CN108586726A - 一种peg化姜黄素衍生物及其在抗肿瘤药物中的应用 - Google Patents
一种peg化姜黄素衍生物及其在抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种漆黄素组合物及其制备方法,该漆黄素组合物的结构通式如下:其中,聚乙二醇的分子式为:
Description
技术领域
本发明涉及医药合成领域,具体涉及一种PEG化姜黄素衍生物及其制备方法及其在制备抗肿瘤药物中的应用。
背景技术
漆黄素(fisetin,FIS,3,3',4',7-四羟基黄酮),又名非瑟酮,是从漆树科植物木腊树(Rhus succedanea L)等植物中提取的一种天然类黄酮化合物。本品亦存在
于蔬菜和水果中,如苹果、柿子、葡萄、猕猴桃、草莓、洋葱和黄瓜等。漆黄素具有抗氧化、抗炎等药理学特性。近年来,随着其抗肿瘤作用机理不断被揭示,非瑟酮在肿瘤治疗方面的潜在价值也越来越引起药学界的关注。然而与其他黄酮类药物相似,其存在的稳定性差、水溶解度低,生物利用度低等问题严重限制了非瑟酮的开发与应用。因此提高其生物利用度,增强抗肿瘤活性,对促进非瑟酮的临床应用具有重要的意义。
聚乙二醇(polyethylene glycol,PEG)是由环氧乙烷与水或乙二醇逐步发生加成聚合而得到的一类分子量较低的水溶性聚醚。小分子量的低聚聚乙二醇为无色、无臭有吸湿性的粘稠液体,分子中既有醚链,又有羟基,故具有独特的溶解性能,生物相容性好,在医药、材料和工程等领域具有很重要的应用前景。
目前,国内外对非瑟酮新型给药系统的研究虽取得一定的进展,所报道的文献也有所增加,但仍比较有限,仅有漆黄素包合物、脂质体、纳米粒等少数新剂型的相关报道。微粒递药系统,如脂质体、纳米粒、纳米乳等对改善非瑟酮的抗肿瘤的理化性质、缓控释作用、靶向性、降低毒副作用等,均存在良好的作用。但是现有研究多基于漆黄素与其他物质通过物理结合的方式,以期达到所需的药物性能。很少有通过化学键结合的方式,改变漆黄素的结构,从而达到药用性能的变化。目前报道的通过化学键连接改变漆黄素结构的仅有聚乳酸和糖类化合物,二者都可以改善漆黄素的水溶性,生物活性,缺点在于无法提高载药量,也无法与其他抗癌药物结合进行协同治疗。
发明内容
因此,本实验提出一种新型的漆黄素组合物,利用PEG无毒、易于结合的特性,把PEG与漆黄素连接起来。PEG负载的漆黄素的前药不仅具有良好的水溶性,而且大大延长了药物的半衰期,使其在血浆中的存在时间显著增加,并且从而提高疗效。最重要的特征是可以在PEG的另一端组合其他需要的抗肿瘤药物,不仅提高了药物的负载量,而且可以实现多种药物协同治疗的效果,提高药物的抗肿瘤活性。
本发明的目的在于提供一种PEG化漆黄素组合物及其制备方法及其在抗肿瘤药物方面的应用,该漆黄素组合物药物负载量高,在体内循环半衰期长,且经过PEG修饰的漆黄素水溶性好,抗肿瘤活性高。
一种PEG化漆黄素组合物及其制备方法,该PEG化漆黄素组合物的结构通式如下:其中,PEG的分子式为:n为20-48的整数,A为氨基,羧基,甲氧基,卤素,巯基等,R为漆黄素,紫檀芪,紫杉醇,姜黄素等。
进一步地,所述PEG具有以下结构:
其中,n为20-48的整数,A为氨基,羧基,甲氧基,卤素,巯基等。
进一步地,所述R具有以下结构:
进一步地,所述PEG化漆黄素组合物是以下化合物中的一种:
其中,n为20-48的整数。
进一步地,所述PEG化漆黄素组合物的合成路线为:
步骤Ⅰ化合物1与三苯基膦和四溴化碳反应得到化合物2;
步骤Ⅱ化合物2与化合物3缩合得到化合物4;
步骤Ⅲ化合物4水解得到化合物5;
步骤Ⅳ化合物5水解得到化合物6;
更进一步地,步骤Ⅰ是以二氯甲烷为溶剂,化合物1、三苯基膦和四溴化碳于0-25℃的反应温度,8-12h的反应时间下进行的。
更进一步地,步骤Ⅱ是以化合物3为底物,丙酮为溶剂,碳酸钾作碱的条件下,于0-25℃的反应温度,搅拌1-4h时间后,加入化合物2,12-18h的反应时间下进行的。
更进一步地,步骤Ⅲ是以甲醇为溶剂,化合物4为底物,3mol/L盐酸存在的条件下,煮沸反应8-12h进行的。
更进一步地,所述步骤Ⅳ是以氢溴酸、冰乙酸为溶剂,化合物5为底物,T密封的条件下,于加热煮沸反应24h进行的。
进一步地,所述PEG化漆黄素组合物用于制备抗肿瘤药物的应用。
本发明具有以下有益效果:
1.PEG修饰后的漆黄素,其药物水溶性增强,半衰期延长,药物负载率高,并同时增加了药物活性;
2.PEG修饰后的漆黄素半衰期延长,具有良好的缓释效果。
具体实施方式
下面结合实施例描述本发明的结合物及其制备方法,它不限制本发明,本发明的范围由权利要求限定。
实施例1:PEG24-漆黄素组合物6e的制备
(1)化合物2的制备
将10mmol化合物1溶于300ml二氯甲烷中,在0℃下,加入11mmol的三苯基膦,11mmol的四溴化碳,然后25℃搅拌10h。反应完毕,旋干溶液,得到粗品。粗品用层析柱纯化,得到9mmol化合物2。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:7.96(d,1H);7.15(d,1H);6.93(d,1H);6.72(d,2H);6.45(d,1H);4.08(t,2H);3.848(t,J=4.0Hz,2H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
