CN114874281A - 一种齐墩果酸衍生物及其制备方法与应用 - Google Patents

一种齐墩果酸衍生物及其制备方法与应用 Download PDF

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CN114874281A
CN114874281A CN202210579763.0A CN202210579763A CN114874281A CN 114874281 A CN114874281 A CN 114874281A CN 202210579763 A CN202210579763 A CN 202210579763A CN 114874281 A CN114874281 A CN 114874281A
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何彬
顾志成
赵永龙
陈蕾
李燕
李勇军
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Abstract

本发明公开了一种齐墩果酸衍生物及其制备方法与应用。本发明基于齐墩果酸设计合成的HDAC抑制剂，筛选出的化合物当中部分化合物对于Hela细胞核蛋白的HDACs具备抑制活性以及血液瘤细胞毒性，并且相较于上市药伏立诺他(SAHA)具备更小的正常细胞毒性以及更高的抗肿瘤选择性。

Description

一种齐墩果酸衍生物及其制备方法与应用
技术领域
本发明涉及化学技术和药学技术领域，尤其是一种齐墩果酸衍生物及其制备方法与应用。
背景技术
组蛋白去乙酰化酶(HDAC)是一类表观遗传酶，它能催化组蛋白和非组蛋白的ε-N-乙酰赖氨酸去乙酰化，这些表观遗传修饰对调控基因转录和蛋白功能具有重要意义。HDAC参与特定的病理以及生理途径，因此HDAC与癌症、神经退行性疾病、炎症和代谢紊乱等人类疾病密切相关，在抗肿瘤药物的研发中组蛋白去乙酰化酶是一类极为重要的明星靶标，目前已有五种HDAC抑制剂批准上市，主要用于治疗T细胞淋巴瘤和多发性骨髓瘤。通常，HDAC抑制剂主要药效团解构包括三个部分，(1)帽子基团(Cap)它与酶活性中心的表面相互作用；(2)连接子(Linker)用于连接Cap和ZBG其长短对活性有影响；(3)锌结合基团(ZBG)活性中心，该部分可以螯合锌离子。通常Linker和Cap部分相对固定，Cap部分通常作为修饰最多的位置，Cap通常以疏水性的刚性大环为主，其主要目的是增强对酶的活性以及选择性。
齐墩果酸(Oleanolicacid，OA)属于五环三萜类化合物，以游离或结合成苷的形式广泛存在于白花蛇舌草、丁香、山楂、丁香、枇杷叶、女贞子、等植物中。在临床上用于急慢性肝炎的辅助治疗药物，除此之外齐墩果酸具有保肝、降糖、抗HIV、和抗肿瘤等药理作用。虽然目前大多数的HDAC抑制剂显示出很好的活性，并且很多已经上市或者处于临床阶段的研究，但是这些抑制剂对于正常细胞同样具备一定的毒性。齐墩果酸作为五环三贴类的化合物，其结构满足HDAC抑制剂Cap部分的设计要求(疏水性的刚性大环)，除此之外齐墩果酸是一个具备一定药理学活性并且毒副作用小的临床用药。因此基于齐墩果酸设计合成的化合物有望去获取一种高效低毒的HDAC抑制剂，并应用到抗肿瘤治疗中。
发明内容
本发明的目的是：提供一种齐墩果酸衍生物及其制备方法与应用，它对于Hela细胞核蛋白的HDACs具备抑制活性以及血液瘤细胞毒性，并且具备更小的正常细胞毒性以及选择性。
本发明是这样实现的：齐墩果酸衍生物，该化合物具有如下通式之一：
Figure BDA0003661894070000021
式中，所述的R为羟基、2-氨基苯基、4-氟-2-氨基苯基、2-硫醇乙基或苯氨基；n为自然数。
Figure BDA0003661894070000022
上述路线中，所述的R为羟基、2-氨基苯基、4-氟-2-氨基苯基、2-硫醇乙基或苯氨基；n为自然数；X为X1、X2、X3或X4中的一种。
具体合成步骤如下：
步骤1：将齐墩果酸溶解于四氢呋喃中，加入N,N-二异丙基乙胺(DIEA)
苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)，室温反应两小时之后TLC检测反应完成之后将溶剂旋干，加入甲醇溶去杂质，过滤得粗产物Q-1；
步骤2：将Q-1和4-氨基丁酸甲酯溶解在N,N-二甲基甲酰胺(DMF)中，加入K2CO3()之后于40℃反应4小时，TLC检测反应完成。用水洗和乙酸乙酯萃取反应液，饱和食盐水萃取乙酸乙酯层2-3遍，无水硫酸钠干燥，旋干有机层过柱得产物Q-2；
步骤3：将纯化之后的Q-2溶解在THF：MeOH＝3:1的混合溶剂中，随之加入LiOH,反应过夜。检测反应完成之后，加水稀释，用1NHCl调节PH到3，二氯甲烷萃取，无水硫酸钠干燥，旋干有机层过柱得Q-3；
