CN110668961B - 芦荟大黄素衍生物 - Google Patents

芦荟大黄素衍生物 Download PDF

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CN110668961B
CN110668961B CN201810708634.0A CN201810708634A CN110668961B CN 110668961 B CN110668961 B CN 110668961B CN 201810708634 A CN201810708634 A CN 201810708634A CN 110668961 B CN110668961 B CN 110668961B
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陈方
石万棋
牛春
黎勇
曹婷婷
杨子耀
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Abstract

本发明提供了如式Ⅰ所示的芦荟大黄素衍生物,
Figure DDA0001716160300000011
R2选自四元至六元含氮脂杂环、四元至六元含氮芳杂环、‑HN‑R21;R21选自稠环芳香烃、苯环取代物、四元至六元含氮芳杂环。本发明还提供了该化合物的制备方法和用途。本发明制备的芦荟大黄素衍生物对人体癌症细胞具有抗凋亡作用,且其生物活性优于芦荟大黄素,为抗肿瘤药物的研究提供了一定实验依据。

Description

芦荟大黄素衍生物
技术领域
本发明涉及芦荟大黄素衍生物。
背景技术
近年来,随着生活节奏的加快,人们压力的进一步增大。癌症已经成为当今社会不能忽视的疾病,严重影响到了社会的正常发展和正常的公共秩序。20世纪起,感染癌症的人数日益增加。世界上每年死于癌症的患者数以百万,并且癌症患者大多数为低收入和中等收入人群。目前癌症的治疗可以经过中药治疗、手术切除、化疗、放射性治疗、免疫治疗以及单克隆抗体治疗或者其他治疗方法,但很少有彻底治愈的病例。如何能够最大程度的降低癌症患者的疼痛,达到好的预防和治疗效果是当前很多研究人员迫切需要解决的问题。
芦荟大黄素是蓼科植物掌叶大黄的根和块茎中含有的一种活性成分,也是芦荟中含有的重要的药理成分羟基蒽醌衍生物中的一种.其作为中药中的一种重要的活性成分,已经发现了很多的药理作用,对诱导癌细凋亡,与DNA作用、对免疫细胞的增殖都有一定的作用。人们对它的研究已经从分离提取等方法的研究逐步上升到在医学领域的应用作用。
由于芦荟大黄素的分子结构与端粒酶抑制剂的分子结构特征有很多相似之处,故以芦荟大黄素为基础进行结构改造,设计合成芦荟大黄素衍生物,提高芦荟大黄素的生物活性,增强芦荟大黄素抗癌细胞增殖作用,可以为目前癌症患者的治疗提供有力依据。
发明内容
本发明的目的在于提供一种芦荟大黄素衍生物,改善芦荟大黄素的生物活性。
本发明提供了如式Ⅰ所示的芦荟大黄素衍生物。
Figure BDA0001716160290000011
R2选自四元至六元含氮脂杂环、四元至六元含氮芳杂环、
Figure BDA0001716160290000012
R21选自稠环芳香烃、苯环取代物、四元至六元含氮芳杂环。
进一步地,所述四元至六元含氮脂杂环、四元至六元含氮芳杂环含有1~3个杂原子;所述杂原子选自N、O。
进一步地,所述四元至六元含氮脂杂环为
Figure BDA0001716160290000021
X为C、O或N。
进一步地,所述四元至六元含氮芳杂环为五元或六元含氮芳杂环。
进一步地,所述四元至六元含氮芳杂环为
Figure BDA0001716160290000022
进一步地,所述苯环取代物为卤代苯或烷基苯。
优选地,所述R2为对氯苯胺基、对甲基苯胺基、
Figure BDA0001716160290000023
Figure BDA0001716160290000024
本发明还提供了上述式I化合物的制备方法。
Figure BDA0001716160290000025
本发明还提供了所述芦荟大黄素衍生物在制备抗肿瘤的药物中的用途。
其中,所述芦荟大黄素衍生物对人体癌症细胞具有抗凋亡作用。
其中,所述药物是治疗乳腺腺癌、非小细胞肺癌或子宫颈癌的药物。
本发明是对芦荟大黄素进行结构修饰,得到一系列芦荟大黄素衍生物,得到芦荟大黄素的衍生物,部分化合物对肿瘤细胞的增殖作用优于先导物。
本发明制备的芦荟大黄素衍生物对人体癌症细胞具有抗凋亡作用,且其生物活性优于芦荟大黄素,为抗肿瘤药物的研究提供了一定实验依据。
具体实施方式
实施例1芦荟大黄素衍生物1的制备
Figure BDA0001716160290000026
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将对氯苯胺(2.543g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离得芦荟大黄素的对氯苯胺衍生物1,黄色粉末,产率80%。m.p.195-198℃。1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO)δ:10.72(s,1H),8.31(s,2H),8.24(s,1H),7.96(s,1H),7.83(d,J=8.7,2H),7.57(d,J=8.2Hz,1H),7.45(d,J=8.7Hz,2H),4.02(s,3H),3.93(s,3H).13C NMR(101MHz,DMSO)δ182.88,180.88,163.89,158.79,139.29,137.66,134.52,134.24,134.08,128.62,127.82,125.40,123.42,122.21,119.10,118.24,117.48,117.16,56.62,56.36;MS(ESI)calcd for C23H16ClNO5[M+H]+421.83 found 422.22。
