CN108863798A - 紫草宁苯甲酰丙烯酸羧酸酯类衍生物的合成及生物活性评价 - Google Patents
紫草宁苯甲酰丙烯酸羧酸酯类衍生物的合成及生物活性评价 Download PDFInfo
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Abstract
本发明属于化学制药技术领域,具体涉及一类紫草宁衍生物及其在肿瘤抑制方面的应用。通过合成手段将相应苯甲酰丙烯酸衍生物与紫草宁连接,获得相应酯类衍生物,体外抗肿瘤的活性研究表明,这类紫草宁苯甲酰丙烯酸羧酸酯类衍生物对肿瘤细胞株有很强的抑制活性。
Description
一、技术领域
本发明属于化学制药技术领域,具体涉及一种紫草宁苯甲酰丙烯酸羧酸酯类 衍生物的制备及其在肿瘤抑制方面的应用。
二、背景技术
紫草(Lithospermum erythrorhizon Sieb.et Zucc0)是一种重要的药用植物,属于一年生或者多年生的草本植物。其产生天然的次生代谢物-紫草宁及其衍生 物紫草宁具有多重药理活性,如杀菌、消炎、抗氧化、抗病毒、抗肿瘤等。近年 来研究表明,它作为先导物在抑制肿瘤细胞增殖的功能分子研究方面有很大的潜 力。Hyo jung L等研究紫草素及其衍生物对血管相关生长因子的活性,抑制血管 生长,最终抑制肺腺癌肿瘤的生长。刘立华等对腹水型肉瘤的研究中发现,紫草 宁衍生物能增强小鼠自然杀伤性细胞的活性,可以长时间内抑制肿瘤生长。同时, 紫草宁衍生物SYUNZ-7(1-18)也能够抑制小鼠鼻咽癌细胞血管的再生并且呈现 时间和浓度的依赖性。H.Jing等研究发现,紫草宁通过FOXO转录因子和线粒 体途径以及抑制蛋白激酶ERK信号通路诱导细胞凋亡。
本课题组在多年的研究过程中,获得了多系列紫草宁衍生物,并申请了相关 专利:紫草宁含氟羧酸酯类衍生物及其合成方法和应用(申请号:201110412497.4) 以及紫草宁肉桂酸酯类衍生物及其合成方法和应用(申请号:201210002020.3), 发现了若干具有高效抑制肿瘤细胞活性的功能分子。
紫草宁本身具有良好的抗肿瘤活性,但是分子本身毒性较大,不利于后期临 床应用。因此对紫草宁进行结构修饰,提高抗癌活性,克服其缺点,获得高效低 毒的衍生物成为主要的研究课题。
三、发明内容
本发明以紫草宁为起始原料,通过半合成获得一类新颖紫草宁苯甲酰丙烯酸 羧酸酯类衍生物。抗肿瘤活性表明,该衍生物对肿瘤细胞株H460、MCF-7、HeLa、 A549具有明显的抑制活性,其中在A549细胞活性结果中,化合物7活性最优, IC50值达到4.37±0.46μM;本发明需要解决的问题是提供一类结构新颖的紫草宁 羧酸酯类衍生物及其制备方法和在肿瘤抑制中的应用。
本发明的紫草宁苯甲酰丙烯酸羧酸酯类衍生物结构式如式I所示:
本发明的式I结构紫草宁羧酸酯类衍生物是通过紫草宁与相应羧酸的半合成得到新颖的结构活性功能化合物。
本发明通过体外肿瘤细胞抑制活性证明紫草宁羧酸衍生物对MCF-7、HeLa、 H460、A549具有明显的抑制活性,化合物7对四种癌细胞的抑制作用非常明显, 而且对A549细胞的抑制活性最强,IC50值达到4.37±0.46μM。详见附图1、2、 3、4。通过毒性实验证明了这一类新颖的化合物对改造后人正常的肝细胞(L02) 毒副作用低,而紫草宁和上市药物gefitinib对其毒性较大。此外,细胞凋亡实验 证明,化合物7对A549细胞凋亡具有浓度和时间依赖性的效果。详见附图5, 附图6。
本发明与现有技术相比较其有益效果:
