CN115819489A - 茯苓酸衍生物、其制备方法及其应用 - Google Patents
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Abstract
本申请公开了药物化学领域的一种茯苓酸衍生物的制备方法，包括以下步骤：S1、以茯苓酸为原料，溶于有机溶剂中，然后加入相应的卤代烃(或卤代糖)和碱性催化剂；S2、将反应混合物置于室温下搅拌2～3h，然后用氯化铵溶液淬灭反应，用二氯甲烷萃取反应。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品；S3、粗品通过柱层析纯化，得到所需的茯苓酸衍生物。该茯苓酸衍生物可用于预防和治疗各种细胞异常增殖、形态变化等相关的疾病。
Description
技术领域
本发明涉及药物化学技术领域，具体涉及一种茯苓酸衍生物、其制备方法及其应用。
背景技术
茯苓酸(Pachymic acid,PA)是从木腐菌茯苓中分离得到的一种重要的天然羊毛甾烷类三萜。茯苓的菌核含β-茯苓聚糖和三萜类茯苓酸、3β-羟基羊毛甾三烯酸等活性成分，其对多种疾病具有潜在的治疗作用，被人们广泛应用于各种中药和保健食品中，其化合物通式如下：
研究表明，茯苓酸具有显著的药理活性，如抗癌、抗炎、抗菌、镇静催眠、降血糖、抗缺血/再灌注等作用。在抗癌方面，茯苓酸是一种新型的RXR特异性激动剂，可诱导白血病HL-60细胞的分化(Chem Biol Drug Des 2020,95:493-502)。同时，它还是丙酮酸激酶的M2的激活剂和己糖激酶2的抑制剂(Biol Pharm Bull 2019,42:123-129)，可以有效抑制乳腺癌SK-BR-3细胞的增殖。此外，茯苓酸在动物模型上也显示出显著的抗癌活性，能够显著抑制NCI-H23、SGC-7901和MIA PaCa-2等异种移植瘤的生长(Cancer Cell Int 2015,15:78；Oncol Lett 2018,16:2517-2524；PLoS One 2015,10:e0122270)。
为此，申请人在茯苓酸的基础上提供一类茯苓酸衍生物，能够有效地抑制人肝癌细胞HepG2和人口腔鳞状肿瘤细胞HSC-2的恶性增殖，尤其对HSC-2细胞的抑制活性较强。
发明内容
本发明意在提供一种茯苓酸衍生物、其制备方法及其应用，以提供一类茯苓酸衍生物可用于预防和治疗各种细胞异常增殖、形态变化等相关的疾病，尤其是用于治疗或预防人肝癌或人口腔鳞状细胞癌的药物。
为了达到上述目的，本发明提供如下技术方案：茯苓酸衍生物，其化合物通式如式(I)所示：
其中，R代表：C1-C6直链或支链烷烃、含有羟基的直链或支链烷烃、酰基保护的糖基。
一种茯苓酸衍生物的制备方法，包括以下步骤：
S1、以茯苓酸为原料，溶于有机溶剂中，然后加入相应的卤代烃(或卤代糖)和碱性催化剂；
S2、将反应混合物置于室温下搅拌2～3h，然后用氯化铵溶液淬灭反应，用二氯甲烷萃取反应，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品；
S3、粗品通过柱层析纯化，得到所需的茯苓酸衍生物；
本通式(I)所示化合物的制备方法如下：
其中R的定义同前，其中a代表反应条件。
进一步，所述有机溶剂为无水N,N-二甲基甲酰胺、四氢呋喃、乙醇、甲醇、二氯甲烷、叔丁醇、二甲基亚砜或丙酮。
进一步，所述有机溶剂为无水N,N-二甲基甲酰胺。
进一步，所述碱性催化剂为三乙胺、哌啶、乙酸钠、碳酸钾、碳酸钠、吡啶、碳酸铯、氢氧化锂或吗啉。
进一步，所述碱性催化剂为碳酸钾。
进一步，茯苓酸加入量、卤代烃(或卤代糖)加入量、碱性催化剂加入量比例为1：2：2。
进一步，茯苓酸衍生物在用于制备预防和治疗各种细胞异常增殖、形态变化相关疾病药物的应用。
进一步，茯苓酸衍生物在用于制备治疗人肝癌或人口腔鳞状细胞癌药物的应用。
本发明的工作原理及有益效果：本方案制备的茯苓酸衍生物药理实验显示，茯苓酸衍生物对人肝癌细胞HepG2和人口腔鳞状肿瘤细胞HSC-2具有一定的体外抗增殖活性。因此，茯苓酸衍生物可用于预防和治疗各种细胞异常增殖、形态变化等相关的疾病，尤其是用于治疗或预防人肝癌或人口腔鳞状细胞癌的药物。
具体实施方式
下面通过具体实施方式进一步详细说明：
质谱仪为Waters Xevo G2-S QTOF型，核磁共振仪为Agilent DD2400-MR-400型，薄层层析板和硅胶购自青岛海洋化工厂，茯苓酸购自成都普菲德生物技术有限公司，其它所用试剂为分析纯。