实施例2芦荟大黄素衍生物2的制备
参照实施例1的方法制备芦荟大黄素衍生物2。
Figure BDA0001716160290000031
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将对甲基苯胺(2.143g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离得黄色固体,收率56%,m.p.175-177℃;1H NMR(400MHz,DMSO-d6)δ:10.52(s,1H),8.31(s,1H),8.24(s,1H),7.96(s,1H),7.77(t,J=7.9Hz,1H),7.67(d,J=8.3Hz,2H),7.56(d,J=8.1Hz,1H),7.19(d,J=8.2Hz,2H),4.03(d,3H),3.93(s,3H),2.30(s,3H).13C NMR(101MHz,DMSO)δ:182.90,180.90,163.54,158.78,139.64,136.14,134.47,134.18,134.09,133.19,129.07,125.21,123.42,120.73,119.06,118.23,117.40,117.15,56.59,56.35,20.52.HRMS(ESI)calcd for C24H19NO5[M+Na]+424.4114 found 424.1169。
实施例3芦荟大黄素衍生物3的制备
参照实施例1的方法制备芦荟大黄素衍生物3。
Figure BDA0001716160290000032
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将对α-氨基吡啶(1.88g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离棕色固体,收率70%,m.p.167-168℃;1H NMR(400MHz,DMSO-d6)δ:8.28-8.03(m,3H),7.92(d,J=24.2Hz,3H),7.80-7.67(m,3H),7.55(d,J=6.8Hz,1H),3.98(s,3H),3.92(s,3H).13C NMR(101MHz,DMSO)δ:183.14,181.34,166.34,162.80,159.33,159.26,148.51,138.78,135.95,135.02,134.82,134.46,123.87,120.70,119.54,119.01,118.72,118.63,115.38,56.96,56.84.;HRMS(ESI)calcd for C22H16N2Os[M+H]+388.3728found 389.1151。
实施例4芦荟大黄素衍生物4的制备
参照实施例1的方法制备芦荟大黄素衍生物4。
Figure BDA0001716160290000041
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将六氢吡啶(1.703g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离淡黄色固体,收率43%,m.p.175-178℃;1H NMR(400MHz,DMSO-d6)δ:7.76(t,J=8.0Hz,1H),7.69(d,J=7.6Hz,1H),7.58-7.53(m,2H),7.47(s,1H),3.94(s,3H),3.92(s,3H),3.62(brs,2H),3.28(brs,2H),1.54(d,J=55.7Hz,6H);13C NMR(101MHz,DMSO)δ:182.86,180.78,166.85,158.91,158.76,141.92,134.39,134.28,134.02,123.70,123.37,119.07,118.19,116.46,115.54,56.63,56.34,47.94,42.30,25.93,25.12,23.97;MS(ESI)calcd for C22H21NOs[M+H]+379.40 found380.21。
实施例5芦荟大黄素衍生物5的制备
参照实施例1的方法制备芦荟大黄素衍生物5。
Figure BDA0001716160290000042
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将四氢吡咯(1.422g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离黄色固体粉末,收率41%,m.p.158-160℃;1H NMR(400MHz,DMSO-d6)δ:7.78-7.72(m,1H),7.67(d,J=6.3Hz,2H),7.53(d,J=9.3Hz,2H),3.92(s,3H),3.89(s,3H),3.48(t,J=6.8Hz,2H),3.37(t,J=6.4Hz,2H),1.87-1.79(m,4H);13C NMR(101MHz,DMSO)δ:183.31,181.45,166.87,159.11,142.70,134.98,134.51,134.30,124.22,123.58,119.45,118.63,117.09,116.49,56.95,56.68,49.18,46.41,26.19,24.20;HRMS(ESI)calcd for C21H19NO5[M+H]+365.3793 found 366.1352。
