CN115057851B - 一种山荷叶素5-取代三唑衍生物在制备抗肿瘤药物中的应用 - Google Patents
一种山荷叶素5-取代三唑衍生物在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明属于药物化学和药理学技术领域,公开了一种山荷叶素5‑取代三唑衍生物在制备抗肿瘤药物中的应用,该山荷叶素5‑取代三唑衍生物具有式(I)所示化学结构式,由山荷叶素与无水碳酸钾、环氧溴丙烷在N,N‑二甲基甲酰胺中反应得到山荷叶素环氧中间体1,然后山荷叶素环氧中间体1与叠氮钠在N,N‑二甲基甲酰胺中反应而得到山荷叶素叠氮中间体2,然后山荷叶素叠氮中间体2与炔类化合物、环戊二烯双(三苯基磷)氯化钌在二氧六环中进行反应得到山荷叶素5‑取代三唑衍生物3。本发明得到的山荷叶素5‑取代三唑衍生物具有较强的抗肿瘤活性,可用于制备抗肿瘤药物。
Description
技术领域
本发明属于药物化学和药理学技术领域,具体涉及一种山荷叶素5-取代三唑衍生物在制备抗肿瘤药物中的应用。
背景技术
随着医学的进步,一般性的传染病逐渐被控制,恶性肿瘤―癌症成为常见并且严重威胁人类生命和生活质量的主要疾病之一。植物来源的抗肿瘤药物在临床治疗中占有重要的地位。近些年研究发现天然木脂素山荷叶素糖苷,如Cleistanthin-A和PatentiflorinA等都具有较强的抗肿瘤活性。但是这些天然山荷叶素糖苷在自然界中的含量并不丰富,并且化学合成较为复杂,且糖苷键在人体内的代谢稳定性不好,容易被内源性的糖苷酶水解失活。
发明内容
有鉴于此,本发明的目的在于提供一种非糖苷结构的山荷叶素5-取代三唑衍生物,该此类化合物结构中不含有容易在体内水解的糖苷键,代谢稳定性优于糖苷类化合物,并且具有较强的肿瘤细胞增殖抑制活性,可用于制备抗肿瘤药物。
本发明提供了一种具有式(I)所示结构的山荷叶素5-取代三唑衍生物在制备抗肿瘤药物中的应用,
其中,R表示苯基、对甲基苯基、对甲氧基苯基、对氯苯基、苯乙基、苯氧甲基和环丙基中的一种。
进一步的,所述山荷叶素5-取代三唑衍生物具有如式3a~3d中任意一项所示的结构:
其中,
R为苯基时,该山荷叶素5-取代三唑衍生物为式3a所示结构的化合物;
R为对甲基苯基时,该山荷叶素5-取代三唑衍生物为式3b所示结构的化合物;
R为苯氧甲基时,该山荷叶素5-取代三唑衍生物为式3c所示结构的化合物;
R为环丙基时,该山荷叶素5-取代三唑衍生物为式3d所示结构的化合物;
本发明还提供了一种山荷叶素5-取代三唑衍生物的制备方法,包括以下步骤:
由山荷叶素与无水碳酸钾、环氧溴丙烷在N,N-二甲基甲酰胺中反应得到山荷叶素环氧中间体1,然后山荷叶素环氧中间体1与叠氮钠、氯化铵在N,N-二甲基甲酰胺中反应而得到山荷叶素叠氮中间体2,然后山荷叶素叠氮中间体2与炔类化合物、环戊二烯双(三苯基磷)氯化钌在二氧六环中进行反应得到山荷叶素5-取代三唑衍生物3。
其中,所述反应的反应式为:
其中,R表示苯基、对甲基苯基、对甲氧基苯基、对氯苯基、苯乙基、苯氧甲基和环丙基中的一种。
具体的,该制备方法包括以下步骤:
(1)将山荷叶素溶于N,N-二甲基甲酰胺中,加入环氧溴丙烷和无水碳酸钾进行反应,得第一反应液,将所述第一反应液冷却后,减压浓缩,用有机溶剂稀释,依次经过水洗,饱和食盐水洗,MgSO4干燥,减压干燥,然后柱层析得到白色固体,所述白色固体为山荷叶素环氧中间体1,其中,山荷叶素、环氧溴丙烷、无水碳酸钾的摩尔比为1:5:6;
(2)将所述白色固体溶于N,N-二甲基甲酰胺,加入叠氮钠和氯化铵进行反应,得第二反应液,将所述第二反应液冷却后,减压浓缩,用有机溶剂稀释,依次经过水洗,饱和食盐水洗,MgSO4干燥,减压干燥,然后柱层析得到白色固体,所述白色固体为山荷叶素叠氮中间体2,其中,山荷叶素环氧中间体1、叠氮钠、氯化铵的摩尔比为1:3:2;
(3)将所述白色固体溶于二氧六环中,加入环戊二烯双(三苯基磷)氯化钌和炔进行反应,得第三反应液,将所述第三反应液减压浓缩,用有机溶剂稀释,依次经过水洗,饱和食盐水洗,MgSO4干燥,减压干燥,然后柱层析得到白色固体,所述白色固体为山荷叶素5-取代三唑3,其中,山荷叶素叠氮中间体2、环戊二烯双(三苯基磷)氯化钌、炔的摩尔比为1:0.05:2;
其中,所述炔为苯乙炔、对甲基苯乙炔、对甲氧基苯乙炔、对氯苯乙炔、4-苯基-1-丁炔、苯基炔丙醚和环丙乙炔中的一种。
进一步的,上述制备方法的步骤(1)中,反应温度为60℃,反应时间为2h。
