CN110885297A - 二苯甲烷-4,4’-二酰腙类化合物及其应用 - Google Patents
二苯甲烷-4,4’-二酰腙类化合物及其应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,涉及二苯甲烷‑4,4’‑二酰腙类化合物及其应用,具体涉及以二苯甲烷‑4,4’‑二甲酸为原料,制备的二苯甲烷‑4,4’‑二酰腙一系列化合物,并测试了它们与DNA的结合、荧光响应性能以及对四种肿瘤细胞生长的抑制性能。结果表明,该系列分子与双螺旋DNA均具有较好的结合,且对AT碱基对数量有明显的荧光响应:表现为375nm处出现较强的荧光,520nm处荧光猝灭;此外,该类化合物也具有较高的体外抗肿瘤活性。可以用于制备抗肿瘤药物。
Description
技术领域
本发明属于生物技术领域,涉及二苯甲烷-4,4’-二酰腙类化合物及其制备方法和应用,具体涉及二苯甲烷-4,4’-二水杨醛-二酰腙及其一系列衍生物,及其在荧光分子探针技术中的应用,还涉及该类化合物的抗肿瘤活性。
背景技术
常见的DNA荧光探针分为季铵盐类和非季铵盐类,其中季铵盐类由于细胞膜通透性不佳,无法染色活细胞,目前广泛商用的DNA荧光探针只有Hoechst。二苯甲烷-4,4--二酰腙类化合物是一类全新结构的DNA荧光分子探针。在没有双螺旋DNA的情况下,两端的两个苯环平面相互重叠,故520nm处有一荧光(excimer)峰。而当有双螺旋DNA存在时,化合物分子同DNA小沟结合,其上的酚羟基同T碱基上未结合羟基氧之间形成氢键,其两端水杨醛部分的重叠构象被解开,原有的推拉电子体系变化,导致520nm处荧光猝灭,同时在375nm处荧光强烈增强。
二苯甲烷二酰腙类DNA荧光探针在与双螺DNA结合前后荧光的明显差异,使其具有成为新型DNA荧光探针荧光探针的潜力。同时这种荧光探针是非季铵盐类,不受细胞膜通透性的限制,有可能实现对活细胞的染色,这对活体细胞体外染色技术带来了一种新的选择。
酰腙类化合物的酰腙键在肿瘤细胞的酸性环境下水解,生成酰肼,酰肼对肿瘤细胞具有较强烈的抑制增殖的作用,因此酰腙可以作为一类抗肿瘤的活性基团作为应用。
二苯甲烷-4,4’-二水杨醛-二酰腙
发明内容
本发明提供了一系列二苯甲烷-4,4’-二酰腙类化合物,其化学结构通式为:
X为氮或碳原子;
Y为氮或碳原子;
Z为氮或碳原子;
R为氢、氨基、硝基、羟基、C1-C6酯基、卤素、取代或未取代的C1-C4胺、取代或未取代的5-10元杂环基或杂芳基,所述杂环基或杂芳基含有1-3个N、O或S的杂原子,所述取代基为:C1-C10烷基、C1-C10烷氧基、C1-C10烷氨基;
n为0-5。
本发明优选具有如下结构的二苯甲烷-4,4’-二酰腙类化合物,
其中,
X为氮或碳原子;
Y为氮或碳原子;
Z为氮或碳原子;
R为氢、氨基、硝基、羟基、C1-C6酯基、卤素、取代或未取代的C1-C4胺、取代或未取代的5-10元杂环基,所述杂环基含有1-3个N、O或S的杂原子,所述取代基为:C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基;
n为0-5。
本发明优选具有如下结构的二苯甲烷-4,4’-二酰腙类化合物,
其中,
X为氮或碳原子;
Y为氮或碳原子;
Z为氮或碳原子;
R为氢、羟基、C1-C6酯基、卤素、取代或未取代的C1-C4胺、取代或未取代的5-6元杂环基,所述杂环基含有1-3个N、O或S的杂原子,所述取代基为:C1-C4烷基、C1-C4烷氧基、C1-C4烷氨基;
n为0-2。
