CN116217642A - 木樨榄苷类化合物及其在制备抗肿瘤药物中的应用 - Google Patents

木樨榄苷类化合物及其在制备抗肿瘤药物中的应用 Download PDF

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CN116217642A
CN116217642A CN202310222751.7A CN202310222751A CN116217642A CN 116217642 A CN116217642 A CN 116217642A CN 202310222751 A CN202310222751 A CN 202310222751A CN 116217642 A CN116217642 A CN 116217642A
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张衍鑫
刘庆超
冯少杰
付宝毅
宋晓萍
许莹
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Abstract

本发明公开了一类木樨榄苷类化合物及其在制备抗肿瘤药物中的应用，该化合物的结构式为
Figure DDA0004117364760000011
式中R1选自2‑甲基烯丙基、肉桂醇基、胡椒醇基、香草醇基、1‑苯氧基‑2‑丙醇基、孕烯醇酮基、薯蓣皂苷元基、植物醇基、油醇基、C5nH8n+1O或CmH2m+1O；R2选自氢或乙酰基，其是以木樨榄苷‑11‑甲酯为起始原料，将其7位羧基与不同的醇单元反应转化为酯基后制备而成。该类化合物对多种肿瘤细胞具有抑制作用，在抗肿瘤方面具有应用价值，可以作为一种新型的抗肿瘤药物加以研究利用。

Description

木樨榄苷类化合物及其在制备抗肿瘤药物中的应用
技术领域
本发明属于化学药物技术领域，具体涉及木樨榄苷类化合物及其在制备抗肿瘤药物中的应用。
背景技术
肿瘤是世界上严重威胁人类健康的慢性疾病。木樨榄苷类化合物(Oleoside-typed glucosides)具有重要的细胞生物学功能，其典型化合物橄榄苦苷已被证实有抗肿瘤作用，且对正常细胞无明显毒性，但其抗肿瘤效果并不出众。目前该类化合物的研究尚不深入，因此，寻找高效、高选择性和药学性质良好的木樨榄苷类化合物具有重要的研究意义和应用前景。
天然产物是新药先导化合物的重要源泉，对天然活性化合物进行化学合成和改性研究又是实现创新药物研究的关键环节和重要课题。研究表明木樨榄苷类化合物有作为一类新型的抗肿瘤药物的潜质。针对其C-7位的修饰相对简便且活性增强的效果明显。
发明内容
本发明的目的是提供一类新的木樨榄苷类化合物，并为该化合物提供一种新用途。
针对上述目的，本发明所采用的木樨榄苷类化合物的结构式如下所示：
Figure SMS_1
式中，R1选自2-甲基烯丙基、肉桂醇基、胡椒醇基、香草醇基、1-苯氧基-2-丙醇基、孕烯醇酮基、薯蓣皂苷元基、植物醇基、油醇基、C5nH8n+1O、CmH2m+1O中任意一种，其中n＝1～5的整数，m＝15～30的整数；R2选自氢或乙酰基。
上述结构式中，优选R1为2-甲基烯丙基、香叶醇基、橙花醇基、金合欢醇基、肉桂醇基、1-苯氧基-2-丙醇基、孕烯醇酮基、薯蓣皂苷元基、植物醇基、油醇基、四氢香叶醇基、硬脂醇基中任意一种，R2为H。
上述结构式中，R2为乙酰基时，所述木樨榄苷类化合物的合成路线和具体合成方法如下：
Figure SMS_2
1、将橄榄苦苷(化合物1)溶于甲醇，并加入1mol/L氢氧化钠水溶液将溶液pH值调至13，室温搅拌反应24h。反应完毕后向溶液中加入1mol/L盐酸溶液，将溶液pH值调至6，减压浓缩除去溶剂后得到化合物2的粗产物，以吡啶溶解化合物2的粗产物，并加入醋酸酐(与化合物1摩尔比为1:8～12)，室温下反应2h。反应完成后减压浓缩除去溶剂，得到的浓缩粗产物通过硅胶柱分离得到化合物3。
2、以二氯甲烷为溶剂，将化合物3与2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲四氟硼酸盐(TATU)和1,8-二氮杂二环十一碳-7-烯(DBU)按摩尔比为1:1.1～1.2:2，在室温下搅拌反应0.5h，随后加入醇类化合物(即R1H)，醇类化合物与化合物3的摩尔比1:1.1～1.3，在室温下反应4h，反应结束后以饱和氯化铵水溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析，得到木樨榄苷类化合物4。
上述结构式中，R2为H时，进一步将化合物4溶解于甲醇中，在0℃搅拌0.5h后加入二乙胺，化合物4与二乙胺的摩尔比为1:0.6，在室温下搅拌6h后，减压浓缩，硅胶柱层析，得到白色固体木樨榄苷类化合物5。反应方程式如下：
Figure SMS_3
本发明木樨榄苷类化合物可用于制备抗肿瘤药物，其按常规药用制剂，与药学上可接受的载体按照各种制剂的常规制备工艺制成，可以是片剂、颗粒剂、胶囊剂。
本发明的有益效果如下：
本发明以木樨榄苷-11-甲酯为母体，将其7位羧基引入不同的醇单元转化为酯基后制备木樨榄苷类化合物。经药理活性检测，此类化合物对A549、HGC27、HepG2、A498、RAW、THP-1、Raji细胞显示出很好的毒性，可以用于制备抗肿瘤的药物。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施例。
实施例1
1、将20g(0.037mol)橄榄苦苷溶于150mL甲醇，室温搅拌下加入1mol/L氢氧化钠水溶液至溶液pH值为13，室温下反应24h。反应完成后向溶液中加入1mol/L盐酸溶液，将溶液pH值调至6，减压浓缩除去溶剂后得到化合物2的粗产物，随后将化合物2的粗产物溶于60mL吡啶，并加入35mL醋酸酐(0.37mol)，室温下反应2h。反应完成后减压浓缩除去溶剂，浓缩粗产物经硅胶柱层析(洗脱剂为二氯甲烷:乙酸乙酯＝1:1，V/V)精制得到固体化合物3(314.9g，产率70.0％)，其结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.03(q,J＝7.1Hz,1H),5.69(s,1H),5.26(t,J＝10.0Hz,1H),5.12(t,J＝9.1Hz,2H),5.03(d,J＝7.9Hz,1H),4.27(d,J＝4.6Hz,1H),4.17(d,J＝12.1Hz,1H),3.99(dd,J＝8.7,4.5Hz,1H),3.75–3.71(m,4H),2.77(dd,J＝14.7,4.6Hz,1H),2.46(dd,J＝14.6,8.5Hz,1H),2.10(d,J＝1.6Hz,3H),2.03(d,J＝5.2Hz,9H),1.76(d,J＝7.1Hz,3H)；HRMS(ESI):m/z理论值C25H33O15[M+H]+573.1814，实测值573.1816。
