CN103833719A - 表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用 - Google Patents
表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用 Download PDFInfo
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Abstract
本发明公开了一种表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用,本发明的表没食子儿茶素没食子酸酯烷基化衍生物具有抑制肝癌的作用,能增强蒽环类抗癌药疗效,并降低其毒性。
Description
技术领域
本发明属于制药领域,具体而言,涉及一种表没食子儿茶素没食子酸酯烷基化衍生物制备及其抗肿瘤应用。
背景技术
肝癌是广西的区域性高发肿瘤,在我国广西、广东等肝癌高发区肝癌死亡率超过总癌症死亡率50%以上,严重危害劳动人民的健康与生命安全,因此如何提高肝癌的治疗疗效迫在眉睫。蒽环类药物是最有效的抗肿瘤药物之一,包括柔红霉素(DNR)和阿霉素(DOX),被广泛应用于肿瘤的临床治疗。但在人类肝脏中广泛存在的羰基还原酶1(carbonylreductase1,CBR1)能将柔红霉素(DNR)转化成一种新的醇代谢物柔红霉素醇(DNROL)。该代谢物不仅抗肿瘤活性降低,还可产生心脏毒性。这一代谢特点大大限制了它的临床应用。寻找羰基还原酶1的抑制剂对于此类抗生素的增效减毒很有必要。
缺氧诱导因子(HIFs)所介导的信号转导通路与肿瘤发生、发展和耐药密切相关。缺氧条件下,细胞通过高表达HIF-1α,促进下游靶基因的转录,这些下游靶基因转录的蛋白在缺氧反应中起关键作用,如血管生成、细胞增殖、糖代谢和细胞存活等。HIF-1α介导肿瘤新生血管形成和多药耐药原因主要有:(1)缺氧情况下,过表达的HIF-1α调控其下游多种与血管生成有关的因子及其受体,如血管内皮生长因子(VEGF),使VEGF高表达,促进肿瘤组织中新生血管的形成。(2)HIF-1α激活CBR1的表达,增加肝癌细胞对顺铂及阿霉素等蒽环类药物的耐受性。(3)HIF-1α通过诱导多药耐药基因1(MDR1)的表达,使糖蛋白(P-gp)表达增高从而实现七对肿瘤耐药的调控。因此,HIF-1α可作为潜在的抗肿瘤药物筛选的靶点。
表没食子儿茶素没食子酸酯(EGCG)药理作用广泛,具有抗氧化、降血脂、抗紫外线辐射、抑菌等作用,也具有明显的抗肿瘤作用。EGCG通过抑制HIF-1α蛋白的增加和VEGF/VEGFR的活性而抑制肝癌细胞的生长和肝癌新生血管的生成。还可通过抑制CBR1活性,增强DNR的抗肿瘤效果,降低其心脏毒性。但由于EGCG结构中含有大量酚羟基,性质不稳定,易氧化变性,脂溶性差,生物利用度低、体内代谢快,维持时间短,作用强度有待提高。因此,对EGCG开展结构修饰优化研究是本领域的一个重要课题。
到目前为止,还没有EGCG烷基化衍生物增强蒽环类抗癌药疗效,并降低其毒性的报道。
发明内容
本发明的目的是提供一种表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用,为了实现本发明的目的,拟采用如下技术方案:
本发明一方面涉及一种表没食子儿茶素没食子酸酯烷基化衍生物,所述的表没食子儿茶素没食子酸酯烷基化衍生物选自:
①5,7,3′,4′,5′,3″,4″,5″-八-O-乙基-EGCG、
②5,7,3′,4′,3″,4″,5″-七-O-乙基-EGCG、
③5,7,4′,5′,3″,4″,5″-七-O-乙基-EGCG、
④5,7,3′,4′,3″,4″-六-O-乙基-EGCG、
⑤5,3′,4′,5′,3″,4″,5″-七-O-乙基-EGCG、
⑥5,3′,4′,3″,4″,5″-六-O-乙基-EGCG、
