CN116063230B - 一类青藤碱1位取代衍生物及其制备方法和应用 - Google Patents
一类青藤碱1位取代衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物及化工的技术领域,公开了一类青藤碱1位取代衍生物及其制备方法和应用。本发明以青藤碱为先导化合物通过简单反应和较高收率制备得到的一类青藤碱1位引入不同酰胺取代基或芳环的衍生物,并且部分化合物对癌细胞表现出显著的抗增殖作用,所述化合物及其药学上可接受的盐在制备抗肿瘤药物具有较大潜力。
Description
技术领域
本发明属于药物与化工技术领域,更具体地,涉及青藤碱衍生物及其制备方法和应用。
背景技术
青藤碱是一种来自中草药青藤的吗啡类生物碱,由四环骨架组成,传统上,青藤在中国一直用于治疗关节炎患者。青藤碱还表现出广泛的生物活性,如抗肿瘤、抗心律失常、抗高血压、免疫抑制和抗炎作用。在中国、日本等亚洲国家用于治疗类风湿性关节炎,疗效好,剂型多样。在病理学研究中,青藤碱表现出抑制角叉菜胶、卵白蛋白、制霉菌素引起的大鼠足爪水肿、棉球肉芽肿形成、乙酸引发的血管通透性增加等病理过程,并且青藤碱及其衍生物已成为具有抗癌活性最重要的合成类似物之一。
酰胺键是生物活性分子的重要组成部分,其中包括多肽,蛋白,化学探针,各种临床批准及天然衍生的药物。酰胺键因其独特的结构和性质受到广泛关注。酰胺的氮原子为sp2杂化,孤对电子所在的p轨道和羰基形成p-π共轭,导致C-N键具有部分双键特征,整个酰胺键具有平面几何结构,与酰胺相连的基团之间可呈反式(trans)或顺式(cis)构象。酰胺官能团中的羰基和氨基,分别作为氢键受和氢键给体,可与靶蛋白形成各种氢键相互作用。酰胺键可作为药效团或连接基团,在药物设计和开发中的作用越来越突出。几种畅销药物都含有酰胺键,如利多卡因(lidocaine),扑热息痛(paracetamol),青霉素类(penicillins),阿托伐他汀(atorvastatin),氯霉素(chloramphenicol),吗氯贝胺(moclobemide),卡托普利(captopril),乙酰唑胺(acetazolamide),帕纳替尼(ponatinib),甲氨蝶呤(methotrexate,),曲美苄胺(trimethobenzamide)。
青藤碱1号位是一个化学反应的最佳活性位点、且化学空间较大,因此本发明在青藤碱1位引入不同酰胺取代基的衍生物并用于抗肿瘤药物的开发。
发明内容
本发明的目的是为了提供一系列新的具有抗肿瘤活性的青藤碱1位取代衍生物
本发明的另一目的在于提供上述青藤碱1位取代衍生物的制备方法。
本发明的再一目的在于提供上述青藤碱1位取代衍生物在制备抗肿瘤药物的应用。
本发明的技术方案:
一类青藤碱1位取代衍生物,其特征在于,该衍生物的结构式如式(Ⅰ)所示:
其中,
R1为烷基、不饱和烃基、环烷基、取代烷基、苯基、取代苯基;
取代烷基取代基选自氟、氯、溴、羟基;取代苯基取代基选自氟、氯、溴、羟基,当取代基为两个时,取代基位于苯环的邻、间、对位。
所的青藤碱1位取代衍生物的结构式如下所示:
一类青藤碱1位取代衍生物的制备方法,制备路线如下所示:
具体步骤如下:
(1)将化合物1加入到盐酸溶液中搅拌,再加多聚甲醛,于40~60℃搅拌反应2~4h;然后用氢氧化钠溶液,将反应液的pH值调节至9~10,化合物2析出,抽滤,用二氯甲烷洗涤,干燥后得白色固体的化合物2;其中,化合物1与多聚甲醛摩尔比为1:3~1:8;
(2)将化合物2和不同的腈基取代化合物R1CN溶解在有机溶剂中,其中化合物2与R1CN的摩尔比为1:1~1:6;向反应混合物中加入酸性物质催化,在温度为20℃~80℃条件下搅拌10-12小时,反应液在旋转蒸发器上减压蒸发,将所得产物经柱色谱或重结晶方法纯化,获得青藤碱1位取代衍生物Ⅰ。
步骤(2)中有机溶剂包括作为反应原料的液体腈、二氯甲烷、1,2-二氯乙烷、氯仿;酸性物质包括乙酸、硫酸、三氟化硼、三氟甲磺酸中的一种或两种以上混合。
