CN102241693B - N,N"-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯及其合成方法和应用 - Google Patents
N,N"-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯及其合成方法和应用 Download PDFInfo
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- CN102241693B CN102241693B CN 201010168258 CN201010168258A CN102241693B CN 102241693 B CN102241693 B CN 102241693B CN 201010168258 CN201010168258 CN 201010168258 CN 201010168258 A CN201010168258 A CN 201010168258A CN 102241693 B CN102241693 B CN 102241693B
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Abstract
本发明公开了N,N"-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯及其合成方法和应用。本发明以赖氨酸为连接臂将两个1-甲基-β-咔啉-3-羧酸抗肿瘤药效团集合到一个分子之中,然后用氨基酸苄酯对这个分子进行修饰,从而得到了通式I化合物。本发明在细胞模型和小鼠S180模型上评价本发明化合物的抗肿瘤活性。体外和体内试验结果表明,本发明化合物无论是在体外或是在体内均具有优秀的抗肿瘤活性,可将其制备成抗肿瘤药物。
Description
技术领域
本发明涉及氨基酸苄酯修饰的咔啉羧酸衍生物,尤其涉及N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯及其合成方法,本发明还涉及N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯作为抗肿瘤剂的临床应用,本发明属于氨基酸苄酯修饰的咔啉羧酸衍生物领域。
背景技术
恶性肿瘤作为一种复杂的疾病,严重危害着人民生命健康,如何有效有力地治疗肿瘤得到了越来越多学者的关注和研究。目前,化学治疗仍然是临床治疗肿瘤的主要手段,寻找抗肿瘤药物是新药研究的热点之一。发明人了解,1-甲基-β-咔啉-3-羧酸是一种优秀的抗肿瘤药效团、氨基酸苄酯修饰可以改善1-甲基-β-咔啉-3-羧酸的抗肿瘤作用、一个分子含两个1-甲基-β-咔啉-3-羧酸抗肿瘤药效团可以增高分子的抗肿瘤活性。按照这些认识,发明人以赖氨酸为连接臂将两个1-甲基-β-咔啉-3-羧酸抗肿瘤药效团集合到一个分子之中,然后用氨基酸苄酯对这个分子进行修饰,从而提出了本发明。
发明内容
本发明的目的之一提供具有抗肿瘤活性的N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯;
本发明目的之二是提供合成上述N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯的方法;
本发明的上述目的是通过以下技术方案来实现的:
具有抗肿瘤活性的N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄 酯,其结构式为通式I所示:
其中,AA选自甘氨酸残基、L-缬氨酸残基、L-色氨酸残基、L-亮氨酸残基、L-丙氨酸残基、L-蛋氨酸残基、L-酪氨酸残基、L-天冬酰胺残基、L-异亮氨酸残基、L-苯丙氨酸残基、L-脯氨酸残基、L-丝氨酸残基、L-苏氨酸残基、L-谷氨酰胺残基、L-天冬氨酸残基、L-谷氨酸残基、L-精氨酸残基、L-赖氨酸残基或L-半胱氨酸残基。
本发明以赖氨酸为连接臂将两个1-甲基-β-咔啉-3-羧酸集合到一个分子之中,然后用氨基酸苄酯对这个分子进行修饰,制备结构为通式I所示的N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯。
本发明的目的之二是提供一种合成上述N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯的方法;
本发明的目的之二是通过以下技术方案来实现的:
一种合成上述N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯的方法,包括:
(1)制备1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸;
(2)将1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸转化成1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯;
(3)将1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯转化成1-甲基-β-咔啉-3-羧酸甲酯;
(4)将1-甲基-β-咔啉-3-羧酸甲酯水解为1-甲基-β-咔啉-3-羧酸;
(5)将1-甲基-β-咔啉-3-羧酸与赖氨酸苄酯缩合,生成N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯;
(6)将N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯水解为N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸;
(7)N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸和氨基酸苄酯缩合,即得。
其中,步骤(1)中所述的1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸包括以下步骤制备得到:浓硫酸(H2SO4)和蒸馏水存在下将L-色氨酸转变为1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸。
步骤(2)中,优选的,在二氯亚枫(SOCl2)和甲醇存在下将1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸转化成1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯;
步骤(3)中,优选的,在N,N-二甲基甲酰胺(DMF)和高锰酸钾(KMnO4)存在下1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯转化成1-甲基-β-咔啉-3-羧酸甲酯;
步骤(4)中,优选的,在氢氧化钠(2N)和甲醇存在下将1-甲基-β-咔啉-3-羧酸甲酯水解为1-甲基-β-咔啉-3-羧酸;
步骤(5)中,优选的,在N,N-二环己基碳二亚胺(DCC)、1-羟基苯并三唑(HOBt)、无水四氢呋喃(THF)存在下将1-甲基-β-咔啉-3-羧酸与赖氨酸苄酯缩合,生成N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯;
