CN103833540A - 一种β-取代查尔酮类似物及其制备方法和在制备组蛋白去乙酰化酶抑制剂中的应用 - Google Patents
一种β-取代查尔酮类似物及其制备方法和在制备组蛋白去乙酰化酶抑制剂中的应用 Download PDFInfo
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Abstract
本发明公开了一种β-取代查尔酮类似物及其制备方法和在制备组蛋白去乙酰化酶抑制剂中的应用。本发明利用两步荧光测试的方法对式I的一类化合物进行了组蛋白去乙酰化酶的活性测试,证实其对组蛋白去乙酰化酶具有选择性的抑制作用,有望用于对肿瘤疾病的治疗。
Description
技术领域
本发明涉及一种化合物及其应用,更具体地,涉及一种β-取代查尔酮类似物及其制备方法和在制备组蛋白去乙酰化酶抑制剂中的应用。
背景技术
在肿瘤的表观遗传学研究中,组蛋白的乙酰化修饰对肿瘤的发生发展起重要作用。正常细胞体一旦出现核内组蛋白乙酰化与去乙酰化的失衡,即会导致正常的细胞周期与细胞代谢行为的改变而诱发肿瘤。组蛋白去乙酰化酶(HDACs)是一类发现于细菌、真菌、植物和动物的蛋白酶,它能去除组蛋白N末端的赖氨酸氨基上的乙酰基,导致该氨基在生理pH条件下带正电荷,从而增加了组蛋白N末端的正电荷,使组蛋白与DNA(DNA上的磷酸基带负电)由于静电作用结合得更紧密,进而阻止转录因子进入DNA,造成染色质高度浓缩、转录抑制和基因沉默,从而抑制癌相关基因的转录表达、细胞增殖分化及细胞凋亡等诸多过程。因此,HDAC抑制剂设计是当前抗癌药物研究领域十分热门的研究方向之一。
组蛋白去乙酰化酶抑制剂(HDACI)是一类化合物,有干扰组蛋白去乙酰化酶的功能。其通过有效上调抑癌基因的表达、阻断肿瘤生长和诱导肿瘤细胞选择性凋亡来治疗肿瘤。HDACIs通过增加细胞内组蛋白的乙酰化程度,提高 p21等基因的表达水平等途径,抑制肿瘤细胞的增殖,诱导细胞分化和(或)凋亡。HDACIs已成为肿瘤靶向治疗的研究新热点,其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实。
发明内容
为了得到一种新的组蛋白去乙酰化酶抑制剂,本发明首先提供一种一种β-取代查尔酮类似物,结构式如式I所示
其中,R1和R2为氢、C1~C4 直链、C1~C4支链烷基,C2~C5 直链、C2~C5 支链烯基、C3~C8环烷烃、C3~C8饱和杂环、C5~C8环烯烃、C5~C8不饱和杂环、卤素、羟基、硝基、羟甲基、酰胺基、C1~C4烷氧基、三氟甲基或苯基;
R3为羟基或氨基。
所述的R1和R2优选为氢。
更进一步提供一种上述化合物的制备方法,包括以下步骤,
S1.将苯乙酮加入溶剂中,加入催化剂,反应,加入饱和Na2CO3溶液,萃取,干燥,层析纯化,得中间体1,
S2.将S1得到的中间体1、N-溴代丁二酰亚胺和过氧化苯甲酰溶解在四氯化碳中,加热回流反应,冷却,过滤,萃取,纯化即得中间体2,
S3. 将步骤S2所得的中间体2和乙酸钠溶解于溶剂中,加热回流反应,萃取,干燥,即得。
步骤S1和S3中所述的溶剂为乙醇。
步骤S1中所述的萃取采用乙酸乙酯;步骤S2和S3中所述的萃取采用水和二氯甲烷的混合液。
更进一步的提供一种上述的β-取代查尔酮类似物在制备组蛋白去乙酰化酶抑制剂中的应用。
另外提供一种上述的β-取代查尔酮类似物在制备抗肿瘤药物中的应用。
所述的β-取代查尔酮类似物为与酸形成的可药用盐。
所述的与酸形成的可药用盐为盐酸盐。
当R1~R2均为氢,R3为氨基或羟基时,所得到的两个化合物分别为β-aminomethyl chalcone和 β-hydroxymethyl chalcone, 本发明经测试发现,这两个化合物对HDAC酶具有选择性的抑制作用,且β-hydroxymethyl chalcone还呈现出了一定的时间依赖性。
本发明利用两步荧光测试的方法对受试化合物进行HDAC酶活性测试,该方法可定量、准确度高、重现性好、快速、不易受其他物质干扰。
两步荧光测试方法能够高效快速的测定化合物对HDAC酶的抑制作用,共分为两步。第一步主要是将乙酰化的赖氨酸底物与HDAC酶进行孵化从而将赖氨酸氨基上的乙酰基去掉,在第二步中通过加入能够与赖氨酸上的氨基结合的显影剂,得到一个具有荧光的产物。通过对荧光产物的荧光强度进行测定以确定酶的活性。在这个过程中,不加抑制剂得到的荧光强度记为F100,不加酶得到的荧光强度记为F0,加入抑制剂得到的荧光强度记为F,那么加入抑制剂后酶的活性则为:%activity=(F-F0)/(F100-F0). 而抑制剂的抑制活性则为1-%activity。