一种药物组合物,其包含所述的青藤碱1位取代衍生物的一种或两种以上。
所述的药物组合物,所述药物组合物含有治疗有效量的所述的青藤碱1位取代衍生物及其药学上可接受的盐。
所述的青藤碱1位取代衍生物、所述的药物组合物在制备治疗肿瘤疾病的药物中的应用。
所述的肿瘤疾病包括乳腺癌肿瘤、肝癌肿瘤和肺癌肿瘤。
本发明具有以下有益效果:本发明提供了一种青藤碱1位取代衍生物,通过一种新的合成条件在青藤碱1号最佳活性位点引入酰胺取代基,通过酰胺键引入的不同取代基较其他方式具有体内代谢稳定、反应条件简单的优点,酰胺本身有与靶蛋白结合的活性位点。本发明制备的青藤碱1位取代衍生物具有非常好的抗肿瘤细胞增殖作用,可以用于进一步制备抗肿瘤药物。
附图说明
图1是本申请实施例2中化合物2的MS检测图;
图2是本申请实施例2中化合物2的1H NMR检测图;
图3是本申请实施例3中化合物S5的MS检测图;
图4是本申请实施例4中化合物S5的1H NMR检测图;
图5是本申请实施例5中化合物S6的MS检测图;
图6是本申请实施例5中化合物S6的1H NMR检测图;
图7是本申请实施例6中化合物S7的MS检测图;
图8是本申请实施例6中化合物S7的1H NMR检测图;
图9是本申请实施例8中化合物S9的MS检测图;
图10是本申请实施例8中化合物S9的1H NMR检测图;
图11是本申请实施例9中化合物S10的MS检测图;
图12是本申请实施例9中化合物S10的1H NMR检测图;
图13是本申请实施例10中化合物S11的MS检测图;
图14是本申请实施例10中化合物S11的1H NMR检测图。
具体实施方式
以下结合技术方案,进一步说明本发明的具体实施方式。
实施例1
化合物2的制备
在250ml圆底烧瓶中加入盐酸青藤碱(1g,2.72mmol),多聚甲醛(2g),以HCl(2mol/l,100ml)溶解混合,在60℃下搅拌2小时。用10% NaOH将混合溶液的pH调至9。然后用二氯甲烷洗涤、过滤、干燥,最后得到青藤碱苄醇中间体化合物2,收率100%。1H NMR(400MHz,CDCl3)δ6.79(s,1H),5.37(d,J=29.9Hz,1H),4.59(dd,J=28.5,12.5Hz,2H),4.34(t,J=18.3Hz,1H),3.83(s,3H),3.18(d,J=18.8Hz,1H),2.81(d,J=13.1Hz,2H),2.54(d,J=12.5Hz,3H),2.35–2.19(m,2H),2.04(t,J=17.1Hz,3H),1.25(s,2H),0.99–0.74(m,2H).MS(ESI)(m/z):[M+H]+calcd for C20H25NO5:360.17,found:359.98.
实施例2
化合物S5的制备
在100ml圆底烧瓶中加入化合物2(50mg,0.14mmol),丙烯腈(5ml),缓慢滴加硫酸(3.2mol/l,3ml),50℃下搅拌12小时,反应液在旋转蒸发器上减压蒸发,将所得产物上样至硅胶柱色谱柱,使用DCM/MeOH(10:1)混合溶液洗脱,获得化合物S5,收率63%。1H NMR(400MHz,CDCl3)δ6.65(s,1H),6.30(dt,J=5.7,2.8Hz,1H),6.09(dd,J=17.0,10.3Hz,1H),5.72–5.64(m,1H),5.42(d,J=1.6Hz,1H),4.48–4.36(m,2H),3.81(d,J=7.3Hz,3H),3.64(s,1H),3.46(s,3H),3.32(d,J=14.3Hz,1H),3.06(d,J=22.6Hz,2H),2.44(s,3H),1.98(d,J=13.2Hz,2H),1.25(s,5H),0.92–0.86(m,1H).MS(ESI)(m/z):[M+H]+calcd forC23H28N2O5:413.20,found:413.17.
