CN104356090B - 一种蓝萼甲素的噻唑衍生物及其制备方法和应用 - Google Patents
一种蓝萼甲素的噻唑衍生物及其制备方法和应用 Download PDFInfo
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- CN104356090B CN104356090B CN201410606018.6A CN201410606018A CN104356090B CN 104356090 B CN104356090 B CN 104356090B CN 201410606018 A CN201410606018 A CN 201410606018A CN 104356090 B CN104356090 B CN 104356090B
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- Prior art keywords
- glaucocalyxin
- thiazole derivative
- preparation
- derivative
- bromo
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Abstract
本发明涉及一种蓝萼甲素的噻唑衍生物,该类衍生物具有式II所示结构,其中R为氢、烷烃基、烯烃基、芳香烃基。本发明涉及的蓝萼甲素的噻唑衍生物,经细胞毒活性评价实验,结果发现具有很强的人肿瘤细胞增殖抑制活性,活性优于母体化合物蓝萼甲素。
Description
技术领域
本发明涉及医药发明领域,具体涉及蓝萼甲素(glaucocalyxinA,GLA)的噻唑衍生物及其制备方法和应用。
背景技术
蓝萼甲素(glaucocalyxinA,GLA),化学名称为:(5β,7α,9β,10α)-7,14-二羟基贝壳杉-16-烯-3,15-二酮;又名leukameninF,分子式为C20H28O4,分子量:332.43,CAS登记号:79498-31-0,密度:1.22g/cm3,熔点:513.4℃,易溶于甲醇、乙醇,其结构式为式Ⅰ所示。
蓝萼甲素是唇形科香茶菜属药用植物蓝萼香茶菜(Isodonjaponicavar.glaucocalyx)的主要药效成分,1981年许云龙等人(许云龙,孙西昌,孙汉董.云南植物研究.1981,3(03):1-3)首次从蓝萼香茶菜中分离得到蓝萼甲素,并用波谱方法鉴定了其结构。其在蓝萼香茶菜的干燥叶子中含量高达1.03%。
体内外抗肿瘤实验表明,蓝萼香茶菜甲素对多种人癌瘤细胞株如CE-1、U87、A549、MCF-7、Hela、K562、HepG2、NCI-H460、KB、LEG-3、K562、HL-60等具有显著的抑制增殖作用,特别对非激素依赖性前列腺癌(DU-145)、直肠癌(Lovo)细胞最为敏感,抗瘤谱广;能抑制Lewis肺癌、S180实体型以及HCA实体型等实体瘤的生长,明显增加荷S180腹水型和荷HCA腹水型小鼠的生命延长率,其抗肿瘤的强弱呈剂量依赖关系。
高丽文(音)等[LiWenGao,JianZhang,WenHuaYang,BinWang,JianWenWang.ToxicologyinVitro2011,25:51-63]报道了蓝萼香茶菜甲素通过线粒体-调节死亡途径诱导凋亡,抑制人早幼粒白血病细胞增殖;2014年文献报道[XiaoX,CaoW,JiangX,ZhangW,ZhangY,LiuB,ChengJ,HuangH,HuoJ,ZhangX.ActaBiochimBiophysSin.2014,45,946-952],蓝萼甲素是蛋白激酶AKT抑制剂,通过抑制AKT磷酸化诱导脑胶质母细胞瘤U87MG凋亡,而对正常神经胶质细胞无影响,是一种很有前景的治疗白血病、恶性胶质瘤的先导化合物。
但是,蓝萼香甲素,极性小,水溶性差,不适合直接作为药物给药;体外具有较强的抗肿瘤作用,但体内需要大剂量长时间才能产生药效[张崇,尚校军,马素英,白素平.医药导报,2013,32,1399-1402]。
另外也有专利[CN101993359A,公开日2011.03.30;CN101993370A,公开日2011.03.30;CN101993373A,公开日2011.03.30;CN102584780A,公开日2012.01.16]报道了其7位和14位羟基的脂肪酸、芳香酸酯、二元酸酯、多肽类及缩醛类结构修饰,但该类衍生物仍然存在水溶性问题。
因此,需要提供一种水溶性好,且能保持抗肿瘤药效的衍生物。
发明内容
本发明的目的是提供一种极性增加、溶于水、体内生物利用度高的蓝萼甲素的衍生物。
本发明的另一个目的在于提供上述蓝萼甲素的衍生物的制备方法。