⑦5,7,3′,4′,5′,3″,4″,5″-八-O-丙基-EGCG、
⑧5,7,4′,5′,3″,4″,5″-七-O-丙基-EGCG;
优选的,所述的表没食子儿茶素没食子酸酯烷基化衍生物为5,7,3′,4′,3″,4″-六-O-乙基-EGCG(y4)或5,3′,4′,3″,4″,5″-六-O-乙基-EGCG(y6)
在本发明的另一方面,本发明还涉及含有上述表没食子儿茶素没食子酸酯烷基化衍生物的药物组合物。
在本发明的一个优选实施方式中,所述的药物组合物中还包括药学上可接受的辅料和/或赋形剂。
在本发明的另一个优选实施方式中,所述的药物组合物中包括有效量的蒽环类抗肿瘤药物,优选的,表没食子儿茶素没食子酸酯烷基化衍生物与蒽环类抗肿瘤药物的重量比是100:1-10:1。
在本发明的一个优选实施方式中,所述的蒽环类抗肿瘤药物为柔红霉素(DNR)和/或阿霉素(DOX)。
本发明另一方面涉及上述表没食子儿茶素没食子酸酯烷基化衍生物或药物组合物在制备治疗肝癌的药物中的应用。
在本发明中,如果无特殊说明,在化学名与结构式发生冲突时,以结构式为准,申请人保留基于结构式修改化学名的权利。
本发明的表没食子儿茶素没食子酸酯烷基化衍生物具有抑制肝癌的作用,能增强蒽环类抗癌药疗效,并降低其毒性。
附图说明
图1.EGCG和其三种衍生物对班马鱼心脏搏出量(strokevolume)的影响
其中:AcEGCG为表没食子儿茶素没食子酸酯全乙酰化衍生物,EGCG为表没食子儿茶素没食子酸酯;Y3为5,7,4′,5′,3″,4″,5″-七-O-乙基-EGCG;Y6为5,3′,4′,3″,4″,5″-六-O-乙基-EGCG。□为空白对照组;■为阿霉素组;其余条图纹为阿霉素加受试药组。
具体实施方式:
一、表没食子儿茶素没食子酸酯(EGCG)烷基化衍生物合成
1.EGCG烷基化衍生物合成
1.1乙基化EGCG合成反应
秤取5gEGCG为反应底物,加入200-800ml丙酮做反应介质,加入2-8gK2CO3做催化剂,水浴50-85℃搅拌回流,用恒压滴液漏斗滴加20-80ml(CH3CH2O)2SO2做乙基供体,水浴搅拌回流反应12-36h,薄层层析检测反应的进程。反应液用冰醋酸调节pH=4-7,转移到烧瓶内,减压蒸馏除去溶剂得到残留物,加入乙酸乙酯溶解残留物,转移到分液漏斗内,并用纯化水洗涤,直到下层流出液为中性为止。取乙酸乙酯层,减压蒸馏除去溶剂,得到乙基化反应的混合产物,有待于进行分离纯化。
1.2丙基化EGCG合成反应
秤取5gEGCG为反应底物,加入200-800ml丙酮做反应介质,加入2-8ggK2CO3做催化剂,水浴50-85℃搅拌回流,用恒压滴液漏斗滴加20-80mlCH3CH2CH2I做丙基供体,水浴搅拌回流反应12-36h,薄层层析检测反应的进程。反应液用冰醋酸调节pH=4-7,转移到烧瓶内,减压蒸馏除去溶剂得到残留物,加入乙酸乙酯溶解残留物,转移到分液漏斗内,并用纯化水洗涤,直到下层流出液为中性为止。取乙酸乙酯层,减压蒸馏除去溶剂,得到丙基化反应的混合产物,有待于进行分离纯化。
2.采用中压制备液相色谱法分离纯化反应产物。对纯化得到的化合物,通过1H-NMR、13C-NMR、2DNMR、质谱等方法进行结构鉴定。
结果:共分离得到8个烷基化程度较高的EGCG衍生物,结构鉴定分别为:
①5,7,3′,4′,5′,3″,4″,5″-八-O-乙基-EGCG(y1)、
②5,7,3′,4′,3″,4″,5″-七-O-乙基-EGCG(y2)、
③5,7,4′,5′,3″,4″,5″-七-O-乙基-EGCG(y3)、
④5,7,3′,4′,3″,4″-六-O-乙基-EGCG(y4)、
⑤5,3′,4′,5′,3″,4″,5″-七-O-乙基-EGCG(y5)、
⑥5,3′,4′,3″,4″,5″-六-O-乙基-EGCG(y6)、
⑦5,7,3′,4′,5′,3″,4″,5″-八-O-丙基-EGCG(b1)、
⑧5,7,4′,5′,3″,4″,5″-七-O-丙基-EGCG(b2)