步骤(6)中,优选的,在氢氧化钠(2N)和甲醇存在下将N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯水解为N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸;
步骤(7)中,优选的,在DCC、HOBt、无水THF存在下N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸和氨基酸苄酯缩合,生成N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯;其中,所述的氨基酸苄酯优选自甘氨酸苄酯、L-缬氨酸苄酯、L-色氨酸苄酯、L-亮氨酸苄酯、L-丙氨酸苄酯、L-蛋氨酸苄酯、L-酪氨酸苄酯、L-天冬酰胺苄酯、L-异亮氨酸苄酯、L-苯丙氨酸苄酯、L-脯氨酸苄酯、L-丝氨酸苄酯、L-苏氨酸苄酯、L-谷氨酰胺苄酯、L-天冬氨酸苄酯、 L-谷氨酸苄酯、L-精氨酸苄酯、L-赖氨酸苄酯或L-半胱氨酸苄酯。
本发明在细胞模型和小鼠S180模型上评价本发明化合物的抗肿瘤活性。体外和体内试验结果表明,本发明化合物无论是在体外或是在体内均具有优秀的抗肿瘤活性,可将其制备抗肿瘤药物。
本发明的又一目的是提供一种抗肿瘤的药用组合物,该药用组合物由治疗上有效剂量的本发明通式I化合物与药学上可接受的赋型剂或者辅加剂组成,即将有效量的本发明通式I化合物与药学上可接受的载体或稀释剂配合后,按本领域常规的制剂方法将其制备成任意一种适宜的药物组合物。通常该组合物适合于口服给药和注射给药,也适合其他的给药方法。该组合物可以是片剂、胶囊剂、粉剂、颗粒剂、锭剂、栓剂,或口服液等液体制剂形式。根据不同的给药方法,本发明药物组合物可以含有0.1%-99%重量,优选10-60%重量的本发明化合物。
附图说明
图1本发明化合物N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯的结构式。
图2本发明化合物的合成路线图;i)稀硫酸、35%甲醛、室温;ii)0℃、SOCl2、甲醇;iii)DMF、KMnO4;iv)甲醇、THF、2N NaOH;v)赖氨酸苄酯、DCC、HOBt、NMM;vi)甲醇、THF、2N NaOH;vii)氨基酸苄酯、DCC、HOBt、NMM。其中,在7a-s中AA=甘氨酸及L-构型的缬氨酸、色氨酸、亮氨酸、丙氨酸、蛋氨酸、酪氨酸、天冬酰胺、异亮氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、谷氨酰胺、天冬氨酸、谷氨酸、精氨酸、赖氨酸、半胱氨酸残基。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1 制备1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸(1)
在80ml水中加入0.2ml浓硫酸,加入2.0g(9.9mmol)L-色氨酸,溶解后加入2ml乙醛溶液(40%),反应室温搅拌6h。中止反应时加入氨水调pH 6-7,混合液于4℃静置过夜,减压过滤得到无色固体1.8g(产率80%)。ESI-MS(m/z):231[M+H]+。
实施例2 制备1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(2)
冰浴下往10ml甲醇中逐滴加入1ml二氯亚砜,搅拌15分钟后,加入2.0g(8.2mmol)1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸,室温下反应48小时。反应混合物用10%碳酸钠溶液中和到pH 7,过滤收集沉淀,得到无色粉末1.9g(产率95%)。ESI-MS(m/z):245[M+H]+。
实施例3 制备1-甲基-β-咔啉-3-羧酸甲酯(3)
冰浴下往50mlDMF溶液中加入5.0g(21.8mmol)1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯,搅拌并加入4.5g高锰酸钾固体,室温下反应48小时。反应混合物吹干,将残余物溶于30ml甲醇中,常压过滤得到滤液。滤液减压浓缩至干得4.5g深色固体。通过硅胶柱分离纯化(石油醚∶丙酮,2∶1)得到2.6g(产率50%)目标物,为淡黄色固体。
实施例4 制备1-甲基-β-咔啉-3-羧酸(4)
将500mg(2.1mmol)1-甲基-β-咔啉-3-羧酸甲酯溶于12ml氢氧化钠(2N)溶液中,60℃搅拌4h,用浓盐酸中止反应并调pH 2。减压过滤收集沉淀,得到386mg(产率81.3%)目标化合物,为黄色粉末。ESI-MS(m/z):227[M+H]+。
实施例5 制备N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯(5)
在100ml的茄形瓶中将0.747g(2.2mmol)1-甲基-β-咔啉-3-羧酸悬浮于适量无水THF中,冰浴下加入0.427g(2.31mmol)HOBt,再缓慢滴入0.83g(2.86 mmol)DCC的无水THF溶液,反应30分钟。在另外一茄瓶中将0.803g(1.0mmol)赖氨酸苄酯用无水THF溶解,缓慢滴入前一反应瓶中,混合液搅拌,并加N-甲基吗啉(NMM)使两者混合液的pH=8-9,0℃反应至冰自然融化。8小时后TLC(氯仿∶甲醇,25∶1)检测反应基本完全。反应混合物减压浓缩至干。残留物用氯仿溶解,滤掉不溶物。滤液依次用5%NaHCO3水溶液洗三遍、饱和氯化钠水溶液洗三遍、饱和NaHCO3水溶液洗三遍、饱和氯化钠水溶液洗三遍。有机层用无水硫酸钠干燥、过滤、滤液减压浓缩至干得淡黄色油状物。经柱层析分离纯化,得到326mg(产率50.0%)目标化合物,为浅黄色固体。Rf=0.42(氯仿∶甲醇,25∶1);Mp:136-137℃;[ ]D 25=-8.3(c=1.0,甲醇/氯仿);ESI-MS(m/z):653[M+H]+.1H NMR(300MHz,DMSO-d6):δ/ppm=11.95(s,1H),11.87(s,1H),8.75-8.62(m,2H),8.57(m,2H),8.35-8.28(m,J=7.5Hz,J=8.0Hz,2H),7.66-7.60(m,J=7.2Hz,J=6.0Hz,2H),7.60-7.53(m,J=5.4Hz,J=7.2Hz,2H),7.40-7.33(m,5H),7.33-7.23(m,2H),5.19(s,2H),4.67(t,J=6.3Hz,1H),3.51-3.40(m,J=7.5Hz,J=6.0Hz,2H),2.82(s,3H),2.79(s,3H),1.98(m,2H),1.61(m,2H),1.46(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.52,165.34,165.21,141.54,141.29,139.68,138.74,136.42,136.25,128.87,128.26,127.87,122.52,121.89,120.32,112.83,112.69,112.40,66.53,52.65,40.83,31.49,29.61,23.35,20.82.