本发明的上述目的是通过下述方案予以实现:
本发明提供了一种蓝萼甲素的噻唑衍生物,该类衍生物具有式II所示结构:
其中R为氢、烷烃基、烯烃基或芳香烃基。
优选地,所述R为氢(H)、甲基(-CH3)、乙基(-C2H5)、正丙基(-(CH2)2CH3)、异丙基(-CH(CH3)2)、正丁基(-(CH2)3CH3)、正己基(-(CH2)5CH3)、烯丙基(-CH2CH=CH2)、环己基(-C6H11)、苯基(-C6H5)或苄基(-CH2C6H5)。
所述噻唑衍生物为式IIa~IIk所示化合物:
本发明还提供了上述噻唑衍生物的制备方法,该方法包括以下步骤:以蓝萼甲素为先导化合物,对其A环进行结构修饰,先得到重要的中间产物2-溴代蓝萼甲素,继而与硫脲类化合物通过Hantzsch反应,得到A环上骈合噻唑的蓝萼甲素衍生物。
具体的,该方法包括如下步骤:
(1)步骤1:以天然产物蓝萼甲素和三溴吡啶鎓为原料,低温条件下于有机溶剂中发生取代反应,硅胶柱层析分离纯化,得蓝萼甲素的α-溴代酮中间产物,即2-溴代蓝萼甲素;
其化学反应式如下所示:
(2)步骤2:将上述步骤1所得的2-溴代蓝萼甲素与硫脲类化合物在有机溶剂中加热回流,硅胶柱层析分离纯化,得到蓝萼甲素的噻唑衍生物;
其化学反应式如下所示:
上述方法中:
所述步骤(1)具体为:取蓝萼甲素溶于有机溶剂中,低温条件下搅拌10-15分钟,三溴吡啶鎓溶于相同有机溶剂中,缓慢逐滴加入反应体系,低温条件下搅拌反应,然后以5-7倍量反应液体积的蒸馏水淬灭反应,二氯甲烷萃取,有机相经饱和食盐水洗涤后无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析分离,洗脱液为石油醚/乙酸乙酯按照体积比2/1,得到所需的重要中间产物2-溴代蓝萼甲素。
所述步骤(1)中:
所述有机溶剂为二氯甲烷、四氢呋喃或二氧六环;
蓝萼甲素与三溴吡啶鎓的摩尔比为1:1~1:1.5;
低温条件是指反应温度为-10℃~0℃;反应时间为15-30分钟。
所述步骤(2)具体为,将步骤(1)制备得到的2-溴代蓝萼甲素和硫脲类化合物溶于有机溶剂中,加热回流,反应结束后冷却,以3-5倍量反应液体积的饱和NaHCO3溶液碱化,再以蒸馏水稀释至反应液体积的10-15倍,二氯甲烷萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析分离,洗脱液为石油醚/乙酸乙酯按照体积比为2/1,即可得到蓝萼甲素的噻唑衍生物。
上述步骤(2):
所述2-溴代蓝萼甲素与硫脲类化合物的摩尔比为1:1~1:1.5;
所述中间产物2-溴代蓝萼甲素与硫脲类化合物,加热回流时间为3-12小时;
所述硫脲类化合物为硫脲、N-烷基取代硫脲、N-烯烃基取代硫脲或N-芳基取代硫脲。优选地,硫脲类化合物为硫脲、N-甲基硫脲、N-乙基硫脲、N-正丙基硫脲、N-异丙基硫脲、N-正丁基硫脲、N-正己基硫脲、N-环己基硫脲、N-烯丙基硫脲、N-苯基硫脲或N-苄基硫脲;
所述有机溶剂为乙醇、甲醇、二氯甲烷或四氢呋喃。
本发明还提供了含蓝萼甲素的噻唑衍生物的制剂,该制剂由噻唑衍生物与药学上可接受的载体组成。
所述制剂,包括但不限于片剂、胶囊剂、软胶剂、喷雾剂、凝胶剂、凝胶吸入剂、口服剂、混悬剂、冲剂、贴剂、软膏、丸剂、散剂、注射剂、输液剂、冻干注射剂、脂质体注射剂、靶向给药注射剂、栓剂、缓释制剂或控释制剂。
所述药学上可接受的载体是指药学领域常规的药物载体,选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、溶剂、表面活性剂或矫味剂中的一种或几种。
所述填充剂选自淀粉、蔗糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素或葡萄糖等;
所述粘合剂选自纤维素衍生物、藻酸盐、明胶或聚乙烯吡咯烷酮等;
所述崩解剂选自微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙基纤维素或交联羧甲基纤维素钠;
所述润滑剂选自硬脂酸、聚乙二醇、碳酸钙、碳酸氢钠、微粉硅胶、滑石粉或硬脂酸镁;
所述助悬剂选自微粉硅胶、蜂蜡、纤维素、固态聚乙二醇;
所述润湿剂选自甘油、吐温-80、乙氧基氢化蓖麻油或卵磷脂;
所述溶剂选自乙醇、液态聚乙二醇、异丙醇、吐温-80、甘油、丙二醇或植物油,所述植物油选自大豆油、蓖麻油、花生油、调和油等;
所述表面活性剂选自十二烷基苯磺酸钠、硬脂酸、聚氧乙烯-聚氧丙烯共聚物、脂肪酸山梨坦或聚山梨酯(吐温)等;
所述甜味剂选自阿斯巴甜、蔗糖素、香精、柠檬酸或糖精钠。
本发明还提供了所述噻唑衍生物在制备治疗肿瘤的药物中的应用,所述肿瘤优选为肝癌、宫颈癌、白血病、绒毛膜癌和肺癌。
