CN112898280B - 一种脱氢水飞蓟宾衍生物及其制备方法及用途 - Google Patents
一种脱氢水飞蓟宾衍生物及其制备方法及用途 Download PDFInfo
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明旨在提供一种脱氢水飞蓟宾衍生物及其制备方法和用途,结构如通式Ⅰ所示,其中,R1、R2分别独立的选自氢或1‑6个碳原子的炔基。相比于水飞蓟宾,本发明的化合物具有更好的药效。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种脱氢水飞蓟宾衍生物及其制备方法和用途。
背景技术
水飞蓟宾(silibinin)是从菊科草本植物水飞蓟分离得到的一种黄酮木脂素类化合物。水飞蓟宾(化合物1,化学式1)具有广泛的生物活性,毒性小(Kidd,P.etc Altern MedRev,2005,10(3):193-203)。近期大量研究发现水飞蓟宾对乳腺癌、肺癌、结肠癌、前列腺癌、胰腺癌、肝癌、宫颈癌等多种肿瘤细胞具有较好的抑制作用,并受到广泛关注。目前其作为治疗前列腺癌、EGFR突变型肺腺癌和乳腺癌放射性皮炎进入Ⅱ期临床试验,治疗晚期肝癌进入Ⅰ期临床试验(Siegel,A.B.etc Integr Cancer Ther,2014,13(1):46-53)。
水飞蓟宾抗肿瘤机制为通过调控CDK、EGFR等(Zhu,X.X.etc Expert Rev ClinPharmacol,2016,18:1-8)多种细胞信号通路,调节肿瘤细胞的生长、增殖、细胞凋亡和血管生成。在100μM的浓度下,水飞蓟宾分别处理胰腺癌AsPC-1,BxPC-3和Panc-1细胞24h,凋亡的比例依次为13.24%、7.02%和6.03%(Ge,Y.K.etc International Journal ofMolecular Sciences,
2011,12(8):4861-4871)。在100μM、250μM和500μM的浓度下,水飞蓟宾处理肝癌细胞Hep3B 8h,分别抑制25%、45%和72%(GarcíaMaceira.P.etc Oncogene,2009,28(3):313–324.)。水飞蓟宾(50-200μM)分别处理人结肠直肠癌LoVo细胞24h、48h、72h,细胞生长依次降低30-49%(P<0.01-0.001)、37-60%(P<0.001)和51-83%(P<0.001)(Kaur,M.etcMol Cancer Ther,2009,8(8):2366–2374)。
在不同的肿瘤细胞中,水飞蓟宾的抗肿瘤活性不同,且与剂量和作用时间有关,抗肿瘤活性有待进一步提高。
发明内容
本发明旨在提供一种脱氢水飞蓟宾衍生物及其制备方法和用途,相比于水飞蓟宾,本发明的化合物具有更好的药效。
本发明的技术方案如下:
一种脱氢水飞蓟宾衍生物及其药学上可接受的盐,结构如通式Ⅰ所示:
其中,R1、R2分别独立的选自氢或1-6个碳原子的炔基。
所述的R1、R2分别独立的选自氢或炔丙基。
所述的脱氢水飞蓟宾衍生物及其药学上可接受的盐,包括以下化合物:
7-炔丙基-脱氢水飞蓟宾醚;
3,7-双炔丙基-脱氢水飞蓟宾醚;
3,7,20-三炔丙基-脱氢水飞蓟宾醚。
所述的脱氢水飞蓟宾衍生物及其药学上可接受的盐,其制备方法包括以下步骤:以水飞蓟宾为原料,在碱的催化下与卤代炔烃反应制备得到。
所述的卤代炔烃为溴代炔烃。
所述的碱为氢氧化钠、氢氧化钾、氢氧化钡、氢氧化钙;碳酸钠;碳酸钾;碳酸钙、碳酸铯;碳酸氢钠,三乙胺、4-二甲氨基吡啶、二异丙基乙胺、1,8-二氮杂环[5,4,0]十一烯。