(2)化合物4的制备
将6mmol化合物3溶于300ml丙酮中,加入60mmol碳酸钾,然后25℃剧烈搅拌4h后,加入9mmol化合物2。TLC监测原料点消失后,滤除固体杂质,用少量丙酮洗涤固体,合并,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到8mmol化合物4。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:7.96-8.02(M,2H);7.15-7.27(M,3H);6.82-6.93(m,3H);6.72(m,3H);6.45(d,1H);6.02(t,J=4.0Hz,4H);4.08(t,4H);3.83(s,J=4.0Hz,3H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);3.3(s,J=4.0Hz,6H)。
(3)化合物5的制备
将8mmol化合物4溶于300ml无水甲醇中,滴加由20ml甲醇,60ml HCl(3mol/L)的混合溶液,30分钟滴完,TLC监测反应至原料点消失,停止反应,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到7mmol化合物5。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:7.96-8.02(M,2H);7.15-7.27(M,3H);6.82-6.93(m,3H);6.72(m,3H);6.45(d,1H);4.08(t,4H);3.83(s,J=4.0Hz,3H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
(4)化合物6的制备
将7mmol化合物5溶于20ml冰醋酸和150ml氢溴酸,密封,油浴加热到回流,保持24h后停止,冷却,转入200水中,然后用200ml二氯甲烷萃取,减压蒸出溶剂,乙醚沉降后干燥,得到6mmol化合物6。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:7.96(d,2H);7.15(d,2H);6.93(d,2H);6.72(d,4H);6.45(d,,2H);4.08(t,2H);3.848(t,J=4.0Hz,2H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
实施例2:PEG24-漆黄素组合物6f的制备
(1)化合物2的制备
将10mmol化合物1溶于300ml二氯甲烷中,在0℃下,加入11mmol的三苯基膦,11mmol的四溴化碳,然后25℃搅拌10h。反应完毕,旋干溶液,得到粗品。粗品用层析柱纯化,得到9mmol化合物2。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:7.82(d,2H);7.29(d,2H);6.95(s,2H);6.84(d,2H);6.22(d,1H);4.31(s,2H);3.87(t,2H);3.83(s,J=4.0Hz,6H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
(2)化合物4的制备
将6mmol化合物3溶于300ml丙酮中,加入60mmol碳酸钾,然后25℃剧烈搅拌4h后,加入9mmol化合物2。TLC监测原料点消失后,滤除固体杂质,用少量丙酮洗涤固体,合并,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到8mmol化合物4。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.02(d,2H);7.82(d,2H);7.29(d,2H);7.15-7.21(M,2H);6.95(m,3H);6.84(m,3H);6.74(d,1H);6.22(d,1H);6.02(t,J=4.0Hz,4H);4.31(s,2H);4.08(t,2H);3.83(s,J=4.0Hz,9H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);3.3(s,J=4.0Hz,6H)。
(3)化合物5的制备
将8mmol化合物4溶于300ml无水甲醇中,滴加由20ml甲醇,60ml HCl(3mol/L)的混合溶液,30分钟滴完,TLC监测反应至原料点消失,停止反应,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到7mmol化合物5。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.02(d,2H);7.82(d,2H);7.29(d,2H);7.15-7.21(M,2H);6.95(m,3H);6.84(m,3H);6.74(d,1H);6.22(d,1H);4.31(s,2H);4.08(t,2H);3.83(s,J=4.0Hz,9H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
(4)化合物6的制备