在本发明中,所获紫草宁苯甲酰丙烯酸羧酸酯类衍生物与紫草宁相比,均具 有明显的肿瘤细胞抑制活性,部分新颖化合物对肿瘤细胞株的抑制活性明显优于 其母体分子紫草宁,并且毒副作用低。同时化合物7对A549细胞增殖的抑制最 为明显。本研究拟通过流式、激光共聚焦及western blot手段对药物作用机制进 行深入探究。
四:附图说明
图1表示化合物1-15及紫草宁对MCF-7细胞增殖的抑制
图2表示化合物1-15及紫草宁对HeLa细胞增殖的抑制
图3表示化合物1-15及紫草宁对H460细胞增殖的抑制
图4表示化合物1-15及紫草宁对A549细胞增殖的抑制
图5表示化合物7处理A549细胞浓度依赖的凋亡分析及误差分析
图6表示化合物7处理A549细胞时间依赖的凋亡分析及误差分析
图7表示化合物1-15合成线路图
五:具体实施方式
实例一:紫草宁苯甲酰丙烯酸羧酸酯类衍生物的制备
化学合成路线
将苯或者苯的衍生物和顺丁烯二酸酐反应得到中间体苯甲酰丙烯酸分子,将 获得的苯甲酰丙烯酸中间体和紫草宁发生酯化反应得到目标分子紫草宁衍生物。 反应示意图详见附图7。
化学合成步骤
中间产物的合成
(E)-4-(2,5-dimethylphenyl)-4-oxobut-2-enoic acid(1a)
将催化剂0.02mol无水氯化铝和0.01mol的顺丁烯二酸酐溶解在40mL的烧 瓶中,室温下搅拌10min,使无水氯化铝和顺丁烯二酸酐能够充分溶解,随后,将 0.01mol对二甲苯缓慢滴加到溶液体系中,溶液的颜色逐渐变为黄褐色。将上述 反应体系在室温条件下搅拌12h,TCL点半检测反应进度。反应完成之后,向反 应体系中滴加浓度为20%的稀盐酸,随后用100mL的分液漏斗进行萃取分离。 萃取三遍。取下层二氯甲烷溶剂层混合,加入适量的无水硫酸钠干燥。用旋转蒸 发仪器蒸干溶剂得到粗糙中间产物的淡黄色固体1a。
将获得的淡黄色中间产物加入到盛有100mL碳酸氢钠的饱和溶液中,不断 搅拌直到固体溶解完全。随后,用稀盐酸调节溶液pH=2,此时溶液中又出现淡 黄色固体。抽滤并且干燥固体得到纯的淡黄色中间产物1a。实验中间产物1a的 合成、分离以及纯化方法适用于所有的中间产物衍生物(1b-1o)。
最终产物的合成
1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (Z)-4-(2,5-dimethylphenyl)-4-oxobut-2-enoate(1)
室温条件下将50mmol中间体苯甲酰丙烯酸衍生物(1a)加入到30mL无水 二氯甲烷中,使之充分溶解。催化剂N,N-二环己基碳二亚胺(DCC)和4-二甲氨 基吡啶(DMAP)按照中间体0.1倍的量投放到溶液体系中,搅拌20min。将25mmol 紫草宁加入到上述反应溶液中,继续搅拌3-4h。TCL检测反应进度。反应完成 之后,用柱层析方法分离紫草宁衍生物。旋蒸、干燥得到终产物1。实验最终产 物的合成、分离以及纯化方法适用于所有的最终产物衍生物
相应化合物的理化数据如下:
化合物1:1H NMR(300MHz,CDCl3)δ12.61(s,1H),12.42(s,1H),7.64(t,J=11.9Hz,1H),7.40(d,J=8.9Hz,1H),7.24(s,1H),7.21-7.14(m,3H),7.02(s,1H),6.76 (d,J=15.7Hz,1H),6.15(dd,J=6.7,4.8Hz,1H),5.15(t,J=7.3Hz,1H),2.75- 2.49(m,2H),2.45(s,3H),2.36(d,J=11.1Hz,3H),1.70(s,3H),1.60(s,3H).MS (ESI):475.17([M+H]+).Anal.Calcd for C28H26O7:C,70.87;H,5.52;O,23.6;Found: C,69.14;H,5.33;O,23.19.