2、将110mg(0.175mmol)化合物3溶解于5mL二氯甲烷中，加入60mg(0.180mmol)TATU和53mg(0.350mmol)DBU，在室温下搅拌0.5h后，加入15mg(0.210mmol)2-甲基烯丙醇，室温下反应4h后，用15mL饱和氯化铵水溶液萃取3次，收集有机相，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析，得到白色固体化合物4-1(92mg，产率77％)。
上述步骤2中，用等摩尔香叶醇、橙花醇、金合欢醇、肉桂醇、胡椒醇、香草醇、1-苯氧基-2-丙醇、孕烯醇酮、薯蓣皂苷元、植物醇、油醇、四氢香叶醇、硬脂醇，依次得到化合物4-2～4-14。
3、将80mg(0.129mmol)化合物4-1溶解于3mL甲醇中，在0℃搅拌0.5h后加入56mg(0.772mmol)二乙胺，在室温下搅拌6h后，加入5mL甲醇及0.5g硅胶，减压浓缩，硅胶柱层析(二氯甲烷/甲醇＝95:5，V/V)，得到白色固体化合物5-1(46mg，产率79％)。
上述步骤3中，以等摩尔的化合物4-2～4-14为反应原料，依次得到化合物5-2～5-14。
表1化合物的取代基和产率
Figure SMS_4
Figure SMS_5
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Figure SMS_6
化合物4-1的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.02(q,J＝7.1Hz,1H),5.72(s,1H),5.27(t,J＝8.7Hz,1H),5.16–5.09(m,2H),5.03(d,J＝8.6Hz,1H),4.92(d,J＝16.5Hz,2H),4.50(d,J＝13.1Hz,1H),4.39(d,J＝13.1Hz,1H),4.30(dd,J＝12.5,4.8Hz,1H),4.11(d,J＝11.9Hz,1H),4.01(dd,J＝9.1,4.3Hz,1H),3.79–3.72(m,4H),2.79(dd,J＝14.7,4.4Hz,1H),2.47(dd,J＝14.6,9.0Hz,1H),2.09(d,J＝1.5Hz,3H),2.03(dd,J＝4.1,1.4Hz,9H),1.74(d,J＝8.5Hz,6H)；13C NMR(100MHz,CDCl3)δ:170.8,170.6,170.2,169.4,169.3,166.8,153.1,139.7,128.0,125.0,113.1,108.8,97.1,93.7,72.5,72.1,70.7,68.2,67.8,61.8,51.4,39.9,30.2,20.7,20.6,20.5,20.4,19.4,13.5；HRMS(ESI):m/z理论值C29H38O15Na[M+Na]+649.2103，实测值649.2106。
化合物4-2的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.46(s,1H),6.00(q,J＝7.1Hz,1H),5.71(s,1H),5.29(dt,J＝16.5,8.3Hz,2H),5.16–5.06(m,3H),5.03(d,J＝7.9Hz,1H),4.62–4.49(m,2H),4.32(dd,J＝12.8,4.8Hz,1H),4.11(d,J＝12.1Hz,1H),3.99(dd,J＝9.3,4.2Hz,1H),3.79–3.71(m,4H),2.74(dd,J＝14.7,4.3Hz,1H),2.41(dd,J＝14.6,8.9Hz,1H),2.11–2.01(m,16H),1.75(d,J＝7.6Hz,3H),1.68(s,6H),1.61(s,3H)；13CNMR(100MHz,CDCl3)δ:171.1,170.6,170.1,169.4,169.3,166.7,153.0,142.1,131.8,128.1,124.8,123.7,118.1,108.7,97.0,93.7,72.5,72.2,70.7,68.2,61.7,61.5,51.4,40.0,39.5,30.2,26.2,24.9,20.7,20.6,20.5,20.4,17.7,16.4,13.6；HRMS(ESI):m/z理论值C35H48O15Na[M+Na]+731.2886，实测值731.2890。
化合物4-3的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.45(s,1H),5.99(q,J＝7.0Hz,1H),5.70(s,1H),5.30–5.23(m,2H),5.11(d,J＝9.5Hz,3H),5.02(d,J＝7.9Hz,1H),4.57–4.46(m,2H),4.31(dd,J＝12.4,4.7Hz,1H),4.11(d,J＝12.4Hz,1H),3.98(dd,J＝9.0,4.2Hz,1H),3.72(s,4H),2.72(dd,J＝14.7,4.3Hz,1H),2.39(dd,J＝14.7,9.0Hz,1H),2.08(d,J＝4.7Hz,6H),2.03(d,J＝3.6Hz,10H),1.75(s,3H),1.73(s,3H),1.67(s,3H),1.59(s,3H)；13C NMR(100MHz,CDCl3)δ:171.1,170.6,170.2,169.4,169.3,166.8,153.0,142.4,132.2,128.0,124.8,123.5,119.1,108.8,97.1,93.7,72.5,72.2,70.7,68.2,61.7,61.3,51.5,40.0,32.2,30.2,26.6,25.7,23.5,20.7,20.4,20.2,20.1,17.7,13.6；HRMS(ESI):m/z理论值C35H48O15Na[M+Na]+731.2886，实测值731.2890。