3.乙基化EGCG产物(y1,y2,y3,y4,y5,y6共6个化合物)结构解析
3.1化合物y1命名为:5,7,3′,4′,5′,3″,4″,5″-八-O-乙基-EGCG,分子式为C38H50O11,结构式如下:
y1的主要图谱数据:
1H-NMR(DMSO,600MHz)δ6.97(s,2H,C2''-H和C6''-H),δ6.77(s,2H,C2'-H和C6'-H),6.20(d,1H,J=1.7Hz,C6-H),6.15(d,1H,J=1.7Hz,C8-H),5.53(m,1H,C3-H),5.22(br,1H,C2-H),3.77~4.00(m,16H,-O-CH2-×8),3.03(dd,1H,J=17.6,4.4Hz,C4-Ha),2.85(d,1H,J=17.0Hz,C4-Hb),1.16~1.32(m,24H,-CH3×8).
13C-NMR(DMSO,600MHz)δ164.30(C=O),158.45(C-7),157.64(C-5),155.09(C-8a),152.20(C-3''和C-5''),152.09(C-3'和C-5'),141.62(C-4''),136.58(C-4'),133.39(C-1'),124.36(C-1''),107.64(C-2''和C-6''),105.15(C-2'和C-6'),99.51(C-4a),93.69(C-6),92.82(C-8),76.47(C-2),68.73(C-3),68.12(-O-CH2-),67.73(-O-CH2-),64.25(-O-CH2-×2),64.00(-O-CH2-×2),63.29(-O-CH2-),63.04(-O-CH2-),25.29(C-4),15.32(-CH3×2),14.69(-CH3×2),14.59(-CH3×4).
MS(ESI)m/z:683([M+1]+).
3.2化合物y2命名为:5,7,3′,4′,3″,4″,5″-七-O-乙基-EGCG,分子式为C36H46O11,结构式如下:
y2的主要图谱数据:
1H-NMR(DMSO,600MHz)δ9.07(s,1H,C5'-OH),6.99(s,2H,C2''-H和C6''-H),6.57(d,1H,J=1.8Hz,C2'-H),6.55(d,1H,J=1.8Hz,C6'-H),6.15(d,1H,J=2.2Hz,C8-H),6.11(d,1H,J=2.2Hz,C6-H),5.22(m,1H,C3-H),5.06(d,1H,J=7.8Hz,C2-H),3.87~4.00(m,14H,-O-CH2-×7),3.01(dd,1H,J=16.3,5.5Hz,C4-Ha),2.69(dd,1H,J=16.3,8.2Hz,C4-Hb),1.16~1.32(m,21H,-CH3×7).
13C-NMR(DMSO,600MHz)δ164.62(C=O),158.76(C-7),157.50(C-5),154.81(C-8a),152.27(C-3''和C-5''),152.36(C-3'),150.87(C-5'),141.50(C-4''),135.11(C-4'),132.97(C-1'),124.33(C-1''),107.68(C-6'),107.52(C-2''和C-6''),103.78(C-2'),100.20(C-4a),93.69(C-6),92.91(C-8),78.06(C-2),70.19(C-3),68.19(-O-CH2-),67.51(-O-CH2-),64.30(-O-CH2-×2),63.89(-O-CH2-),63.47(-O-CH2-),63.12(-O-CH2-),24.96(C-4),15.43(-CH3),15.22(-CH3),14.75(-CH3),14.67(-CH3×2),14.65(-CH3×2).
MS(ESI)m/z:655([M+1]+).