具体实施方式
下面结合具体实施例进一步详细说明本发明。除非特别说明,本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。
在以下具体的实例中,我们所用的HDAC1、HDAC2和HDAC3酶均购自于Epigentek(U.S.A), β-aminomethyl chalcone和 β-hydroxymethyl chalcone这两个化合物均为合成得到,纯度均达到90%以上。阳性对照物MS-275从武汉星熠艾克生物医药有限责任公司(NCE Biomedical) 购得,纯度为99.21%
为了更清楚地说明本发明,列举以下实例。但其对本发明的范围无任何限制。
实例1 β-hydroxymethyl chalconez的合成
一、(E)-1,3-二苯丁-2-烯-1-酮(中间体1)的合成
将苯乙酮(18.0 g,0.15 mol)和无水乙醇(750 mL)置于2 L单口反应瓶中,缓慢滴加二氯亚砜(200 mL)。反应2小时,加入饱和Na2CO3溶液,乙酸乙酯萃取两次,合并有机相,无水硫酸镁干燥,蒸干溶剂。残余物柱层析纯化[石油醚:乙酸乙酯=1:80],得到淡黄色油状液体(E)-1,3-二苯丁-2-烯-1-酮9.4 g,收率为56.45 %。
二、(Z)-4-溴-1,3-二苯丁-2-烯-1-酮(中间体2)的合成
将(E)-1,3-二苯丁-2-烯-1-酮(11.10 g,50 mmol)、N-溴代丁二酰亚胺(8.9 g, 50 mmol)、过氧化苯甲酰(0.30 g, 1.2 mmol)溶解在50 mL的四氯化碳中,加热回流,反应5小时,冷却至室温,过滤,蒸干溶剂。加入水和二氯甲烷萃取三次,合并有机相,无水硫酸镁干燥,蒸干溶剂。残余物柱层析纯化[石油醚:乙酸乙酯=1:100],得到淡黄色针状晶体(Z)-4-溴-1,3-二苯丁-2-烯-1-酮3.5 g,收率为23.27 %。M.P. 96-98 ℃。
三、(Z)-4-羟基-1,3-二苯丁-2-烯-1-酮的合成
将(Z)-4-溴-1,3-二苯丁-2-烯-1-酮(2.5 g,8.3 mmol)和乙酸钠(1.37g,16.6 mmol)的无水甲醇(30 mL)溶液置于100 mL单口瓶中,加热回流反应过夜。蒸干溶剂,加水和二氯甲烷萃取三次,合并有机相,无水硫酸镁干燥,蒸干溶剂。残余物柱层析纯化[石油醚:乙酸乙酯=1:20],得到淡黄色油状物(Z)-4-羟基-1,3-二苯丁-2-烯-1-酮0.20 g,收率为10.11 %。1H NMR (400MHz,CDCl3): δ 5.50(s,2H,CH2),7.16-7.57(m,9H,ArH),8.00-8.01(d,J = 4Hz,2H,ArH). ESI-MS:(m/z)=237.94[M]+.
实例2 β-aminomethyl chalconez的合成
一、(E)-1,3-二苯丁-2-烯-1-酮(中间体1)的合成(同实例1)
二、(Z)-4-溴-1,3-二苯丁-2-烯-1-酮(中间体2)的合成(同实例2)
三、(Z)-4-三苯甲氨基-1,3-二苯丁-2-烯-1-酮(中间体3)的合成
将(Z)-4-溴-1,3-二苯丁-2-烯-1-酮(0.5g,1.6mmol)、三苯甲胺(0.85g,3.3mmol)、乙腈20ml和3ml的三乙胺加入50ml的圆底烧瓶中,在氮气保护下,加热回流反应过夜。加入水和二氯甲烷萃取三次,合并有机相,无水硫酸镁干燥蒸干溶剂,残余物柱层析纯化[乙酸乙酯:石油醚=80:1]。得到(Z)-4-三苯甲氨基-1,3-二苯丁-2-烯-1-酮0.1g。收率为12.67%。
四、(Z)-4-氨基-1,3-二苯丁-2-烯-1-酮的合成
将(Z)-4-三苯甲氨基-1,3-二苯丁-2-烯-1-酮(0.1g,0.2mmol)溶解在10ml的60%三氟乙酸的二氯甲烷溶液中,室温搅拌过夜。加水,乙酸乙酯萃取,蒸干溶剂。得到浅棕色固体物(Z)-4-氨基-1,3-二苯丁-2-烯-1-酮,室温下放置易变质为墨绿色。产率未计。1H NMR(400 MHz,CDCl3):δ1.29(s,2H,NH2),4.61(s,2H,CH2),6.86(s,2H,ArH),7.17-7.42(m,7H,ArH),8.51(s,2H,ArH).