进一步的,上述制备方法的步骤(2)中,反应温度为70℃,反应时间为12h。
进一步的,上述制备方法的步骤(3)中,反应温度为70℃,反应时间为36h。
进一步的,上述制备方法中,所述有机溶剂为乙酸乙酯、乙醚和苯中的至少一种。
进一步的,所述肿瘤为结肠癌、乳腺癌和肝癌中的一种。
与现有技术相比,本申请提供了一类新的化合物山荷叶素5-取代三唑衍生物及其制备方法,该化合物的结构不含有容易在体内水解的糖苷键,代谢稳定性优于糖苷类化合物,并且具有较强的肿瘤细胞增殖抑制活性,能明显提高对肿瘤细胞的增殖抑制作用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为本发明实施例3提供的山荷叶素5-取代三唑衍生物(3a)的核磁共振1H谱图;
图2为本发明实施例3提供的山荷叶素5-取代三唑衍生物(3a)的核磁共振13C谱图;
图3为本发明实施例4提供的山荷叶素5-取代三唑衍生物(3d)的核磁共振1H谱图;
图4为本发明实施例4提供的山荷叶素5-取代三唑衍生物(3d)的核磁共振13C谱图;
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
将190mg(0.5mmol)的山荷叶素、343mg环氧溴丙烷(2.5mmol)、414mg无水碳酸钾(3mmol)溶于N,N-二甲基甲酰胺(5ml),60℃反应2小时。反应液减压浓缩,然后加入乙酸乙酯(15ml)稀释,然后依次水洗、饱和食盐水洗,MgSO4干燥,减压干燥,柱层析(石油醚:乙酸乙酯=1:1)得到174mg白色固体,即山荷叶素环氧中间体1(产率=80%)。
1H NMR(400MHz,CDCl3)δ:7.62(s,1H,ArH),7.07(s,1H,ArH),6.95(d,J=7.8Hz,1H,ArH),6.76(m,2H,ArH),6.07(dd,J=18.6,1.2Hz,2H,OCH2O),5.47(s,2H,ArCH2O),4.55(dd,J=11.2,1H,OCH2),4.09(s,3H,OCH3),4.03(dd,J=11.2,6.4Hz,1H,OCH2),3.81(s,3H,OCH3),3.47–3.45(m,1H,CH),2.98(t,J=4.5Hz,1H,OCH2),2.83(dd,J=4.8,2.6Hz,1H,OCH2);13C NMR(100MHz,CDCl3)δ:169.6,151.8,150.3,147.5,147.5,146.5,135.5,130.8,128.3,127.4,126.8,123.6,119.1,110.7,108.2,106.3,101.3,100.5,73.7,66.4,56.2,55.9,50.5,44.4;HRMS(ESI):m/z calcd for C24H20O8:437.1192;found:437.1186[M+H]+
实施例2
将750mg(1.72mmol)山荷叶素环氧中间体1溶于N,N-二甲基甲酰胺(20ml)与水(5ml)的混合溶液中,然后加入335mg(5.16mmol)叠氮钠与182mg(3.44mmol)氯化铵,70℃反应12小时。反应液减压浓缩,然后加入乙酸乙酯(15ml)稀释,然后依次水洗、饱和食盐水洗,MgSO4干燥,减压干燥,柱层析(石油醚:乙酸乙酯=1:1)得到600mg白色固体,即山荷叶素叠氮中间体2(73%)
1H NMR(400MHz,CDCl3)δ7.58(s,1H,ArH),7.06(s,1H,ArH),6.93(d,J=7.8Hz,1H,ArH),6.81-6.71(m,2H,ArH),6.05(dd,J=19.6,1.4Hz,2H,OCH2O),5.44(s,2H,COOCH2),4.28(p,J=5.2Hz,1H,HOCH),4.21(d,J=4.6Hz,2H,OCH2),4.06(s,3H,OCH3),3.80(s,3H,OCH3),3.64(qd,J=12.6,5.3Hz,2H,N3CH2).13C NMR(100MHz,CDCl3)δ169.8,151.9,150.4,147.5,146.3,135.5,130.8,128.2,127.1,126.6,123.6,119.1,110.7,108.2,106.3,101.3,100.3,73.7,69.7,66.4,56.2,55.9,53.3.HRMS(ESI):m/z calcd for C24H21N3O8:480.1407;found:480.1411[M+H]+.