实施例6 制备N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸(6)
在100ml的茄形瓶中将1.0g(1.5mmol)N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯溶解于适量THF/甲醇溶液中,冰浴下加入2N NaOH,调pH12-13反应,反应过程中保持冰浴。12小时后TLC检测(氯仿∶甲醇,25∶1)反应基本完全。反应混合物先减压浓缩除去部分溶剂,然后用浓盐酸调溶液pH2,过滤,得694mg(产率82%)目标化合物,为金黄色固体。
实施例7 制备N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯(7a-s)的通法
在100ml的茄形瓶中将0.845g(1.5mmol)N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸溶于适量无水THF中,冰浴下先加入0.214g(1.575mmol)HOBt,再缓慢滴入0.403g(1.95mmol)DCC的无水THF溶液,反应30分钟。在另外一茄瓶中先将1.65mmol氨基酸苄酯用无水THF溶解,然后缓慢滴入前一反应瓶中,混合液搅拌,并加NMM使两者混合液的pH 8-9左右,0℃反应至冰自然融化。8小时后TLC(氯仿∶甲醇,25∶1)检测反应基本完全。反应混合物减压浓缩至干。残留物用氯仿溶解,滤掉不溶物。滤液依次用5%NaHCO3水溶液洗三遍、饱和氯化钠水溶液洗三遍、饱和NaHCO3水溶液洗三遍、饱和氯化钠水溶液洗三遍。有机层用无水硫酸钠干燥、过滤、滤液减压浓缩至干。得到的淡黄色油状物经柱层析分离纯化,得到浅黄色固体。
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰甘氨酸苄酯(7a)
853mg(产率80%);Rf=0.30(氯仿∶甲醇,25∶1);Mp:159-160℃;[ ]D 25=-7.6(c=1.0,甲醇);ESI-MS(m/z):710[M+H]+.IR(KBr):3375,3264,3062,2930,2858,1744,1649,1600,1525,1498,1375,1348,1250,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.96(s,1H),11.89(s,1H),8.76-8.58(m,2H),8.58-8.48(m,1H),8.32(t,J=7.5Hz,J=7.8Hz,2H),7.67-7.60(m,J=7.8Hz,J=5.7Hz,2H),7.60-7.53(m,J=5.4Hz,J=8.1Hz,2H),7.40-7.28(m,5H),7.28-7.23(m,J=6.6Hz,J=6.9Hz,2H),5.15-5.07(m,2H),4.75-4.65(m,1H),4.09-4.03(m,J=3.9Hz,J=4.5Hz,2H),3.28-3.20(m,2H),2.82(s,3H),2.79(s,3H),1.68-1.45(m,2H),1.45-1.36(m,2H),1.25-1.03(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.74,170.00,165.27,164.76,141.51,141.31,141.27,139.58,138.87,136.45,136.24,128.85,128.72,128.51,128.34,127.86,122.43,121.85,120.48,120.38,112.66,112.32,66.37,52.58,41.26,33.37,29.64,23.00,20.87,20.77.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰缬氨酸苄酯(7b)
989mg(产率88%);Rf=0.42(氯仿∶甲醇,25∶1);Mp:134-135℃;[ ]D 25= -10.6(c=1.0,甲醇);ESI-MS(m/z):752[M+H]+.IR(KBr):3271,3184,2961,2859,1738,1649,1630,1530,1499,1375,1348,1250,750.1H NMR(300MHz,DMSO-d6):δ/ppm=11.97(s,1H),11.91(s,1H),8.72-8.62(m,2H),8.62-8.58(m,1H),8.52-8.47(m,J=5.4Hz,J=7.5Hz,2H),8.34-8.29(m,J=7.5Hz,J=7.5Hz,2H),7.67-7.61(m,J=8.1Hz,J=4.5Hz,2H),7.60-7.52(m,J=5.1Hz,J=4.8Hz,2H),7.37-7.28(m,5H),7.28-7.24(m,J=4.2Hz,J=7.2Hz,2H),5.17-5.07(m,2H),4.87-4.75(m,1H),4.30-4.25(m,J=7.1Hz,J=7.8Hz,2H),2.82(s,3H),2.79(s,3H),2.15-2.06(m,4H),1.91-1.72(m,2H),1.67-1.50(m,2H),1.49-1.32(m,4H),0.92-0.86(m,6H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.59,171.69,171.54,165.14,164.67,141.48,141.35,141.22,139.71,139.00,136.46,136.27,128.84,128.75,128.66,128.52,128.40,127.91,122.53,122.47,120.40,120.31,112.64,112.30,66.40,58.12,52.41,40.90,33.68,30.74,29.81,23.14,20.92,20.81,19.40,18.64.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰色氨酸苄酯(7c)
941mg(产率75%);Rf=0.29(氯仿∶甲醇,25∶1);Mp:121-123℃;[ ]D 25=-6.4(c=1.0,甲醇);ESI-MS(m/z):839[M+H]+.IR(KBr):3253,3194,2930,2860,1738,1649,1630,1525,1499,1375,1348,1250,739.1H NMR(300MHz,DMSO-d6):δ/ppm=11.96(s,1H),11.90(s,1H),10.89(s,1H),8.68-8.62(m,2H),8.62-8.52(m,1H),8.37-8.28(m,J=7.8Hz,J=7.2Hz,2H),7.68-7.50(m,5H),7.39-7.34(m,J=7.8Hz,J=5.4Hz,2H),7.34-7.22(m,5H),7.20-7.13(m,J=9.0Hz,J=6.0Hz,2H),7.03-6.93(m,J=6.9Hz,J=7.8Hz,2H),5.14-4.98(m,2H),4.73-4.62(m,2H),3.32-3.05(m,4H),2.82(s,3H),2.79(s,3H),1.92-1.71(m,2H),1.70-1.59(m,2H),1.47-1.39(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.24,172.12,165.18,164.64,141.48,141.34,141.31,141.24,139.69,127.92,127.55,124.41,124.20,122.49,121.92,121.45,120.42,120.33,118.93,118.48,112.65,112.35,111.91,109.79,66.49,55.49,53.81,40.86,33.73,29.81,27.44,23.08,20.91,20.81.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰亮氨酸苄酯(7d)