优选的,所述的脱氢水飞蓟宾衍生物及其药学上可接受的盐,其制备方法包括以下步骤:
A、在室温和惰性气体保护的条件下,将水飞蓟宾溶于溶剂,加入碳酸钾搅拌均匀,然后再加入溴代炔烃,将体系升温至20-50℃,搅拌反应6~7小时;所述的溶剂为丙酮或N,N-二甲基甲酰胺;
B、然后加入水和乙酸乙酯,搅拌、静置,分离有机相,重复两次以上,合并有机相,然后合并的有机相依次用水、盐水洗涤,加入干燥剂干燥,旋干溶剂后得粗产物,经硅胶柱层析分离纯化后得到产物。
水飞蓟宾、溶剂、溴丙炔的重量比为8-15:120-200:2-4。
本发明还公开了通式I脱氢水飞蓟宾衍生物及其药学上可接受的盐在制备抗肿瘤药物方面的用途。
所述肿瘤选自非小细胞肺癌、乳腺癌、肝癌、结肠癌。
本发明的新型脱氢水飞蓟宾炔丙基醚,经药理实验证实具有很好的抗肿瘤活性,从而可预期其发展成为防治肿瘤疾病药物的制药用途,具有潜在的巨大社会效益和经济效益。
本发明中式Ⅰ化合物由天然药物为母体制备而得,合成方法简单,成本低,污染小,适于产业化。
具体实施方式
实施例1
为更好地理解本发明的实质,下面首先用实施例的形式说明化合物的制备过程,实施例给出了化合物的部分物理和化学及波谱学数据。必须说明,本发明的实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1:7-炔丙基-脱氢水飞蓟宾醚的制备
在氩气保护下,将120.6mg(0.25mmol)水飞蓟宾溶于1.8mL N,N-二甲基甲酰胺,加入17.3mg(0.125mmol)碳酸钾,然后加入30.0mg(0.25mmol)溴丙炔,在45℃下搅拌反应6~7小时。反应完毕后,向体系中加入10mL水和10mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入10mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入10mL水洗涤,分离有机相,加入10mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到167.6mg浅黄色油状物,加入1mL二氯甲烷及0.5甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1的展缸中进行展开,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,得到22.6mg黄色固体。
经检测得到化合物为:2-[2,3-二氢-3-(4-羟基-3-甲氧基苯基)-2-羟甲基-1,4-苯并二氧六环-6-]-7-(炔丙基氧基)-3,5-二羟基-4H-1-苯并吡喃-4-酮;
1H NMR(DMSO-d6):δ3.30-3.38(m,1H),3.56-3.59(m,1H),3.67-3.68(t,J=2.28,1H),3.79(s,3H),4.27-4.31(m,1H),4.92-4.93(d,J=2.08,2H),4.96-4.98(d,J=7.92,1H),5.01(br,1H),6.41-6.42(d,J=2.12,1H),6.81-6.83(d,J=8.04,1H),6.85-6.86(d,J=1.84,1H),6.88-6.91(dd,J=8.20,1.76,1H),7.05-7.06(d,J=1.76,1H),7.13-7.15(d,J=8.56,1H),7.79-7.82(dd,1H),7.82(s,1H),9.18(s,1H),9.76(s,1H),12.42(s,1H).ESI-MS(m/z):519.3(M++1).