化合物4-4的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.45(s,1H),5.99(q,J＝7.1Hz,1H),5.70(s,1H),5.31(t,J＝6.8Hz,1H),5.25(d,J＝9.4Hz,1H),5.10(q,J＝7.8,6.0Hz,4H),5.02(d,J＝8.0Hz,1H),4.59–4.49(m,2H),4.31(dd,J＝12.5,4.8Hz,1H),4.11(d,J＝12.3Hz,1H),3.98(dd,J＝9.0,4.3Hz,1H),3.78–3.69(m,4H),2.73(dd,J＝15.0,4.2Hz,1H),2.40(dd,J＝14.8,9.1Hz,1H),2.11–1.93(m,20H),1.74(d,J＝7.1Hz,3H),1.67(s,6H),1.59(s,6H)；13C NMR(100MHz,CDCl3)δ:171.1,170.6,170.2,169.4,169.3,166.7,153.0,142.2,135.5,131.3,128.1,124.8,124.3,123.6,118.1,108.8,97.0,93.7,72.5,72.2,70.7,68.2,61.7,61.5,51.4,40.0,39.7,39.5,30.2,26.7,26.2,25.7,20.7,20.6,20.3,20.0,17.7,16.4,16.0,13.6；HRMS(ESI):m/z理论值C40H56O15Na[M+Na]+799.3512，实测值799.3516。
化合物4-5的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.46(s,1H),7.40–7.29(m,5H),6.61(d,J＝15.8Hz,1H),6.29–6.18(m,1H),5.99(q,J＝7.1Hz,1H),5.72(s,1H),5.26(dd,J＝17.9,10.3Hz,1H),5.19–5.09(m,2H),5.00(d,J＝8.0Hz,1H),4.74(dd,J＝12.8,6.6Hz,1H),4.63(dd,J＝12.8,6.3Hz,1H),4.27(dd,J＝11.6,4.6Hz,1H),4.08(d,J＝12.7Hz,1H),4.00(dd,J＝9.1,4.4Hz,1H),3.75–3.67(m,4H),2.78(dd,J＝14.5,3.7Hz,1H),2.46(dd,J＝14.4,9.1Hz,1H),2.10–1.99(m,12H),1.72(d,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)δ:170.8,170.6,170.2,169.4,169.3,166.7,153.1,136.1,134.2,128.6,128.1,127.9,126.6,124.9,123.0,108.7,97.1,93.8,72.5,72.1,70.7,68.2,65.1,61.7,51.5,39.9,30.3,20.6,20.6,20.1,13.6；HRMS(ESI):m/z理论值C34H40O15Na[M+Na]+711.2260，实测值711.2263。
化合物4-6的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.43(s,1H),6.85–6.74(m,3H),5.98(s,2H),5.92(q,J＝7.0Hz,1H),5.69(s,1H),5.27(t,J＝9.4Hz,1H),5.17–5.10(m,2H),5.04–4.98(m,2H),4.87(d,J＝12.0Hz,1H),4.29(dd,J＝12.4,4.9Hz,1H),4.14–4.10(m,1H),3.97(dd,J＝9.1,4.5Hz,1H),3.78–3.73(m,1H),3.71(s,3H),2.76(dd,J＝14.2,4.5Hz,1H),2.45(dd,J＝14.2,9.1Hz,1H),2.05–2.02(m,12H),1.64(d,J＝5.6Hz,3H)；13C NMR(100MHz,CDCl3)δ:170.9,170.6,170.2,169.4,169.3,166.7,153.1,147.7,147.6,129.5,127.7,124.8,122.3,109.2,108.6,108.1,101.1,97.0,93.6,72.5,72.2,70.7,68.2,66.3,61.7,51.4,39.9,30.3,20.6,20.5,20.3,20.1,13.4；HRMS(ESI):m/z理论值C33H38O17Na[M+Na]+729.2002，实测值729.2005。
化合物4-7的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.51(s,1H),7.01–6.84(m,3H),6.10(q,J＝7.1Hz,1H),5.85(s,1H),5.27(t,J＝9.4Hz,1H),5.12(dt,J＝13.2,9.5Hz,2H),5.01(d,J＝9.7Hz,1H),4.64(d,J＝4.4Hz,2H),4.18–4.10(m,1H),4.06(dd,J＝8.9,4.4Hz,1H),3.95(d,J＝12.3Hz,1H),3.78(s,3H),3.75(d,J＝1.5Hz,4H),3.06–2.93(m,1H),2.88–2.75(m,1H),2.03(d,J＝8.2Hz,9H),1.95(s,3H),1.76(d,J＝7.1Hz,3H)；13CNMR(100MHz,CDCl3)δ:170.8,170.2,169.4,169.3,166.8,153.3,151.0,140.1,138.9,128.0,125.2,122.6,119.0,111.1,108.3,97.4,94.4,72.5,72.0,70.7,68.3,65.0,62.0,55.7,51.5,38.9,30.1,20.7,20.6,20.5,20.2,13.7；HRMS(ESI):m/z理论值C33H40O17Na[M+Na]+731.2158，实测值731.2161。