实施例3
将95mg(0.2mmol)山荷叶素叠氮中间体2溶于2ml二氧六环中,依次加入7mg(0.01mmol)环戊二烯双(三苯基磷)氯化钌、40mg(0.4mmol)苯乙炔,70℃反应36小时。反应液减压浓缩,柱层析(二氯甲烷:乙酸乙酯=5:1)得到64mg白色固体,即山荷叶素5-取代三唑衍生物3a(产率55%)。
1H NMR(400MHz,CDCl3)δ7.71(s,1H,C=CH),7.56(s,1H,ArH),7.49(s,5H,ArH),7.05(s,1H,ArH),6.94(d,J=7.8Hz,1H,ArH),6.82-6.75(m,2H,ArH),6.06(d,J=20.1Hz,2H,OCH2O),5.41(m,2H,COOCH2),4.72(m,1H,NCH2),4.70-4.58(m,2H),4.30(m,2H),4.15(s,1H,OH),3.98(s,3H,OCH3),3.80(s,3H,OCH3).13C NMR(100MHz,CDCl3)δ169.6,151.8,150.3,147.5,146.3,139.3,135.3,132.9,130.7,129.9,129.3,129.1,128.2,126.5,126.4,123.6,119.1,110.7,108.2,106.2,101.3,100.4,76.7,73.7,69.6,66.4,56.2,55.8,50.6.HRMS(ESI):m/z calcd for C32H27N3O8:582.7816;found:582.7819[M+H]+.
实施例4-6
根据以上实施例3的方法制备实施例化合物。
下面列出是3b-3d各化合物的理化数据:
3b:产率58%,1H NMR(400MHz,CDCl3)δ7.67(s,1H,C=CH),7.56(s,1H,ArH),7.36(d,J=8.1Hz,2H,ArH),7.29(m,1H,ArH),7.06(s,1H,ArH),6.94(d,J=7.8Hz,1H,ArH),6.83-6.74(m,3H,ArH),6.07(d,J=19.3Hz,2H,OCH2O),5.40(m,2H,COOCH2),4.76-4.68(m,1H,CHOH),4.66(m,2H,NCH2),4.34-4.23(m,2H,CH2OAr),4.15(s,1H,OH),3.98(s,3H,OCH3),3.80(s,3H,OCH3),2.40(s,3H,ArCH3).13C NMR(100MHz,CDCl3)δ169.6,151.8,150.3,147.5,147.5,146.3,140.1,139.2,135.3,132.8,130.7,129.9,128.9,128.3,126.4,126.4,123.6,123.4,119.1,110.7,108.2,106.2,101.3,100.4,73.6,69.6,66.4,56.1,55.8,50.5,21.4.HRMS(ESI):m/z calcd for C33H29N3O8:596.2033;found:596.2037[M+H]+.
3c:产率55%,1H NMR(400MHz,CDCl3)δ7.69(s,1H,C=CH),7.63(s,1H,ArH),7.29(t,J=8.0Hz,2H,ArH),7.03(d,J=8.2Hz,2H,ArH),6.92(t,J=8.3Hz,3H,ArH),6.78-6.71(m,2H,ArH),6.04(d,J=23.1Hz,2H,OCH2O),5.40(s,2H,COOCH2),5.28-5.17(m,2H,ArOCH2),4.86-4.76(m,1H,CHOH),4.69(dd,J=12.3,5.1Hz,2H,NCH2),4.27(qd,J=9.8,4.4Hz,2H,CH2OAr),4.11(d,J=3.8Hz,1H,OH),4.00(s,3H,OCH3),3.79(s,3H,OCH3).HRMS(ESI):m/z calcd for C33H29N3O9:612.1982;found:612.1985[M+H]+.
