CN111171011B - 一种山荷叶素杂环衍生物及其制备方法和应用 - Google Patents
一种山荷叶素杂环衍生物及其制备方法和应用 Download PDFInfo
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Abstract
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杂环衍生物及其制备方法和应用。
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的木糖糖苷Cleistanthin-A和喹诺糖苷PatentiflorinA都具有较强的抗肿瘤活性。但是糖苷类化合物的化学合成较为复杂,并且糖苷键的代谢稳定性不好,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杂环衍生物,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。
本发明提供了一种山荷叶素杂环衍生物,该山荷叶素杂环衍生物具有式(I)所示结构:
其中,n表示直链亚烷基的碳原子数,n=2-8,R表示吗啉基、N-氨基吗啉基、羟乙基哌嗪基、N-甲基哌嗪基、哌啶基、4-羟基哌啶基、3-羟基哌啶基、4-哌啶基哌啶基、四氢吡咯基或咪唑基。
进一步的,所述山荷叶素杂环衍生物具有如式2a~2f中任意一项所示的结构:
其中,
n为2,R为N-甲基哌嗪基、4-羟基哌啶基时,该山荷叶素杂环衍生物为式2a和2b所示结构的化合物;
化合物2a:4-O-[2’-(N-甲基哌嗪基)-乙基]-山荷叶素
化合物2b:4-O-[2’-(4”-羟基哌啶基)-乙基]-山荷叶素
n为4,R为吗啉基、N-甲基哌嗪基时,该山荷叶素杂环衍生物为式2c和2d所示结构的化合物;
化合物2c:4-O-[4’-(吗啉基)-正丁基]-山荷叶素
化合物2d:4-O-[4’-(N-甲基哌嗪基)-正丁基]-山荷叶素
n为7,R为4-羟乙基哌嗪基、4-羟基哌啶基时,该山荷叶素杂环衍生物为式2e和2f所示结构的化合物:
化合物2e:4-O-[7’-(4”-羟乙基哌嗪基)-正庚基]-山荷叶素
化合物2f:4-O-[7’-(4”-羟基哌啶基)-正庚基]-山荷叶素
本发明还提供了一种山荷叶素杂环衍生物的制备方法,包括以下步骤:
由山荷叶素与无水碳酸钾、相应的二溴烷烃在N,N’-二甲基甲酰胺中反应得到溴代烷基山荷叶素,然后再与无水碳酸钾、相应的杂环在N,N’-二甲基甲酰胺中反应而得到,
其中,所述反应的反应式为:
其中,n=2-8,
R表示4-羟基哌啶基、N-甲基哌嗪基、羟乙基哌嗪基、吗啉基、哌啶基或咪唑基。
本发明还提供了一种上述的山荷叶素杂环衍生物在制备防治食管癌、胃癌、胶质瘤、卵巢癌、结肠癌、肺癌、肝癌、子宫颈癌及肝癌的药物中的应用。
与现有技术相比,本发明中提供的具有非糖苷结构的山荷叶素杂环衍生物,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。并且通过体外肿瘤细胞增殖抑制实验发现此类化合物具有较强的肿瘤细胞增殖抑制活性,与阳性对照药紫杉醇相当或优于紫杉醇,可应用于防治食管癌、胃癌、胶质瘤、卵巢癌、结肠癌、肺癌、肝癌、子宫颈癌及肝癌的药物的制备。
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1提供的4-O-[2’-(N-甲基哌嗪基)-乙基]-山荷叶素(2a)的核磁共振1H谱图;
图2为本发明实施例1提供的4-O-[2’-(N-甲基哌嗪基)-乙基]-山荷叶素(2a)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114mg(0.3mmol)的山荷叶素溶于3mL的DMF中,加入282mg(1.5mmol)的1,2-二溴乙烷和248mg(1.8mmol)的无水碳酸钾,室温反应6h。TLC检测反应结束,加入30mL的乙酸乙酯稀释,然后依次水洗、饱和食盐水洗,MgSO4干燥,减压干燥,柱层析(prtroleum ether:EtOAc=3:1,Rf=0.3)得到淡黄色固体100mg。将该固体溶于3ml的DMF中,加入200mg(2mmol)的N-甲基哌嗪和552mg(4mmol)的无水碳酸钾,120℃反应2h,TLC监测反应结束,加入20ml的乙酸乙酯稀释,然后依次水洗、饱和食盐水洗,MgSO4干燥,减压干燥,柱层析(DCM:MeOH=30:1,Rf=0.2)得到淡黄色固体4-O-[2’-(N-甲基哌嗪基)-乙基]-山荷叶素(2a)83mg(两步产率55%)。