3.3化合物y3命名为:5,7,4′,5′,3″,4″,5″-七-O-乙基-EGCG,分子式为C36H46O11,结构式如下
y3的主要图谱数据:
1H-NMR(DMSO,600MHz)δ8.97(s,1H,C3'-OH),6.96(s,2H,C2''-H和C6''-H),6.67(d,1H,J=1.6Hz,C2'-H),6.59(d,1H,J=1.6Hz,C6'-H),6.16(d,1H,J=2.1Hz,C6-H),6.13(d,1H,J=2.1Hz,C8-H),5.44(m,1H,C3-H),5.17(br,1H,C2-H),3.87~4.02(m,14H,-O-CH2-×7),3.03(dd,1H,J=17.6,4.5Hz,C4-Ha),2.85(d,1H,J=16.0Hz,C4-Hb),1.17~1.31(m,21H,-CH3×7).
13C-NMR(DMSO,600MHz)δ164.73(C=O),158.49(C-7),157.71(C-5),155.09(C-8a),152.25(C-3''和C-5''),152.18(C-5'),150.58(C-3'),141.47(C-4''),134.66(C-4'),133.45(C-1'),124.49(C-1''),107.48(C-2''和C-6''),107.39(C-2'),102.84(C-6'),99.56(C-4a),93.69(C-6),92.80(C-8),76.33(C-2),69.06(C-3),68.16(-O-CH2-),67.55(-O-CH2-),64.28(-O-CH2-×2),63.81(-O-CH2-),63.36(-O-CH2-),63.08(-O-CH2-),25.16(C-4),15.40(-CH3),15.23(-CH3),14.75(-CH3),14.64(-CH3×4).
MS(ESI)m/z:655([M+1]+).
3.4化合物y4命名为:5,7,3′,4′,3″,4″-六-O-乙基-EGCG,分子式为
C34H42O11,结构式如下
y4主要图谱数据:
1H-NMR(DMSO,600MHz)δ9.45(s,1H,C5''-OH),8.95(s,1H,C5'-OH),6.98(d,1H,J=1.9Hz,C6''-H),6.84(d,1H,J=1.9Hz,C2''-H),6.61(d,1H,J=1.8Hz,C6'-H),6.60(d,1H,J=1.8Hz,C2'-H),6.15(d,1H,J=2.1Hz,C6-H),6.14(d,1H,J=2.1Hz,C8-H),5.45(m,1H,C3-H),5.12(br,1H,C2-H),3.86~4.01(m,12H,-O-CH2-×6),3.03(dd,1H,J=17.6,4.6Hz,C4-Ha),2.78(d,1H,J=16.9Hz,C4-Hb),1.17~1.32(m,18H,-CH3×6).
13C-NMR(DMSO,600MHz)δ164.69(C=O),158.42(C-7),157.74(C-5),155.20(C-8a),152.36(C-3''),152.16(C-3'),150.85(C-5''),150.49(C-5'),139.81(C-4''),134.72(C-4'),133.29(C-1'),124.25(C-1''),110.45(C-6''),107.68(C-6'),105.48(C-2''),103.01(C-2'),99.65(C-4a),93.87(C-6),92.78(C-8),76.57(C-2),68.48(C-3),67.77(-O-CH2-),67.55(-O-CH2-),64.04(-O-CH2-),63.76(-O-CH2-),63.34(-O-CH2-),63.07(-O-CH2-),25.46(C-4),15.27(-CH3×2),14.73(-CH3),14.69(-CH3),14.65(-CH3×2).
MS(ESI)m/z:627([M+1]+).
3.5化合物y5命名为:5,3′,4′,5′,3″,4″,5″-七-O-乙基-EGCG,分子式为C36H46O11,结构式如下
y5主要图谱数据:
1H-NMR(DMSO,600MHz)δ9.32(s,1H,C7-OH),6.98(s,2H,C2''-H和C6''-H),6.75(s,2H,C2'-H和C6'-H),6.02(d,1H,J=2.0Hz,C6-H),6.01(d,1H,J=2.0Hz,C8-H),5.50(m,1H,C3-H),5.18(br,1H,C2-H),3.77~3.99(m,14H,-O-CH2-×7),3.00(dd,1H,J=17.5,4.6Hz,C4-Ha),2.81(dd,1H,J=17.6,1.9Hz,C4-Hb),1.16~1.31(m,21H,-CH3×7).
