CN105541780B - 一类缬草素衍生物、含其的药物组合物及其在抗肿瘤中的应用 - Google Patents
一类缬草素衍生物、含其的药物组合物及其在抗肿瘤中的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
本发明提供了一类缬草素衍生物、含其的药物组合物及其在抗肿瘤中的应用。本发明以简单易得的天然产物京尼平为原料,通过半合成的方法,改变以往天然提取物的结构限制,设计并合成了一系列具有抗肿瘤活性的缬草素衍生物,并在体外实验显示出了较好的抗肿瘤活性,可以通过进一步的实验将此类化合物应用于抗肿瘤药物研究。
Description
技术领域
本发明属于新化合物制备领域,具体是一类缬草素衍生物、含其的药物组合物及其在抗肿瘤中的应用。
背景技术
肿瘤是当今危害人类生命和健康的严重疾病之一。并逐渐成为了人类的头号杀手。因此,提高肿瘤的治疗能力、寻找有效的治疗药物意义重大。
缬草素,是一大类天然化合物家族,属于环烯醚萜类。其具有多种生物活性,在传统中药中用于治疗癫痫,精神分裂,神经障碍疾病。而在现代临床应用中,其主要作为温和镇静剂来治疗轻度神经衰弱和神经紧张。通过对良好活性分子的结构修饰和改造,是合成高活性分子的重要手段,也是药物研发的有效途径之一。本发明涉及了对缬草素及其类似物的衍生化,获得了一系列具有抗肿瘤活性的化合物。
发明内容
针对现有技术的不足,本发明旨在合成一系列缬草素衍生物,为开发一种良好的缬草素类抗肿瘤药物奠定基础。
术语说明:本文所用术语“芳基”是指5到12个碳原子的全碳单环或稠合多环基团,具有完全共轭的π电子系统。芳环的非限制性实例有:苯环、萘环和蒽环。芳环可以是无取代或取代的。芳环的取代基选自卤素、硝基、氨基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基;
术语“药学可接受衍生物”是指所选化合物的盐和溶剂合物。
本文所用术语“溶剂合物”是指由溶质(例如:本发明的通式(I)~通式(Ⅸ)化合物)和溶剂形成的可变化学计量的复合物。为了本发明的目的,所述溶剂不能干扰溶质的生物学活性。合适的溶剂的实例包括但不限于水、甲醇、乙醇和乙酸。优选使用的溶剂为药学可接受溶剂。合适的药学可接受溶剂包括但不限于水、乙醇和乙酸。更优选地,所用溶剂为水。
为实现上述目的,本发明的技术方案是:
缬草素衍生物及其在药学上可接受的盐,结构如通式Ⅰ,Ⅱ所示:
其中,R1为1-10个碳的烷基,1-10个碳的芳基;
R2为1-10个碳的烷基或1-10个碳的脂肪酰基;
含所画结构及其光学异构体及其溶剂合物;
所述烷基包括有取代基的烷基及环烷基;
所述芳基包括有取代的芳基。
本发明进一步优选包括以下具体的化合物:以下命名将设定为双烯甲基缬草素、环氧甲基缬草素;
1-甲基-7-异戊酸基双烯甲基缬草素、
1-甲基-7-异戊酸基环氧甲基缬草素、
1-异戊酰基-7-乙酸基双烯甲基缬草素、
1-异戊酰基-7-乙酸基环氧甲基缬草素、
1-异戊酰基-7-异戊酸基环氧甲基缬草素、
1-异戊酰基-7-环己酸基环氧甲基缬草素、
1-异戊酰基-7-苯甲酸基环氧甲基缬草素、
1-异戊酰基-7-异辛酸基环氧甲基缬草素、
1-异戊酰基-7-正己酸基环氧甲基缬草素、
1-异戊酰基-7-正辛酸基环氧甲基缬草素、
1-异戊酰基-7正葵酸基环氧甲基缬草素;
所述缬草衍生物及其上述化合物的光学异构体或其药学上可接受的溶剂合物。
本发明的第二个目的是提供一种药物组合物,所述药物组合物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂,所述的活性组分可以是本发明的取代氮杂环类化合物、所述化合物的光学异构体、所述化合物或其光学异构体在药学上可接受的盐、所述化合物或其光学异构体的溶剂合物中的任意一种或任意多种。
所述载体包括药学领域的常规稀释剂,赋形剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味剂,甜味剂等。本发明药物可以制成片剂,粉剂,粒剂,胶囊,口服液及注射用药等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明还提供通式Ⅰ,Ⅱ所述的化合物、及其光学异构体或其药学上可接受的盐或溶剂合物在制备抗肿瘤药物中的用途。所述的肿瘤为乳腺癌、肉瘤、肺癌、前列腺癌、结肠癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、肝癌、卵巢癌、外阴癌、子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌、多发性骨髓瘤。