实施例3
化合物S6的制备
在100ml圆底烧瓶中加入化合物2(50mg,0.14mmol),氯乙腈(80μl),缓慢滴加硫酸/磷酸混合液(1:8,1ml),50℃下搅拌10小时,反应液在旋转蒸发器上减压蒸发,将所得产物上样至硅胶柱色谱柱,使用DCM/MeOH(10:1)混合溶液洗脱,获得化合物S6,收率40%。1HNMR(400MHz,CDCl3)δ6.67(s,1H),5.42(d,J=1.8Hz,1H),4.42–4.32(m,3H),4.10(d,J=8.3Hz,2H),3.84(s,3H),3.48(d,J=1.3Hz,3H),3.15(dd,J=29.7,12.7Hz,2H),2.88–2.69(m,2H),2.54(s,3H),2.08–2.01(m,2H).MS(ESI)(m/z):[M+H]+calcd forC22H27ClN2O5:435.16,found:435.28.
实施例4
化合物S7的制备
在100ml圆底烧瓶中加入化合物2(200mg,0.56mmol),溴乙腈(80μl),缓慢滴加三氟化硼·乙醚溶液(80μl),50℃下搅拌10小时,反应液在旋转蒸发器上减压蒸发,将所得产物上样至硅胶柱色谱柱,使用DCM/MeOH(20:1)混合溶液洗脱,获得化合物S7,收率53%。1HNMR(600MHz,MeOD)δ6.79–6.74(m,1H),5.63(s,1H),4.28–4.19(m,2H),4.01–3.94(m,1H),3.83(s,1H),3.75(s,1H),3.73(s,3H),3.61–3.52(m,4H),3.42–3.40(m,3H),2.78(d,J=18.5Hz,3H),2.57(d,J=15.5Hz,1H),2.47(d,J=16.7Hz,2H),2.16(t,J=7.4Hz,1H),1.87(s,1H).MS(ESI)(m/z):[M+H]+calcd forC22H27BrN2O5:479.11,found:479.11.
实施例5
化合物S9的制备
在100ml圆底烧瓶中加入化合物2(179.50mg,0.5mmol),二氯乙腈(161μl,0.2mmol),缓慢滴硫酸/冰乙酸混合液(1:8,3ml),50℃下搅拌10小时,反应液在旋转蒸发器上减压蒸发,将所得产物上样至硅胶柱色谱柱,使用DCM/MeOH(20:1)混合溶液洗脱,获得化合物S9,收率11%。1H NMR(400MHz,CD3OD)δ6.82(s,1H),6.22(d,J=6.4Hz,1H),5.65(s,1H),4.35(dt,J=23.7,15.3Hz,2H),3.77(s,3H),3.68(dd,J=7.8,5.4Hz,2H),3.60(t,J=5.2Hz,1H),3.58–3.51(m,1H),3.45(s,3H),3.18(d,J=7.2Hz,1H),3.12–3.06(m,1H),2.87(s,2H),2.56(d,J=16.4Hz,1H),2.50(s,1H),2.02(d,J=9.5Hz,1H),1.87–1.79(m,2H).MS(ESI)(m/z):[M+H]+calcd forC22H26Cl2N2O5:469.12,found:469.11.
化合物S10的制备
在100ml圆底烧瓶中加入化合物2(179.50mg,0.5mmol),苯甲腈(4ml),缓慢滴硫酸/冰乙酸混合液(1:8,3ml),50℃下搅拌10小时,反应液在旋转蒸发器上减压蒸发,将所得产物上样至硅胶柱色谱柱,使用DCM/MeOH(20:1)混合溶液洗脱,获得化合物S10,收率41%。1HNMR(400MHz,CDCl3)δ7.78–7.73(m,2H),7.53–7.47(m,1H),7.41(t,J=7.5Hz,2H),6.71(s,1H),6.20(s,1H),5.38(s,1H),4.63(dd,J=14.4,5.9Hz,1H),4.46(dd,J=14.4,4.8Hz,1H),4.31(dd,J=13.3,6.5Hz,1H),3.83(s,3H),3.67–3.61(m,5H),3.40(s,3H),3.15(d,J=18.0Hz,2H),2.48(t,J=7.8Hz,4H).MS(ESI)(m/z):[M+H]+calcd forC27H30N2O5:463.22,found:463.35.