13C-NMR(DMSO,600MHz)δ164.39(C=O),157.72(C-7),157.14(C-5),155.07(C-8a),152.26(C-3''和C-5''),152.14(C-3'和C-5'),141.67(C-4''),136.59(C-4'),133.58(C-1'),124.44(C-1''),107.69(C-2''和C-6''),105.16(C-2'和C-6'),97.96(C-4a),95.18(C-6),92.96(C-8),76.40(C-2),68.95(C-3),68.19(-O-CH2-),67.79(-O-CH2-),64.32(-O-CH2-×2),64.04(-O-CH2-×2),63.17(-O-CH2-),25.31(C-4),15.37(-CH3×2),14.73(-CH3×2),14.68(-CH3),14.64(-CH3×2).
MS(ESI)m/z:655([M+1]+).
3.6化合物y6命名为:5,3′,4′,3″,4″,5″-六-O-乙基-EGCG,分子式为C34H42O11,结构式如下:
y6主要图谱数据:
1H-NMR(DMSO,600MHz)δ9.31(s,1H,C7-OH),8.97(s,1H,C5'-OH),6.97(s,2H,C2''-H和C6''-H),6.66(d,1H,J=1.8Hz,C6'-H),6.57(d,1H,J=1.8Hz,C2'-H),6.01(d,1H,J=2.0Hz,C6-H),6.00(d,1H,J=2.0Hz,C8-H),5.42(m,1H,C3-H),5.13(br,1H,C2-H),3.87~3.98(m,12H,-O-CH2-×6),2.99(dd,1H,J=17.5,4.5Hz,C4-Ha),2.82(dd,1H,J=17.6,1.9Hz,C4-Hb),1.17~1.32(m,18H,-CH3×6).
13C-NMR(DMSO,600MHz)δ164.76(C=O),157.71(C-7),157.13(C-5),155.00(C-8a),152.25(C-3''和C-5''),152.17(C-3'),150.57(C-5'),141.45(C-4''),134.62(C-4'),133.58(C-1'),124.51(C-1''),107.45(C-2''和C-6''),107.36(C-6'),102.78(C-2'),97.95(C-4a),95.15(C-6),92.92(C-8),76.17(C-2),69.22(C-3),68.16(-O-CH2-),67.54(-O-CH2-),64.27(-O-CH2-×2),63.79(-O-CH2-),63.17(-O-CH2-),25.10(C-4),15.40(-CH3),15.24(-CH3),14.74(-CH3),14.69(-CH3),14.65(-CH3×2).
MS(ESI)m/z:627([M+1]+).
2丙基化EGCG产物(b1,b2共2个化合物)结构解析
2.1化合物b1命名为:5,7,3′,4′,5′,3″,4″,5″-八-O-丙基-EGCG,分子式为C46H66O11,结构式如下:
b1主要图谱数据:
1H-NMR(DMSO,600MHz)δ6.99(s,2H,C2''-H和C6''-H),6.74(s,2H,C2'-H和C6'-H),6.19(d,1H,J=2.0Hz,C6-H),6.15(d,1H,J=2.0Hz,C8-H),5.54(m,1H,C3-H),5.21(br,1H,C2-H),3.76~3.91(m,16H,-O-CH2-×8),3.04(dd,1H,J=17.5,4.3Hz,C4-Ha),2.83(d,1H,J=16.6Hz,C4-Hb),1.57~1.71(m,16H,-CH2-×8),0.87~0.98(m,24H,-CH3×8).