本发明所提供的蓝萼甲素衍生物具有以下优点:
1、本发明在保留式Ⅰ结构药效基团α或β不饱和环戊酮的前提下,通过对A环进行结构修饰引入噻唑环,进而制备成相应的草酸盐或盐酸盐,可以提高水溶性,制备水溶剂型,提高其体内的生物利用度。
2、本发明涉及的蓝萼甲素的噻唑衍生物,经细胞毒活性评价实验,结果发现具有很强的人肿瘤细胞增殖抑制活性,活性优于母体化合物蓝萼甲素。
附图说明
图1A和图1B分别为中间体2-溴蓝萼甲素的1HNMR和13CNMR;
图2为蓝萼甲素的2-胺基噻唑衍生物IIa的13C-NMR;
图3为蓝萼甲素的2-甲胺基噻唑衍生物IIb的13C-NMR;
图4为蓝萼甲素的2-乙胺基噻唑衍生物IIc的13C-NMR;
图5为蓝萼甲素的2-丙胺基噻唑衍生物IId的13C-NMR;
图6为蓝萼甲素的2-异丙胺基噻唑衍生物IIe的13C-NMR;
图7为蓝萼甲素的2-正丁胺基噻唑衍生物IIf的13C-NMR;
图8为蓝萼甲素的2-正己胺基噻唑衍生物IIg的13C-NMR;
图9为蓝萼甲素的2-烯丙胺基噻唑衍生物IIh的13C-NMR;
图10为蓝萼甲素的2-环己胺基噻唑衍生物IIi的13C-NMR;
图11为蓝萼甲素的2-苯胺基噻唑衍生物IIj的13C-NMR;
图12为蓝萼甲素的2-苄胺基噻唑衍生物IIk的13C-NMR。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
以下实施例所述制备过程,所采用的所有化学试剂如无特别标注均为分析纯。
实施例1:2-溴代蓝萼甲素的制备
称取166mg(0.5mmol)蓝萼甲素溶于5mLTHF,冰浴,然后将160mg(0.5mmol)三溴吡啶鎓溶于1mLTHF,冰浴后缓慢逐滴加入反应体系,30min后加入30mL蒸馏水淬灭反应,以二氯甲烷萃取,每次30mL,萃取3次,合并萃取液,以饱和食盐水洗涤后无水硫酸钠干燥,减压浓缩,硅胶柱层析分离,石油醚-乙酸乙酯(2:1)洗脱,得白色固体(C-2差向异构体)145.5mg,产率70.8%。mp.203-205℃
异构体1:1HNMR(400MHz,CDCl3)δ6.15(s,1H),5.42(s,1H),4.90(dd,J=12.2,6.8Hz,1H),4.84(s,1H),4.33(dd,J=11.9,3.9Hz,1H),3.07(brs,1H),2.65(dd,J=13.4,6.8Hz,1H),2.09(dd,J=13.4,9.3Hz,1H),1.98–1.86(m,2H),1.83–1.66(m,2H),1.60–1.38(m,4H),1.27(s,3H),1.16(s,3H),1.12(s,3H);13CNMR(100MHz,CDCl3)δ207.90,207.18,147.08,118.99,75.05,74.23,61.54,52.88,52.49,50.70,49.78,48.59,45.90,41.53,30.79,29.47,28.86,22.22,21.27,18.19.其核磁共振波谱图见附图1A和1B.
异构体2:1HNMR(400MHz,CDCl3)δ6.15(s,1H),5.42(s,1H),5.04(dd,J=10.9,9.5Hz,1H),4.71(s,1H),4.33(dd,J=11.9,3.9Hz,1H),3.07(brs,1H),2.36(dd,J=13.4,11.6Hz,1H),2.09(dd,J=13.6,9.3Hz,1H),1.98–1.86(m,2H),1.83–1.66(m,2H),1.60–1.38(m,4H),1.25(s,3H),1.17(s,3H),0.99(s,3H).13CNMR(100MHz,CDCl3)δ207.27,206.70,147.08,118.99,74.78,73.55,61.25,52.51,52.35,50.18,49.73,47.32,45.90,40.84,30.61,29.20,27.82,20.32,18.53,17.81.其核磁共振波谱图见附图1A和1B。
实施例2:蓝萼甲素的噻唑衍生物的制备
反应式如下:
实施例2.1:蓝萼甲素的2-胺基噻唑衍生物IIa的制备
称取82mg(0.2mmol)实施例1制备所得2-溴代蓝萼甲素和15mg(0.2mmol)硫脲溶于2mL乙醇,加热回流5h后自然冷却,加入10mL饱和NaHCO3溶液碱化后再加入18mL蒸馏水,以二氯甲烷萃取3次,每次30mL,合并萃取液,以饱和食盐水洗涤2次,以无水硫酸钠干燥,过滤后减压浓缩,硅胶柱层析分离纯化,以石油醚/乙酸乙酯2/1洗脱,得白色固体28.6mg,即为本实施例的蓝萼甲素的2-胺基噻唑衍生物IIa,产率36.8%。mp.254-256℃.