所述缬草衍生物的合成方法如图1所示。
与现有技术相比,本发明的优势是:
以简单易得的天然产物京尼平为原料,通过半合成的方法,改变以往天然提取物的结构限制,设计并合成了一系列具有抗肿瘤活性的缬草素衍生物,并在体外实验显示出了较好的抗肿瘤活性,可以通过进一步的实验将此类化合物应用于抗肿瘤药物研究。
附图说明
图1是本申请的衍生物的合成路线图;
图2是不同浓度的缬草素(DI)以及缬草素类似物Y7对肿瘤细胞的体外增殖抑制作用结果示意图。
具体实施方式
下面通过实施例进一步详细描述本发明,但本发明不仅仅局限于以下实施例。
实施例1缬草素衍生物的合成
1.1仪器与试剂
1H核磁共振谱采用Bruker AVII 500型超导核磁共振仪;质谱采用Agilent LCMS-2020。
京尼平从嘉兴艾森化工购买,Amberlyst15树脂从上海达瑞购买,其他试剂均为国产分析纯试剂,使用前均未经进一步纯化。
1.2中间体的合成
中间体s2的合成:
将京尼平s1(1.19g,5.38mmol)溶于10ml甲醇,再加入3.51g的Amberlyst15树脂,搅拌过夜。过滤除去树脂,滤液减压回收溶剂,柱层析得无色油状物1.07g,收率84.7%。LC-MS:241.3(M+H)。
中间体s3的合成:
将中间体s2(1.07g,4.42mmol)溶于11ml甲苯中,依次加入二苯基二硫醚(847mg,5.52mmol)和三正丁基磷(1.32ml,5.31mmol)。室温下搅拌1个小时,减压回收溶剂,柱层析得无色油状物1.0g,收率71%。LC-MS:333(M+H)。
中间体s3.5的合成:
冰浴条件下,将中间体s3(1.0g,3.01mmol)溶于10ml甲醇中,缓慢加入过硫酸氢钾复合盐(1.1g,1.81mmol),搅拌1h,反应完全后,加入5ml饱和亚硫酸钠溶液淬灭,用乙酸乙酯(15mlx3)萃取,合并有机层,饱和食盐水洗,无水硫酸钠干燥,减压回收溶剂得无色油状物785mg,收率75%。LC-MS:349(M+H)。
中间体s4的合成:
将中间体s3.5(300mg,0.86mmol)溶于15ml甲醇中,加入亚磷酸三甲酯(152μl,1.29mmol),90℃回流,搅拌过夜,冷却到室温后,加入15ml饱和食盐水,反应液用乙酸乙酯(30mlx3)萃取,合并有机层,饱和食盐水洗,无水硫酸钠干燥,减压回收溶剂,柱层析得无色油状物206mg,收率99%。LC-MS:241(M+H)。
中间体s5的合成:
将中间体s4(46.5mg,0.15mmol)溶于8ml甲苯中,加入乙酰丙酮氧钒(3.9mg,0.015mmol),搅拌均匀后加入70%叔丁基过氧化氢水溶液(62μl,0.45mmol),室温下反应2小时,待反应完全后加入5ml碳酸氢钠水溶液,搅拌10分钟,用乙酸乙酯(5mlx3)萃取,合并有机层,饱和食盐水洗,无水硫酸钠干燥,减压回收溶剂得无色油状物50mg,收率100%。
中间体Z1的合成
将中间体s3(500mg,1.50mmol)溶于8ml四氢呋喃中,加入10%的盐酸溶液4ml,加热至60℃,搅拌过夜。反应结束后冷却到室温,用乙酸乙酯(15mlx3)萃取,合并有机层,饱和食盐水洗,无水硫酸钠干燥,减压回收溶剂,得无色油状物198mg,收率41.3%。LC-MS:319(M+H)。
中间体Z2的合成
在冰浴条件下,将羰基二咪唑(6.74g,41.6mmol)溶于60ml二氯甲烷中,再加入DBU(250μl,1.66mmol)、异戊酸(4.6ml,41.6mmol),搅拌10分钟后,加入中间体Z1(2.64g,8.32mmol),室温下搅拌过夜。待反应完全后,减压回收溶剂,加入60ml饱和食盐水,用乙酸乙酯(20mlx3)萃取,合并有机层,再分别用5%盐酸(15mlx2),30ml饱和碳酸氢钠溶液,饱和食盐水洗,无水硫酸钠干燥,减压回收溶剂,柱层析得淡黄色油状物1.18g,收率35.2%。LC-MS:403(M+H)。
中间体s6的合成,参照中间体s3.5的合成,淡黄色油状液体,收率95%。LC-MS:419(M+H)。