本发明优选具有如下结构的二苯甲烷-4,4’-二酰腙类化合物,
其中,
X为氮或碳原子;
Y为氮或碳原子;
Z为氮或碳原子;
R为氢、羟基、C1-C6酯基、卤素、取代或未取代的C1-C4胺、取代或未取代的5-6元杂环基,所述杂环基含有1-3个N原子,所述取代基为:C1-C4烷基、C1-C4烷氧基、C1-C4烷氨基;
n为0。
本发明优选具有如下结构的二苯甲烷-4,4’-二酰腙类化合物,
当X、Y或Z为N原子时,R为氢、甲基、乙基、叔丁基、二甲胺基、二乙胺基、氯、溴、碘、氟、BOC保护的哌嗪、哌嗪-N盐酸盐、甲氧酰基、乙氧酰基,哌嗪-N溴酸盐,哌嗪-N碘酸盐;
当X和Y和Z同时为C原子时,R为氢、甲基、乙基、叔丁基、二甲胺基、二乙胺基、氯、溴、碘、氟、BOC保护的哌嗪、4-哌嗪-N盐酸盐、甲氧酰基、乙氧酰基。
本发明优选如下结构通式的二苯甲烷-4,4’-二酰腙类化合物:
本发明的化合物还包括上述结构式所示化合物所形成的在药学上可接受的盐及其水合物,这些药学上可接受的盐包括该化合物与酸所形成的盐。所述的酸可以为盐酸、硫酸、氢溴酸、磷酸的无机酸或选自乙酸、柠檬酸、草酸、酒石酸、苯甲酸、苹果酸的有机酸。所述水合物的结晶水数目为0~4中的任意实数。
本发明的二苯甲烷-4,4’-二酰腙类化合物制备方法包括以下步骤:
(1)二苯甲烷-4,4’-二酰肼的制备
二苯甲烷-4,4’-二甲酸首先与乙醇发生酯化反应,其后与水合肼发生氨解反应制备目标产物:
(2)二苯甲烷-4,4’-二酰腙的制备
二苯甲烷-4,4’-二酰肼与醛发生醛胺缩合反应,只酯化反应,制备目标产物。
具体地,本发明的二苯甲烷-4,4’-二酰腙类化合物制备方法如下:
(1)二苯甲烷-4,4’-二酰肼的制备
1.1二苯甲烷-4,4’-二羧酸溶于无水乙醇中,冰浴条件下滴加二氯亚砜,转移至油浴,加热搅拌。反应结束,恢复至室温。将反应液倒入二氯甲烷中,饱和碳酸氢钠溶液洗涤两遍,清水洗涤一遍。二氯甲烷用无水硫酸钠干燥后,减压蒸馏得到化合物A。
1.2化合物A,溶于水甲醇,加入水合肼,室温搅拌,至反应结束,离心,取沉淀,分别用无水甲醇,二氯,石油醚,洗涤两次,得化合物B。
(2)二苯甲烷-4,4’-二水杨醛-二酰腙类化合物的制备
取化合物B和水杨醛,溶于甲醇和乙醚的混合溶液中,搅拌,至反应结束,恢复至室温,离心。分别用无水甲醇,二氯甲烷,石油醚洗涤两次,得化合物1。
取化合物B和邻羟基苯甲醛、间羟基苯甲醛、2-吡啶甲醛、3-吡啶甲醛、4-吡啶甲醛、5-溴水杨醛、4-氟水杨醛、4-N,N-二乙基胺基水杨醛、3-甲酰基-4-羟基苯甲酸甲酯、4-(3-甲酰基-4-羟基苯基)哌嗪-1-羧酸叔丁酯,溶于甲醇和乙醚的混合溶液中,搅拌,至反应结束,恢复至室温,离心。分别用无水甲醇,二氯甲烷,石油醚洗涤两次,得化合物2、3、4、5、6、7、8、9、10、11。
取化合物11,溶于二氯甲烷,滴入浓盐酸,室温搅拌。反应结束,有白色固体颗粒析出,黏附于反应瓶壁上。用二氯甲烷,石油醚分别洗涤两次,棕黄色粉末状固体纯品,得到化合物12。
本发明中二苯甲烷-4,4’-二酰腙类化合物可以用于荧光分子探针技术中,用于检测核酸,还可以用于制备抗肿瘤药物。
具体地,所述的二苯甲烷-4,4’-二酰腙类化合物可以作为小分子荧光探针使用,小分子荧光探针可与双螺旋DNA结合,并产生AT碱基对的荧光选择性。
包括:
(1)紫外检测
将化合物溶于缓冲溶液中逐渐加入一定比例的DNA溶液,得230nm–500nm的紫外吸收值,将其数据代入1:1结合方程,求得结合能K。
(2)荧光检测