843mg(产率79%);Rf=0.48(氯仿∶甲醇,25∶1);Mp:160-161℃;[ ]D 25=-10.2(c=1.0,甲醇);ESI-MS(m/z):710[M+H]+.IR(KBr):3265,2954,2868,1744,1657,1530,1448,1348,1250,737.1H NMR(300MHz,DMSO-d6):δ/ppm=12.02(s,1H),11.94(s,1H),8.77-8.69(m,1H),8.72-8.61(m,2H),8.60-8.50(m,1H),8.34-8.29(m,J=7.8Hz,J=8.1Hz,2H),7.66-7.61(m,J=7.8Hz,J=6.3Hz,2H),7.59-7.53(m,J=6.3Hz,J=7.5Hz,2H),7.38-7.28(m,5H),7.28-7.22(m,J=7.2Hz,J=7.2Hz,2H),5.09(s,2H),4.75-4.67(m,1H),4.39-4.35(m,J=4.5Hz,J=4.8Hz,2H),2.82(s,3H),2.79(s,3H),1.86-1.80(m,2H),1.80-1.72(m,2H),1.69-1.59(m,2H),1.59-1.54(m,2H),1.48-1.38(m,2H),1.22-1.15(m,2H),0.89-0.79(m,4H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.62,172.51,165.29,164.71,164.61,141.52,141.32,141.28,139.56,138.89,136.44,136.26,128.85,128.83,128.73,128.50,128.43,128.13,127.87,122.47,122.39,121.84,120.50,120.39,112.73,112.67,112.29,66.45,52.43,51.03,40.68,39.01,33.74,33.55,39.67,24.71,23.10,22.99,21.74,20.75。
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰丙氨酸苄酯(7e)
851mg(产率78%);Rf=0.37(氯仿∶甲醇,25∶1);Mp:105-106℃;[ ]D 25=-7.2(c=1.0,甲醇);ESI-MS(m/z):725[M+H]+.IR(KBr):3262,2934,2855,1744,1645,1530,1499,1348,1250,1148,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.95(s,1H),11.89(s,1H),8.76-8.68(m,2H),8.72-8.61(m,2H),8.64-8.57(m,2H),8.51-8.47(m,1H),8.34-8.29(m,J=6.9Hz,J=7.2Hz,2H),7.66-7.58(m,J=8.1Hz,J=4.8Hz,2H),7.58-7.54(m,J=5.1Hz,J=7.5Hz,2H),7.35-7.29(m,5H),7.29-7.23(m,J=6.9Hz,J=6.9Hz,2H),5.15(s,2H),4.69-4.65(m,1H),4.44-4.34(m,J=6.9Hz,J=8.1Hz,2H),2.82(s,3H),2.79(s,3H),1.78-1.68(m,2H),1.68-1.52(m,2H),1.45-1.42(m,2H),1.36-1.31(m,3H),1.29-1.12(s,3H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.64,172.00,165.13,164.60,141.48,141.34,141.30,141.21,139.69,138.97,136.45,136.39, 136.26,128.84,128.67,128.45,128.42,128.10,127.90,122.50,121.91,120.42,120.31,112.64,112.33,66.41,52.33,48.22,40.87,33.70,29.77,23.05,20.92,20.81,17.22
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰蛋氨酸苄酯(7f)
914mg(产率76%);Rf=0.40(氯仿∶甲醇,25∶1);Mp:124-125℃;[ ]D 25=-9.8(c=1.0,甲醇);ESI-MS(m/z):806[M+H]+.IR(KBr):3240,3188,2934,2855,1744,1649,1530,1499,1452,1348,1250,1192,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.97(s,1H),11.89(s,1H),8.74-8.66(m,2H),8.65-8.59(m,2H),8.57-8.48(m,1H),8.36-8.28(m,J=8.4Hz,J=7.8Hz,2H),7.68-7.61(m,J=8.1Hz,J=6.0Hz,2H),7.60-7.54(m,J=6.3Hz,J=8.1Hz,2H),7.38-7.29(m,5H),7.29-7.23(m,J=9.0Hz,J=6.9Hz,2H),5.15(s,2H),4.81-4.74(m,1H),4.47-4.41(m,J=6.0Hz,J=5.4Hz,2H),3.80-3.65(m,2H),2.82(s,3H),2.79(s,3H),1.90-1.71(m,2H),1.70-1.52(m,2H),1.43-1.35(m,2H),1.23-1.07(m,2H). 13C NMR(75MHz,DMSO-d6):δ/ppm=172.40,171.95,165.16,164.66,152.69,152.69,141.50,141.31,139.63,138.91,136.47,136.27,128.83,128.45,128.37,128.23,127.87,122.48,121.88,120.41,120.31,112.67,112.33,66.54,52.52,51.55,47.98,33.80,32.76,29.97,29.74,25.79,24.90,23.07,20.93。
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰酪氨酸苄酯(7g)
1.09g(产率89%);Rf=0.31(氯仿∶甲醇,25∶1);Mp:145-146℃;[ ]D 25=-8.8(c=1.0,甲醇);ESI-MS(m/z):816[M+H]+.IR(KBr):3302,2934,2864,1744,1653,1518,1452,1348,1248,1115,745.1H NMR(300MHz,DMSO-d6):δ/ppm=11.95(s,1H),11.88(s,1H),9.34(s,1H),8.76-8.63(m,2H),8.63-8.61(m,1H),8.56-8.49(m,J=8.7Hz,J=6.0Hz,2H),8.35-8.29(m,J=7.8Hz,J=7.8Hz,2H),7.66-7.63(m,J=8.1Hz,J=9.0Hz,2H),7.63-7.51(m,J=7.5Hz,J=6.9Hz,2H),7.35-7.28(m,5H),7.28-7.23(m,J=7.5Hz,J=7.5Hz,2H),7.04-6.94(m,J=7.8Hz,J=8.1Hz,2H),6.68-6.55(m,J=7.5Hz,J=8.1Hz, 2H),5.10-5.00(m,2H),4.70-4.62(m,1H),4.56-4.45(m,1H),3.02-2.84(m,2H),2.82(s,3H),2.79(s,3H),1.71-1.64(m,2H),1.56-1.52(m,2H),1.38-1.36(m,2H),1.23-1.11(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.14,171.10,165.12,164.58,156.52,141.46,141.29,139.69,138.97,136.45,136.25,130.46,128.77,128.42,128.32,127.90,127.41,122.52,121.91,120.32,115.54,112.67,112.34,66.45,54.60,52.38,36.30,33.65,29.81,23.08,20.91,20.80.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰天冬酰胺苄酯(7h)