中间体Z5的合成,参照中间体s4的合成,淡黄色油状液体,收率62%。LC-MS:311(M+H)。
中间体s7的合成,参照中间体s5的合成,淡黄色油状液体,收率100%。LC-MS:327(M+H)。
1.3目标化合物的合成
目标化合物Z3的合成:
在冰浴条件下,将羰基二咪唑(675mg,4.16mmol)溶于6ml二氯甲烷中,再加入DBU(25μl,0.166mmol)、异戊酸(459μl,4.16mmol),搅拌10分钟后,加入中间体s4(200mg,0.832mmol),室温下搅拌过夜。待反应完全后,减压蒸馏除去大部分有机溶剂,加入6ml饱和食盐水,用乙酸乙酯(5ml)萃取3次,合并有机层,分别用5%盐酸(3mlx2),3ml饱和碳酸氢钠溶液,饱和食盐水洗,无水硫酸钠干燥,减压回收溶剂,柱层析得淡黄色油状物97.6mg,收率36.2%。
目标化合物Y1的合成:
冰浴条件下,将中间体s5(38.4mg,0.15mmol)溶于10ml甲苯中,加入三苯基膦(184mg,0.75mmol),异戊酸(46μl,0.45mmol),搅拌10分钟后加入偶氮二甲酸二乙酯(40μl,0.75mmol),室温下搅拌30分钟,减压蒸馏除去有机溶剂,柱层析得无色油状物50mg,收率92%。
所有目标化合物结构及核磁数据见表1。
表1目标化合物及部分中间体的核磁数据
实施例2缬草素衍生物抗肿瘤活性检测:
2.1仪器与试剂:
胎牛血清,0.25%胰酶-EDTA,PBS:美国Life Technologies公司;
RMPI-1640培养基:吉诺生物医药技术有限公司;
SRB粉末:美国Sigma Aldrich公司;
CO2培养箱:美国Thermo scientific公司;
Spectramax M3酶标仪:美国Molecular Devices公司;
细胞培养板:美国corning公司;
2.2实验步骤:
1)消化肿瘤细胞,调整细胞浓度为6×104/mL,96孔板中每孔加100μl(每孔含6,000个细胞),37℃、5%CO2培养24h后进行下一步试验;
2)分组:空白对照;缬草素阳性对照;0.8μM、4μM、20μM和40μM药物处理组;
3)用含不同浓度药物的培养基预处理肿瘤细胞,48h后,吸弃含药培养基;
4)每孔加入60μL预冷的10%三氯乙酸置于4℃冰箱固定1h。用水洗5遍后烘干,加入由1%冰醋酸配制的4mg/mL的SRB溶液50μL,染色20min。弃去SRB染液用1%冰醋酸洗5遍,烘干后加入150μL 10mM Tris-base,轻微振荡使晶体完全溶解,用酶标仪于515nm处测定每孔的吸光度(OD值),计算3个复孔的平均值和标准差。
2.3实验结果:通过在乳腺癌、胃癌、肺癌和胰腺癌共7个细胞株上得到的结果,所制备的缬草素类似物Y1-Y10,Z5对以上细胞株均表现出了较好的抗肿瘤活性,如表2所示。并且如图2所示,所制备的缬草素类似物表现出了较好的浓度相关性。另外,化合物Y7效果最优,对乳腺癌MCF-7、乳腺癌MDA-MB-231、肺癌H1975细胞株的IC50值达10.7μM、13.2μM、11.3μM。
表2:缬草素衍生物的IC50值
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均包含在本发明的保护范围之内。
Claims (3)
1.缬草素衍生物,结构如通式Ⅰ,Ⅱ所示:
其中,R1为1-10个碳的烷基或1-10个碳的芳基;
R2为1-10个碳的烷基或1-10个碳的脂肪酰基,且不包括通式Ⅰ中R1和R2为甲基的化合物。
2.根据权利要求1所述的缬草素衍生物,进一步包括以下具体的化合物:
1-甲基-7-异戊酸基双烯甲基缬草素、
1-甲基-7-异戊酸基环氧甲基缬草素、
1-异戊酰基-7-乙酸基双烯甲基缬草素、
1-异戊酰基-7-乙酸基环氧甲基缬草素、
1-异戊酰基-7-异戊酸基环氧甲基缬草素、
1-异戊酰基-7-环己酸基环氧甲基缬草素、
1-异戊酰基-7-苯甲酸基环氧甲基缬草素、
1-异戊酰基-7-异辛酸基环氧甲基缬草素、
1-异戊酰基-7-正己酸基环氧甲基缬草素、
1-异戊酰基-7-正辛酸基环氧甲基缬草素、
1-异戊酰基-7正葵酸基环氧甲基缬草素,
其中分别为双烯甲基缬草素、环氧甲基缬草素。
3.如权利要求1或2所述的缬草素衍生物在抗肿瘤方面的应用。
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