实施例1：化合物I-1的制备
茯苓酸(0.09mmol)加入到无水N,N-二甲基甲酰胺(2mL)中，再加入2-溴乙醇(0.18mmol)和碳酸钾(0.18mmol)。反应液在室温下搅拌2小时。氯化铵溶液淬灭反应，二氯甲烷萃取三次，合并有机层，饱和食盐水洗，无水硫酸钠干燥过夜，过滤，得到粗品。柱层析纯化，得到白色固体(化合物I-1)，收率83％。
表征数据为：1H(400MHz,CDCl3):δ4.74(s,1H),4.68(s,1H),4.48-4.45(m,1H),4.23-4.14(m,2H),4.12-4.07(m,1H),3.82(t,J＝4.0Hz,2H),2.50-2.45(m,1H),2.27-2.09(m,4H),2.03-1.90(m,11H),1.84-1.46(m,7H),1.29-1.22(m,2H),1.19-1.14(m,2H),1.09(s,3H),1.01-0.95(m,9H),0.85(s,6H),0.70(s,3H)；13C(100MHz,CDCl3):δ176.23,171.14,154.98,134.25,134.03,106.93,80.77,76.92,65.83,61.07,56.80,50.34,48.04,46.88,45.89,42.67,37.74,36.84,35.07,33.62,32.17,30.52,28.92,27.86,26.34,25.16,24.04,21.82,21.69,21.35,20.40,19.10,17.95,17.49,16.51；HRMS(ESI):calculatedfor C35H56O6Na[M+Na]+595.3969,found595.3971。
实施例2：化合物I-2的制备
将3-溴-1-丙醇代替2-溴乙醇，按实施例1所述的方法，其余所需原料、试剂同实施例1，得到无色黏性固体(化合物I-2)，收率87％。
表征数据为：1H(400MHz,CDCl3):δ4.74(s,1H),4.67(s,1H),4.47(dd,J＝4.2,11.3Hz,1H),4.26-4.13(m,2H),4.11-4.07(m,1H),3.72(t,J＝5.9Hz,2H),2.47-2.41(m,1H),2.23-2.07(m,4H),2.03(s,3H),1.99-1.97(m,2H),1.94-1.86(m,6H),1.82-1.74(m,2H),1.72-1.64(m,4H),1.60-1.46(m,2H),1.29-1.22(m,3H),1.19-1.14(m,2H),1.09(s,3H),1.00-0.95(m,9H),0.85(s,6H),0.69(3H)；13C(100MHz,CDCl3):δ176.19,171.13,154.99,134.23,134.06,106.91,80.79,61.21,59.34,56.85,50.34,48.04,47.02,45.86,42.67,37.74,36.84,35.08,33.65,32.20,31.55,30.57,28.88,27.87,26.34,25.15,24.05,21.83,21.70,21.35,20.41,19.11,17.95,17.40,16.51；HRMS(ESI):calculatedfor C36H58O6Na[M+Na]+609.4125,found 609.4125。
实施例4：化合物I-3的制备
将乙酰溴代葡萄糖代替2-溴乙醇，按实施例1所述的方法，其余所需原料、试剂同实施例1，得到白色固体(化合物I-3)，收率69％。
表征数据为：1H(400MHz,CDCl3):δ5.68(d,J＝7.9Hz,1H),5.28-5.10(m,3H),4.73(s,3H),4.65(s,3H),4.46(dd,J＝4.0,11.4Hz,1H),4.20(dd,J＝4.2,12.4Hz,1H),4.09-4.03(m,2H),3.83-3.79(m,1H),2.46(t,J＝11.0Hz,1H),2.21-2.06(m,4H),2.02-1.96(m,18H),1.93-1.62(m,9H),1.58-1.40(m,2H),1.31-1.23(m,2H),1.18-1.08(m,5H),0.97-0.94(m,6H),0.90(s,3H),0.85(s,3H),0.84(s,3H),0.61(s,3H)；13C(100MHz,CDCl3):δ174.31,171.01