反应8h。TLC监测反应完全,DCM/H2O萃取,饱和NaCl 盐洗,无水NaSO4干燥,浓缩,柱层析纯化(PE∶EA=3∶1,V∶V),得到大黄素衍生物化合物 1(0.684g,产率:49%)。1H NMR(400MHz,CDCl3)δ7.64(s,1H),7.48(s,1H),7.11(s,1H), 4.10(s,3H),4.03(s,3H),4.01(s,3H),2.47(s,3H),0.30(s,9H),13C NMR(100MHz,CDCl3)δ 183.8,181.2,164.2,164.0,145.5,134.7,122.8,121.2,112.0,119.1,115.0,108.8,103.9,96.1,62.0,56.8,56.7,22.3,0.00.
大黄素衍生物化合物1对Hela细胞的IC50值为:0.50±0.16μM.。
实施例2
大黄素衍生物化合物2的合成方法:
取上述1.0g(2.45mmol)大黄素衍生物化合物1于烧瓶中,加入5mL THF,5mL超纯水溶解,在冰浴下加入0.85mL(2.95mmol)TBAF(四丁基氟化铵的1.0mmol/mL四氢呋喃溶液),室温下反应10h。TLC监测反应完全,DCM/H2O萃取,饱和NaCl盐洗,无水 NaSO4干燥,浓缩,柱层析纯化(PE∶EA=3∶1,V∶V),得到化合物5(0.563g,产率:68%)。
在无水无氧条件下进行反应。冰浴下取0.1g(0.3mmol)化合物5、乙酸铜0.011mg(0.06mmol)、碳酸铯0.098mg(0.30mmol)、4-甲基苯磺酸三氟甲硒基0.115g(0.36mmol) 于除水冷却后的支口瓶中,换气除氧;加入无水无氧溶剂甲苯2.5mL溶解;最后加入 N,N,N,N-四甲基乙二胺0.014g(0.12mmol);缓慢升至室温。TLC监测反应完全,DCM/H2O 萃取,饱和NaCl盐洗,无水NaSO4干燥,浓缩,柱层析纯化(PE∶EA=3∶1,V∶V),得到大黄素衍生物化合物2(36mg,产率:25%)。1H NMR(400MHz,CDCl3)δ7.66(s,1H),7.52(s, 1H),7.12(s,1H),4.10(s,3H),4.04(s,3H),4.01(s,3H),2.49(s,3H).19F(376MHz,CDCl3)δ -35.6(s,F).13C NMR(100MHz,CDCl3)δ183.5,180.7,167.7,163.6,159.9,145.4,135.2,134.5, 132.2,128.5(q,J=376Hz,1C),130.9,129.9,128.8,127.8,122.5,120.9,119.9,119.0,113.8, 103.9,96.2,65.6,62.3,56.6,22.3.
大黄素衍生物化合物2对Hela细胞的IC50值为:3.87±0.71μM。
Claims (3)
1.大黄素衍生物化合物1或化合物2的结构如下:
2.根据权利要求1所述的大黄素衍生物化合物1或化合物2的合成路线如下:
RT=室温。
3.根据权利要求1所述的大黄素衍生物化合物1或化合物2在制备抗人宫颈癌药物中的应用,其特征在于:所述化合物在细胞水平对Hela细胞的增殖有抑制作用。
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Citations (3)
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DK1399411T3 (da) * | 2001-05-10 | 2011-01-24 | Univ Padova | Aloe-emodinderivater og anvendelse deraf i behandlingen af neoplasier |
CN102173997A (zh) * | 2011-02-24 | 2011-09-07 | 福州大学 | 抗肝癌、胃癌和子宫颈癌的大黄素衍生物及其制备方法 |
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