692mg(产率60%);Rf=0.06(氯仿∶甲醇,25∶1);Mp:158-159℃;[ ]D 25=-6.0(c=1.0,甲醇);ESI-MS(m/z):767[M+H]+.IR(KBr):3385,3281,2934,2862,1744,1668,1530,1499,1468,1348,1250,735.1H NMR(300MHz,DMSO-d6):δ/ppm=11.96(s,1H),11.89(s,1H),8.75-8.68(m,2H),8.64-8.60(m,2H),8.53-8.50(m,1H),8.34-8.29(m,J=7.2Hz,J=7.2Hz,2H),7.67-7.61(m,J=7.5Hz,J=6.0Hz,2H),7.61-7.52(m,J=7.5Hz,J=5.4Hz,2H),7.45(s,1H),7.37-7.29(m,5H),7.29-7.22(m,J=6.6Hz,J=7.5Hz,2H),7.04-6.94(m,J=7.8Hz,J=8.1Hz,2H),6.98(s,1H),5.09(s,2H),4.73-4.68(m,J=6.3Hz,J=6.0Hz,2H),2.82(s,3H),2.79(s,3H),2.68-2.58(m,2H),1.83-1.65(m,2H),1.65-1.56(m,2H),1.48-1.39(m,2H),1.32-1.08(m,2H),1.06-0.94(m,2H).13CNMR(75MHz,DMSO-d6):δ/ppm=172.03,171.53,171.17,165.12,164.56,141.47,141.32,141.28,141.22,139.68,138.98,136.45,136.35,136.25,128.77,128.69,128.36,128.14,128.05,122.52,121.90,120.42,120.32,112.63,112.34,66.51,52.32,59.44,41.21,36.94,33.78,29.78,29.44,23.04,20.92,20.80.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰异亮氨酸苄酯(7i)
950mg(产率83%);Rf=0.31(氯仿∶甲醇,25∶1);Mp:125-127℃;[ ]D 25=-4.1(c=1.0,甲醇);ESI-MS(m/z):767[M+H]+.IR(KBr):3267,2932,2855,1738,1649,1530,1499,1452,1346,1250,1146,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.99(s,1H),11.92(s,1H),8.70-8.64(m,2H),8.64-8.61(m, 1H),8.58-8.49(m,2H),8.34-8.28(m,J=7.5Hz,J=7.8Hz,2H),7.68-7.61(m,J=8.1Hz,J=5.4Hz,2H),7.60-7.53(m,J=5.7Hz,J=7.8Hz,2H),7.38-7.32(m,5H),7.32-7.27(m,2H),7.27-7.18(m,2H),5.16-5.10(m,2H),4.82-4.72(m,J=7.2Hz,J=6.6Hz,2H),4.48(s,1H),4.31-4.28(m,1H),2.82(s,3H),2.79(s,3H),1.90-1.72(m,2H),1.70-1.48(m,3H),1.48-1.32(m,2H),1.30-1.18(m,2H),0.89-0.72(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.20,171.81,165.15,164.20,141.49,141.34,141.30,139.67,136.26,128.83,128.68,128.52,128.38,127.89,122.47,121.89,120.32,112.65,112.31,66.38,51.22,49.07,38.27,29.23,25.26,20.92,20.80,15.90,11.58.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰苯丙氨酸苄酯(7j)
842mg(产率70%);Rf=0.33(氯仿∶甲醇,25∶1);Mp:119-121℃;[ ]D 25=-16.0(c=1.0,甲醇);ESI-MS(m/z):801[M+H]+.IR(KBr):3374,3252,2934,2859,1734,1661,1533,1499,1452,1348,1250,899,735,698.1HNMR(300MHz,DMSO-d6):δ/ppm=11.96(s,1H),11.89(s,1H),8.76-8.62(m,2H),8.58-8.53(m,1H),8.53-8.46(m,1H),8.35-8.26(m,J=8.1Hz,J=7.8Hz,2H),7.68-7.61(m,J=5.1Hz,J=4.8Hz,2H),7.61-7.53(m,J=3.9Hz,J=7.5Hz,2H),7.36-7.27(m,5H),7.27-7.23(m,5H),7.23-7.18(m,2H),7.18-7.10(m,2H),5.11-5.02(m,2H),4.69-4.51(m,J=6.3Hz,J=5.1Hz,2H),3.15-2.98(m,2H),2.82(s,3H),2.79(s,3H),1.90-1.72(m,2H),1.70-1.48(m,3H),1.48-1.32(m,2H),1.30-1.18(m,2H),0.89-0.72(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.17,171.55,165.14,164.60,141.45,141.36,141.33,141.23,139.71,138.99,137.50,136.46,136.27,136.15,129.53,128.77,128.43,128.36,127.90,126.98,122.46,121.91,120.10,120.630,112.65,112.30,66.54,54.21,52.44,37.21,36.98,33.59,29.78,23.06,20.92,20.81.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰脯氨酸苄酯(7k)
816mg(产率73%);Rf=0.33(氯仿∶甲醇,25∶1);Mp:147-148℃;[ ]D 25= -14.3(c=1.0,甲醇);ESI-MS(m/z):750[M+H]+.IR(KBr):3377,3254,2930,2860,1744,1645,1626,1599,1499,1449,1346,1250,1170,903,750.1H NMR(300MHz,DMSO-d6):δ/ppm=11.98(s,1H),11.90(s,1H),8.71-8.62(m,3H),8.58-8.52(m,J=4.8Hz,J=3.9Hz,2H),7.67-7.60(m,J=8.1Hz,J=7.5Hz,2H),7.60-7.52(m,J=6.6Hz,J=8.1Hz,2H),7.39-7.28(m,5H),7.28-7.20(m,2H),5.10(s,2H),4.93-4.83(m,J=7.8Hz,J=7.8Hz,1H),4.49-4.35(m,J=5.1Hz,J=5.4Hz,1H),3.85-3.71(m,1H),3.69-3.65(m,1H),2.82(s,3H),2.79(s,3H),2.20-2.12(m,1H),1.99-1.86(m,3H),1.79-1.67(m,2H),1.67-1.51(m,2H),1.50-1.41(m,2H),1.29-1.06(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.41,171.94,165.15,164.57,152.69,141.50,141.35,141.31,141.24,139.64,138.92,136.48,136.27,128.85,128.82,128.44,127.87,126.87,122.48,121.89,120.41,120.30,112.67,112.33,66.53,52.53,50.98,47.98,39.17,33.80,32.76,19.94,25.79,23.06,20.93,20.83.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰丝氨酸苄酯(7l)