设定波谱范围在300nm-650nm,激发波长为299nm,向一定浓度的化合物缓冲液中逐渐加入一定比例的DNA溶液,得到其荧光吸收的谱图。以[CDNA/C化合物]为横坐标,以F375/F520为纵坐标作图,可得荧光变化率图,检测限为0.26μM。
本发明的二苯甲烷-4,4’-二酰腙类化合物具有较好的抑制肿瘤细胞增殖活性,在制备抗肿瘤药物中具有较好的发展前景。
附图说明
图1为二苯甲烷-4,4’-二水杨醛-二酰腙(化合物1)的与DNA(AT序列)的紫外滴定谱图:化合物浓度为20μM,[CDNA/C化合物]从0开始以每0.3个当量增加到4.5;随DNA增加,峰值降低持续降低。
图2为二苯甲烷-4,4’-二水杨醛-二酰腙(化合物1)的与DNA(GC序列)的紫外滴定谱图:化合物浓度为20μM,[CDNA/C化合物]从0开始以每0.3个当量增加到4.5;随DNA增加,峰值降低持续降低。
图3为二苯甲烷-4,4’-二水杨醛-二酰腙(化合物1)的与DNA(AT序列)的荧光滴定谱图:化合物浓度为10μM,[CDNA/C化合物]从0开始以每0.25个当量增加到4.0;随DNA增加,525nm峰值降低,375nm峰值升高。
图4为二苯甲烷-4,4’-二水杨醛-二酰腙(化合物1)的与DNA(GC序列)的荧光滴定谱图:化合物浓度为10μM,[CDNA/C化合物]从0开始以每0.25个当量增加到4.0;随DNA增加,525nm峰值降低,375nm峰值不变。
具体实施方式
实施例1
化合物A的合成
取200mg(0.78mmol,1.0eq)二苯甲烷-4,4’-二羧酸溶于100mL无水乙醇中,冰浴条件下滴加2mL二氯亚砜,转移至油浴,90℃搅拌3h。反应结束,恢复至室温。将反应液倒入500mL二氯甲烷中,饱和碳酸氢钠溶液洗涤两遍,清水洗涤一遍。二氯甲烷用无水硫酸钠干燥后,40℃减压蒸馏得到纯品145.2mg。收率:72.6%,TLC(二氯甲烷/甲醇=40:1,v/v),Rf=0.3。
实施例2
化合物B的合成
取150mg(0.48mmol,1.0eq)化合物A,溶于50mL无水甲醇,加入10mL水合肼(80%,V),室温搅拌8h,有大量白色针状固体析出,离心,取沉淀,分别用无水甲醇,二氯,石油醚,洗涤两次,得到白色粉末状固体纯品102.4mg。收率:75.0%,TLC(二氯甲烷:甲醇:氨水=40:7:1)。
实施例3
目标化合物1的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),水杨醛22.3mg(0.1828mmol,4.0eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。分别用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品16.5mg。收率73.5%。
1H NMR(600MHz,DMSO-d6)δ12.05(s,1H),11.30(s,1H),8.63(s,1H),7.89(d,J=8.1Hz,2H),7.54(d,J=7.5Hz,1H),7.44(d,J=7.9Hz,2H),7.30(t,J=7.7Hz,1H),6.94(d,J=8.1Hz,2H),6.92(d,J=7.5Hz,1H),4.13(s,1H);13C NMR(151MHz,DMSO-d6)δ163.0,157.8,148.5,145.3,131.7,131.1,129.8,129.3,128.3,119.7,119.0,116.7,41.0;HRMS(ESI):m/z:[M+Na]+calc.:515.1690;found:515.1695.