化合物4-8的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.46(s,1H),7.30(s,1H),7.26(d,J＝5.5Hz,1H),7.01–6.84(m,3H),6.01(q,J＝6.9Hz,1H),5.77–5.68(m,1H),5.29–5.20(m,1H),5.21–5.05(m,3H),5.01(t,J＝7.6Hz,1H),4.33–4.22(m,1H),4.17–4.03(m,2H),4.02–3.94(m,2H),3.76–3.71(m,4H),2.78–2.70(m,1H),2.51–2.42(m,1H),2.07–2.01(m,12H),1.74(t,J＝7.0Hz,3H),1.32(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ:171.0,170.6,170.1,169.4,169.3,166.7,158.5,153.1,129.5,128.1,124.9,121.2,114.5,108.6,97.0,93.7,72.5,72.1,71.4,70.7,69.8,68.2,61.7,51.4,40.0,30.2,20.6,20.6,20.0,16.8,13.6；HRMS(ESI):m/z理论值C34H42O16Na[M+Na]+729.2366，实测值729.2369。
化合物4-9的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.45(s,1H),6.00(d,J＝7.1Hz,1H),5.73(t,J＝1.6Hz,1H),5.36(d,J＝5.4Hz,1H),5.26(d,J＝9.4Hz,1H),5.16–5.06(m,2H),5.02(d,J＝8.0Hz,1H),4.53(dtd,J＝11.2,7.5,6.6,3.4Hz,1H),4.30(dd,J＝12.4,4.9Hz,1H),4.13–4.10(m,1H),3.97(dd,J＝9.0,4.3Hz,1H),3.79–3.71(m,4H),2.70(dd,J＝14.5,4.3Hz,1H),2.53(t,J＝8.9Hz,1H),2.40(dd,J＝14.5,9.0Hz,1H),2.27(d,J＝7.3Hz,2H),2.21–2.14(m,1H),2.12(s,3H),2.08(s,3H),2.03(t,J＝4.0Hz,10H),1.90–1.78(m,2H),1.75(dd,J＝7.1,1.5Hz,3H),1.70–1.64(m,2H),1.61(s,3H),1.57–1.50(m,2H),1.51–1.41(m,3H),1.21–1.07(m,3H),1.00(s,3H),0.62(s,3H)；13C NMR(100MHz,CDCl3)δ:209.5,170.6,170.2,169.4,169.3,166.8,153.0,139.5,128.2,124.7,122.4,108.8,97.1,93.8,74.1,72.5,72.2,70.7,68.2,63.6,61.8,56.8,51.4,49.8,43.9,40.1,38.7,38.0,36.9,36.5,31.8,31.7,31.5,30.1,27.6,24.4,22.8,21.0,20.7,20.6,20.5,20.0,19.2,13.7,13.2；HRMS(ESI):m/z理论值C46H62O16Na[M+Na]+893.3931，实测值893.3935。
化合物4-10的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.45(s,1H),6.00(q,J＝7.1Hz,1H),5.72(s,1H),5.35(d,J＝4.9Hz,1H),5.25(d,J＝9.5Hz,1H),5.11(t,J＝9.6Hz,2H),5.02(d,J＝7.9Hz,1H),4.40(q,J＝7.5Hz,1H),4.29(dd,J＝12.6,4.8Hz,1H),4.09(d,J＝12.2Hz,1H),3.96(dd,J＝9.3,4.2Hz,1H),3.79–3.70(m,4H),3.46(d,J＝6.9Hz,1H),3.36(t,J＝10.9Hz,1H),2.69(dd,J＝15.2,4.0Hz,1H),2.40(dd,J＝14.5,9.0Hz,1H),2.25(d,J＝7.9Hz,2H),2.07(d,J＝1.7Hz,3H),2.03–1.94(m,11H),1.92–1.77(m,4H),1.74(d,J＝6.9Hz,3H),1.67(s,2H),1.60(t,J＝12.8Hz,5H),1.55–1.39(m,4H),1.27(dt,J＝19.8,6.7Hz,2H),1.22–1.05(m,4H),1.01(s,3H),0.96(d,J＝6.8Hz,3H),0.78(d,J＝4.9Hz,6H)；13C NMR(100MHz,CDCl3)δ:170.6,170.1,169.4,169.3,166.8,153.0,139.6,128.2,124.7,122.4,109.2,108.8,97.1,93.8,80.8,74.2,72.5,72.2,70.7,68.2,66.8,62.0,61.8,56.4,51.4,49.9,41.6,40.2,40.1,39.7,38.0,36.9,36.7,32.0,31.8,31.3,30.1,30.0,28.8,27.6,20.8,20.7,20.6,20.2,20.0,19.3,17.1,16.2,14.5,13.7；HRMS(ESI):m/z理论值C52H72O17Na[M+Na]+991.4662，实测值991.4669。
化合物4-11的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.49(s,1H),6.04(q,J＝7.6Hz,1H),5.75(s,1H),5.38–5.26(m,2H),5.21–5.11(m,2H),5.06(d,J＝7.9Hz,1H),4.63–4.53(m,2H),4.35(dd,J＝12.4,4.7Hz,1H),4.15(dd,J＝12.4,2.4Hz,1H),4.02(dd,J＝9.0,4.3Hz,1H),3.84–3.74(m,4H),2.77(dd,J＝14.7,4.3Hz,1H),2.44(dd,J＝14.6,9.0Hz,1H),2.16–2.01(m,14H),1.78(dd,J＝7.0,1.5Hz,6H),1.57(s,1H),1.46(s,2H),1.29(s,16H),0.89(d,J＝2.4Hz,12H)；13C NMR(100MHz,CDCl3)δ:171.2,170.6,170.2,169.4,169.1,166.8,153.0,142.7,128.1,124.8,117.9,108.8,97.1,93.7,72.5,72.2,70.7,68.2,61.7,61.6,51.5,40.0,39.9,39.4,37.4,37.3,37.2,37.1,32.8,32.7,30.2,28.0,24.8,24.5,22.7,22.6,22.6,20.7,20.3,20.1,20.0,16.4,13.6；HRMS(ESI):m/z理论值C45H70O15Na[M+Na]+873.4607，实测值873.4610。