3d:产率52%,1H NMR(400MHz,CDCl3)δ7.68(s,1H,ArH),7.21(s,1H,C=CH),7.04(s,1H,ArH),6.91(d,J=7.8Hz,1H,ArH),6.78-6.73(m,2H,ArH),6.04(d,J=22.0Hz,2H,OCH2O),5.46(m,2H,COOCH2),4.76-4.58(m,3H,CHOH,NCH2),4.43(s,1H,OH),4.31(dt,J=9.8,5.8Hz,2H,ArOCH2),4.05(s,3H,OCH3),3.79(s,3H,OCH3),1.89(tt,J=8.5,5.2Hz,1H,CHC=C),1.07(d,J=8.5Hz,2H,CH2CH2CHC=C),0.73(dd,J=14.3,5.0Hz,2H,CH2CH2CHC=C).HRMS(ESI):m/z calcd for C29H27N3O8:546.1876;found:546.1872[M+H]+.
为了更好地理解本发明的实质,下面分别用本发明提供的山荷叶素5-取代三唑衍生物对三种肿瘤细胞株的生长的抑制作用的药理实验结果,说明其在抗肿瘤药物研究领域中的新用途。药理实施例给出了代表性化合物的部分活性数据。必须说明,本发明的药理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。
药物实验例1:化合物3a-3d和紫杉醇对人结肠癌(HT-29)细胞毒活性测试
人结肠癌细胞HT-29用DMEM培养基培养。细胞以每孔5×103的浓度加入到96孔板中,在37℃含有5%CO2的潮湿空气的培养箱中培养24小时。
将化合物3a-3d溶于DMSO中,配制1×10-2mol/L的母液,用完全培养基将母液稀释到相应浓度取对数生长期细胞接种于96孔板,24h贴壁后加入不同浓度的化合物溶液,每个浓度设4个平行孔,培养68h后加入四甲基偶氮唑盐(MTT)溶液,继续培养4h,弃去培养液,加入二甲亚砜150μL,振荡10min,用酶标仪测定570nm吸收度(A)值,计算半数抑制浓度(IC50),具体如表1所示。根据表1可知,化合物3a的IC50为821nM,而阳性对照紫杉醇对HT-29细胞的IC50为11nM。
药物实验例2-3:化合物3a~3d和紫杉醇对人乳腺癌细胞(MCF-7),人肝癌细胞(HepG2)细胞毒活性测试。
采用药物实验例1所示方法,对人结肠癌(HT-29),人乳腺癌细胞(MCF-7),人肝癌细胞(HepG2)的生长抑制作用进行药理实验,计算半数抑制浓度(IC50),具体如表1所示。
表1化合物3a~3d和紫杉醇的细胞毒活性测试结果(IC50,nM)
化合物 | HT-29 | MCF-7 | HepG2 |
3a | 821 | 13 | 656 |
3b | 248 | 31 | 717 |
3c | 170 | 125 | 300 |
3d | 288 | 332 | 535 |
紫杉醇 | 11 | 1 | 23 |
根据表1可知,本发明提供的山荷叶素5-取代三唑衍生物具有重要的生物活性,体外对人结肠癌细胞(HT-29),人乳腺癌细胞(MCF-7),人肝癌细胞(HepG2)三种肿瘤细胞的细胞毒活性试验结果表明:这些化合物对这三种肿瘤细胞都显示了较强的细胞毒活性,细胞毒活性接近阳性对照紫杉醇,说明本发明提供的山荷叶素5-取代三唑衍生物对肿瘤细胞生长具有抑制作用,具有开发成抗肿瘤药物的潜力。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (3)
1.一种山荷叶素5-取代三唑衍生物在制备抗肿瘤药物中的应用,所述山荷叶素5-取代三唑衍生物的结构如下式所示:
其中,R表示苯基、对甲基苯基、对甲氧基苯基、对氯苯基、苯乙基、苯氧甲基和环丙基中的一种。
2.根据权利要求1所述的应用,其特征在于,所述山荷叶素5-取代三唑衍生物具有如式3a~3d中任意一项所示的结构:
3.根据权利要求1所述的应用,其特征在于,所述肿瘤为结肠癌、人乳腺癌和肝癌中的一种。
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