对4-O-[2’-(N-甲基哌嗪基)-乙基]-山荷叶素(2a)进行核磁共振检测,请参阅图1和图2,结果为:1HNMR(400MHz,CDCl3)δ:7.58(s,1H,ArH),7.06(s,1H,ArH),6.96(d,J=7.9Hz,1H,ArH),6.80(m,2H,ArH),6.07(dd,J=18.6,1.4Hz,2H,OCH2O),5.50(s,2H,ArCH2O),4.35(t,J=5.5Hz,2H,OCH2),4.07(s,3H,OCH3),3.81(s,3H,OCH3),2.91(t,J=5.6Hz,2H,NCH2),2.67(s,4H,NCH2),2.50(s,4H,NCH2),2.31(s,3H,NCH3).13C NMR(100MHz,CDCl3)δ:169.7,151.5,150.2,147.5,147.4,146.9,134.6,130.6,128.4,126.4,125.8,123.6,119.2,110.7,108.2,106.1,101.2,100.7,70.4,66.7,58.1,56.1,55.8,55.0,53.7,46.0.HRMS(ESI):m/z calcdfor C28H31O7N2:507.2129;found:507.2126[M+H]+。
实施例2-5
根据以上实施例1的方法制备实施例化合物。
下面列出是2b-2f各化合物的理化数据:
2b:1H NMR(400MHz,CDCl3)δ:7.58(s,1H,ArH),7.06(s,1H,ArH),6.96(d,J=7.9Hz,1H,ArH),6.80(m,2H,ArH),6.07(dd,J=18.0,1.3Hz,2H,OCH2O),5.50(s,2H,ArCH2O),4.33(t,J=5.6Hz,2H,OCH2),4.07(s,3H,OCH3),3.81(s,3H,OCH3),3.76(m,1H,CH),2.93(m,2H,NCH2),2.90(t,J=5.7Hz,2H,NCH2),2.36(m,2H,NCH2),1.95(m,2H,CH2),1.64(m,2H,CH2);13C NMR(100MHz,CDCl3)δ:169.7,151.5,150.2,147.5,147.4,146.9,134.7,130.6,128.4,126.5,125.9,123.6,119.2,110.7,108.2,106.1,101.2,100.6,70.6,66.7,58.0,56.1,55.8,51.7,34.4.HRMS(ESI):m/z calcdfor C28H3O8N:508.1969;found:508.1966[M+H]+.
2c:1HNMR(400MHz,Chloroform-d)δ:7.55(s,1H,ArH),7.06(s,1H,ArH),6.96(d,J=7.9Hz,1H,ArH),6.80(m,2H,ArH),6.07(d,J=18.0Hz,2H,OCH2O),5.49(s,2H,ArCH2O),4.25(t,J=6.4Hz,2H,OCH2),4.06(s,3H,OCH3),3.81(s,3H,OCH3),3.72(m,4H,OCH2),2.46(t,J=7.3Hz,6H,NCH2),1.97(m,2H,CH2),1.81(m,2H,CH2);13C NMR(100MHz,CDCl3)δ:169.7,151.5,150.3,147.5,147.4,147.0,134.4,130.7,128.5,126.4,125.3,123.6,119.3,110.8,108.2,106.2,101.2,100.6,72.3,67.0,66.7,58.5,56.0,55.8,53.8,28.3,23.2.HRMS(ESI):m/z calcd for C29H32NO8:522.2083;found:522.2050[M+H]+.
2d:1H NMR(400MHz,Chloroform-d)δ:7.55(s,1H,ArH),7.06(s,1H,ArH),6.96(d,J=7.9Hz,1H,ArH),6.81(m,2H,ArH),6.08(dd,J=19.0,1.4Hz,2H,OCH2O),5.49(s,2H,ArCH2O),4.25(t,J=6.4Hz,2H,OCH2),4.06(s,3H,OCH3),3.81(s,3H,OCH3),3.00–2.36(m,10H,NCH2),2.30(s,3H,NCH3),1.96(m,2H,CH2),1.80(m,2H,CH2);13C NMR(100MHz,CDCl3)δ:169.7,151.5,150.3,147.5,147.4,147.0,134.4,130.7,128.5,126.4,125.3,123.6,119.3,110.8,108.2,106.2,101.2,100.6,72.4,66.7,58.1,56.0,55.8,55.1,53.2,46.0,28.4,23.5.HRMS(ESI):m/z calcd for C30H35N2O7:535.2434;found:535.2428[M+H]+.