,170.54,170.17,169.38,168.98,154.74,134.21,134.05,106.69,91.51,80.65,76.90,72.91,72.35,69.91,67.74,61.44,56.47,50.34,48.02,46.29,45.86,42.62,37.72,36.80,35.06,34.08,31.05,30.63,29.25,27.85,26.35,25.04,24.01,21.69,21.60,21.31,20.59,20.57,20.43,19.10,17.93,17.69,16.50；HRMS(ESI):calculated for C47H70O14Na[M+Na]+881.4657,found 881.4639。
药理活性测试方法及结果：
CCK-8法测试体外抗肿瘤活性
阳性药：茯苓酸(PA)和顺铂(Cisplatin)
实验方法：
将对数生长期的细胞HepG2和HSC-2细胞分别加入96孔板中，在5％ CO2，37℃条件下培养24后，加入不同浓度的测试化合物，设立阴性阳性对照组。共同孵化72小时，加入CCK-8试剂(10μL)，继续孵化2小时。最后用酶标仪读出每孔的OD值，计算半数抑制浓度(IC50)值。
部分化合物体外抗肿瘤活性结果如下：
表1本发明部分化合物对HepG2和HSC-2细胞的体外抗增殖活性
结果表明，本发明物对HepG2和HSC-2两种肿瘤细胞株有不同程度的抑制活性。整体上，化合物对HSC-2口腔癌细胞的抑制活性强于HepG2肝癌细胞。其中，化合物I-1的活性最强，其对HSC-2的IC50值为6.79±0.23μM，强于母体化合物茯苓酸和阳性药顺铂。
对于本领域的技术人员来说，在不脱离本发明结构的前提下，还可以作出多个变形和改进，这些也应该视为本发明的保护范围，这些都不会影响本发明实施的效果和专利的实用性。本申请要求的保护范围应当以其权利要求的内容为准，说明书中的具体实施方式等记载可以用于解释权利要求的内容。
Claims (9)
1.茯苓酸衍生物其特征在于，其化合物通式如式(I)所示：
其中，R代表：C1-C6直链或支链烷烃、含有羟基的直链或支链烷烃、酰基保护的糖基。
2.根据权利要求1所述的茯苓酸衍生物的制备方法，其特征在于，包括以下步骤：
S1、以茯苓酸为原料，溶于有机溶剂中，然后加入相应的卤代烃(或卤代糖)和碱性催化剂；
S2、将反应混合物置于室温下搅拌2～3h，然后用氯化铵溶液淬灭反应，用二氯甲烷萃取反应，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品；
S3、粗品通过柱层析纯化，得到茯苓酸衍生物；
本通式(I)所示化合物的制备方法如下：
其中R的定义同前，其中a代表反应条件。
3.根据权利要求2所述的茯苓酸衍生物的制备方法，其特征在于，所述有机溶剂为无水N,N-二甲基甲酰胺、四氢呋喃、乙醇、甲醇、二氯甲烷、叔丁醇、二甲基亚砜或丙酮。
4.根据权利要求3所述的茯苓酸衍生物的制备方法，其特征在于,所述有机溶剂为无水N,N-二甲基甲酰胺。
5.根据权利要求4所述的茯苓酸衍生物的制备方法，其特征在于，所述碱性催化剂为三乙胺、哌啶、乙酸钠、碳酸钾、碳酸钠、吡啶、碳酸铯、氢氧化锂或吗啉。
6.根据权利要求5所述的茯苓酸衍生物的制备方法，其特征在于，所述碱性催化剂为碳酸钾。
7.根据权利要求2所述的茯苓酸衍生物的制备方法，其特征在于，茯苓酸加入量、卤代烃(或卤代糖)加入量、碱性催化剂加入量比例为1：2：2。
8.根据权利要求1～7任一项所述的茯苓酸衍生物在用于制备预防和治疗各种细胞异常增殖、形态变化相关疾病药物的应用。
9.根据权利要求8的茯苓酸衍生物在用于制备治疗人肝癌或人口腔鳞状细胞癌药物的应用。
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| US3369032A (en) * | 1966-10-31 | 1968-02-13 | Squibb & Sons Inc | Methyl-3beta-acetoxy-16-ketoburico-8, 24(28)-dien-21-oate |
| JPH0925232A (ja) * | 1995-07-14 | 1997-01-28 | Kotarou Kanpo Seiyaku Kk | 発癌予防剤 |
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