步骤4：将所得到的Q-3溶解于THF中，加入三乙胺和N,N-二异丙基乙胺(DIEA)于冰浴下反应1小时之后留取少量反应液，加入盐酸羟胺(提前用少量甲醇和三乙胺游离出羟胺)或邻苯二胺或对氟邻苯二胺或盐酸氨基乙硫醇，反应2小时之后旋干溶剂，二氯甲烷饱和食盐水萃取，无水硫酸钠干燥，旋干过柱分离。
以上举例说明通式化合物A的合成，目标产物B,C和D步骤同上。
齐墩果酸衍生物在靶向HDAC的抑制剂中的应用。
齐墩果酸衍生物在制备治疗抗肿瘤药物中的应用。
通过采用上述技术方案，本发明基于齐墩果酸设计合成的HDAC抑制剂，筛选出的化合物当中部分化合物对于Hela细胞核蛋白的HDACs具备抑制活性以及血液瘤细胞毒性，并且相较于上市药伏立诺他(SAHA)具备更小的正常细胞毒性以及更高的抗肿瘤选择性。
附图说明
图1为LO2细胞毒性。
具体实施方式
实施列1：合成路线及化合物鉴定
采用以下合成路线合成Q5-1,Q6-1,Q7-1,Q8-1:
Figure BDA0003661894070000041
化合物Q5-1,Q6-1,Q7-1,Q8-1的13C-NMR、1H-NMR和HR-MS数据：
化合物Q5-1:1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.66(s,1H),7.24-7.26(t,J＝5.5Hz,1H),5.20(s,1H),4.30(d,J＝5.1Hz,1H),2.98(m,J＝9.8,5.8Hz,2H),2.78(d,J＝9.9Hz,1H),1.91(t,J＝7.2Hz,3H),1.79(d,J＝5.9Hz,2H),1.69–1.54(m,3H),1.49–1.40(m,9H),1.35–1.27(m,4H),1.19(d,J＝11.3Hz,1H),1.07(s,5H),0.86(m,J＝11.9,5.5Hz,15H),0.66(d,J＝5.1Hz,8H).13CNMR(100MHz,DMSO-d6)δ176.09,169.01,144.09,121.31,77.06,54.87,47.24,47.09,46.17,45.96,45.20,41.25,38.58,38.41,38.21,36.61,33.68,33.00,32.50,32.00,30.47,28.76,28.27,27.00,25.73,23.61,22.96,22.74,18.06,16.82,16.08,15.13.HRMS(ESI)m/z:[M+H]+calcd for C35H59N2O4 571.44301,found 571.44653.
化合物Q6-1:1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),7.21(t,J＝5.6Hz,1H),5.20(t,J＝3.3Hz,1H),4.27(s,1H),3.02–2.95(m,2H),2.78(m,J＝13.2,3.5Hz,1H),1.96–1.73(m,5H),1.72–1.52(m,3H),1.44(m,J＝15.4,12.7,8.1Hz,10H),1.38–1.27(m,5H),1.19(d,J＝7.2Hz,3H),1.08(s,5H),0.92–0.81(m,15H),0.66(d,J＝3.5Hz,8H).13C NMR(100MHz,DMSO-d6)δ176.06,169.04,144.13,121.36,76.85,54.91,54.84,47.13,46.06,45.19,41.25,40.47,38.73,38.39,38.09,36.59,33.67,32.97,32.78,32.48,32.29,30.44,28.90,28.25,26.97,26.25,25.68,24.97,23.59,22.94,22.27,18.02,16.84,16.04,15.09.HRMS(ESI)m/z:[M+Na]+calcd for C36H60N2O4Na607.44508,found 607.44421.
化合物Q7-1:1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.65(s,1H),7.21(t,J＝5.3Hz,1H),5.20(s,1H),4.29(d,J＝5.1Hz,1H),2.97(m,J＝13.0,5.9Hz,2H),2.81–2.74(m,1H),1.92(t,J＝7.3Hz,2H),1.79(d,J＝5.7Hz,2H),1.68–1.53(m,3H),1.50–1.40(m,9H),1.36–1.28(m,4H),1.20(s,6H),1.07(s,5H),0.86(m,J＝13.0,6.0Hz,15H),0.66(d,J＝3.9Hz,8H).13C NMR(100MHz,DMSO-d6)δ176.55,169.57,144.65,121.86,77.36,55.43,55.38,47.65,46.57,45.70,41.75,40.96,39.32,38.90,38.61,37.09,34.20,33.50,33.30,33.00,32.79,30.96,29.55,28.99,28.76,27.48,26.94,26.21,25.75,24.11,23.47,22.78,18.53,17.35,16.56,15.60.HRMS(ESI)m/z:[M+H]+calcd for C37H63N2O4599.47431,found 599.47711.