788mg(产率71%);Rf=0.21(氯仿∶甲醇,25∶1);Mp:151-152℃;[ ]D 25=-5.9(c=1.0,甲醇);ESI-MS(m/z):740[M+H]+.IR(KBr):3385,3279,2934,1744,1645,1518,1452,1348,1250,897,737,660.1H NMR(300MHz,DMSO-d6):δ/ppm=11.97(s,1H),11.90(s,1H),8.73-8.61(m,2H),8.59-8.50(m,1H),8.36-8.27(m,J=8.4Hz,J=8.1Hz,2H),7.68-7.61(m,J=7.5Hz,J=6.0Hz,2H),7.61-7.53(m,J=5.1Hz,J=7.8Hz,2H),7.38-7.30(m,5H),7.29-7.23(m,J=7.5Hz,J=6.3Hz,2H),5.12(s,2H),4.82-4.73(m,1H),4.52-4.39(m,1H),3.81-3.65(m,2H),2.82(s,3H),2.79(s,3H),1.90-1.70(m,2H),1.62-1.51(m,2H),1.49-1.35(m,2H),1.12-1.03(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.41,170.69,165.20,164.65,141.49,141.28,139.62,138.96,136.45,136.34,136.25,128.81,128.41,128.14,128.02,127.88,122.47,121.87,120.44,120.34,112.65,112.32,67.70,61.59,56.51,55.37,33.69,29.73,25.91,23.07,20.91,20.80.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰苏氨酸苄酯(7m)
871mg(产率77%);Rf=0.33(氯仿∶甲醇,25∶1);Mp:146-147℃;[ ]D 25=-12.3(c=1.0,甲醇);ESI-MS(m/z):754[M+H]+.IR(KBr):3273,2932,2859,1746,1655,1501,1452,1348,1250,1013,903,748.1H NMR(300MHz,DMSO-d6):δ/ppm=11.99(s,1H),11.92(s,1H),8.71-8.67(m,2H),8.67-8.62(m,1H),8.58-8.45(m,1H),8.38-8.28(m,2H),7.78-7.60(m,J=8.1Hz,J=5.1Hz,4H),7.60-7.52(m,J=4.5Hz,J=8.1Hz,2H),7.40-7.32(m,5H),7.32-7.28(m,2H),7.28-7.22(m,2H),5.18-5.05(m,4H),4.92-4.80(m,1H),4.43-4.38(m,1H),4.23-4.18(m,1H),2.82(s,3H),2.79(s,3H),1.91-1.75(m,2H),1.70-1.51(m,2H),1.45-1.38(m,2H),1.18-1.01(m,5H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.81,170.84,165.12,164.67,164.63,162.71,141.47,141.33,139.68,128.06,127.89,122.56,122.50,121.90,120.41,112.68,112.33,66.74,66.35,58.58,56.50,52.53,36.24,22.80,29.79,24.91,23.15.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰谷氨酰胺苄酯(7n)
739mg(产率63%);Rf=0.09(氯仿∶甲醇,25∶1);Mp:126-128℃;[ ]D 25=-5.5(c=1.0,甲醇);ESI-MS(m/z):781[M+H]+.IR(KBr):3271,2940,2367,1744,1668,1530,1454,1348,1250,1013,739.1H NMR(300MHz,DMSO-d6):δ/ppm=11.99(s,1H),11.92(s,1H),8.82-8.65(m,2H),8.65-8.58(m,2H),8.53-8.49(m,1H),8.37-8.27(m,J=6.0Hz,J=7.8Hz,2H),7.78-7.62(m,J=8.1Hz,J=5.1Hz,2H),7.61-7.53(m,J=5.7Hz,J=7.5Hz,2H),7.38-7.29(m,5H),7.29-7.23(m,J=6.6Hz,J=7.5Hz,2H),6.89-6.78(m,2H),6.98(s,1H),5.11(s,2H),4.75-4.69(m,1H),4.40-4.31(m,1H),3.49-3.41(m,2H),2.82(s,3H),2.79(s,3H),2.22-2.15(m,2H),2.09-1.83(m,2H),1.81-1.71(m,2H),1.51-1.41(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=173.70,172.37,171.99,165.15,164.64,141.50,141.29,139.66,138.96,136.46,136.32,136.26,128.85,128.69,128.49,128.32,128.18,127.89,122.51,121.89,120.43,120.32,112.65,112.34,66.48,56.50,52.37,39.17,33.91,33.70,31.56,29.77,23.16,20.93,20.82.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰天冬氨酸苄酯(7o)
892mg(产率69%);Rf=0.32(氯仿∶甲醇,25∶1);Mp:118-119℃;[ ]D 25=-4.1(c=1.0,甲醇);ESI-MS(m/z):858[M+H]+.IR(KBr):3370,3181,2938,2864,1738,1649,1530,1499,1454,1380,1348,1250,1171,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.96(s,1H),11.89(s,1H),8.93-8.83(m,2H),8.70-8.69(m,1H),8.66-8.58(m,2H),8.34-8.26(m,J=8.4Hz,J=8.1Hz,2H),7.68-7.60(m,J=8.1Hz,J=8.4Hz,2H),7.60-7.53(m,J=7.2Hz,J=6.9Hz,2H),7.38-7.32(m,5H),7.38-7.32(m,5H),7.32-7.28(m,5H),7.28-7.21(m,2H),5.13-5.02(m,4H),4.84-4.75(m,1H),4.72-4.62(m,1H),3.32-3.28(m,2H),3.01-2.85(m,2H),2.82(s,3H),2.79(s,3H),1.86-1.74(m,2H),1.67-1.49(m,2H),1.48-1.30(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.15,170.74,170.69,165.16,164.66,141.48,141.34,141.30,141.22,139.67,138.96,136.47,136.25,136.08,128.82,128.79,128.68,128.45,128.43,128.31,128.24,128.15,127.91,122.53,122.47,121.89,120.44,112.70,112.64,66.87,66.83,52.44,49.31,39.18,36.23,33.59,29.70,23.02,20.90,20.79.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰谷氨酸苄酯(7p)
