CN111423395A - 一种具有药物活性的1,3,4-硒二唑类化合物 - Google Patents
一种具有药物活性的1,3,4-硒二唑类化合物 Download PDFInfo
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Abstract
本发明属于生物医药领域,本发明提供了一种具有药物活性的1,3,4‑硒二唑类化合物,通过多种官能团的取代,来达到对肿瘤的抑制作用,抗氧化作用和细胞保护功能。本发明还提供了所述化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。目前有很多药物都含有噻二唑,因此合成带多种官能团的硒二唑衍生物使硒二唑可以作为噻二唑的生物电子等排体进行取代,进一步优化药用噻二唑类化合物活性,这将为新药物开发和应用等方面具有重要意义。
Description
本申请是分案申请,原申请发明创造名称为:一种具有药物活性的1,3,4-硒二唑类化合物,原申请的申请日是2015年12月14日,原申请的申请号为CN201510929374.6。
技术领域
本发明属于生物医药领域,具体涉及到一种具有药物活性的1,3,4-硒二唑类化合物。
背景技术
含硒的杂环具有抗氧化剂,抗炎,抗菌,抗病毒,抗肿瘤功效。硒化合物的抗肿瘤机制一般包括以下几个方面:具有细胞毒性作用,能够清除自由基,阻断癌细胞分裂增殖的信息传递,诱导细胞凋亡,调节机体免疫功能,抑制新生血管的生成和改变某些致癌物代谢的过程等。
有机硒化合物包括含硒杂环、二硒醚、硒醚、硒氰、甲基硒酸、含硒氨基酸(蛋白)、硒糖等几大类。含硒杂环化合物是有机硒化合物中的一大类,因其潜在的药理学活性引起越来越多的重视.比如依布硒啉(Ebselen)是最成功模拟谷胱甘肽过氧化物酶的小分子化合物,现已经进入三期临床研究。硒氰是硒化合物的一类,最早的硒氰要数4-亚苯基双(亚甲基)硒代氰酸酯(P-XSC)。硒唑呋喃对小鼠H1210白血病具有明显的抑制作用,硒唑呋喃也进入了I期临床的研究。1,3,4-硒二唑化合物对MCF-7人乳腺癌细胞表现出很好的抑制作用。硒形式的毒性较低,对小鼠的体重,肝毒性和肾毒很少,但却保留了硒对癌细胞的毒副作用。
发明内容
本发明的目的在于克服现有技术中的不足,提供一种硒二唑化合物并应用在抗氧化功能以及细胞保护功能药物中。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种具有药物活性的1,3,4-硒二唑类化合物,所述的化合物的化学结构式如下:
或者
所述(1)中的R6选自-NO2,H或卤素中的一种;R3选自-NO2和H中的一种;R2为-BoC,或者R2同时包含芳香杂环和羰基;R4、R5和R7均为H;
所述Cn代表1~20个碳的碳链;
所述X为N、O、S、P、Si中的一种。
在本发明中,所述(1)中化合物的结构式如下:
或者
或者
或者
本发明还提供了所述化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。
本发明提供了一种硒二唑类化合物,通过多种官能团的取代,来达到对肿瘤的抑制作用,抗氧化作用和细胞保护功能。
本发明还提供了所述化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。目前有很多药物都含有噻二唑,因此合成带多种官能团的硒二唑衍生物使硒二唑可以作为噻二唑的生物电子等排体进行取代,进一步优化药用噻二唑类化合物活性,这将为新药物开发和应用等方面具有重要意义。
附图说明
图1为化合物抗氧化作用示意图。
具体实施方式
本发明提供了一种具有药物活性的1,3,4-硒二唑类化合物,所述的化合物的化学结构式如下:
或者
所述(1)中的R6选自-NO2,H或卤素中的一种;R3选自-NO2和H中的一种;R2为-BoC,或者R2同时包含芳香杂环和羰基;R4、R5和R7均为H;
所述Cn代表1~20个碳的碳链;
所述X为N、O、S、P、Si中的一种。
在本发明中,所述(1)中化合物的结构式优选如下:
或者
或者
或者
本发明还提供了所述化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
制备方法过程以苯基硒脲为例列举如下:
苯基硒脲(1mmol;或其它硒脲),带羧酸基团化合物(0.2-4mmol),与5mlPOCl3混合均匀搅拌。升温至50-80℃,反应0.5-12h,停止油浴加热,将反应液减压抽干,缓慢倒入冰水,抽滤得滤饼,柱层析分离,干燥。得到产物,产率40~95%。
2-溴乙基-N-苯基胺基-1,3,4-硒二唑:
m/z 332(100%,M+H+)
1HNMR(500MHz,)δ10.37(s,1H),7.65–7.53(m,2H),7.35(d,J=9.0Hz,2H),6.99(dt,J=7.4,3.7Hz,1H),3.6(t,J=6.5Hz,2H),3.38-3.29(t,J=6.5Hz,2H)
2-溴乙基-N-苯基胺基-1,3,4-硒二唑:
取代硒脲(1mmol;或其它硒脲),与多官能团羧酸化合物(0.2-4mmol),与5mlPOCl3混合均匀搅拌;升温至50-80℃,反应0.5-12h,停止油浴加热,将反应液缓慢倒入冰水、沉淀、柱层析分离,干燥;得到产物,产率40-95%。
m/z 332(100%,M+H+)
1HNMR(500MHz,)δ10.37(s,1H),7.65–7.53(m,2H),7.35(d,J=9.0Hz,2H),6.99(dt,J=7.4,3.7Hz,1H),3.6(t,J=6.5Hz,2H),3.38-3.29(t,J=6.5Hz,2H)
为了进一步探索各个反应条件对反应产率的影响,选取一组反应物在不同的反应条件下进行了探索,具体反应数据如下:
各种不同的反应物及其反应方程式如下,需要特别说明的是下述反应中的反应条件均在前述反应所提供的反应条件内及多官能团羧酸化合物(0.2~4mmol),与5ml POCl3混合均匀搅拌;升温至50~80℃,反应0.5~12h,停止油浴加热,将反应液缓慢倒入冰水、沉淀、柱层析分离,干燥;得到产物,反应产率在40-95%;还有包括说明书中其他未列出的化合物通式也能按此条件进行反应。
实施例1
2-水杨酰胺戊烷基5-苯胺基-1,3,4-硒二唑
m/z 472(100%,M+H+)
1HNMR(500MHz,)δ10.34(s,1H),7.61-6.98(m,9H),2.4(s,3H),3.18-1.3(m,10H)。
实施例2
m/z 428(100%,M+H+)
1H NMR(500MHz,)δ10.34(s,1H),7.61-6.98(m,10H),3.18-1.3(m,10H)。
实施例3
2-叔丁氧羰基氨基戊烷基-5-萘胺基-1,3,4-硒二唑
m/z 460(100%,M+H+)
1HNMR(500MHz,)δ10.34(s,1H),7.61-6.98(m,7H),3.18-1.3(m,10H),,1.4(s,9H)。
实施例4
2-叔丁氧羰基氨基戊烷-5-二硝基苯胺基-1,3,4-硒二唑
m/z 500(100%,M+H+)
1HNMR(500MHz,)δ10.34(s,1H),8.5-6.98(m,3H),3.18-1.3(m,10H),,1.4(s,9H)。
实施例5
2-叔丁氧羰基氨基戊烷基5-邻氟基苯胺基-1,3,4-硒二唑
m/z 428(100%,M+H+)
1HNMR(500MHz)δ10.34(s,1H),8.06(d,J=7.8Hz,1H),7.59(m,2H),7.46(m,1H),7.37(d,J=8.0,1H),3.18-1.3(m,10H),1.4(s,9H).
应用实施例1
本应用实施例采用实施例2中的1,3,4-硒二唑的相关衍生化合物进行抗氧化实验。
PC12细胞(1000个每孔)在双氧水环境或无氧条件下,加1,3,4-硒二唑类化合物(10000nM),生长3天,观察细胞生长;具体效果见附图1。
对比应用实施例1
本对比应用实施例不添加任何的1,3,4-硒二唑的相关衍生化合物。
PC12细胞(1000个每孔)在双氧水环境或无氧条件下,加入DMSO,生长3天,观察细胞生长;具体效果见附图1。
由以上应用实施例可知,添加了DMSO的细胞不生长,添加了硒二唑类化合物的细胞生长。
本发明提供了一种硒二唑类化合物,通过多种官能团的取代,来达到对肿瘤的抑制作用,抗氧化作用和细胞保护功能。
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1~3任意一项所述的化合物在制备具有抗氧化功能以及细胞保护功能的药物中的应用。
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