13C-NMR(DMSO,600MHz)δ164.14(C=O),158.70(C-7),157.77(C-5),155.20(C-8a),152.30(C-3''和C-5''),152.21(C-3'和C-5'),141.81(C-4''),136.76(C-4'),133.36(C-1'),124.30(C-1''),107.44(C-2''和C-6''),105.05(C-2'和C-6'),99.66(C-4a),93.73(C-6),92.80(C-8),76.66(C-2),68.56(C-3),74.26(-O-CH2-),73.98(-O-CH2-),70.02(-O-CH2-×2),69.87(-O-CH2-×2),69.10(-O-CH2-),69.03(-O-CH2-),25.40(C-4),22.97(-CH2-),22.96(-CH2-),22.21(-CH2-×2),22.06(-CH2-×2),22.04(-CH2-×2),10.48(-CH3),10.45(-CH3),10.43(-CH3),10.38(-CH3),10.32(-CH3×4).
MS(ESI)m/z:795([M+1]+).
2.2化合物b2命名为:5,7,4′,5′,3″,4″,5″-七-O-丙基-EGCG,分子式为C43H60O11,结构式如下
b2主要图谱数据:
1H-NMR(DMSO,600MHz)δ8.97(s,1H,C3'-OH),6.97(s,2H,C2''-H和C6''-H),6.65(d,1H,J=1.3Hz,C2'-H),6.56(d,1H,J=1.3Hz,C6'-H),6.16(d,1H,J=2.1Hz,C6-H),6.14(d,1H,J=2.1Hz,C8-H),5.47(m,1H,C3-H),5.16(br,1H,C2-H),3.74~3.89(m,14H,-O-CH2-×7),3.04(dd,1H,J=17.5,4.4Hz,C4-Ha),2.84(d,1H,J=16.2Hz,C4-Hb),1.59~1.72(m,14H,-CH2-×7),0.87~0.97(m,21H,-CH3×7).
13C-NMR(DMSO,600MHz)δ164.55(C=O),158.67(C-7),157.77(C-5),155.13(C-8a),152.31(C-3''和C-5''),152.26(C-5'),150.42(C-3'),141.67(C-4''),134.99(C-4'),133.30(C-1'),124.39(C-1''),107.53(C-2'),107.33(C-2''和C-6''),102.66(C-6'),99.67(C-4a),93.72(C-6),92.76(C-8),76.42(C-2),68.87(C-3),74.25(-O-CH2-),73.73(-O-CH2-),70.00(-O-CH2-×2),69.62(-O-CH2-),69.10(-O-CH2-),69.01(-O-CH2-),25.17(C-4),22.99(-CH2-),22.78(-CH2-),22.23(-CH2-),22.09(-CH2-×2),22.06(-CH2-),22.04(-CH2-),10.44(-CH3×2),10.41(-CH3),10.38(-CH3×3),10.35(-CH3).
MS(ESI)m/z:753([M+1]+).
二、筛选出抑制肝癌细胞增殖作用较强的EGCG烷基化衍生物
方法:用MTT法分别测定乙基化EGCG和丙基化EGCG对肝癌细胞SMMC-7721、HepG2增殖的抑制作用,筛选出有药效的EGCG衍生物。并比较EGCG和有药效的EGCG衍生物对2株肝癌细胞SMMC-7721、HepG2增殖的抑制效果;
结果:
①衍生物5,7,3′,4′,5′,3″,4″,5″-八-O-乙基-EGCG(y1)、5,7,3′,4′,3″,4″,5″-七-O-乙基-EGCG(y2)、5,7,4′,5′,3″,4″,5″-七-O-乙基-EGCG(y3)、5,3′,4′,5′,3″,4″,5″-七-O-乙基-EGCG(y5)、5,7,3′,4′,5′,3″,4″,5″-八-O-丙基-EGCG(b1)、5,7,4′,5′,3″,4″,5″-七-O-丙基-EGCG(b2)的水溶性较小,难溶于培养基,在培养基内析出沉淀,难于对细胞产生作用。