化合物S11的制备
在100ml圆底烧瓶中加入化合物2(35.9mg,0.1mmol),临氯苯甲腈(55.02mg,0.4mmol),二氯甲烷(1ml),缓慢滴加三氟甲磺酸溶液(22μl),50℃下搅拌10小时,反应液在旋转蒸发器上减压蒸发,将所得产物上样至硅胶柱色谱柱,使用DCM/MeOH(20:1)混合溶液洗脱,获得化合物S11,收率39%。1H NMR(400MHz,CDCl3)δ7.71–7.62(m,1H),7.46–7.31(m,3H),6.77(s,1H),5.39(d,J=1.8Hz,1H),4.54(qd,J=14.7,5.7Hz,2H),4.37(d,J=15.6Hz,1H),3.85(d,J=8.8Hz,3H),3.67(t,J=12.9Hz,1H),3.45(s,4H),3.34(t,J=14.0Hz,1H),2.96(dd,J=19.5,8.0Hz,2H),2.70(s,3H),1.29–1.23(m,5H).MS(ESI)(m/z):[M+H]+calcd for C27H29ClN2O5:497.18,found:497.15.
应用例1
本发明青藤碱1位取代衍生物对肿瘤细胞抗增殖作用
测试方法:用细胞传代的方法将各个细胞系(Hela、MCF-7)制备成单细胞悬液,以每孔5000个细胞密度接种到96孔板种,每孔体积100μL。置于培养箱于饱和湿度、5%CO2、37℃培养24h。将药物稀释至所需终作用浓度。然后加入至96孔板中,每个药物浓度设置4个复孔,每孔100μL。每块板均设置4个复孔的对照组(含细胞,不加药)空白组(含培养液,未种细胞),继续置于培养箱于饱和湿度、5%CO2、37℃孵育24h。每孔加入20μL MTT溶液(5mg/mL)。在37℃下孵育4小时后,吸出培养基。每孔加入150μL DMSO,线性振荡10min使结晶物充分均匀溶解。将96孔培养板放入酶标仪中检测,检测条件:490/570nm波长、37℃。测定各孔光吸收值,收集数据。细胞存活率=[(对照组相对OD值-实验组相对OD值)/对照组相对OD值]×100%,计算出药物的IC50值。
本发明青藤碱1位取代衍生物对肿瘤细胞抗增殖实验结果:
以顺铂、D1、D2为阳性对照,对合成的藤碱1位取代衍生物进行了肿瘤细胞抗增殖实验,研究结果表明,化合物S9、S10和S15表现出中等的抑制活性,化合物S7和S11表现出较强的抑制活性,S6对人乳腺癌细胞系有较强的选择性。
Claims (7)
1.一类青藤碱1位取代衍生物,其特征在于,该青藤碱1位取代衍生物的结构式如下所示:
2.一类权利要求1所述的青藤碱1位取代衍生物的制备方法,其特征在于,制备路线如下所示:
其中,
R1:
具体步骤如下:
(1)将化合物1加入到盐酸溶液中搅拌,再加多聚甲醛,于40~60℃搅拌反应2~4h;然后用氢氧化钠溶液,将反应液的pH值调节至9~10,化合物2析出,抽滤,用二氯甲烷洗涤,干燥后得白色固体的化合物2;其中,化合物1与多聚甲醛摩尔比为1:3~1:8;
(2)将化合物2和不同的腈基取代化合物R1CN溶解在有机溶剂中,其中化合物2与R1CN的摩尔比为1:1~1:6;向反应混合物中加入酸性物质催化,在温度为20℃~80℃条件下搅拌10-12小时,反应液在旋转蒸发器上减压蒸发,将所得产物经柱色谱或重结晶方法纯化,获得青藤碱1位取代衍生物Ⅰ。
3.根据权利要求2所述的制备方法,其特征在于,步骤(2)中有机溶剂选自作为反应原料的液体腈、二氯甲烷、1,2-二氯乙烷、氯仿;酸性物质选自乙酸、硫酸、三氟化硼、三氟甲磺酸中的一种或两种以上混合。
4.一种药物组合物,其包含权利要求1中所述的青藤碱1位取代衍生物的一种或两种以上。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物含有治疗有效量的所述的青藤碱1位取代衍生物及其药学上可接受的盐。
6.一种权利要求1所述的青藤碱1位取代衍生物中的S6-S8、S10-S12在制备治疗子宫颈癌的药物中的应用。
7.一种权利要求1所述的青藤碱1位取代衍生物中的S2-S8、S10-S12在制备治疗乳腺癌的药物中的应用。
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