实施例2:3,7-双炔丙基-脱氢水飞蓟宾醚的制备
将氢化钠分散于矿物油中,制备得到氢化钠分散液,氢化钠分散液中氢化钠质量分数为60%;
在氩气保护下,将120.6mg(0.25mmol)水飞蓟宾溶于1.8mL N,N-二甲基甲酰胺中,搅拌下将体系降温至0~5℃,将12.0mg氢化钠分散液加入反应瓶中,然后加入30.0mg(0.25mmol)溴丙炔,让体系自然回温至室温,同时搅拌6~7小时进行反应。反应完毕后,向体系中加入10mL水和10mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入10mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入10mL水洗涤,分离有机相,加入10mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到170.0mg亮黄色固体,加入1mL二氯甲烷及0.5甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=16/1的展缸中进行展开,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,得到15.6mg黄色固体。
经检测得到化合物为:2-[2,3-二氢-3-(4-炔丙基氧基-3-甲氧基苯基)-2-羟甲基-1,4-苯并二氧六环-6-]-7-(炔丙基氧基)-3,5-二羟基-4H-1-苯并吡喃-4-酮;
1H NMR(DMSO-d6):δ3.30-3.38(m,1H),3.54-3.60(t,J=2.44,1H),3.56-3.60(m,1H),3.68-3.69(t,J=2.24,1H),3.79(s,3H),4.33-4.35(m,1H),4.94-4.95(d,J=2.32,2H),4.95-4.96(d,J=2.36,2H),4.97-4.99(d,J=7.92,1H),5.03(br,1H),6.46-6.47(d,J=2.20,2H),6.81-6.83(d,J=7.92,1H),6.89-6.91(m,2H),7.06-7.07(d,J=0.96,1H),7.15-7.17(d,J=8.36,1H),7.75(s,1H),7.75-7.77(dd,J=8.40,1.36,1H),9.20(s,1H),12.46(s,1H).ESI-MS(m/z):557.3(M++1).
实施例3:3,7,20-三炔丙基-脱氢水飞蓟宾醚的制备
将氢化钠分散于矿物油中,制备得到氢化钠分散液,氢化钠分散液中氢化钠质量分数为60%;
在氩气保护下,将120.6mg(0.25mmol)水飞蓟宾溶于1.8mL N,N-二甲基甲酰胺中,搅拌下将体系降温至0~5℃,将22.0mg氢化钠分散液加入反应瓶中,然后加入30.0mg(0.25mmol)溴丙炔,让体系自然回温至室温,同时搅拌6~7小时进行反应。反应完毕后,向体系中加入10mL水和10mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入10mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入10mL水洗涤,分离有机相,加入10mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到151.4mg黄色粘稠物,加入1mL二氯甲烷及0.5甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=20/1的展缸中进行展开,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,得到17.5mg黄色固体。
经检测得到化合物为:2-[2,3-二氢-3-(4-炔丙基氧基-3-甲氧基苯基)-2-羟甲基-1,4-苯并二氧六环-6-]-3,7-双(炔丙基氧基)-5-二羟基-4H-1-苯并吡喃-4-酮;1H NMR(DMSO-d6):
δ3.39-3.42(m,1H),3.54-3.55(t,J=2.40,1H),3.59-3.60(t,J=2.36,1H),3.61-3.62(m,1H),3.68-3.69(t,J=2.32,1H),3.80(s,3H),4.36-4.40(m,1H),4.82-4.83(d,J=2.32,2H),4.94-4.95(d,J=2.28,2H),4.95-4.96(d,J=2.40,2H),5.05-5.07(d,J=7.84,1H),5.07(br,1H),6.46-6.47(d,J=1.04,1H),6.89-6.90(d,J=2.24,1H),7.03-7.05(dd,J=8.20,1.56,1H),7.08-7.10(d,J=8.36,1H),7.14-7.15(d,J=1.68,1H),7.16-7.18(d,J=9.20,1H),7.76(s,1H),7.76-7.79(dd,J=7.68,2.24,1H),12.46(s,1H).ESI-MS(m/z):595.4(M++1).