化合物4-12的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.49(s,1H),6.06(q,J＝7.6Hz,1H),5.75(s,1H),5.40–5.23(m,2H),5.23–5.09(m,2H),5.05(d,J＝7.9Hz,1H),4.65–4.55(m,2H),4.35(dd,J＝12.4,4.7Hz,1H),4.17(dd,J＝12.4,2.4Hz,1H),4.02(dd,J＝9.0,4.3Hz,1H),3.88–3.74(m,4H),2.76(dd,J＝14.7,4.3Hz,1H),2.44(dd,J＝14.6,9.0Hz,1H),2.19–2.02(m,14H),1.78(dd,J＝7.0,1.5Hz,6H),1.59(s,1H),1.45(s,2H),1.30(m,18H),0.89(m14H)；13C NMR(100MHz,CDCl3)δ:171.2,170.6,170.2,169.4,169.1,166.8,153.0,142.7,128.1,124.8,117.9,108.8,97.1,93.7,72.5,72.2,70.7,68.2,61.7,61.6,51.5,40.0,39.9,39.4,37.4,37.3,37.2,37.1,32.5,32.1,30.2,28.0,24.6,24.3,22.8,22.7,22.6,20.2,20.0,16.4,13.6；HR-MS(ESI):m/z理论值C43H66O15[M+Na]+845.4294，实测值845.4299。
化合物4-13的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.46(s,1H),6.01(q,J＝7.3Hz,1H),5.72(s,1H),5.27(t,J＝9.4Hz,1H),5.13(t,J＝9.8Hz,2H),5.03(d,J＝7.9Hz,1H),4.32(dd,J＝12.4,4.8Hz,1H),4.14–3.95(m,4H),3.80–3.69(m,4H),2.72(dd,J＝14.7,4.3Hz,1H),2.41(ddd,J＝14.7,8.8,2.1Hz,1H),2.11–2.01(m,12H),1.75(dd,J＝7.1,1.5Hz,3H),1.53(d,J＝6.6Hz,4H),1.15(d,J＝2.1Hz,6H),0.87–0.86(m,9H)；13C NMR(100MHz,CDCl3)δ:171.3,170.6,170.2,169.4,169.4,166.8,153.0,128.2,124.8,108.8,97.1,93.7,72.5,72.2,70.7,68.2,63.3,61.8,51.5,40.0,39.2,37.1,35.5,30.2,30.1,29.4,24.5,22.7,22.6,20.7,20.7,20.6,20.6,19.7；HR-MS(ESI):m/z理论值C35H52O15Na[M+Na]+735.3199，实测值735.3202。
化合物4-14的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.44(s,1H),6.00(q,J＝7.4Hz,1H),5.70(s,1H),5.24(t,J＝9.6Hz,1H),5.11(t,J＝9.6Hz,2H),5.03(d,J＝7.8Hz,1H),4.32–3.92(m,5H),3.77–3.65(m,4H),2.73(dd,J＝14.2,4.4Hz,1H),2.54–2.32(m,1H),2.14–1.68(m,23H),1.57–0.86(m,31H)；13C NMR(100MHz,CDCl3)δ:171.6,170.5,170.1,169.4,169.3,166.9,152.8,128.1,124.8,108.8,97.1,93.7,72.4,72.0,70.6,68.1,63.3,61.6,51.4,40.1,39.2,37.0,35.3,29.8,29.6,29.2,24.5,22.7,22.6,20.7,20.6,19.5,19.1,17.8,16.5,16.4,14.7；HR-MS(ESI):m/z理论值C43H72O15Na[M+Na]+851.4762，实测值857.4749。
化合物5-1的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.44(s,1H),6.01(q,J＝7.1Hz,1H),5.73(s,1H),5.03(d,J＝8.6Hz,1H),4.92(d,J＝16.5Hz,2H),4.50(d,J＝13.1Hz,1H),4.34(d,J＝13.1Hz,1H),4.10(d,J＝11.9Hz,1H),3.79–3.72(m,4H),2.79(dd,J＝14.7,4.4Hz,1H),2.47(dd,J＝14.6,9.0Hz,1H),2.09(d,J＝1.5Hz,3H),2.03(dd,J＝4.1,1.4Hz,9H),1.74(d,J＝8.5Hz,6H)；13C NMR(100MHz,CDCl3)δ:171.8,165.8,153.2,138.7,128.0,125.0,113.1,108.6,97.7,93.2,72.4,71.4,70.2,67.7,67.1,62.8,51.4,39.9,30.2,13.5；HR-MS(ESI):m/z理论值C21H30O11Na[M+Na]+481.1681，实测值481.1686。
化合物5-2的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.06(q,J＝7.4Hz,1H),5.79(s,1H),5.30(t,J＝7.3Hz,1H),5.08(d,J＝6.5Hz,1H),4.84(d,J＝7.6Hz,1H),4.59–4.47(m,2H),3.99–3.80(m,3H),3.70(s,4H),3.57–3.42(m,3H),2.79(dd,J＝14.5,4.0Hz,1H),2.42–2.31(m,1H),2.05(dd,J＝15.1,6.8Hz,4H),1.72–1.65(m,9H),1.59(s,3H)；13C NMR(100MHz,CDCl3)δ:171.7,166.9,153.7,142.4,131.9,128.6,124.4,123.7,118.0,108.4,100.0,94.8,77.2,73.2,69.9,61.8,51.5,40.5,39.6,29.7,26.3,25.7,17.7,16.5,13.5；HR-MS(ESI):m/z理论值C27H40O11Na[M+Na]+563.2463，实测值563.2467。