化合物Q8-1:1H NMR(400MHz,)δ10.20(s,1H),8.49(s,1H),7.05(s,1H),5.18(s,1H),4.13(s,1H),2.94(dd,J＝12.6,6.2Hz,2H),2.74(d,J＝11.4Hz,1H),1.88(d,J＝7.2Hz,2H),1.77(d,J＝7.3Hz,2H),1.62(t,J＝13.7Hz,1H),1.53(d,J＝12.5Hz,2H),1.49–1.39(m,9H),1.32(s,3H),1.19(s,9H),1.05(s,5H),0.84(dd,J＝12.6,5.5Hz,15H),0.64(s,8H).13C NMR(100MHz,DMSO-d6)δ176.16,172.19,144.15,121.37,76.85,59.78,54.87,47.12,45.99,45.35,45.20,41.30,40.60,38.90,38.41,38.12,36.76,36.59,33.69,33.02,32.89,32.60,30.48,29.95,28.68,28.27,27.00,25.70,23.67,22.96,22.23,20.79,18.06,16.90,16.07,15.14,14.12.HRMS(ESI)m/z:[M+H]+calcd for C38H64N2O4613.49443,found 613.49323.
采用以下合成路线合成Q9-1,Q10-1,Q11-1:
Q9-1的路线合成：
Figure BDA0003661894070000051
Q10-1的路线合成：
Figure BDA0003661894070000061
Q11-1的路线合成:
Figure BDA0003661894070000062
化合物Q9-1,Q10-1,Q11-1的13C-NMR、1H-NMR和HR-MS数据：
化合物Q9-1:1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.61(s,1H),7.26(t,J＝5.4Hz,1H),5.21(s,1H),4.28(d,J＝5.1Hz,1H),2.98(dd,J＝9.9,5.3Hz,1H),2.89–2.76(m,3H),1.89(td,J＝12.3,3.3Hz,2H),1.79(s,2H),1.73–1.54(m,7H),1.47(dd,J＝18.6,10.2Hz,7H),1.38–1.24(m,6H),1.18(dd,J＝13.7,6.5Hz,2H),1.06(d,J＝14.5Hz,5H),0.88(dt,J＝18.3,9.0Hz,15H),0.66(t,J＝5.4Hz,7H).13C NMR(100MHz,DMSO-d6)δ176.16,172.19,144.15,121.37,76.85,59.78,54.87,47.12,45.99,45.35,45.20,41.30,40.60,38.90,38.41,38.12,36.76,36.59,33.69,33.02,32.89,32.60,30.48,29.95,28.68,28.27,27.00,25.70,23.67,22.96,22.23,20.79,18.06,16.90,16.07,15.14,14.12.
化合物Q10-1:1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.93(s,1H),7.86(t,J＝5.9Hz,1H),7.63(d,J＝8.3Hz,2H),7.24(d,J＝8.4Hz,2H),5.17(t,J＝3.4Hz,1H),4.24(d,J＝5.1Hz,1H),4.20(t,J＝5.1Hz,2H),2.79(dd,J＝13.2,3.7Hz,1H),1.89(d,J＝3.1Hz,1H),1.74(d,J＝6.6Hz,2H),1.68–1.52(m,3H),1.46–1.38(m,6H),1.35–1.09(m,6H),1.04(s,4H),0.90–0.76(m,15H),0.62(d,J＝11.7Hz,4H),0.52(s,3H).13C NMR(100MHz,DMSO-d6)δ176.93,164.58,144.49,144.07,131.46,127.51,127.18,122.03,77.37,55.35,47.65,46.52,45.87,42.57,41.76,41.07,38.91,38.61,37.10,34.14,33.47,33.34,33.00,30.98,28.77,27.50,26.22,24.12,23.45,22.79,18.54,17.32,16.57,15.60.