实例3β-hydroxymethyl chalcone的HDAC酶活性测试
一、活性测试试剂
1.缓冲液:从Cayman(U.S.A)购得
2.人重组HDAC酶溶液:从Epigentek(U.S.A)购得
HDAC1 6ng/μl
HDAC2 5.5ng/μl
HDAC3 1.5ng/μl
3.乙酰赖氨酸底物溶液:从Cayman(U.S.A)购得,3.4mM。
4. 阳性对照物:从武汉星熠艾克生物医药有限责任公司(NCE Biomedical) 购得,MS-275,纯度为99.21%。
5. 显影剂溶液:从Cayman(U.S.A)购得,其化学成分以及浓度均不知, 但里面含有用于终止去乙酰化反应的终止化合物TSA(也是一种HDAC抑制剂)。
6. 测试化合物:β-hydroxymethyl chalcone,合成所得,纯度 > 90%。
二、操作步骤(两步荧光测试法)
1. 向96孔板中的三个孔中依次加入150 μl缓冲液和10 μl HDAC1/HDAC2/HDAC3溶液。
2. 再向另外三个孔中加入160 μl缓冲液
3. 在选取另外三个孔,向其中依次加入140 μl缓冲液,10 μl HDAC1/HDAC2/HDAC3溶液和10 μl 测试化合物β-hydroxymethyl chalcone或者阳性对照物MS-275溶液(一种浓度). 由于测试化合物和MS-275存在着一系列浓度,在这里其他浓度的也依次效仿第三步的操作。
4. 1h之后,向上述所有孔中都加入10 μl 乙酰赖氨酸底物溶液,并在37℃下在摇床上晃动30min。
5. 之后再向上述所有的孔中加入40 μl显影剂溶液,摇晃15min后立即测试荧光强度。在上述过程中,第一组三个孔得到的荧光强度记为F100,第二组三个孔得到的荧光强度记为F0,加入抑制剂得到的荧光强度记为F,那么加入抑制剂后酶的活性则为:%activity = (F-F0)/(F100-F0). 而抑制剂的抑制活性则为inhibition% = 1-%activity. 最后根据测试化合物和阳性对照物不同浓度下的抑制活性进行S曲线拟合并得到相应的IC50值。
三、实验结果
经对测试化合物β-hydroxymethyl chalcone和阳性对照物MS-275进行三次测试,结果见下表:
β-aminomethyl chalcone的HDAC酶活性测试与β-hydroxymethyl chalcone方法是一致的。
实例4 β-hydroxymethyl chalcone抑制活性的时间依赖性
一、活性测试试剂(同实例2)
二、操作步骤
基本的操作同实例2,但与实例2唯一不同的是在加乙酰赖氨酸底物之前的抑制剂与HDAC酶的孵化时间有所改变,在实例2中孵化时间设置为1h,在这里我们分别考虑了4h,8h,12h,16h,20h,24h。
三、实验结果
经对测试化合物β-hydroxymethyl chalcone和阳性对照物MS-275进行三次测试,结果见下表:
Claims (9)
2. 根据权利要求1所述的β-取代查尔酮类似物,其特征在于,所述的R1和R2为氢。
3. 一种根据权利要求1所述的制备方法,其特征在于,包括以下步骤,
S1.将苯乙酮加入溶剂中,加入催化剂,反应,加入饱和Na2CO3溶液,萃取,干燥,层析纯化,得中间体1,
S2.将S1得到的中间体1、N-溴代丁二酰亚胺和过氧化苯甲酰溶解在四氯化碳中,加热回流反应,冷却,过滤,萃取,纯化即得中间体2,
S3. 将步骤S2所得的中间体2和乙酸钠溶解于溶剂中,加热回流反应,萃取,干燥,即得。
4. 根据权利要求3所述的制备方法,其特征在于,步骤S1和S3中所述的溶剂为乙醇。
5. 根据权利要求3所述的制备方法,其特征在于,步骤S1中所述的萃取采用乙酸乙酯;步骤S2和S3中所述的萃取采用水和二氯甲烷的混合液。
6. 一种根据权利要求1所述的β-取代查尔酮类似物在制备组蛋白去乙酰化酶抑制剂中的应用。
7. 一种根据权利要求1所述的β-取代查尔酮类似物在制备抗肿瘤药物中的应用。
8. 根据权利要求6或7所述的应用,其特征在于,所述的β-取代查尔酮类似物为与酸形成的可药用盐。
9. 根据权利要求8所述的应用,其特征在于,所述的与酸形成的可药用盐为盐酸盐。
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