②乙基化EGCG产物y4、y6对肝癌细胞SMMC-7721、HepG2增殖均有抑制作用,其中y6对肝癌细胞的抑制作用比EGCG明显增强。
三、EGCG烷基化衍生物对柔红霉素(DNR)体外抗肝癌作用具有协同作用
方法:
1.EGCG及y6增效DNR抑制肝癌细胞增值的检测结果
选择几乎无细胞毒作用浓度的EGCG和y6,分别联合不同浓度的DNR作用于SMMC-7721,HepG2细胞24小时,通过MTT法初步判断,联合用药组抑制率与DNR单独用药的抑制率相比,均出现比DNR单独用药的抑制率增大的趋势。同时,EGCG和y6联合DNR用药后,IC50比DNR单独用药的低,可见EGCG和y6可能有增效DNR抗癌效果。y6的联合用药浓度比EGCG小,对DNR的增效作用强于EGCG。结果见表1,表2,表3。
表1EGCG及y6联合DNR对SMMC-7721细胞增殖的抑制作用
表2EGCG及y6联合DNR对HepG2细胞增殖的抑制作用
2.EGCG及y6增效DNR诱导肝癌细胞凋亡的检测结果
2.1EGCG及y6增效DNR诱导SMMC-7721肝癌细胞凋亡
0.30μg/mlDNR单独作用SMMC-7721细胞24h,对细胞的凋亡诱导率为10.59%;DNR与30μg/mlEGCG联合用药,凋亡诱导率增加到16.31%,P<0.05,差异有统计学意义;DNR与15μg/mly6联合用药,凋亡诱导率增加到16.19%,P<0.05,差异有统计学意义。由此可见,EGCG和y6可能有增效DNR诱导SMMC-7721细胞凋亡的作用。0.30μg/mlDNR+30μg/mlEGCG组与0.30μg/mlDNR+15μg/mly6组的凋亡诱导率之间比较,P>0.05,说明两组间的凋亡诱导率差异无统计学意义,而联合用药的y6的给药剂量明显小于EGCG,可见y6增效DNR诱导SMMC-7721细胞凋亡的作用强于EGCG。
2.2EGCG及y6增效DNR诱导HepG2肝癌细胞凋亡
0.75μg/mlDNR单独作用HepG2细胞24h,对细胞的凋亡诱导率为27.19%;DNR与30μg/mlEGCG联合用药,凋亡诱导率增加到35.23%,P<0.05,差异有统计学意义;DNR与8μg/mly6联合用药,凋亡诱导率增加到33.16%,P<0.05,差异有统计学意义。由此可见,EGCG和y6可能有增效DNR诱导HepG2细胞凋亡的作用。0.75μg/mlDNR+30μg/mlEGCG组与0.75μg/mlDNR+8μg/mly6组的凋亡诱导率之间比较,P>0.05,说明两组间凋亡诱导率差异无统计学意义,而联合用药的y6的给药剂量明显小于EGCG,可见y6增效DNR诱导HepG2细胞凋亡的作用强于EGCG。
结论:乙基化EGCG产物y4、y6对肝癌细胞SMMC-7721、HepG2均有抑制作用,其中y6的抑制作用比EGCG明显增强;对于肝癌细胞SMMC-7721、HepG2,y6对柔红霉素的增敏作用比EGCG明显增强。
四、EGCG烷基化衍生物降低蒽环类药物的毒性
EGCG烷基化衍生物抗阿霉素诱导斑马鱼心脏毒性的研究
方法:
1.选择状态良好,发育至24hpf(hourspostfertilization)的转基因斑马鱼Tg(cmlc:gfp)胚胎,放入含有0.003%PTU的培养液中进行培养(PTU可以抑制幼鱼的黑色素生长,确保在荧光显微镜下能清晰看见幼鱼心脏),培养箱温度为28.5℃;
2.培养24小时后(此时的幼鱼是48hpf)用镊子除去卵壳,把幼鱼从卵中释放出来。将发育一致的幼鱼放在24孔板中(每组不少于10条),分别加入用培养液配置的阿霉素(10-20μM)和不同浓度的化合物。以含有0.1%DMSO的培养液作为空白对照组,加入阿霉素组为模型组以及阿霉素和化合物一起混合的加药组。加药完成后,将24孔板放入28.5℃的培养箱中培养48小时(其中在24h时要更换新鲜的含药物培养液,防止药物变质等因素);
3.药物处理48小时后(此时的幼鱼是96hpf),在荧光显微镜下拍照观察不同加药组对斑马鱼心脏的影响,观察指标为心脏形态及心脏搏出量(strokevolume),实验结果如图1所示。