939mg(产率72%);Rf=0.33(氯仿∶甲醇,25∶1);Mp:98-99℃;[ ]D 25=-9.0(c=1.0,甲醇);ESI-MS(m/z):872[M+H]+.IR(KBr):3378,3273,3065,2934,2818,1736,1649,1537,1452,1348,1250,1169,903,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.96(s,1H),11.89(s,1H),8.72-8.64(m,2H),8.64-8.58(m,1H),8.54-8.47(m,1H),8.35-8.27(m,J=4.5Hz,J=4.8Hz,2H),7.68-7.60(m,J=8.1Hz,J=5.1Hz,2H),7.60-7.57(m,J=5.4Hz,J=4.5Hz,2H),7.38-7.33(m,5H),7.33-7.28(m,5H),7.28-7.22(m,2H),5.15(s,2H),5.06(s,2H),4.74-4.65(m,1H),4.49-4.37(m,1H),2.82(s,3H),2.79(s,3H),2.46-2.40(m,2H),2.18-1.77(m,4H),1.70-1.52(m,2H),1.58-1.40(m,2H),1.28-0.82(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.42,171.76,171.69,165.14,164.90,164.69,164.61,141.34,141.21,139.70,139.00,136.61,136.55,136.46, 136.18,128.82,128.67,128.49,128.36,128.32,128.27,128.20,127.91,126.88,122.48,121.92,120.42,120.32,112.64,112.32,66.59,65.98,52.49,51.80,39.21,33.75,33.53,30.30,27.60,24.96,20.90,20.80.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰精氨酸苄酯(7q)
849mg(产率66%);Rf=0.18(氯仿∶甲醇,25∶1);Mp:137-139℃;[ ]D 25=-2.2(c=1.0,甲醇);ESI-MS(m/z):854[M+H]+.IR(KBr):3296,2930,2860,1742,1645,1533,1499,1452,1348,1252,907,752.1H NMR(300MHz,DMSO-d6):δ/ppm=11.98(s,1H),11.91(s,1H),8.72-8.58(m,2H),8.58-8.50(m,1H),8.36-8.27(m,J=8.1Hz,J=7.8Hz,2H),7.68-7.60(m,J=8.1Hz,J=5.4Hz,2H),7.60-7.53(m,J=6.0Hz,J=8.1Hz,2H),7.38-7.29(m,5H),7.29-7.22(m,J=6.6Hz,J=6.9Hz,2H),5.11(s,2H),4.72-4.62(m,2H),4.41-4.35(m,J=4.5Hz,J=5.1Hz,2H),3.35-3.25(m,2H),3.22-3.12(m,2H),2.82(s,3H),2.79(s,3H),1.90-1.83(m,2H),1.82-1.69(m,4H),1.59-1.50(m,2H),1.47-1.43(m,2H),1.32-1.14(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.38,172.00,172.00,165.16,164.68,159.82,157.16,141.48,141.31,141.23,139.69,138.98,136.47,136.28,128.85,128.81,128.76,128.67,128.19,126.88,122.54,122.48,121.91,120.41,120.31,112.65,112.53,66.53,52.47,52.36,40.87,39.20,33.80,29.79,25.80,24.90,23.10,20.92,20.81.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰赖氨酸苄酯(7r)
967mg(产率73%);Rf=0.34(氯仿∶甲醇,25∶1);Mp:116-118℃;[ ]D 25=-4.6(c=1.0,甲醇);ESI-MS(m/z):882[M+H]+.IR(KBr):3275,2934,2862,1744,1657,1522,1454,1348,1250,1175,1010,903,737.1H NMR(300MHz,DMSO-d6):δ/ppm=11.94(s,1H),11.87(s,1H),8.72-8.63(m,2H),8.63-8.57(m,2H),8.53-8.48(m,1H),8.34-8.26(m,J=6.9Hz,J=7.2Hz,2H),7.67-7.60(m,J=8.1Hz,J=5.1Hz,2H),7.60-7.52(m,2H),7.38-7.30(m,5H),7.30-7.23(m,J=4.8Hz,J=6.9Hz,2H),6.76-6.68(m,1H),5.11(s,2H),4.75-4.66(m,J=7.5Hz, J=7.8Hz,2H),4.48-4.42(m,J=4.8Hz,J=7.8Hz,2H),2.89-2.84(m,2H),2.82(s,3H),2.79(s,3H),1.92-1.70(m,2H),1.70-1.58(m,8H),1.35(s,9H).13CNMR(75MHz,DMSO-d6):δ/ppm=172.32,165.11,164.60,156.62,141.46,141.32,141.28,139.68,138.98,128.84,128.48,128.33,127.89,122.51,121.90,120.41,120.31,112.64,112.34,77.78,66.41,51.22,51.01,40.86,40.58,30.87,19.79,29.54,28.71,23.18,20.92,20.87.
N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰半胱氨酸苄酯(7s)
915mg(产率75%);Rf=0.33(氯仿∶甲醇,25∶1);Mp:133-134℃;[ ]D 25=-8.7(c=1.0,甲醇);ESI-MS(m/z):812[M+H]+.IR(KBr):3372,3258,2934,2862,1744,1655,1531,1459,1350,1250,901,743.1H NMR(300MHz,DMSO-d6):δ/ppm=11.99(s,1H),11.92(s,1H),8.89-8.81(m,1H),8.72-8.63(m,2H),8.63-8.59(m,1H),8.56-8.48(m,2H),8.37-8.27(m,J=8.4Hz,J=8.1Hz,2H),7.68-7.60(m,J=7.8Hz,J=5.7Hz,2H),7.60-7.52(m,J=6.3Hz,J=7.5Hz,2H),7.39-7.28(m,5H),7.28-7.22(m,J=7.5Hz,J=6.9Hz,2H),7.04-6.94(m,J=7.8Hz,J=8.1Hz,2H),6.98(s,1H),5.19(s,2H),4.79-4.68(m,J=8.1Hz,J=6.0Hz,2H),4.58-4.45(m,J=7.8Hz,J=7.2Hz,2H),3.04-2.86(m,3H),2.83(s,3H),2.79(s,3H),2.78-2.73(m,1H),1.67-1.53(m,2H),1.48-1.38(m,2H),1.24(s,9H),1.23-1.19(m,2H).13C NMR(75MHz,DMSO-d6):δ/ppm=172.25,170.70,165.14,164.61,162.78,141.48,141.34,139.67,138.96,136.47,136.26,136.26,128.60,128.67,128.48,128.44,128.20,127.90,127.06,122.53,122.47,121.90,120.42,112.69,112.65,112.32,66.74,53.57,52.36,42.81,36.24,31.25,31.16,31.03,29.61,23.06,20.92,20.81.