实施例4
目标化合物2的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),间羟基苯甲醛22.0mg(0.1801mmol,3.9eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。分别用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品11.4mg。收率50.6%。
1H NMR(600MHz,DMSO-d6)δ11.73(s,1H),9.62(s,1H),8.35(s,1H),7.86(d,J=7.6Hz,2H),7.42(d,J=7.6Hz,3H),7.24(d,J=7.7Hz,1H),7.20(s,1H),7.09(d,J=7.3Hz,1H),6.83(d,J=7.6Hz,1H),4.10(s,0H);13C NMR(151MHz,DMSO-d6)δ163.2,158.0,148.1,145.1,135.9,131.8,130.3,129.2,128.3,119.2,117.8,112.9,48.9;HRMS(ESI):m/z:[M+Na]+calc.:515.1690;found:515.1688.
实施例5
目标化合物3的合成
取化合物B 13mg(0.0457mmol,1.0eq),对羟基苯甲醛22.0mg(0.1801mmol,3.9eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。分别用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品12.8mg。收率56.9%。
1H NMR(600MHz,DMSO-d6)δ11.57(s,1H),9.91(s,1H),8.33(s,1H),7.84(d,J=7.6Hz,2H),7.55(d,J=8.1Hz,2H),7.40(d,J=7.5Hz,3H),6.83(d,J=8.1Hz,2H),4.11(s,1H);13C NMR(151MHz,DMSO-d6)δ163.0,159.7,148.3,144.9,131.9,129.2,129.2,128.2,125.7,116.1,41.0;HRMS(ESI):m/z:[M+Na]+calc.:515.1690;found:515.1631.
实施例6
目标化合物4的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),2-吡啶甲醛20.0mg(0.187mmol,4.1eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品13.3mg。收率62.9%。
1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),8.62(s,1H),8.47(s,1H),7.98(d,J=7.4Hz,1H),7.90(s,1H),7.88(d,J=7.3Hz,4H),7.45(s,1H),7.43–7.39(m,3H);13C NMR(151MHz,DMSO-d6)δ163.5,153.6,149.9,148.2,145.3,137.2,131.5,129.3,128.4,124.8,120.3,41.1;HRMS(ESI):m/z:[M+H]+calc.:462.1882;found:462.1877.
实施例7
目标化合物5的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),3-吡啶甲醛20.0mg(0.187mmol,4.1eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品15.5mg。收率73.3%。
1H NMR(600MHz,DMSO-d6)δ11.96(s,1H),8.86(s,0H),8.61(s,1H),8.50(s,1H),8.14(d,J=7.1Hz,1H),7.87(d,J=7.1Hz,3H),7.56–7.46(m,1H),7.44(d,J=7.3Hz,3H),4.13(s,1H);13C NMR(151MHz,DMSO-d6)δ163.4,151.1,149.1,145.3,133.8,131.6,130.6,129.3,128.4,124.4,123.5,41.1;HRMS(ESI):m/z:[M+H]+calc.:462.1882;found:462.1877
实施例8
目标化合物6的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),4-吡啶甲醛20.0mg(0.187mmol,4.1eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品13.8mg。收率65.3%。
1H NMR(600MHz,DMSO-d6)δ12.06(s,1H),8.66(s,2H),8.44(s,1H),7.88(d,J=6.5Hz,3H),7.67(s,2H),7.44(d,J=7.1Hz,3H),4.13(s,1H).;13C NMR(151MHz,DMSO-d6)δ163.6,150.6,145.5,145.4,141.9,131.4,129.3,128.5,121.4,41.1;HRMS(ESI):m/z:[M+H]+calc.:462.1882;found:462.1877.