化合物5-3的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.06(q,J＝7.4Hz,1H),5.79(s,1H),5.30(t,J＝7.3Hz,1H),5.08(d,J＝6.5Hz,1H),4.84(d,J＝7.6Hz,1H),4.59–4.47(m,2H),3.97–3.78(m,3H),3.76–3.67(m,4H),3.57–3.46(m,3H),2.77(dd,J＝14.5,4.0Hz,1H),2.42–2.31(m,1H),2.10–2.00(m,4H),1.72–1.65(m,9H),1.59(s,3H)；13C NMR(100MHz,CDCl3)δ:171.7,166.9,153.7,142.4,131.9,128.6,124.5,123.7,118.0,109.3 100.0,94.8,77.2,73.2,69.9,61.8,51.8,40.5,39.6,29.5,26.3,25.5,17.7,16.5,13.5；HR-MS(ESI):m/z理论值C27H40O11Na[M+Na]+563.2463，实测值563.2467。
化合物5-4的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.06(q,J＝7.0Hz,1H),5.79(s,1H),5.37–5.27(m,1H),5.13–5.04(m,2H),4.84(d,J＝7.6Hz,1H),4.60–4.46(m,2H),3.97(dd,J＝9.5,4.4Hz,1H),3.88(d,J＝11.4Hz,1H),3.83–3.75(m,1H),3.73–3.65(m,4H),3.64–3.51(m,3H),2.80(dd,J＝13.9,4.4Hz,1H),2.38(dd,J＝13.9,9.6Hz,1H),2.09–2.05(m,4H),2.03–1.95(m,4H),1.71(d,J＝6.2Hz,3H),1.68(s,6H),1.60(s,6H)；13C NMR(100MHz,CDCl3)δ:171.7,166.8,153.6,142.5,135.5,131.3,128.6,124.3,123.6,117.9,108.5,100.1,94.8,77.2,73.3,69.9,61.8,51.5,40.4,39.7,39.6,32.0,26.7,26.3,25.7,17.7,16.5,16.0,13.5；HR-MS(ESI):m/z理论值C32H48O11Na[M+Na]+631.3089，实测值631.3092。
化合物5-5的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.46(s,1H),7.38–7.25(m,5H),6.61(d,J＝15.7Hz,1H),6.29–6.18(m,1H),6.00(q,J＝7.2Hz,1H),5.69(s,1H),5.02(d,J＝7.8Hz,1H),4.74(dd,J＝12.9,6.5Hz,1H),4.63(dd,J＝12.8,6.5Hz,1H),4.27(dd,J＝11.7,4.8Hz,1H),4.08–4.00(m,3H),3.78–3.60(m,6H),2.78(dd,J＝14.5,3.9Hz,1H),2.46(dd,J＝14.4,9.0Hz,1H),2.12–1.99(m,12H),1.72(d,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)δ:170.3,166.5,153.2,136.4,134.4,128.6,128.1,127.7,126.8,124.7,123.0,108.7,97.2,93.8,72.6,72.2,70.4,68.2,65.1,61.6,51.4,39.8,30.2,13.6；HR-MS(ESI):m/z理论值C26H32O11Na[M+Na]+543.1837，实测值543.1840。
化合物5-6的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.48(s,1H),6.89–6.75(m,3H),6.05(q,J＝7.3Hz,1H),5.95(s,1H),5.90(s,1H),5.03(d,J＝12.0Hz,1H),4.91(d,J＝12.0Hz,1H),4.77(d,J＝7.7Hz,1H),3.98(dd,J＝9.0,4.6Hz,1H),3.88(d,J＝11.9Hz,1H),3.71(d,J＝3.9Hz,4H),3.69–3.60(m,2H),3.39(q,J＝8.9Hz,2H),2.71(dd,J＝13.6,4.6Hz,1H),2.54(dd,J＝13.9,9.1Hz,1H),1.64(d,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ:171.5,167.2,153.7,147.7,147.6,129.7,129.0,123.4,122.2,108.8,107.8,107.5,101.1,99.4,93.7,77.0,76.5,73.3,70.1,66.0,61.4,50.4,39.6,30.5,13.1；HR-MS(ESI):m/z理论值C25H30O13Na[M+Na]+561.1579，实测值567.1582。