化合物Q11-1:1H NMR(1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.64(s,1H),7.21(t,J＝5.6Hz,1H),5.20(t,J＝3.3Hz,1H),4.27(s,1H),3.02–2.95(m,2H),2.78(dd,J＝13.2,3.5Hz,1H),1.96–1.73(m,5H),1.72–1.52(m,3H),1.44(ddd,J＝15.4,12.7,8.1Hz,10H),1.38–1.27(m,5H),1.19(d,J＝7.2Hz,3H),1.08(s,4H),0.92–0.81(m,15H),0.66(d,J＝3.5Hz,7H).13C NMR(100MHz,DMSO-d6)δ176.58,169.56,144.65,121.88,77.37,55.43,55.36,47.65,46.58,45.71,41.77,40.99,39.25,38.91,38.61,37.11,34.19,33.49,33.30,33.00,32.81,30.96,29.42,27.49,26.77,26.20,25.49,24.11,23.46,22.79,18.54,17.36,16.56,15.61.
实施列2：化合物对Hela核蛋白体外HDACs活性检测
以临床上使用的抗肿瘤药物Vorinostat(SAHA)作为阳性对照药，所有化合物以终浓度为1μM进行HDACs抑制活性检测，具体步骤如下：
(1)将缓冲液(5μL 1M PH-8Tris-HCl,3μL 5M NaCl,10μL 30mM KCl,10μL 10mMMgCl)同底物1μL Boc-Lys(Ac)-AMC(100μM)混合；
(2)加入配置好的化合物1μL(100uM)；
(3)12μL(6mg/mL)的Hela核蛋白，于冰上完成；
(4)37℃孵育箱中发反应1小时；
(5)加入50μL 2×胰酶，混匀后继续37℃孵育1小时；
(6)加入50μL终止液(200mM HCl，300mM AcOH)终止反应；
(7)取反应液180μL加于96孔黑色板中，随之使用多功能酶标仪在360mM/460mM检测其荧光值；将不同浓度下的抑制率计算，通过GraphPad Prism 5模拟IC50值。
表1.反应体系中对应用量
Figure BDA0003661894070000081
*对应化合物的用量为1μL(100μM)
所测定化合物的酶抑制活性如表2，由表可知，所设计合成的化合物中，Q6-1的活性最佳，伴随Linker的缩短或者增加都会降低酶的活性。
表2.Hela核蛋白体外HDACs抑制活性
Figure BDA0003661894070000082
实施例3：齐墩果酸衍生物作为HDAC抑制剂对不同细胞系的毒性
采用公认的可用于大规模抗肿瘤药物筛选、细胞毒性试验测定的CCK-8法,评价Q5-1,Q6-1,Q7-1,Q8-1,OA,Q9-1,Q10-1和Q11-1对于A549(人非小细胞肺癌细胞)，Hela(人宫颈癌细胞)，血液瘤K562(人慢性髓系白血病细胞)和RS4；11(人急性淋巴白血病细胞)的细胞毒性种人癌细胞株的抗细胞增殖活性；阴性对照组为不加药组；阳性对照药为临床上使用的抗肿瘤药物Vorinostat(SAHA)。
细胞增殖抑制率＝(阴性对照组0D值-药物组0D值)*100％/阴性对照组0D值。通过化合物不同浓度的抑制率由GraphPad Prism 5模拟曲线得出IC50值(单位为μM)。
表3.对于不同肿瘤细胞的IC50
Figure BDA0003661894070000091
由表3可知，所设计的化合物Q6-1,Q7-1对于K562,RS4；11，的IC50值同上市药SAHA相当，并且对于A549和Hela活性较低，随着Linker长度的增加或者缩短，都会对两种血液瘤细胞活性有影响。
在此有必要指出的是，以上实施例和试验例仅限于对本发明技术方案做进一步阐述和理解，不能理解为对本发明的技术方案做进一步的限定，本领域技术人员作出的非突出实质性特征和显著进步的发明创造，仍然属于本发明的保护范畴。

Claims (4)

1.一种齐墩果酸衍生物，其特征在于：该化合物具有如下通式之一：
Figure FDA0003661894060000011
式中，所述的R为羟基、2-氨基苯基、4-氟-2-氨基苯基、2-硫醇乙基或苯氨基；n为自然数。
2.一种如权利要求1所述的齐墩果酸衍生物的制备方法，其特征在于，其合成路线如下：
Figure FDA0003661894060000012
上述路线中，所述的R为羟基、2-氨基苯基、4-氟-2-氨基苯基、2-硫醇乙基或苯氨基；n为自然数；X为X1、X2、X3或X4中的一种。
3.一种如权利要求1所述的齐墩果酸衍生物在靶向HDAC的抑制剂中的应用。
4.一种如权利要求1所述的齐墩果酸衍生物在制备治疗抗肿瘤药物中的应用。
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