1HNMR(400MHz,C5D5N)δ7.59(s,1H),7.26(s,1H),6.36(s,1H),5.42(s,1H),5.15(s,1H),4.90(s,1H),4.82(dt,J=11.9,4.0Hz,1H),3.29(brs,1H),2.61(d,J=15.2Hz,1H),2.30(d,J=12.6Hz,1H),2.18–2.00(m,2H),1.72(dd,J=9.3,4.4Hz,1H),1.64(dd,J=17.1,4.8Hz,2H),1.56–1.47(m,2H),1.43(s,3H),1.35(s,3H),1.12(s,3H).13CNMR(100MHz,C5D5N)δ208.14,167.19,152.91,150.19,116.72,114.13,75.87,74.14,62.23,53.31,51.04,47.33,41.12,38.95,37.82,31.76,31.22,31.16,22.74,18.69,18.58.(13CNMR的具体图谱见附图2)
实施例2.2:蓝萼甲素的2-甲胺基噻唑衍生物IIb的制备
称取82mg(0.2mmol)实施例1制备所得2-溴代蓝萼甲素和18mg(0.2mmol)N-甲基硫脲,具体操作过程同实施例2.1,得白色固体70.5mg,即为本实施例的蓝萼甲素的2-甲胺基噻唑衍生物IIb,产率87.7%。mp.255℃分解。
1HNMR(400MHz,C5D5N)δ8.12(brs,1H),7.85(q,J=4.2Hz,1H),7.22(brs,1H),6.34(s,1H),5.41(s,1H),5.14(s,1H),4.80(d,J=9.0Hz,1H),3.28(brs,1H),3.05(d,J=4.2Hz,3H),2.63(d,J=15.2Hz,1H),2.29(m,1H),2.08(m,2H),1.95(m,1H),1.72(m,1H),1.63(m,2H),1.52(m,2H),1.43(s,3H),1.35(s,3H),1.11(s,3H).13CNMR(100MHz,C5D5N)δ208.1,168.6,153.3,150.2,116.7,113.0,75.9,74.1,62.2,53.3,51.1,47.3,41.1,39.0,37.9,32.0,31.8,31.2,31.2,22.7,18.7,18.6..(13CNMR的具体图谱见附图3)
实施例2.3:蓝萼甲素的2-乙胺基噻唑衍生物IIc的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和16mg(0.15mmol)N-乙基硫脲,具体操作过程同实施例2.1,得白色固体38.5mg,即为本实施例的蓝萼甲素的2-乙胺基噻唑衍生物IIc,产率61.7%。mp.196-198℃。
1HNMR(400MHz,CDCl3)δ6.16(s,2H),5.43(s,1H),4.87(s,1H),4.41(dd,J=12.0,3.2Hz,1H),3.21(m,1H),3.14(brs,1H),3.09(m,1H),2.60(d,J=15.5Hz,1H),2.15(d,J=13.4Hz,1H),2.05(m,2H),1.94(dd,J=25.1,12.5Hz,1H),1.81(m,1H),1.43-1.61(m,4H),1.34(t,J=7.2Hz,3H),1.27(d,J=6.0Hz,3H),1.22(s,3H),1.13(s,3H).13CNMR(100MHz,CDCl3)δ209.6,169.5,151.2,148.3,118.1,112.1,75.1,72.6,62.0,52.8,50.9,46.2,41.5,40.6,38.9,37.0,31.8,31.0,30.4,21.9,18.4,18.3,14.5.(13CNMR的具体图谱见附图4)
实施例2.4:蓝萼甲素的2-丙胺基噻唑衍生物IId的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和18mg(0.15mmol)N-丙基硫脲,具体操作过程同实施例2.1,得白色固体28.5mg,即为本实施例的蓝萼甲素的2-丙胺基噻唑衍生物IId,产率44.2%。mp.186-188℃。
1HNMR(400MHz,CDCl3)δ6.13(s,1H),5.40(s,1H),4.85(s,1H),4.39(dd,J=12.1,3.2Hz,1H),3.11(m,2H),3.02(m,1H),2.58(d,J=15.3Hz,1H),2.10(m,1H),1.90(m,1H),1.80(m,1H),1.70(m,3H),1.56(m,1H),1.18-1.33(m,4H),1.25(s,3H),1.19(s,3H),1.10(s,3H),0.96(t,J=7.3Hz,3H).13CNMR(100MHz,CDCl3)δ209.2,169.6,148.1,147.5,118.1,112.0,75.1,73.0,61.9,52.68,50.9,48.9,46.2,40.6,38.9,37.0,31.5,31.0,30.1,22.6,21.8,18.4,18.3,11.8..(13CNMR的具体图谱见附图5)