化合物5-7的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.56(s,1H),7.00–6.81(m,3H),6.11(q,J＝7.1Hz,1H),5.85(s,1H),4.64(d,J＝4.4Hz,2H),4.18–4.00(m,3H),3.96–3.85(m,2H),3.78–3.55(m,9H),3.06–2.93(m,1H),2.88–2.75(m,1H),2.10–2.00(m,9H),1.95(s,3H),1.76(d,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ:170.3,153.3,151.0,140.1,138.9,128.0,125.2,122.1,118.8,110.7,108.3,97.4,94.4,72.5,72.2,70.4,68.1,65.0,62.3,55.7,51.5,38.9,30.0,13.7；HR-MS(ESI):m/z理论值C25H32O13Na[M+Na]+563.1736，实测值563.1739。
化合物5-8的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.46(s,1H),7.30(s,1H),7.21(d,J＝5.4Hz,1H),7.02–6.87(m,3H),6.01(q,J＝6.9Hz,1H),5.75–5.66(m,1H),5.29–5.20(m,1H),5.11–5.04(m,1H),4.33–4.22(m,2H),4.20–4.03(m,3H),4.00–3.86(m,3H),3.76–3.70(m,4H),2.75–2.68(m,1H),2.51–2.42(m,1H),2.07–2.01(m,12H),1.74(t,J＝7.0Hz,3H),1.32(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ:171.1,165.3,158.4,153.1,129.4,128.1,124.9,121.8,114.3,109.1,97.0,93.7,72.5,72.1,71.4,70.7,69.4,68.3,61.9,51.4,40.2,30.0,16.3,13.7；HR-MS(ESI):m/z理论值C26H34O12Na[M+Na]+561.1943，实测值561.1947。
化合物5-9的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.03(q,J＝7.1Hz,1H),5.78(s,1H),5.35(d,J＝5.2Hz,1H),4.82(d,J＝7.6Hz,1H),4.45–4.36(m,1H),3.95(dd,J＝9.1,4.4Hz,1H),3.86–3.68(m,4H),2.71(dd,J＝14.3,4.4Hz,1H),2.52(t,J＝8.9Hz,1H),2.40(dd,J＝14.5,9.2Hz,1H),2.27–2.14(m,8H),1.90–1.07(m,18H),1.00(s,3H),0.62(s,3H)；13C NMR(100MHz,CDCl3)δ:209.5,171.0,166.8,153.2,139.5,128.8,124.5,122.5,109.0,97.6,94.0,74.1,72.4,72.5,70.2,68.0,63.6,61.6,56.9,51.4,49.8,43.5,40.0,38.5,38.1,36.5,36.7,31.8,31.6,31.5,30.2,27.1,24.3,22.9,21.0,19.3,13.8,13.2；HR-MS(ESI):m/z理论值C38H54O12Na[M+Na]+725.3508，实测值725.3512。
化合物5-10的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.05(q,J＝7.1Hz,1H),5.78(s,1H),5.35(d,J＝4.9Hz,1H),4.82(d,J＝7.6Hz,1H),4.40(q,J＝7.4Hz,1H),3.95(dd,J＝9.2,4.4Hz,1H),3.86(d,J＝11.3Hz,1H),3.79–3.68(m,4H),3.63(d,J＝9.3Hz,1H),3.55–3.31(m,5H),2.71(d,J＝10.0Hz,1H),2.38(dd,J＝13.9,9.3Hz,1H),2.28(d,J＝8.3Hz,2H),1.98(dd,J＝12.9,5.8Hz,2H),1.83–1.62(m,14H),1.55–1.37(m,4H),1.25–1.00(m,9H),0.96(d,J＝6.8Hz,3H),0.78(d,J＝5.3Hz,6H)；13C NMR(100MHz,CDCl3)δ:171.0,166.8,153.5,139.5,128.8,124.2,122.5,109.2,108.5,100.0,94.8,80.8,77.2,74.5,73.2,69.9,66.8,62.1,61.8,56.4,51.4,49.8,41.6,40.6,40.2,39.7,38.0,36.8,36.7,32.0,31.8,31.4,30.5,30.3,29.7,28.8,27.6,20.8,19.3,17.1,16.3,14.5,13.6；HR-MS(ESI):m/z理论值C44H64O13Na[M+Na]+823.4240，实测值823.4244。
化合物5-11的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.06(q,J＝7.0Hz,1H),5.79(s,1H),5.23–5.09(m,1H),5.04(d,J＝7.8Hz,1H),4.61–4.46(m,2H),4.00–3.75(m,6H),3.83–3.75(m,8H),2.80(dd,J＝13.9,4.5Hz,1H),2.48(dd,J＝13.9,9.5Hz,1H),2.19–2.00(m,2H),1.78–0.79(m,37H)；13C NMR(100MHz,CDCl3)δ:171.7,166.8,153.6,142.5,135.5,131.3,128.6,124.3,123.6,117.9,108.8,97.2,93.6,72.5,72.1,70.7,68.2,61.7,51.5,40.4,38.7,37.6,32.8,32.7,30.2,28.0,24.8,24.5,22.7,22.6,22.6,16.0,13.5；HR-MS(ESI):m/z理论值C37H62O11Na[M+Na]+705.4185，实测值705.4190。