化合物2:1H NMR(300MHz,CDCl3)δ12.61(d,J=2.3Hz,1H),12.41(d,J=2.4 Hz,1H),8.02-7.86(m,3H),7.31(t,J=7.6Hz,2H),7.18(d,J=8.7Hz,2H),7.03 (t,J=4.2Hz,1H),6.94(t,J=10.3Hz,1H),6.17(dd,J=6.4,4.7Hz,1H),5.15(t,J =7.3Hz,1H),2.77-2.49(m,3H),2.48-2.37(m,2H),1.70(s,3H),1.61(s,3H). MS(ESI):461.16([M+H]+).Anal.Calcd for C27H24O7:C,70.43;H,5.25;O,24.32; Found:C,70.14;H,5.;O,24.19.
化合物3:1H NMR(300MHz,CDCl3)δ12.61(d,J=2.3Hz,1H),12.41(d,J=2.4 Hz,1H),7.97(d,J=15.5Hz,1H),7.82-7.69(m,2H),7.28(d,J=7.2Hz,1H),7.19 (s,2H),7.04(d,J=0.9Hz,1H),6.95(d,J=15.5Hz,1H),6.17(dd,J=6.4,4.7Hz, 1H),5.16(t,J=7.3Hz,1H),2.79-2.47(m,2H),2.35(s,6H),1.70(s,3H),1.61(s, 3H).MS(ESI):475.17([M+H]+).Anal.Calcd for C28H26O7:C,70.87;H,5.52;O, 23.6;Found:C,70.34;H,5.42;O,23.19.
化合物4:1H NMR(300MHz,CDCl3)δ12.61(s,1H),12.41(s,1H),7.70-7.58(m,1H),7.52(dd,J=20.1,8.2Hz,1H),7.33-7.26(m,2H),7.19(s,2H),7.01(d,J=0.8 Hz,1H),6.76(dd,J=15.7,1.6Hz,1H),6.15(dd,J=6.5,4.8Hz,1H),5.14(t,J=7.3 Hz,1H),2.75-2.53(m,2H),2.45(d,J=27.0Hz,3H),1.70(s,3H),1.59(s,3H). MS(ESI):496.11([M+H]+).Anal.Calcd for C27H23ClO7:C,65.52;H,4.68;O, 22.63;Found:C,65.34;H,4.62;O,22.61.
化合物5:1H NMR(300MHz,CDCl3)δ12.61(s,1H),12.41(s,1H),7.95(dd,J= 11.9,7.4Hz,3H),7.35(d,J=8.1Hz,2H),7.19(s,2H),7.04(s,1H),6.95(d,J= 15.5Hz,1H),6.17(dd,J=7.1,4.6Hz,1H),5.16(t,J=7.2Hz,1H),2.79-2.71(m, 2H),2.70-2.50(m,2H),1.70(s,3H),1.61(s,3H),1.25-1.23(m,3H).MS(ESI): 475.17([M+H]+).Anal.Calcdfor C28H26O7:C,70.87;H,5.52;O,23.60;Found:C, 70.76;H,5.73;O,23.43.
化合物6:1H NMR(300MHz,CDCl3)δ12.62(s,1H),12.41(s,1H),7.93(t,J=11.9Hz,3H),7.49(dd,J=12.8,11.0Hz,2H),7.19(s,2H),7.00(dd,J=18.2,8.2Hz, 2H),6.17(dd,J=6.7,4.9Hz,1H),5.15(s,1H),2.77-2.47(m,2H),1.70(s,3H), 1.61(s,3H).MS(ESI):482.09([M+H]+).Anal.Calcd for C26H21ClO7:C,64.94;H, 4.40;O,23.29;Found:C,64.74;H,4.52;O,22.89.