试验例1 本发明化合物(7a-7s)抑制肿瘤细胞增殖试验
本发明的化合物(本发明实施例7所制备的化合物,依次编号为7a-7s)均用含1%二甲基亚砜(DMSO)的PBS配制。共使用了U937(人白血病单核淋巴瘤细胞)、K562(慢性粒细胞白血病细胞)2株肿瘤细胞(购自Lineberger Cancer Center,UNC-CH)。
分别将生长状态良好、处于对数生长期的U937、K562细胞按照3×104个/mL的密度接种于96孔板,每孔100μl。在37℃、5%CO2培养箱中培养4小时,按预设的浓度梯度10μM、5μM、100nM、5nM和1nM加入经灭菌处理的本发明的化合物,对照组加入等体积溶解样品的溶媒。继续培养48小时后,每孔加25μl浓度为5mg/mL的四噻唑兰(MTT)溶液,置于37℃孵育4小时,小心除去上清液(悬浮细胞经离心后除去上清液)后每孔加入100μl DMSO,振荡约15min溶解沉淀。立即于酶标仪上570nm波长下测定吸光度(O.D.)值。计算抑瘤率及IC50。结果列入表1。结果表明本发明的化合物7a-7s对2株肿瘤细胞增殖有明确的抑制作用。
表1 本发明化合物7a-7s的体外抗肿瘤活性(IC50,μM)
试验例2 本发明化合物(7a-s)在S180小鼠模型上的抗肿瘤活性
测定前将本发明的化合物(本发明实施例7所制备的化合物,依次编号为7a-7s)加吐温80助溶,溶于生理盐水。无菌条件下取接种于ICR小鼠7天的S180肉瘤,加入适量生理盐水配制成瘤细胞悬液,细胞数为1×107/mL,接种于健康雄性ICR小鼠前肢腋皮下,每只小鼠注射0.2ml。肿瘤接种24h后,治疗组小鼠每日腹腔注射0.2ml本发明化合物7a-s的水溶液,连续给药7天,剂量为8.9μmol/kg。空白组小鼠每日腹腔注射0.2ml生理盐水。以阿霉素(剂量为4μmol/kg)作阳性对照。实验进行至第8天,称小鼠体重,并剖取各组小鼠的肿瘤称重,最后统计各组动物的抑瘤率。实体瘤的疗效以瘤重抑制百分率表示,计算如下:瘤重抑制率%=(1-给药组瘤重/空白组瘤重)×100%。结果列入表2。表2的数据表明在8.9μmol/kg剂量下,本发明化合物7a,7n和7s的活性最强。
表2 本发明化合物(7a-s)对S180荷瘤小鼠瘤重的影响
注:n=12,瘤重表示为均值±SD g;a)与空白对照组比较p<0.05;b)与空白对照组比较p<0.01;c)与空白对照组比较p<0.001。
试验例3 本发明化合物7a,7n和7s的剂量依赖试验
按照试验例2的方法,选择活性较强的本发明实施例7所制备的化合物7a,7n和7s,测定8.9μmol/kg、0.89μmol/kg和0.089μmol/kg三种剂量下的活性,结果见表3。表3的数据表明,在8.9μmol/kg、0.89μmol/kg剂量下,7a,7n和7s都具有明显的抗肿瘤活性。在0.089μmol/kg的剂量下7a,7n和7s不再显示抗肿瘤活性。三种剂量下的活性显示明显差异,呈现剂量依赖关系。
表3 不同剂量的7a,7n和7s对S180荷瘤小鼠瘤重的影响
注:n=12,瘤重表示为均值±SD g;a)与生理盐水组比较p<0.05;b)与生理盐水组比较p<0.01;c)与生理盐水组比较p<0.001。
Claims (10)
2.一种合成权利要求1所述N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯的方法,包括:
(1)制备1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸;
(2)将1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸转化成1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯;
(3)将1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯转化成1-甲基-β-咔啉-3-羧酸甲酯;
(4)将1-甲基-β-咔啉-3-羧酸甲酯水解为1-甲基-β-咔啉-3-羧酸;
(5)将1-甲基-β-咔啉-3-羧酸与赖氨酸苄酯缩合,生成N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯;
(6)将N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯水解为N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸;
(7)N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸和氨基酸苄酯缩合,即得。
3.按照权利要求2所述的方法,其特征在于:步骤(1)中所述的1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸包括以下步骤制备得到:浓硫酸和蒸馏水存在下将L-色氨酸转变为1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸;步骤(2)中,在二氯亚砜和甲醇存在下将1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸转化成1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯。
4.按照权利要求2所述的方法,其特征在于:步骤(3)中,在N,N-二甲基甲酰胺和高锰酸钾存在下1-甲基-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯转化成1-甲基-β-咔啉-3-羧酸甲酯。
5.按照权利要求2所述的方法,其特征在于:步骤(4)中,在2N氢氧化钠和甲醇存在下将1-甲基-β-咔啉-3-羧酸甲酯水解为1-甲基-β-咔啉-3-羧酸。
6.按照权利要求2所述的方法,其特征在于:步骤(5)中,在N,N-二环己基碳二亚胺、1-羟基苯并三唑、无水四氢呋喃存在下将1-甲基-β-咔啉-3-羧酸与赖氨酸苄酯缩合,生成N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯。
7.按照权利要求2所述的方法,其特征在于:步骤(6)中,在2N氢氧化钠和甲醇存在下将N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸苄酯水解为N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸。
8.按照权利要求2所述的方法,其特征在于:步骤(7)中,在DCC、HOBt、无水THF存在下N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酸和氨基酸苄酯缩合,生成N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯;其中,所述的氨基酸苄酯选自甘氨酸苄酯、L-缬氨酸苄酯、L-色氨酸苄酯、L-亮氨酸苄酯、L-丙氨酸苄酯、L-蛋氨酸苄酯、L-酪氨酸苄酯、L-天冬酰胺苄酯、L-异亮氨酸苄酯、L-苯丙氨酸苄酯、L-脯氨酸苄酯、L-丝氨酸苄酯、L-苏氨酸苄酯、L-谷氨酰胺苄酯、L-天冬氨酸苄酯、L-谷氨酸苄酯、L-精氨酸苄酯、L-赖氨酸苄酯或L-半胱氨酸苄酯。
9.一种抗肿瘤的药物组合物,由治疗上有效量的权利要求1所述的通式I化合物和药学上可接受的载体或辅料组成。
10.权利要求1所述的N,N’-二-(1-甲基-β-咔啉-3-甲酰基)-赖氨酰氨基酸苄酯在制备抗肿瘤药物中的用途。
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