实施例2.5:蓝萼甲素的2-异丙胺基噻唑衍生物IIe的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和18mg(0.15mmol)N-异丙基硫脲,具体操作过程同实施例2.1,得白色固体53.3mg,即为本实施例的蓝萼甲素的2-异丙胺基噻唑衍生物IIe,产率82.6%。mp.166-168℃。
1HNMR(400MHz,CDCl3)δ6.13(s,1H),5.40(s,1H),4.85(s,1H),4.40(dd,J=12.0,3.1Hz,1H),3.34(heptet,J=6.2Hz,1H),3.11(brs,1H),2.56(d,J=15.3Hz,1H),2.12(m,1H),1.92(m,1H),1.79(m,1H),1.58-1.49(m,3H),1.47-1.39(m,3H),1.36(d,J=6.2Hz,3H),1.25(s,3H),1.22(d,J=6.2Hz,3H),1.20(s,3H),1.10(s,3H).13CNMR(100MHz,CDCl3)δ208.9,168.3,150.3,148.1,117.8,111.6,74.9,72.6,61.7,52.5,50.7,48.9,46.0,40.5,38.6,36.8,31.4,30.8,30.6,21.6,18.2,18.1,13.7,13.7..(13CNMR的具体图谱见附图6)
实施例2.6:蓝萼甲素的2-正丁胺基噻唑衍生物IIf的制备
称取49mg(0.12mmol)实施例1制备所得2-溴代蓝萼甲素和16mg(0.12mmol)N-正丁基硫脲,具体操作过程同实施例2.1,得白色固体38.8mg,,即为本实施例的蓝萼甲素的2-正丁胺基噻唑衍生物IIf,产率产率72.8%。mp.212-214℃。
1HNMR(400MHz,CDCl3)δ6.20(s,1H),5.47(s,1H),4.92(s,1H),4.46(dd,J=12.0,3.2Hz,1H),3.23(m,1H),3.18(brs,1H),3.09(m,1H),2.65(d,J=15.3Hz,1H),2.19(m,1H),2.12(m,1H),2.08(m,1H),1.98(m,1H),1.86(m,1H),1.77-1.70(m,2H),1.63(m,1H),1.52-1.44(m,5H),1.32(s,3H),1.27(s,3H),1.18(s,3H),1.13(s,1H),0.99(t,J=7.3Hz,3H).13CNMR(100MHz,CDCl3)δ209.2,169.5,151.1,148.1,117.8,111.8,74.9,72.6,61.8,52.6,50.8,46.6,46.0,40.5,38.8,36.9,31.6,31.2,30.9,30.1,21.7,20.1,18.2,18.1,13.8.(13CNMR的具体图谱见附图7)
实施例2.7:蓝萼甲素的2-正己胺基噻唑衍生物IIg的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和122mg(0.15mmol)N-正己基硫脲,具体操作过程同实施例2.1,得白色固体27.4mg,即为本实施例的蓝萼甲素的2-正己胺基噻唑衍生物IIg,产率38.7%。mp.164-166℃。
1HNMR(400MHz,CDCl3)δ6.20(s,1H),5.47(s,1H),4.92(s,1H),4.46(dd,J=12.0,3.3Hz,1H),3.22(m,1H),3.18(brs,1H),3.09(m,1H),2.65(d,J=15.4Hz,1H),2.19(d,J=12.3Hz,1H),2.10(m,2H),1.98(q,J=12.5Hz,1H),1.86(m,1H),1.75(sextet,J=7.0Hz,2H),1.66-1.59(m,2H),1.49(m,2H),1.43(m,2H),1.37-1.35(m,4H),1.32(s,3H),1.27(s,3H),1.18(s,3H),0.93(t,J=6.8Hz,3H).13CNMR(100MHz,CDCl3)δ209.1,169.4,151.1,148.1,117.8,111.8,74.9,72.7,61.8,52.6,50.8,46.9,46.0,40.5,38.8,36.9,31.5,31.5,30.9,30.0,29.1,26.7,22.6,21.7,18.2,18.1,14.0.(13CNMR的具体图谱见附图8)
实施例2.8:蓝萼甲素的2-烯丙胺基噻唑衍生物IIh的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和17mg(0.15mmol)N-烯丙基硫脲,具体操作过程同实施例2.1,得白色固体35.6mg,即为本实施例的蓝萼甲素的2-烯丙胺基噻唑衍生物IIh,产率55.4%。mp.162-164℃。