2e:1H NMR(400MHz,CDCl3)δ:7.56(s,1H,ArH),7.06(s,1H,ArH),6.96(d,J=7.9Hz,1H,ArH),6.81(m,2H,ArH),6.07(d,J=18.6Hz,2H,OCH2O),5.48(s,2H,ArCH2O),4.22(t,J=6.4Hz,2H,OCH2),4.06(s,3H,OCH3),3.81(s,3H,OCH3),3.62(t,J=5.4Hz,2H,OCH2),2.53(m,10H,NCH2),2.33(t,J=7.6Hz,2H,NCH2),1.92(m,2H,CH2),1.63(m,2H,CH2),1.54(m,2H,CH2),1.46(m,2H,CH2),1.38(m,2H,CH2);13CNMR(100MHz,CDCl3)δ:169.7,151.4,150.2,147.5,147.4,147.0,134.3,130.6,128.5,126.4,125.4,123.6,119.3,110.8,108.2,106.1,101.2,100.6,72.6,66.7,59.3,58.7,57.7,56.0,55.8,53.3,52.8,30.3,29.4,27.6,26.9,26.1.HRMS(ESI):m/z calcd for C34H43N2O8:607.3009;found:607.3002[M+H]+.
2f:1H NMR(400MHz,CDCl3)δ:7.56(s,1H,ArH),7.06(s,1H,ArH),6.95(d,J=7.9Hz,1H,ArH),6.80(m,2H,ArH),6.07(d,J=18.4Hz,2H,OCH2O),5.48(s,2H ArCH2O),4.21(t,J=6.4Hz,2H,OCH2),4.06(s,3H,OCH3),3.81(s,3H,OCH3),3.70(m,1H,CH),2.78(m,2H,NCH2),2.32(t,J=7.6Hz,2H,NCH2),2.12(m,2H,NCH2),1.90(m,4H,CH2),1.59(m,4H,CH2),1.52(m,2H,CH2),1.43(m,2H,CH2),1.37(m,2H,CH2);13C NMR(100MHz,CDCl3)δ:169.7,151.4,150.2,147.4,147.4,147.0,134.3,130.6,128.5,126.4,125.4,123.6,119.2,110.8,108.2,106.1,101.2,100.6,72.6,66.7,58.6,56.0,55.8,51.2,34.4,30.3,29.4,27.6,27.1,26.1.HRMS(ESI):m/z calcd for C33H40NO8:578.2747;found:578.2745[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杂环衍生物对八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2a~2f和紫杉醇对人食管癌细胞(TE-13)细胞毒活性测试
人食管癌细胞TE-13用RPMI1640培养基培养,培养基中含有10%的胎牛血清,100U/mL青霉素和100U/mL的链霉素。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2a~2f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2a的IC50为3×10-7M,而阳性对照紫杉醇对TE-13细胞的IC50为4×10-7M。
药物实验例2-8:化合物2a~2f和紫杉醇对人卵巢腺癌细胞(SK-OV-3),人胶质瘤细胞(U251),人胃癌细胞(MGC803),人结肠癌细胞(HCT-116),人肺腺癌细胞(A549),人子宫颈癌细胞(Hela),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,对人卵巢腺癌细胞(SK-OV-3),人胶质瘤细胞(U251),人胃癌细胞(MGC803),人结肠癌细胞(HCT-116),人肺腺癌细胞(A549),人子宫颈癌细胞(Hela),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2a~2f和紫杉醇的细胞毒活性测试结果
根据表1可知,本发明提供的山荷叶素杂环衍生物具有重要的生物活性,体外对人卵巢腺癌细胞(SK-OV-3),人胶质瘤细胞(U251),人胃癌细胞(MGC803),人食管癌细胞(TE-13),人结肠癌细胞(HCT-116),人肺腺癌细胞(A549),人子宫颈癌细胞(Hela),人肝癌细胞(HepG2)共八种肿瘤细胞的细胞毒活性试验表明:此类式(1)所示结构的山荷叶素杂环衍生物对肿瘤细胞生长具有抑制作用,有可能发展成为新的防治肿瘤药物。从以上药理实施例中我们可以看出这些化合物对这八种肿瘤细胞都显示了较强的细胞毒活性,细胞毒活性超过或与阳性对照紫杉醇相当,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 (4)
4.权利要求1或2所述的山荷叶素杂环衍生物在制备防治食管癌、胃癌、胶质瘤、卵巢癌、结肠癌、肺癌、子宫颈癌及肝癌的药物中的应用。
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