实施例9
目标化合物7的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),5-溴水杨醛35mg(0.174mmol,3.8eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品19.4mg。收率65.3%。
1H NMR(600MHz,DMSO-d6)δ12.13(s,1H),11.30(s,1H),8.60(s,1H),7.89(d,J=8.0Hz,3H),7.79(s,1H),7.44(d,J=7.5Hz,3H),7.42(d,J=2.0Hz,2H),6.91(d,J=8.7Hz,1H),4.13(s,1H);13C NMR(151MHz,DMSO-d6)δ163.1,156.8,145.8,145.4,133.9,131.1,130.8,129.3,128.4,121.7,119.1,110.8,56.4,41.1;HRMS(ESI):m/z:[M+H]+calc.:672.9885;found:672.9811.
实施例10
目标化合物8的制备
取化合物B 13.0mg(0.0457mmol,1.0eq),4-氟水杨醛25mg(0.178mmol,3.9eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品15.6mg。收率64.6%。
1H NMR(600MHz,DMSO-d6)δ12.05(s,0H),11.78(s,0H),8.60(s,0H),7.88(d,J=8.1Hz,1H),7.62(d,J=15.5Hz,0H),7.43(s,1H),6.80–6.79(m,0H),6.77(d,J=9.5Hz,1H),4.13(s,1H);13C NMR(151MHz,DMSO-d6)δ163.3,162.9,159.6,159.5,147.6,145.4,131.6,131.1,129.3,128.3,116.2,107.2,107.1,103.9,103.7,41.1,40.4;HRMS(ESI):m/z:[M+H]+calc.:529.1687;found:529.1682.
实施例11
目标化合物9的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),4-N,N-二乙基胺基水杨醛30.0mg(0.155mmol,3.4eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品18.7mg。收率64.5%。
1H NMR(600MHz,DMSO-d6)δ11.73(s,1H),11.46(s,1H),8.40(s,175H),7.85(d,J=7.9Hz,2H),7.41(d,J=8.0Hz,3H),7.18(d,J=8.7Hz,1H),6.26(d,J=10.4Hz,1H),6.12(s,1H),4.11(s,1H),3.36(q,J=6.8Hz,6H),2.50(p,J=1.8Hz,12H),1.10(t,J=6.9Hz,7H);13C NMR(151MHz,DMSO-d6)δ162.4,160.1,150.5,150.2,145.0,131.9,131.5,129.2,128.2,106.8,103.9,97.9,44.2,12.9;HRMS(ESI):m/z:[M+2H]2+calc.:318.1712;found:318.1709.
实施例12
目标化合物10的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),3-甲酰基-4-羟基苯甲酸甲酯20.0mg(0.111mmol,2.4eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有白色固体颗粒析出。恢复至室温,离心,得到白色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到白色粉末状固体纯品12.3mg。收率44.2%。
1H NMR(600MHz,DMSO-d6)δ12.11(s,1H),11.83(s,1H),8.70(s,1H),8.28(s,1H),7.89(d,J=7.9Hz,3H),7.87(s,1H),7.44(d,J=7.9Hz,3H),7.04(d,J=8.6Hz,1H),4.14(s,1H),3.84(s,3H);13C NMR(151MHz,DMSO-d6)δ166.1,163.2,161.5,146.1,145.4,132.6,131.2,130.3,129.3,128.4,121.2,119.8,117.0,52.3,41.1,40.4;HRMS(ESI):m/z:[M+H]+calc.:609.1985;found:609.1980.
实施例13
目标化合物11的合成
取化合物B 13.0mg(0.0457mmol,1.0eq),4-(3-甲酰基-4-羟基苯基)哌嗪-1-羧酸叔丁酯25.0mg(0.178mmol,3.9eq),溶于4mL甲醇和4mL乙醚的混合溶液中,60℃搅拌4h。反应结束,有淡黄色固体颗粒析出。恢复至室温,离心,得到淡黄色固体。用0.5mL无水甲醇,0.5mL二氯甲烷,0.5mL石油醚洗涤两次,得到淡黄色粉末状固体纯品28.3mg。收率60.1%。
1H NMR(600MHz,DMSO-d6)δ12.03(s,1H),10.78(s,1H),8.58(s,1H),7.88(d,J=8.0Hz,3H),7.44(d,J=8.0Hz,3H),7.11(s,1H),7.00(d,J=11.2Hz,1H),6.84(d,J=8.8Hz,1H),4.13(s,1H),3.46(s,6H),2.97(s,6H);13C NMR(151MHz,DMSO-d6)δ163.0,154.2,152.0,148.5,145.3,144.6,131.2,129.3,128.4,121.8,118.9,117.3,117.2,79.3,50.4,28.5;HRMS(ESI):m/z:[M+H]+calc.:861.4294;found:861.4294.