实施例4
化合物抗肿瘤活性测试
一、乳腺癌
1.细胞培养条件:10%胎牛血清的MEM完全培养基(含0.01mg/mL胰岛素),37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期MCF-7细胞,制成细胞悬液。根据细胞增长速率以每孔100μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔,培养48h。
3.向每孔加入10μL的CCK-8溶液,将培养板置于培养箱内孵育1-4小时。
4.用酶标仪测定在450nm处的吸光度,计算抑制率。
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液);
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物);
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)。
测试结果见表1,抗人类乳腺癌MCF-7增殖活性测试结果显示,7-炔丙基-脱氢水飞蓟宾醚很强的活性。
表1本发明实施例1-3所示化合物和在不同浓度下对人类乳腺癌MCF-7细胞株的抑制率
实验结论:如表1所示,7-炔丙基-脱氢水飞蓟宾醚和3,7-双炔丙基-脱氢水飞蓟宾醚的抗人类乳腺癌MCF-7增殖活性明显优于水飞蓟宾;7-炔丙基-脱氢水飞蓟宾醚显示了很强的抗人类乳腺癌MCF-7增殖活性,具有很高的开发价值。此外,3,7,20-三炔丙基-脱氢水飞蓟宾醚也具有一定的抗人类乳腺癌MCF-7增殖活性。
二、非小细胞肺癌
实验方法
1.细胞培养条件:10%胎牛血清的RPMI-1640完全培养基,37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期NCI-H1299细胞,制成细胞悬液。根据细胞增长速率以每孔100μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔,培养48h。
3.向每孔加入10μL的CCK-8溶液,将培养板置于培养箱内孵育1-4小时。
4.用酶标仪测定在450nm处的吸光度,计算抑制率。
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液);
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物);
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)。
实验结论:经预实验表明,7-炔丙基-脱氢水飞蓟宾醚、3,7-双炔丙基-脱氢水飞蓟宾醚、3,7,20-三炔丙基-脱氢水飞蓟宾醚均具有一定的抗人非小细胞肺癌NCI-H1299增殖活性。
三、肝癌
1.细胞培养条件:10%胎牛血清的MEM完全培养基,37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期HepG2细胞,制成细胞悬液。根据细胞增长速率以每孔100μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔,培养48h。
3.向每孔加入10μL的CCK-8溶液,将培养板置于培养箱内孵育1-4小时。
4.用酶标仪测定在450nm处的吸光度,计算抑制率。
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液);
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物);
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)。
实验结论:经预实验表明,7-炔丙基-脱氢水飞蓟宾醚、3,7-双炔丙基-脱氢水飞蓟宾醚、3,7,20-三炔丙基-脱氢水飞蓟宾醚均具有一定的抗人肝细胞癌HepG2增殖活性。
四、结肠癌
实验方法
1.细胞培养条件:10%胎牛血清的McCOY's 5A完全培养基,37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期HT-29细胞,制成细胞悬液。根据细胞增长速率以每孔100μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔,培养48h。
3.向每孔加入10μL的CCK-8溶液,将培养板置于培养箱内孵育1-4小时。
4.用酶标仪测定在450nm处的吸光度,计算抑制率。
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液);
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物);
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)。
实验结论:经预实验表明,7-炔丙基-脱氢水飞蓟宾醚、3,7-双炔丙基-脱氢水飞蓟宾醚、3,7,20-三炔丙基-脱氢水飞蓟宾醚均具有一定的抗人结肠癌HT-29增殖活性。
Claims (4)
1.一种脱氢水飞蓟宾衍生物及其药学上可接受的盐,结构如通式Ⅰ所示:
其中,R1、R2均为氢。
2.一种根据权利要求1所述的脱氢水飞蓟宾衍生物及其药学上可接受的盐的制备方法,其特征在于,其制备方法包括以下步骤:
A、在室温和惰性气体保护的条件下,将水飞蓟宾溶于溶剂,加入碳酸钾搅拌均匀,然后再加入溴代炔烃,将体系升温至20-50℃,搅拌反应6~7小时;所述的溶剂为:丙酮或N,N-二甲基甲酰胺;
B、然后加入水和乙酸乙酯,搅拌、静置,分离有机相,重复两次以上,合并有机相,然后合并的有机相依次用水、盐水洗涤,加入干燥剂干燥,旋干溶剂后得粗产物,经硅胶柱层析分离纯化后得到产物。
3.根据权利要求2所述的制备方法,其特征在于:
水飞蓟宾、溶剂、溴丙炔的重量比为8-15:120-200:2-4。
4.根据权利要求1所述的脱氢水飞蓟宾衍生物及其药学上可接受的盐在制备抗乳腺癌药物方面的用途。
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