将7mmol化合物5溶于20ml冰醋酸和150ml氢溴酸,密封,油浴加热到回流,保持24h后停止,冷却,转入200水中,然后用200ml二氯甲烷萃取,减压蒸出溶剂,乙醚沉降后干燥,得到6mmol化合物6。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.02(d,2H);7.82(d,2H);7.29(d,2H);7.15-7.21(M,2H);6.95(m,3H);6.84(m,3H);6.74(d,1H);6.22(d,1H);4.31(s,2H);4.08(t,2H);3.83(s,J=4.0Hz,6H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
实施例3:PEG24-漆黄素组合物6g的制备
(1)化合物2的制备
将10mmol化合物1溶于300ml二氯甲烷中,在0℃下,加入11mmol的三苯基膦,11mmol的四溴化碳,然后25℃搅拌10h。反应完毕,旋干溶液,得到粗品。粗品用层析柱纯化,得到9mmol化合物2。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.03-8.07(m,4H);7.63-7.70(m,6H);7.40(d,2H);7.22-7.29(m,3H);6.49(t,1H);5.59(d,1H);5.51(s,1H);5.06-5.11(m,3H);4.8(d,2H);4.4(t,1H);4.01(d,1H);;3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);2.8(s,1H);2.21(s,6H);1.77-1.82(m,7H);1.44(s,2H);1.3(s,3H)。
(2)化合物4的制备
将6mmol化合物3溶于300ml丙酮中,加入60mmol碳酸钾,然后25℃剧烈搅拌4h后,加入9mmol化合物2。TLC监测原料点消失后,滤除固体杂质,用少量丙酮洗涤固体,合并,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到8mmol化合物4。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.03-8.07(m,5H);7.5-7.70(m,6H);7.40(d,2H);7.22-7.29(m,5H);;6.94(d,1H);6.82(s,1H);6.74(d,2H);6.02(s,4H);5.83(d,1H);5.51(s,1H);4.80-5.05(m,2H);4.68(d,1H);4.4(t,1H);4.01(m,3H);3.83(s,3H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);3.3(s,6H);2.8(d,1H);2.21(s,6H);1.77-1.82(m,7H);1.44(s,2H);1.3(s,3H)。
(3)化合物5的制备
将8mmol化合物4溶于300ml无水甲醇中,滴加由20ml甲醇,60ml HCl(3mol/L)的混合溶液,30分钟滴完,TLC监测反应至原料点消失,停止反应,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到7mmol化合物5。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.03-8.07(m,5H);7.5-7.70(m,6H);7.40(d,2H);7.22-7.29(m,5H);;6.94(d,1H);6.82(s,1H);6.74(d,2H);5.83(d,1H);5.51(s,1H);4.80-5.05(m,2H);4.68(d,1H);4.4(t,1H);4.01(m,3H);3.83(s,3H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);2.8(d,1H);2.21(s,6H);1.77-1.82(m,7H);1.44(s,2H);1.3(s,3H)。
(4)化合物6的制备
将7mmol化合物5溶于20ml冰醋酸和150ml氢溴酸,密封,油浴加热到回流,保持24h后停止,冷却,转入200水中,然后用200ml二氯甲烷萃取,减压蒸出溶剂,乙醚沉降后干燥,得到6mmol化合物6。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.03-8.07(m,5H);7.5-7.70(m,6H);7.40(d,2H);7.22-7.29(m,5H);;6.94(d,1H);6.82(s,1H);6.74(d,2H);5.83(d,1H);5.51(s,1H);4.80-5.05(m,2H);4.68(d,1H);4.4(t,1H);4.01(m,3H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);2.8(d,1H);2.21(s,6H);1.77-1.82(m,7H);1.44(s,2H);1.3(s,3H)。
实施例4:PEG24-漆黄素组合物6h的制备
(1)化合物2的制备