实施例14
目标化合物12的合成
取20mg(0.0232mmol,1.0eq)化合物13,溶于5mL二氯甲烷,滴入50μL的36%浓盐酸,室温搅拌15min。反应结束,有白色固体颗粒析出,黏附于反应瓶壁上。用2mL二氯甲烷,2mL石油醚分别洗涤两次,得到棕黄色粉末状固体纯品14.2mg。收率83.4%。
1H NMR(600MHz,DMSO-d6)δ12.24(s,1H),10.24(s,0H),9.27(s,2H),8.70(s,1H),7.92(d,J=7.7Hz,2H),7.43(d,J=7.8Hz,3H),7.19(s,1H),7.06(d,J=7.4Hz,2H),6.90(d,J=8.8Hz,1H),4.13(s,1H),3.28(s,6H),3.24(s,7H);13C NMR(151MHz,,DMSO-d6)δ163.1,152.7,147.9,145.3,143.1,131.2,129.3,128.4,121.8,119.3,117.5,117.1,47.5,43.1,41.1;HRMS(ESI):m/z:[M-2Cl]2+calc.:331.1645;found:331.1687.
实施例15
紫外检测用于求得探针与双螺旋DNA(AT序列)结合的结合常数K
设定波谱范围在230nm–500nm,向比色皿中加入1440μL的缓冲溶液溶液(pH=7.25-7.35),加入浓度为5mM的化合物(DMSO为溶剂)6.4μl,73.6μL DMSO,80μL的甲醇,使其终浓度达20μM,逐渐加入12AT-DNA,[CDNA/C化合物]依次为0、0.3、0.6、0.9、1.2、1.5、1.8、2.1、2.4、2.7,随DNA加入,峰值先降低后,得到其紫外吸收值变化图(见附图1)。
利用数值导入1:1结合方程,求得化合物1与12AT双螺旋DNA结合常数为K=2.97×104M-1。
实施例16
紫外检测(GC序列)
设定波谱范围在230nm–500nm,向比色皿中加入1440μL的缓冲溶液溶液(pH=7.25-7.35),加入浓度为5mM的化合物(DMSO为溶剂)6.4μl,73.6μL DMSO,80μL的甲醇,使其终浓度达20μM,逐渐加入12GC-DNA,[CDNA/C化合物]依次为0、0.3、0.6、0.9、1.2、1.5、1.8、2.1、2.4、2.7、3.0、3.3、3.6、3.9、4.2,随DNA加入,峰值降低,得到其紫外吸收值变化图(见附图2)。
实施例17
荧光检测(AT序列)
设定波谱范围在300nm–660nm,激发波长为299nm,向比色皿中加入1440μl的缓冲溶液(pH=7.25-7.35)加入浓度为5mM的化合物(DMSO为溶剂)6.4μl,73.6μL DMSO,80μL的甲醇,使其终浓度达20μM,逐渐加入12AT-DNA,随DNA加入量的增加,得到其荧光发射值的全谱图(图3)。在375nm处出现一个新的荧光峰并逐渐升高,在520nm处逐渐降低。
以[CDNA/C化合物]为横坐标,以F375/F520为纵坐标描点作图。
实施例18
荧光检测(GC序列)
在实例17相同检测条件下,加入12GC-DNA得到附图4,520nm处出现明显的下降,在375处并未出现新的荧光峰。
以上实验证明化合物1对12AT的有荧光响应选择性。
实施例19
化合物1-12的体外抗肿瘤活性测试
体外活性测试方法和结果如下:其中,临床常用的抗肿瘤药物5-氟尿嘧啶、阿霉素(ADM)和紫杉醇为阳性对照实验组。
抗肿瘤活性体外筛选试验-1
筛选方法:四氮唑盐(micoculture tetrozolium,MTT)还原法
细胞株:人结肠癌细胞(HT29)
作用时间:48h
各化合物对肿瘤细胞生长的半数抑制浓度IC50(%,μM)见表-1。
抗肿瘤活性体外筛选试验-2
筛选方法:四氮唑盐(micoculture tetrozolium,MTT)还原法
细胞株:人肝癌细胞(HepG2)
作用时间:48h
各化合物对肿瘤细胞生长的半数抑制浓度IC50(%,μM)见表-1。
抗肿瘤活性体外筛选试验-3