化合物5-12的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),6.06(q,J＝7.0Hz,1H),5.74(s,1H),5.13–5.04(m,1H),5.01(d,J＝7.7Hz,1H),4.60–4.41(m,2H),4.21–4.01(m,3H),3.83–3.71(m,7H),2.78(dd,J＝14.0,4.4Hz,1H),2.31(dd,J＝13.7,9.1Hz,1H),2.09–0.80(m,27H)；13C NMR(100MHz,CDCl3)δ:171.7,166.8,153.6,142.5,135.5,131.3,128.6,124.8,118.0,108.4,97.3,93.5,72.3,73.3,69.9,61.8,51.5,40.4,39.7,39.6,32.0,26.7,26.3,25.7,17.7,16.5,16.0,13.5；HR-MS(ESI):m/z理论值C35H58O11Na[M+Na]+677.3872，实测值677.3876。
化合物5-13的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.47(s,1H),5.79(s,1H),5.06(d,J＝6.5Hz,1H),4.84(d,J＝7.6Hz,1H),4.62–4.49(m,2H),3.99–3.85(m,3H),3.70(s,4H),3.59–3.45(m,3H),2.79(dd,J＝14.5,4.0Hz,1H),2.42–2.35(m,3H),2.11–2.05(m,6H),1.74–1.63(m,9H),1.59(s,3H)；13C NMR(100MHz,CDCl3)δ:171.7,166.9,153.7,142.4,131.9,128.6,124.4,123.7,108.5,97.6,93.7,77.2,73.2,69.9,61.8,51.5,40.5,39.6,29.7,26.3,25.7,24.2,17.7,16.5,13.5；HR-MS(ESI):m/z理论值C24H44O11Na[M+Na]+567.2776，实测值567.2782。
化合物5-14的结构表征数据为：1H NMR(400MHz,CDCl3)δ:7.45(s,1H),6.01(q,J＝7.4Hz,1H),5.74(s,1H),5.03(d,J＝7.4Hz,1H),4.41–3.95(m,2H),3.82–3.62(m,7H),2.79–2.30(m,2H),2.15–1.60(m,11H),1.57–0.86(m,31H)；13C NMR(100MHz,CDCl3)δ:171.6,170.5,170.1,169.4,169.3,166.9,152.8,128.1,124.8,108.8,97.1,93.7,72.4,72.0,70.6,68.1,63.3,61.6,51.4,40.1,39.2,37.0,35.3,29.8,29.6,29.2,24.5,22.7,22.6,20.7,20.6,20.5,19.5,19.3,19.2,17.8,16.7,16.5,14.7；HR-MS(ESI):m/z理论值C32H64O11Na[M+Na]+647.4348，实测值647.4339。
实施例2
本发明木樨榄苷类化合物在制备抗肿瘤药物中的应用
分别将上述化合物4-1～4-13及化合物5-1～5-13作为受试化合物，测试其对A549、HGC27、HepG2、A498、RAW、THP-1、Raji细胞毒性。
贴壁细胞(A549、HGC27、HepG2、A498、RAW)以CCK-8试剂盒检测，具体实验步骤为：取培养各细胞，消化并调整细胞浓度至4*104细胞/mL浓度，以100μL/孔分别接种于96孔板，将培养板放在培养箱(37℃，5％ CO2)中预培养4h。向每个细胞系分别加入终浓度为5μM的受试化合物，等体积的DMSO作为阴性对照，37℃、5％ CO2条件下培养48h。弃去各孔上清，每孔加入100μL溶液(10％CCK-8溶液+90％培养基)，细胞培养箱内继续孵育1h。酶标仪测定450nm吸光度，计算各样品各细胞系活率，计算公式为：细胞存活率＝[(As-Ab)/(Ac-Ab)]×100％，As为实验孔(含有细胞的培养基、CCK-8、待测药物)的吸光度，Ac为对照孔(含有细胞的培养基、CCK-8、没有待测药物)的吸光度，Ab为空白孔(不含细胞和待测药物的培养基、CCK-8)的吸光度。
悬浮细胞(THP-1、Raji)以乳酸脱氢酶细胞毒性检测试剂盒检测，具体实验步骤为：取培养各细胞，消化并调整细胞浓度至4*104细胞/mL浓度，以150μL/孔分别接种于96孔板，将培养板放在培养箱(37℃，5％ CO2)中预培养4h。向每个细胞系分别加入终浓度为5μM的受试化合物，等体积的DMSO作为阴性对照，37℃、5％ CO2条件下培养48h。在“样品最大酶活性对照孔”中加入原有培养液体积10％的LDH释放试剂，继续在细胞培养箱中孵育1h。将细胞培养板用多孔板离心机400g离心5min，分别取各孔的上清液100μL，加入到一新的96孔板相应孔中。各孔分别加入60μL LDH检测工作液，混匀并室温(约25℃)避光孵育30min，在490nm处测定吸光度。细胞存活率(％)＝1-(处理样品吸光度－样品对照孔吸光度)/(细胞最大酶活性的吸光度－样品对照孔吸光度)×100。
抑制率试验结果见表2。
表2受试化合物细胞毒活性
Figure SMS_7
Figure SMS_8
由表2的活性结果可见，本发明的木樨榄苷类化合物对A549、HGC27、HepG2、A498、RAW、THP-1、Raji细胞表现出了很好的抑制活性可用于制备抗肿瘤的药物。

Claims (3)

1.木樨榄苷类化合物，其特征在于所述化合物的结构式如下所示：
Figure FDA0004117364730000011
其中，R1选自2-甲基烯丙基、肉桂醇基、胡椒醇基、香草醇基、1-苯氧基-2-丙醇基、孕烯醇酮基、薯蓣皂苷元基、植物醇基、油醇基、C5nH8n+1O、CmH2m+1O中任意一种，其中n＝1～5的整数，m＝15～30的整数；R2选自氢或乙酰基。
2.根据权利要求1所述的木樨榄苷类化合物，其特征在于：所述R1选自香叶醇基、橙花醇基、金合欢醇基、肉桂醇基、1-苯氧基-2-丙醇基、孕烯醇酮基、薯蓣皂苷元基、植物醇基、油醇基、四氢香叶醇基、硬脂醇基中任意一种，R2选自氢。
3.权利要求1的木樨榄苷类化合物在制备抗肿瘤药物中的应用。
CN202310222751.7A 2023-03-09 2023-03-09 木樨榄苷类化合物及其在制备抗肿瘤药物中的应用 Pending CN116217642A (zh)

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