1HNMR(400MHz,CDCl3)δ6.21(s,1H),5.87(ddt,J=17.2,10.2,5.6Hz,1H),5.48(s,1H),5.37(dd,J=17.2,1.4Hz,1H),5.25(dd,J=10.2,1.4Hz,1H),4.92(brs,1H),4.45(dd,J=12.0,3.4Hz,1H),3.90(dd,J=15.3,5.6Hz,1H),3.79(dd,J=15.3,5.6Hz,1H),3.18(brs,1H),2.65(d,J=15.3Hz,1H),2.17(d,J=12.6Hz,1H),2.11–2.08(m,2H),1.98(q,J=12.5Hz,1H),1.86(m,1H).1,61-1.48(m,4H),1.32(s,3H),1.26(s,3H),1.17(s,3H).13CNMR(100MHz,CDCl3)δ209.4,169.1,151.1,148.0,133.7,118.4,117.6,112.6,75.1,73.0,62.0,52.7,50.9,49.3,46.1,40.6,38.9,37.1,31.5,31.0,30.1,21.9,18.4,18.3.(13CNMR的具体图谱见附图9)
实施例2.9:蓝萼甲素的2-环己胺基噻唑衍生物IIi的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和24mg(0.15mmol)N-环己基硫脲,具体操作过程同实施例2.1,得白色固体61.3mg,即为本实施例的蓝萼甲素的2-环己胺基噻唑衍生物IIi,产率87.0%。mp.196-198℃。
1HNMR(400MHz,CDCl3)δ6.15(s,1H),5.42(s,1H),4.85(s,1H),4.41(dd,J=12.0,3.3Hz,1H),3.12(brs,1H),2.98(m,1H),2.56(d,J=15.3Hz,1H),2.10(m,2H),2.00(m,2H),1.90(m,2H),1.81-1.70(m,4H),1.63-1.50(m,3H),1.47-1.42(m,4H),1.29(m,2H),1.26(s,3H),1.20(s,3H),1.10(s,3H).13CNMR(100MHz,CDCl3)δ208.8,168.1,148.1,148.1,118.1,111.7,75.1,73.2,61.9,56.4,52.7,50.8,46.2,40.7,38.8,37.0,33.1,32.9,31.4,31.1,29.9,25.9,25.7,25.1,21.9,18.4,18.3.(13CNMR的具体图谱见附图10)
实施例2.10:蓝萼甲素的2-苯胺基噻唑衍生物IIj的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和23mg(0.15mmol)N-苯基硫脲,具体操作过程同实施例2.1,得白色固体20.7mg,即为本实施例的蓝萼甲素的2-苯胺基噻唑衍生物IIj,产率29.7%。mp.166-168℃。
1HNMR(400MHz,CDCl3)δ7.39–7.26(m,4H),7.02(tt,J=7.4,1.2Hz,1H),6.17(s,1H),5.43(s,1H),4.89(s,1H),4.48(dd,J=12.1,3.5Hz,1H),3.13(brs,1H),2.64(d,J=15.5Hz,1H),2.15(m,1H),2.06(m,1H),1.84-1.79(m,3H),1.58-1.48(m,4H),1.32(s,3H),1.26(s,3H),1.14(s,3H).13CNMR(100MHz,CDCl3)δ209.2,163.5,151.6,147.9,140.9,129.5,129.5,123.0,118.7,118.6,118.6,113.9,75.2,73.6,62.1,52.6,51.0,46.2,40.7,38.7,37.2,31.4,31.1,29.7,22.2,18.4,18.3.(13CNMR的具体图谱见附图11)
实施例2.11:蓝萼甲素的2-苄胺基噻唑衍生物IIk的制备
称取61mg(0.15mmol)实施例1制备所得2-溴代蓝萼甲素和225mg(0.15mmol)N-苄基硫脲,具体操作过程同实施例2.1,得白色固体43.8mgmg,即为本实施例的蓝萼甲素的2-苯胺基噻唑衍生物IIk,产率61.1%。mp.160-162℃。
1HNMR(400MHz,CDCl3)δ7.40(d,J=7.2Hz,2H),7.34(t,J=7.2Hz,2H),7.28(d,J=7.2Hz,1H),5.93(s,1H),5.34(s,1H),4.86(s,1H),4.43-4.31(m,3H),3.10(brs,1H),2.57(d,J=15.4Hz,1H),2.12(m,1H),2.02(m,2H),1.92(q,J=12.3Hz,1H),1.78(m,1H),1.53-1.43(m,4H).13CNMR(400MHz,CDCl3)δ209.3,169.0,151.2,147.8,137.6,128.7,128.7,127.9,127.9,127.3,118.4,112.7,75.0,73.0,61.9,52.6,50.8,50.6,48.0,40.5,38.8,37.0,31.4,30.9,29.9,21.8,18.3,18.2.(13CNMR的具体图谱见附图12)