筛选方法:四氮唑盐(micoculture tetrozolium,MTT)还原法
细胞株:人黑色素瘤细胞(A375)
作用时间:48h
各化合物对肿瘤细胞生长的半数抑制浓度IC50(%,μM)见表-1。
抗肿瘤活性体外筛选试验-4
筛选方法:四氮唑盐(micoculture tetrozolium,MTT)还原法
细胞株:人乳腺癌细胞(MCF-7)
作用时间:48h
各化合物对肿瘤细胞生长的半数抑制浓度IC50(%,μM)见表-1。
表-1化合物的体外细胞毒性测试数据(IC50(μmol/L))
Claims (10)
2.如权利要求1所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物,
其中,
R为氢、氨基、硝基、羟基、C1-C6酯基、卤素、取代或未取代的C1-C4胺、取代或未取代的5-10元杂环基,所述杂环基含有1-3个N、O或S的杂原子,所述取代基为:C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基。
3.如权利要求1或2所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物,
其中,
R为氢、羟基、C1-C6酯基、卤素、取代或未取代的C1-C4胺、取代或未取代的5-6元杂环基,所述杂环基含有1-3个N原子,所述取代基为:C1-C4烷基、C1-C4烷氧基、C1-C4烷氨基。
4.如权利要求1-3任何一项所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物,
其中,
当X、Y或Z为N原子时,R为氢、甲基、乙基、叔丁基、二甲胺基、二乙胺基、氯、溴、碘、氟、BOC保护的哌嗪、哌嗪-N盐酸盐、甲氧酰基、乙氧酰基,哌嗪-N溴酸盐,哌嗪-N碘酸盐;
当X和Y和Z同时为C原子时,R为氢、甲基、乙基、叔丁基、二甲胺基、二乙胺基、氯、溴、碘、氟、BOC保护的哌嗪、4-哌嗪-N盐酸盐、甲氧酰基、乙氧酰基。
6.如权利要求1-5任何一项所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物,其中,所述的药学上可接受的盐为该化合物与酸所形成的盐,所述的酸为有机酸或无机酸,所述的无机酸为盐酸、硫酸、氢溴酸或磷酸,所述的有机酸为乙酸、柠檬酸、草酸、酒石酸、苯甲酸或苹果酸的有机酸,所述水合物的结晶水数目为0~4中的任意实数。
8.一种药物组合物,包含权利要求1-6中任何一项所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物和药学上可接受的载体。
9.权利要求1-6任何一项所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物或权利要求8所述的组合物在荧光分子探针技术中的应用。
10.权利要求1-6任何一项所述的二苯甲烷-二酰腙类化合物及其药学上可接受的盐或水合物或权利要求8所述的组合物在制备抗肿瘤药物中的应用。
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CN103087054A (zh) * | 2013-02-27 | 2013-05-08 | 山东大学 | 4-吡啶苯基醚类化合物及其制备方法与应用 |
CN104829487A (zh) * | 2015-03-27 | 2015-08-12 | 福州大学 | 聚集发光增强的氨敏金属-有机凝胶复合软材料及其制备 |
CN106831489A (zh) * | 2017-03-23 | 2017-06-13 | 郑州大学 | 苯环丙胺酰腙类化合物、制备方法及其应用 |
CN107827776A (zh) * | 2017-11-10 | 2018-03-23 | 上海应用技术大学 | 具有抗肿瘤活性的酰腙类化合物、制备方法及其应用 |
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