由图1可知:EGCG、全乙酰化衍生物(AcEGCG)、EGCG烷化衍生物Y3和Y6均可不同程度的对抗阿霉素所致斑马鱼的心脏毒性,改善心脏形态、增加心脏搏出量,其中以Y6能的减毒作用最强,用量最小,并且其效果优于乙酰化衍生物。结合表2、3,Y6的该作用与其增效蒽环类抗癌抗生素,柔红霉素(DNR)抗人肝癌细胞(两株)的作用和剂量一致,表明EGCG烷化衍生物和乙酰化衍生物有增效蒽环类抗癌抗生素抗肝癌作用的同时可减轻其严重的不良反应-心脏毒性。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何不经过创造性劳动想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求书所限定的保护范围为准。
Claims (7)
1.一种表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用,所述的表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用,所述的衍生物选自:
①5,7,3′,4′,5′,3″,4″,5″-八-O-乙基-EGCG、
②5,7,3′,4′,3″,4″,5″-七-O-乙基-EGCG、
③5,7,4′,5′,3″,4″,5″-七-O-乙基-EGCG、
④5,7,3′,4′,3″,4″-六-O-乙基-EGCG、
⑤5,3′,4′,5′,3″,4″,5″-七-O-乙基-EGCG、
⑥5,3′,4′,3″,4″,5″-六-O-乙基-EGCG、
⑦5,7,3′,4′,5′,3″,4″,5″-八-O-丙基-EGCG、
⑧5,7,4′,5′,3″,4″,5″-七-O-丙基-EGCG;
优选的,所述的表没食子儿茶素没食子酸酯烷基化衍生物及其抗肿瘤应用为5,7,3′,4′,3″,4″-六-O-乙基-EGCG或5,3′,4′,3″,4″,5″-六-O-乙基-EGCG。
2.含有权利要求1所述的表没食子儿茶素没食子酸酯烷基化衍生物的药物组合物。
3.根据权利要求2所述的药物组合物,所述的药物组合物中还包括药学上可接受的辅料和/或赋形剂。
4.根据权利要求2所述的药物组合物,所述的药物组合物中包括有效量的蒽环类抗肿瘤药物,优选的,表没食子儿茶素没食子酸酯烷基化衍生物与蒽环类抗肿瘤药物的重量比是100:1-10:1;优选是40:1-60:1。
5.根据权利要求4所述的药物组合物,所述的蒽环类抗肿瘤药物为柔红霉素(DNR)和/或阿霉素(DOX)。
6.权利要求1所述的表没食子儿茶素没食子酸酯烷基化衍生物制备及其抗肿瘤作用在制备治疗肝癌的药物中的应用。
7.权利要求2-5任意一项所述的组合物在制备治疗肝癌的药物中的应用。
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KR20190114500A (ko) * | 2018-03-30 | 2019-10-10 | 건국대학교 산학협력단 | 에피갈로카테킨 갈레이트 프로드러그, 이의 제조방법 및 이를 포함하는 미토콘드리아 생합성 촉진용 조성물 |
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CN105030756A (zh) * | 2015-07-23 | 2015-11-11 | 广西医科大学 | Egcg结构修饰衍生物在制备血管调控类药物中的应用 |
CN108129438A (zh) * | 2017-12-25 | 2018-06-08 | 中国海洋大学 | 一种含2-苯色满母核的化合物及其制备方法 |
KR20190114500A (ko) * | 2018-03-30 | 2019-10-10 | 건국대학교 산학협력단 | 에피갈로카테킨 갈레이트 프로드러그, 이의 제조방법 및 이를 포함하는 미토콘드리아 생합성 촉진용 조성물 |
KR102082041B1 (ko) | 2018-03-30 | 2020-02-26 | 건국대학교 산학협력단 | 에피갈로카테킨 갈레이트 프로드러그, 이의 제조방법 및 이를 포함하는 미토콘드리아 생합성 촉진용 조성물 |
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