将10mmol化合物1溶于300ml二氯甲烷中,在0℃下,加入11mmol的三苯基膦,11mmol的四溴化碳,然后25℃搅拌10h。反应完毕,旋干溶液,得到粗品。粗品用层析柱纯化,得到9mmol化合物2。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:7.82(d,1H);7.22(s,2H);6.7-7.16(m,9H);4.31(t,2H);3.87(t,2H);3.83(s,J=4.0Hz,6H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
(2)化合物4的制备
将6mmol化合物3溶于300ml丙酮中,加入60mmol碳酸钾,然后25℃剧烈搅拌4h后,加入9mmol化合物2。TLC监测原料点消失后,滤除固体杂质,用少量丙酮洗涤固体,合并,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到8mmol化合物4。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.02(d,1H);7.82(d,1H);6.74-7.22(m,15H);6.02(s,J=4.0Hz,4H);4.31(t,2H);4.08(t,2H);3.83(s,J=4.0Hz,9H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H);3.3(s,J=4.0Hz,6H)。
(3)化合物5的制备
将8mmol化合物4溶于300ml无水甲醇中,滴加由20ml甲醇,60ml HCl(3mol/L)的混合溶液,30分钟滴完,TLC监测反应至原料点消失,停止反应,减压蒸出溶剂,得到粗品。粗品用层析柱纯化,得到7mmol化合物5。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.02(d,1H);7.82(d,1H);6.74-7.22(m,15H);4.31(t,2H);4.08(t,2H);3.83(s,J=4.0Hz,9H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
(4)化合物6的制备
将7mmol化合物5溶于20ml冰醋酸和150ml氢溴酸,密封,油浴加热到回流,保持24h后停止,冷却,转入200水中,然后用200ml二氯甲烷萃取,减压蒸出溶剂,乙醚沉降后干燥,得到6mmol化合物6。收率:90%。核磁数据如下:1 HNMR(400MHz,CDCl3):δ:8.02(d,1H);7.82(d,1H);6.74-7.22(m,15H);4.31(t,2H);4.08(t,2H);3.83(s,J=4.0Hz,6H);3.579~3.540(m,92H);3.490(t,J=4.0Hz,2H)。
Claims (9)
1.一种PEG化漆黄素衍生物,该PEG化漆黄素衍生物的结构通式如下:其中,PEG的分子式为:n为20-48的整数,A为氨基,羧基,甲氧基,卤素,巯基,R为漆黄素,紫檀芪,紫杉醇,姜黄素。
2.根据权利要求1所述的一种PEG化漆黄素衍生物,其特征在于,所述R具有以下结构:
3.根据权利要求2所述的一种PEG化漆黄素衍生物,其特征在于,所述PEG化漆黄素组合物是以下化合物中的一种:
其中,n为20-48的整数。
4.制备如权利要求1所述的一种PEG化漆黄素衍生物,其特征在于,所述PEG化漆黄素衍生物的合成路线为:
5.根据权利要求4所述的一种PEG化漆黄素组合物的制备方法,其特征在于,步骤Ⅰ是以二氯甲烷为溶剂,化合物1、三苯基膦和四溴化碳于0-25℃的反应温度,8-12h的反应时间下进行的。
6.根据权利要求4所述的一种PEG化漆黄素组合物的制备方法,其特征在于,步骤Ⅱ是以化合物3为底物,丙酮为溶剂,碳酸钾作碱的条件下,于0-25℃的反应温度,反应1-4h时间后,加入化合物2,反应12-18h。
7.根据权利要求6所述的一种PEG化漆黄素组合物的制备方法,其特征在于,步骤Ⅲ是以甲醇为溶剂,化合物4为底物,3mol/L盐酸存在的条件下,煮沸反应8-12h进行的。
8.根据权利要求7所述的一种PEG化漆黄素组合物的制备方法,其特征在于,所述步骤Ⅳ是以氢溴酸、冰乙酸为溶剂,化合物5为底物,T密封的条件下,于加热煮沸反应24h进行的。
9.根据权利要求1-3任一项所述的PEG化漆黄素衍生物,其特征在于,所述PEG化漆黄素衍生物用于制备抗肿瘤药物的应用。
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CN114981263A (zh) * | 2019-11-26 | 2022-08-30 | 贝诺生物有限公司 | 新型槲皮素氧化还原衍生物及作为bet抑制剂的用途 |
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CN112194788A (zh) * | 2020-09-15 | 2021-01-08 | 石家庄学院 | 一种水溶性氟苯尼考及其制备方法 |
CN112194788B (zh) * | 2020-09-15 | 2022-08-02 | 石家庄学院 | 一种水溶性氟苯尼考及其制备方法 |
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