CN115819488B - 一种24,31-氢化茯苓酸、制备方法及其应用 - Google Patents
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- SRDNLMOBFKJOSD-UHFFFAOYSA-N pachymic acid Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C(O)=O)C(O)CC21C SRDNLMOBFKJOSD-UHFFFAOYSA-N 0.000 claims abstract description 14
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Abstract
本申请公开了药物化学领域的一种24,31‑氢化茯苓酸的制备方法,包括以下步骤:将茯苓酸溶于有机溶剂,加入催化剂,在氢气氛围中,反应液搅拌反应,反应结束后,将反应液过滤、浓缩,得到化合物I。在茯苓酸的基础上提供24,31‑氢化茯苓酸,用于治疗各种细胞异常增殖等相关的疾病,尤其是用于治疗肿瘤疾病的药物,能够对人肝癌细胞和人口腔鳞状肿瘤细胞具有较强的体外抗增殖活性。
Description
技术领域
本发明涉及药物化学技术领域,具体涉及一种24,31-氢化茯苓酸、制备方法及其应用。
背景技术
茯苓酸(Pachymic acid,PA)是从多孔菌科真菌茯苓的干燥菌核中分离得到的一种重要的天然羊毛甾烷类三萜化合物,具有抗菌、抗病毒、抗肿瘤等药理活性。在抗肿瘤方面,茯苓酸可以通过下调CDK1、CDK2、CDK4和cyclinE的表达来抑制多种肿瘤细胞的增殖,从而阻断细胞周期,包括MDA-MB-231、SGC-7901和MKN-49P等细胞(J Ethnopharmacol 2020,257:112851;Oncol Lett 2018,16:2517;Anticancer Drugs 2017,28:170)。同时,茯苓酸还能诱导多种肿瘤细胞的凋亡,包括EJ、SK-BR-3、PANC-1、MIAPaCa 2、DU145等细胞(Phytother Res 2015,29:1516;Biochem Biophys Res Commun 2005,332:1153;PLoSOne2015 10:e0122270),茯苓酸的化合物通式如下:
为此,申请人在茯苓酸的基础上提供新型的24,31-氢化茯苓酸,用于治疗各种细胞异常增殖等相关的疾病,尤其是用于治疗肿瘤疾病的药物,能够对人肝癌细胞和人口腔鳞状肿瘤细胞具有较强的体外抗增殖活性。
发明内容
本发明意在提供一种24,31-氢化茯苓酸、制备方法及其应用,以提供24,31-氢化茯苓酸,可用于治疗各种细胞异常增殖等相关的疾病,尤其是用于治疗肿瘤疾病的药物,该衍生物对人肝癌细胞和人口腔鳞状肿瘤细胞具有较强的体外抗增殖活性。
为了达到上述目的,本发明提供如下技术方案:一种24,31-氢化茯苓酸,其化合物通式如式(I)所示:
本通式(I)所示化合物的制备方法,包括以下步骤:
将茯苓酸溶于有机溶剂,加入催化剂,在氢气氛围中,反应液室温搅拌反应,反应结束后,将反应液过滤、浓缩,得到化合物I。
24,31-氢化茯苓酸的合成路线为:
进一步,所述a:催化剂为Pd/C、Pd(OH)2/C或Raney Ni;溶剂:N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙醇、甲醇、二氯甲烷、叔丁醇或丙酮;反应温度为20~35℃。
进一步,所述催化剂选用Pd/C。
进一步,所述溶剂选用甲醇。
一种24,31-氢化茯苓酸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,24,31-氢化茯苓酸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24,31-氢化茯苓酸药理实验显示,24,31-氢化茯苓酸对人肝癌细胞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,24,31-氢化茯苓酸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:化合物I的制备
将茯苓酸(0.18mmol)溶解于甲醇(30mL)中,加入10% Pt/C(100mg)。在氢气氛围中,反应液30℃拌反应12h。将反应液过滤、浓缩,得到白色固体(化合物I),收率100%。
表征数据为:1H(400MHz,Pyridin-d5):δ4.68(dd,J=4.0,11.5Hz,1H),4.59(s,1H),2.91-2.77(m,2H),2.42-1.97(m,10H),1.87-1.34(m,16H),1.16-1.10(m,5H),0.97-0.91(m,9H),0.82-0.72(m,9H);13C(100MHz,Pyridin-d5):δ171.89,136.31,135.57,81.87,77.60,58.65,51.96,49.96,47.59,44.76,40.29,39.25,38.38,36.67,34.26,33.77,32.82,32.10,30.79,29.23,27.98,26.82,25.73,22.43,22.13,21.72,20.50,19.61,19.14,18.58,18.06,16.81,16.59;HRMS(ESI):calculated for C33H54O5Na[M+Na]+553.3863,found 553.3856。
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)
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。
24,31-氢化茯苓酸的体外抗肿瘤活性结果如下:
表1本发明化合物对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,且活性均强于母体化合物茯苓酸。
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 (3)
1.一种24,31-氢化茯苓酸,其特征在于,化合物通式如式(I)所示,
。
2.根据权利要求1所述的24,31-氢化茯苓酸的制备方法,其特征在于,包括以下步骤:
将茯苓酸溶于有机溶剂,加入催化剂,在氢气氛围中,反应液在一定反应温度下搅拌反应,反应结束后,将反应液过滤、浓缩,得到化合物I;
24,31-氢化茯苓酸的合成路线为:
其中a代表反应条件,所述a:催化剂为Pt/C、溶剂为甲醇、反应温度为20 ~ 35℃。
3.根据权利要求1所述的24,31-氢化茯苓酸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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Non-Patent Citations (3)
Title |
---|
Extractives of fungi. I. Constituents of Trametes lilacino;Pinhey, John T等;《Australian Journal of Chemistry》;第23卷(第10期);第2141页 * |
Extractives of fungi. III. Introduction of a (Z)-17(20)-double bond into a tumulosic acid derivative;Batey, I. L.等;《Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry》(第18期);第2261页化合物VI * |
Synthesis and bioactivity evaluation of pachymic acid derivatives as potential cytotoxic agents.;Hezhen Wang等;《Medicinal Chemistry Research 》;第32卷;第342-354页 * |
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