实施例3蓝萼甲素噻唑衍生物盐酸盐的制备及水溶性测定
实施例3.1:蓝萼甲素噻唑衍生物盐酸盐的制备
实施例2制备得到的蓝萼甲素噻唑衍生物IIa~IIk溶于甲醇中,冰浴条件下滴加等当量的甲醇饱和的浓盐酸,沉淀过滤,少量甲醇洗涤,即得到衍生物的盐酸盐。
优选地,蓝萼甲素2-胺基噻唑衍生物IIa的盐酸盐的制备:称取10mg实施例2.1制备所得蓝萼甲素2-胺基噻唑衍生物IIa溶于甲醇中,冰浴下滴加5mL甲醇饱和的浓盐酸(浓盐酸:甲醇=1:1,体积比),析出沉淀,过滤,少量甲醇洗涤后干燥。
优选地,蓝萼甲素2-甲胺基噻唑衍生物IIb的盐酸盐的制备:称取20mg实施例2.2制备所得蓝萼甲素2-甲胺基噻唑衍生物IIb溶于甲醇中,冰浴下滴加10mL甲醇饱和的浓盐酸(浓盐酸:甲醇=1:1,体积比),析出沉淀,过滤,少量甲醇洗涤后干燥。
优选地,蓝萼甲素2-烯丙胺基噻唑衍生物IIh的盐酸盐的制备:称取15mg实施例2.2制备所得蓝萼甲素2-烯丙胺基噻唑衍生物IIh溶于甲醇中,冰浴下滴加6μL甲醇饱和的浓盐酸(浓盐酸:甲醇=1:1,体积比),析出沉淀,过滤,少量甲醇洗涤后干燥。
实施例3.2:蓝萼甲素及蓝萼甲素噻唑衍生物盐酸盐水溶性测定
步骤(1):蓝萼甲素、IIa盐酸盐、IIb盐酸盐、IIh盐酸盐的饱和溶液的制备:称取2~4mg蓝萼甲素、实施例3.1制备所得IIa盐酸盐、IIb盐酸盐、IIh盐酸盐,分别加入到1mL蒸馏水中,25℃条件下震荡24小时,离心后得上清液。
步骤(2):蓝萼甲素、IIa盐酸盐、IIb盐酸盐、IIh盐酸盐的饱和溶液浓度的测定:用HPLC一点标定法测定所述化合物的水溶性。
具体地,取上述步骤(1)制备的饱和溶液10mL,注入HPLC,测定吸收峰面积。HPLC条件:WatersμBondapakC18(300mm×3.9mm);流速0.5mL/min;紫外检测波长254nm。流动相:蓝萼甲素,70%乙腈-水(0.1%三氟乙酸);IIa盐酸盐、IIb盐酸盐、IIh盐酸盐,40%乙腈-水(0.1%三氟乙酸)。取配制的已知准确浓度的蓝萼甲素、IIa、IIb、IIh水溶液100mL,与上述相同的HPLC条件下,测定吸收峰面积。比较吸收峰面积,计算饱和水溶液的浓度。
实验结果显示:蓝萼甲素、IIa盐酸盐、IIb盐酸盐、IIh盐酸盐饱和水溶液的浓度分别为:0.22mg/mL,80.5mg/mL,35.2mg/mL,60.8mg/mL。
实施例4:蓝萼甲素及蓝萼甲素噻唑衍生物的药效实验
针对人肝癌HepG2细胞、人大细胞肺癌NCI-H460细胞、人绒毛膜癌JEG-3细胞、人急性(早幼)粒细胞白血病HL-60细胞、人慢性粒细胞白血病K562细胞、人宫颈癌Hela细胞的生长抑制作用的药效学实验。
1.药物与试剂:受试样品,DMEM、1640培养基,10%灭活小牛血清(FBS),PBS溶解液,二甲基亚砜(DMSO),三联液(10%SDS+5%异丙醇+12mMHCl),噻唑蓝(MTT),阿霉素(阳性对照药)。
2.仪器:超净工作台,CO2培养箱,多功能倒置显微镜,离心机,自动酶标仪,96孔培养板。
3.细胞株:人肝癌HepG2肿瘤细胞、人大细胞肺癌NCI-H460细胞、人绒毛膜癌JEG-3细胞、人急性(早幼)粒细胞白血病HL-60细胞、人慢性粒细胞白血病K562细胞、人宫颈癌Hela细胞。
4.样品配制:取按照上述实施例2制备得到的蓝萼甲素的2-胺基噻唑衍生物IIa、蓝萼甲素的2-甲胺基噻唑衍生物IIb、蓝萼甲素的2-乙胺基噻唑衍生物IIc、蓝萼甲素的2-丙胺基噻唑衍生物IId、蓝萼甲素的2-异丙胺基噻唑衍生物IIe、蓝萼甲素的2-正丁胺基噻唑衍生物IIf、蓝萼甲素的2-正己胺基噻唑衍生物IIg、蓝萼甲素的2-烯丙胺基噻唑衍生物IIh、蓝萼甲素的2-环己胺基噻唑衍生物IIi、蓝萼甲素的2-苯胺基噻唑衍生物IIj、蓝萼甲素的2-苄胺基噻唑衍生物IIk,用DMSO溶解化合物,超声溶解,浓度为100mM,所得药物溶液-20℃条件下储存。
5.实验方法
步骤1:贴壁细胞的药物MTT实验,其进一步包括:
所述贴壁细胞包括人肝癌HepG2肿瘤细胞、人大细胞肺癌NCI-H460细胞、人绒毛膜癌JEG-3细胞、人大细胞肺癌NCI-H460细胞、人宫颈癌Hela细胞。
步骤1.1:收集对数生长期细胞,用完全DMEM培养基悬浮,并调整细胞悬液浓度为3×104/mL,接种96孔细胞培养板,100mL/孔。置37℃,5%CO2培养箱培养24小时,弃去上清,加入新鲜完全DMEM培养基,90mL/孔,并加入不同浓度待测药物溶液,10mL/孔,每个浓度设3个复孔;空白孔加入DMEM培养基10mL/孔;本底孔加入不含细胞的培养基100mL/孔。
步骤1.2:置37℃,5%CO2孵育48小时。
步骤1.3:每孔加入100uLMTT溶液(0.5mg/mL,不完全DMEM培养基配制),继续置培养箱孵育4小时。
步骤1.4:4小时后终止培养,弃去上清,每孔加入150mL二甲基亚砜,置摇床上低速振荡5min,使结晶物充分溶解。