化合物7:1H NMR(300MHz,CDCl3)δ12.61(d,J=2.3Hz,1H),12.41(d,J=2.4 Hz,1H),8.10-7.99(m,2H),7.93(d,J=15.5Hz,1H),7.25-7.21(m,1H),7.21- 7.14(m,3H),7.04(d,J=0.9Hz,1H),6.95(t,J=12.6Hz,1H),6.23-6.11(m,1H),5.15(t,J=7.3Hz,1H),2.79-2.44(m,2H),1.70(s,3H),1.61(s,3H).MS(ESI): 465.13([M+H]+).Anal.Calcd forC26H21FO7:C,67.24;H,4.56;O,24.11;Found:C, 67.64;H,4.54;O,24.10.
化合物8:1H NMR(300MHz,CDCl3)δ12.61(d,J=2.3Hz,1H),12.41(d,J=2.4 Hz,1H),7.99-7.79(m,3H),7.19(s,2H),7.14(t,J=8.8Hz,1H),7.04(d,J=0.9 Hz,1H),6.94(t,J=11.1Hz,1H),6.17(dd,J=6.5,4.7Hz,1H),5.15(t,J=7.3Hz, 1H),2.89-2.44(m,2H),2.34(t,J=7.4Hz,3H),1.70(s,3H),1.61(s,3H).MS (ESI):479.15([M+H]+).Anal.Calcd for C26H21FO7:C,67.78;H,4.85;O,23.41; Found:C,67.74;H,4.64;O,23.12.
:化合物9:1H NMR(300MHz,CDCl3)δ12.61(d,J=2.3Hz,1H),12.41(d,J=2.4 Hz,1H),7.97(d,J=15.5Hz,1H),7.75(dd,J=12.8,4.9Hz,2H),7.29(s,1H),7.19 (s,2H),7.04(d,J=0.9Hz,1H),6.95(d,J=15.5Hz,1H),6.17(dd,J=6.4,4.7Hz, 1H),5.16(t,J=7.3Hz,1H),2.79-2.44(m,2H),2.35(s,6H),1.70(s,3H),1.61(s, 3H).MS(ESI):475.17([M+H]+).Anal.Calcd for C28H26O7:C,67.78;H,4.85;O, 23.41;Found:C,67.74;H,4.64;O,23.12.
化合物10:1H NMR(300MHz,CDCl3)δ12.62(s,1H),12.41(s,1H),7.97-7.78 (m,2H),7.74-7.33(m,2H),7.19(s,2H),7.07-6.89(m,2H),6.17(dd,J=6.7,4.9 Hz,1H),5.15(t,J=7.4Hz,1H),2.79-2.52(m,2H),2.46(d,J=18.4Hz,3H),1.70 (s,3H),1.61(s,3H).MS(ESI):540.06([M+H]+).Anal.Calcd for C27H23BrO7:C, 60.12;H,4.30;O,20.76;Found:C,60.14;H,4.26;O,20.72.
化合物11:1H NMR(300MHz,CDCl3)δ12.60(d,J=2.2Hz,1H),12.41(s,1H), 7.70-7.45(m,2H),7.30(dd,J=8.7,1.6Hz,2H),7.19(s,2H),7.03(t,J=5.8Hz, 1H),6.76(dd,J=15.7,1.7Hz,1H),6.15(dd,J=6.4,4.7Hz,1H),5.14(t,J=7.3Hz, 1H),2.63(ddd,J=22.3,15.0,8.3Hz,2H),2.45(d,J=27.0Hz,3H),1.70(s,3H), 1.59(s,3H).MS(ESI):496.11([M+H]+).Anal.Calcd for C27H23ClO7:C,65.52;H, 4.68;O,22.63;Found:C,65.54;H,4.65;O,22.61.
化合物12:1H NMR(300MHz,CDCl3)δ12.62(s,1H),12.42(s,1H),7.98(dd,J=13.3,11.5Hz,3H),7.70-7.59(m,1H),7.53(t,J=7.5Hz,2H),7.18(d,J=9.0Hz, 2H),7.04(s,1H),6.95(t,J=12.3Hz,1H),6.17(dd,J=6.7,4.8Hz,1H),5.16(t,J= 7.2Hz,1H),2.79-2.46(m,2H),1.71(s,3H),1.61(s,3H).MS(ESI):447.14 ([M+H]+).Anal.Calcd forC26H22O7:C,69.95;H,4.97;O,25.05;Found:C,69.80;H, 4.85;O,25.11.