实施例6芦荟大黄素衍生物6的制备
参照实施例1的方法制备芦荟大黄素衍生物6。
Figure BDA0001716160290000051
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将吗啉(1,74g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离黄色固体,收率60%,m.p.177-180℃;1H NMR(400MHz,DMSO-d6)δ:7.76(t,J=8.0Hz,1H),7.68(d,J=7.6Hz,1H),7.61(d,J=1.3Hz,1H),7.58-7.49(m,2H),3.95(s,3H),3.92(s,3H),3.62(d,8H);13C NMR(101MHz,DMSO)δ:182.82,180.78,167.12,158.87,158.76,141.03,134.42,134.32,134.00,123.85,123.33,119.08,118.19,116.79,115.99,66.01,65.83,56.66,56.34,47.50,47.40;HRMS(ESI)calcd for C21H19NO6[M+H]+382.3787found 382.1295。
实施例7芦荟大黄素衍生物7的制备
参照实施例1的方法制备芦荟大黄素衍生物7。
Figure BDA0001716160290000052
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将咪唑(1.36g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离黄色固体,收率70%,m.p.181-182℃;1H NMR(400MHz,DMSO)δ8.17(d,J=1.2Hz,1H),7.89(d,J=5.0Hz,1H),7.86-7.65(m,4H),7.57(dd,J=17.1,8.0Hz,2H),3.99(s,3H),3.93(s,3H);MS(ESI)calcd for C20H14N2O5[M+H]+362.09 found 362.32。
实施例8芦荟大黄素衍生物8的制备
参照实施例1的方法制备芦荟大黄素衍生物8。
Figure BDA0001716160290000061
将化合物1,8-二甲氧基芦荟大黄酸(化合物0)(0.312g,1mmol,1eq)、SOCl2(5mL)溶液加入圆底烧瓶中,加热回流,TLC检测反应完全,停止反应,减压蒸馏回收溶剂,得绿色固体,二氯甲烷(20mL)作溶剂,将萘胺(2.86g,20mmol,20eq)、碳酸钾(1.38g,10mmol,10eq)加入反应液中,加热回流,TLC检测反应完全,停止反应,过滤,减压回收溶剂,得黄色固体,柱层析分离黄色固体,收率67%,m.p.177-179℃;1H NMR(400MHz,DMSO)δ10.84(s,1H),8.38(s,1H),8.12(s,1H),7.96-7.89(m,3H),7.77(m,3H),7.65-7.59(m,4H),4.05(s,3H),3.95(s,3H);HRMS(ESI)calcd for C27H19NO5[M+H]+438.4435 found 438.1323.
以下通过试验例具体说明发明的有益效果。
试验倒1芦荟大黄素及其衍生物的三种癌细胞抗增殖实验
将人乳腺腺癌(MDA-MB-231),人非小细胞肺癌(A549)和人子宫颈癌(HeLa)细胞在补充有115单位/mL青霉素G,115μg/mL链霉素,和10%胎牛血清的DMEM培养基中培养。将细胞接种在含有50μL生长液的96孔板(5×103个细胞/孔)中24小时,除去培养基,向每个孔中加入100μL含不同浓度(3.00E-05和3.00E-06)的各个类似物的新鲜培养基,并在37℃下孵育5天,同时,使用相同体积的DMSO-d6作为载体对照。计算经各个化合物处理的肿瘤细胞数与载体处理的细胞数的比率,即为存活率。结果见表1-3。
表1化合物2.1,1-8对人乳腺癌细胞存活率的影响
Figure BDA0001716160290000071
表2化合物2.1,1-8对人非小细胞肺癌细胞存活率的影响
Figure BDA0001716160290000072
表3化合物2.1,1-8对人子宫颈癌细胞存活率的影响
Figure BDA0001716160290000081
由表结果可知,在对三种癌细胞进行抗增殖实验中,部分化合物比芦荟大黄素的抗癌细胞增殖作用要强。如对人乳癌细胞抗增殖实验中,在3.00E-06浓度下,化合物1、3、4相对于芦荟大黄素存活率降低了10%以上。在对人非小细胞肺癌细胞抗增殖实验中,3.00E-06浓度下,与原料相比,化合物1组中癌细胞的存活率降低了20%以上。在对人子宫颈癌细胞的抗增殖实验中,化合物3.00E-06浓度下,衍生物对癌细胞的影响与原料相当。

Claims (2)

1.芦荟大黄素衍生物在制备抗肿瘤的药物中的用途,其特征在于:所述药物是治疗乳腺腺癌的药物;所述芦荟大黄素衍生物为:
Figure 256279DEST_PATH_IMAGE001
Figure 803060DEST_PATH_IMAGE002
2.根据权利要求1所述的用途,其特征在于:所述芦荟大黄素衍生物对人体癌症细胞具有抗增殖作用。
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