步骤1.5:在酶联免疫检测仪570nm处测量各孔的吸光值。
步骤2:悬浮细胞的药物MTT实验,其进一步包括:
所述悬浮细胞包括人急性(早幼)粒细胞白血病HL-60细胞、人慢性粒细胞白血病K562细胞。
步骤2.1:收集对数生长期细胞,用完全RPMI1640培养基悬浮,细胞计数,并调整细胞浓度为3×105/mL,接种96孔细胞培养板,90mL/孔。加入不同浓度待测药物溶液,10mL/孔,每个浓度设3个复孔;空白孔加入1640培养基10mL/孔;本底孔加入不含细胞的培养基100mL/孔。
步骤2.2:置37℃,5%CO2孵育48小时。
步骤2.3:每孔加入10mLMTT溶液(5mg/1mL,1640培养基配制),继续置培养箱孵育4小时。
步骤2.4:加入三联液(10%SDS+5%异丙醇+12mMHCl),10mL/孔,37℃孵育12小时。
步骤2.5:在酶标仪检测各孔OD值,检测波长570nm。
6.实验结果:蓝萼甲素的噻唑衍生物对人肝癌HepG2细胞、人大细胞肺癌NCI-H460细胞、人绒毛膜癌JEG-3细胞、人急性(早幼)粒细胞白血病HL-60细胞、人慢性粒细胞白血病K562细胞、人宫颈癌Hela细胞生长抑制作用如下表所示:
表1:蓝萼甲素的噻唑衍生物IIa-IIk对癌瘤细胞株增殖抑制结果
7.实验结果表明:实施例2制备所得蓝萼甲素的噻唑衍生物IIa-IIk对人肝癌HepG2细胞、人大细胞肺癌NCI-H460细胞、人绒毛膜癌JEG-3细胞、人急性(早幼)粒细胞白血病HL-60细胞、人慢性粒细胞白血病K562细胞、人宫颈癌Hela细胞等癌瘤细胞株显示很强的细胞增殖抑制活性。
8.结论:实施例2制备所得蓝萼甲素的噻唑衍生物IIa-IIk,具有制备抗癌药物的应用前景,以及其应用于癌症患者。其在治疗肝癌、肺癌、宫颈癌、绒毛膜癌、急性粒细胞白血病及慢性粒细胞白血病方面有特效,尤其是白血病方面明显优于蓝萼甲素。
上述内容为本发明的具体实施例的例举,对于其中未详尽表述的试剂、设备、操作方法等,应当理解为采取本领域已有的普通及常规试剂、设备、操作方法等来予以实施。
虽然上文中已经用一般性说明及具体实施方案做了详尽的阐述,但本发明上述实施例仅为说明本发明技术方案之用,仅为本发明技术方案的例举,并不限于本发明的技术方案及其保护范围。在本发明基础上采用等同技术手段、等同试剂等对本发明权利要求书及说明公开书所公开的技术方案的一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的修改或改进均属于本发明要求保护的范围,应当认为是没有超出本发明权利要求书及说明书所公开的范围。
Claims (8)
1.一种蓝萼甲素的噻唑衍生物,其特征在于,该类衍生物具有式II所示结构:
其中R为氢、甲基、乙基、正丙基、异丙基、正丁基、正己基、烯丙基、环己基、苯基或苄基。
2.权利要求1所述的噻唑衍生物的制备方法,其特征在于,该方法包括以下步骤:以蓝萼甲素为先导化合物,对其A环进行结构修饰,先得到重要的中间产物2-溴代蓝萼甲素,继而与硫脲类化合物通过Hantzsch反应,得到A环上骈合噻唑的蓝萼甲素衍生物。
3.根据权利要求2所述的制备方法,其特征在于,该方法包括如下步骤:
(1)步骤1:以天然产物蓝萼甲素和三溴吡啶鎓为原料,低温条件下于有机溶剂中发生取代反应,硅胶柱层析分离纯化,得蓝萼甲素的α-溴代酮中间产物,即2-溴代蓝萼甲素;
其化学反应式如下所示:
(2)步骤2:将上述步骤1所得的2-溴代蓝萼甲素与硫脲类化合物在有机溶剂中加热回流,硅胶柱层析分离纯化,得到蓝萼甲素的噻唑衍生物;
其化学反应式如下所示:
4.根据权利要求2或3所述的方法,其特征在于,所述步骤(1)具体为:取蓝萼甲素溶于有机溶剂中,低温条件下搅拌10-15分钟,三溴吡啶鎓溶于相同有机溶剂中,缓慢逐滴加入反应体系,低温条件下搅拌反应,然后以5-7倍量反应液体积的蒸馏水淬灭反应,二氯甲烷萃取,有机相经饱和食盐水洗涤后无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析分离,洗脱液为石油醚/乙酸乙酯按照体积比2/1,得到所需的重要中间产物2-溴代蓝萼甲素。
5.根据权利要求2或3所述的方法,其特征在于,所述步骤(2)具体为,将步骤(1)制备得到的2-溴代蓝萼甲素和硫脲类化合物溶于有机溶剂中,加热回流,反应结束后冷却,以3-5倍量反应液体积的饱和NaHCO3溶液碱化,再以蒸馏水稀释至反应液体积的10-15倍,二氯甲烷萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱层析分离,洗脱液为石油醚/乙酸乙酯按照体积比为2/1,即可得到蓝萼甲素的噻唑衍生物。
6.含权利要求1所述噻唑衍生物的制剂,该制剂由噻唑衍生物与药学上可接受的载体组成。
7.权利要求1所述噻唑衍生物在制备治疗肿瘤的药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述肿瘤为肝癌、宫颈癌、白血病、绒毛膜癌和肺癌。
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