:化合物13:1H NMR(300MHz,CDCl3)δ12.60(s,1H),12.41(d,J=1.6Hz, 1H),7.74-7.55(m,2H),7.19(s,2H),7.09-6.93(m,3H),6.77(d,J=15.7Hz,1H), 6.15(dd,J=6.7,5.1Hz,1H),5.14(t,J=7.3Hz,1H),2.65(ddd,J=28.8,14.9,6.5 Hz,2H),2.52(d,J=7.7Hz,3H),1.70(s,3H),1.60(s,3H).MS(ESI):479.15 ([M+H]+).Anal.Calcd forC26H21FO7:C,67.78;H,4.85;O,23.41;Found:C,67.80; H,4.73;O,23.32.
:化合物14:1H NMR(300MHz,CDCl3)δ12.60(s,1H),12.41(d,J=2.1Hz,1H), 7.82(dd,J=15.6,3.4Hz,1H),7.61(ddd,J=18.8,13.5,8.3Hz,1H),7.37(ddd,J= 14.7,8.2,6.0Hz,1H),7.22-7.15(m,2H),7.13-6.99(m,2H),6.96-6.83(m,1H), 6.16(dd,J=6.4,4.6Hz,1H),5.15(s,1H),2.79-2.50(m,2H),2.43-2.29(m,3H), 1.70(s,3H),1.60(s,3H).MS(ESI):479.15([M+H]+).Anal.Calcd for C26H21FO7:C, 67.78;H,4.85;O,23.41;Found:C,67.52;H,4.73;O,23.22.
化合物15:1H NMR(300MHz,CDCl3)δ12.61(s,1H),12.41(s,1H),7.89(dd,J=12.1,9.5Hz,3H),7.73-7.53(m,2H),7.19(s,2H),7.03(d,J=0.8Hz,1H),6.97(d, J=15.5Hz,1H),6.17(dd,J=6.4,4.6Hz,1H),5.14(d,J=7.4Hz,1H),2.79-2.49 (m,2H),1.70(s,3H),1.61(s,3H).MS(ESI):526.05([M+H]+).Anal.Calcd for C26H21BrO7:C,59.44;H,4.03;O,21.32;Found:C,59.42;H,4.15;O,21.52.
实例二:式I类紫草宁硫辛酸酯类衍生物的应用
以H460、HeLa、MCF-7、A549细胞株作为检测株,MTT比色法为检测方法, 通过对式I类紫草宁羧酸酯类衍生物体外肿瘤细胞抑制活性研究发现,该类新颖 结构衍生物具有明显的体外肿瘤细胞抑制活性,并且对正常细胞毒性较低。结果 见附图1、2、3、4。
实例三:化合物7诱导A549细胞凋亡
附图5显示,化合物7以药物浓度0、2、4、8、12μM处理24h之后,可 以得出,在时间相同的情况下,随着药物浓度的不断上升,A549细胞的凋亡比 例明显升高。早期凋亡细胞比例由1.15%上升至42.6%,晚期凋亡细胞比例由5.69 上升至38.1%。与此同时,对实验结果具有影响的破碎细胞比例没有明显的变化。 由此得出结论:化合物7促进A549细胞凋亡具有浓度依赖性的效果。
化合物7对A549细胞时间依赖性凋亡的影响。从附图6中显示,用8μM 的化合物PMMB-135处理A549细胞12h,24h以及36h。早期凋亡细胞比例由 2.02%上升至43.8%,晚期凋亡细胞比例由6.55%上升至41.0%。与此同时,对实 验结果具有影响的破碎细胞比例没有明显的变化。由此得出结论:化合物7促进 A549细胞凋亡具有时间依赖性的效果。
本发明所述紫草宁硫辛酸酯类衍生物可制备成抗肿瘤药物。
Claims (2)
1.紫草宁苯甲酰丙烯酸羧酸酯类衍生物,其结构式如下:
2.权利要求1所述紫草宁苯甲酰丙烯酸羧酸酯类衍生物在肿瘤治疗中的应用。
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