CN101597290B - β-咔啉-3-甲酰色氨酰氨基酸苄酯及其制备方法和应用 - Google Patents
β-咔啉-3-甲酰色氨酰氨基酸苄酯及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了具有抗肿瘤活性的通式I化合物及其制备方法,本发明还公开了该化合物在制备抗肿瘤药物中的用途。式I中AA选自苯丙氨酸、丙氨酸、甘氨酸、NG-硝基精氨酸、天冬酰胺、异亮氨酸、蛋氨酸、丝氨酸、酪氨酸、苏氨酸、亮氨酸、色氨酸、缬氨酸、苄基组氨酸、脯氨酸、谷氨酰胺、Nω-苄氧羰基赖氨酸、对-甲氧基苄基半胱氨酸、β-丙氨酸、羟脯氨酸、β-苄基天冬氨酸或γ-苄基谷氨酸残基。本发明采用S180小鼠模型评价了通式1化合物的抗肿瘤活性,实验结果表明通式1化合物具有优秀的抗肿瘤作用,临床可作为抗肿瘤剂应用。
Description
技术领域
本发明涉及通式I的22种β-咔啉-3-甲酰色氨酰氨基酸苄酯,涉及这22种β-咔啉-3-甲酰色氨酰氨基酸苄酯的制备方法,进一步涉及这22种β-咔啉-3-甲酰色氨酰氨基酸苄酯。本发明属于生物医药领域。
背景技术
恶性肿瘤是一种严重威胁人类健康的常见病和多发病,人类因恶性肿瘤而引起的死亡率是所有疾病死亡率的第二位,仅次于心脑血管疾病。肿瘤的治疗方法有手术治疗,放射治疗和药物治疗(化学治疗)。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。发明人认识到,在β-咔啉-3-羧酸的3位引入色氨酸并在色氨酸羧端引入氨基酸苄酯可能产生抗肿瘤作用。按照这种构想,发明人提出本发明。
发明内容
本发明目的之一是提供一类具有抗肿瘤活性的化合物;
本发明目的之二是提供一种制备上述具有抗肿瘤活性化合物的方法;
本发明上述目的是通过以下技术方案来实现的:
具有抗肿瘤活性的通式I化合物:
其中,AA选自苯丙氨酸、丙氨酸、甘氨酸、NG-硝基精氨酸、天冬酰胺、异亮氨酸、蛋氨酸、丝氨酸、酪氨酸、苏氨酸、亮氨酸、色氨酸、缬氨酸、苄基组氨酸、脯氨酸、谷氨酰胺、Nω-苄氧羰基赖氨酸、对-甲氧基苄基半胱氨酸、β-丙氨酸、羟脯氨酸、β-苄基天冬氨酸或γ-苄基谷氨酸残基。
一种制备上述通式I化合物的方法,该方法包括:
(1)(在甲醛和浓硫酸存在下)将L-色氨酸转变为β-咔啉-3-羧酸;
(2)将叔丁氧羰基(Boc)引到β-咔啉-3-羧酸的2位,得到2-Boc-β-咔啉-3-羧酸;
(3)将色氨酸苄酯引到2-Boc-β-咔啉-3-羧酸的3位羧基上,得到2-Boc-β-咔啉-3-甲酰色氨酸苄酯;
(4)将2-Boc-β-咔啉-3-甲酰色氨酸苄酯转化为2-Boc-β-咔啉-3-甲酰色氨酸;
(5)将2-Boc-β-咔啉-3-甲酰色氨酸与氨基酸苄酯偶联,得到2-Boc-β-咔啉-3-甲酰色氨酰氨基酸苄酯;
(6)将2-Boc-β-咔啉-3-甲酰色氨酰氨基酸苄酯脱去保护基Boc,即得。
上述制备方法中,步骤(5)中所述的氨基酸苄酯选自苯丙氨酸苄酯、丙氨酸苄酯、甘氨酸苄酯、NG-硝基精氨酸苄酯、天冬酰胺苄酯、异亮氨酸苄酯、蛋氨酸苄酯、丝氨酸苄酯、酪氨酸苄酯、苏氨酸苄酯、亮氨酸苄酯、色氨酸苄酯、缬氨酸苄酯、苄基组氨酸苄酯、脯氨酸苄酯、谷氨酰胺苄酯、Nω-苄氧羰基赖氨酸苄酯、对-甲氧基苄基半胱氨酸苄酯、β-丙氨酸苄酯、羟脯氨酸苄酯、天冬氨酸二苄酯或谷氨酸二苄酯。
本发明的又一目的是提供一种治疗肿瘤的药用组合物,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。
本发明在小鼠S180肉瘤模型上评价通式1的化合物的抗肿瘤活性。实验结果表明,本发明通式1化合物具有优秀的抗肿瘤活性,可作为抗肿瘤剂应用。
附图说明
图1本发明通式I化合物的结构式。
图2本发明通式I化合物的合成路线图;i)甲醛,浓硫酸,25℃;ii)Boc酸酐,DMF,三己胺;iii)THF,DCC,HOBt,MM,色氨酸苄酯,冰浴;iv)Pd/C,氢气;v)THF,DCC,HOBt,NMM,AA-OBzl;vi)4N/氯化氢-乙酸乙酯,冰浴;通式1的AA选自苯丙氨酸、丙氨酸、甘氨酸、NG-硝基精氨酸、天冬酰胺、异亮氨酸、蛋氨酸、丝氨酸、酪氨酸、苏氨酸、亮氨酸、色氨酸、缬氨酸、苄基组氨酸、脯氨酸、谷氨酰胺、Nω-苄氧羰基赖氨酸、对-甲氧基苄基半胱氨酸、β-丙氨酸、羟脯氨酸、β-苄基天冬氨酸或γ-苄基谷氨酸。
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β-咔啉-3-羧酸
将400ml水放入500ml圆底烧瓶中,缓慢加入0.2ml浓硫酸。在得到的稀硫酸水溶液中加入5.0g(24.5mmol)L-色氨酸并超声振荡至L-色氨酸完全溶解。往得到的溶液中加入10ml35%的甲醛溶液。反应混合物室温搅拌8小时,薄层层析监测到L-色氨酸点消失终止反应。往反应溶液中缓慢滴加浓氨水,调反应混合物至pH6,静置半小时。减压滤出生成的沉淀并用水洗,将滤出的无色固体平铺于表面皿,置于空气中干燥后得5.05g(95.4%)β-咔啉-3-羧酸,为无色固体。ESI-MS(m/e)217[M+H]+。
实施例2制备2-Boc-β-咔啉-3-羧酸
将14g(Boc)2O放入250ml圆底烧瓶中,10gβ-咔啉-3-羧酸,用DMF溶解,三己胺调节pH11,室温反应48小时左右,薄层监测原料基本消失时停反应,将反应混合液室温蒸发吹干,残留物用乙醚萃取三次后用饱和硫酸氢钾调节pH2,用乙酸乙酯萃取4次,无水硫酸钠干燥合并的酯层,过滤,滤液浓缩得到的固体用二氯甲烷洗涤3次,得到10g(66.9%)标题化合物,为无色固体。ESI-MS(m/e)317[M+H]+。
实施例3制备色氨酸苄酯
将10g色氨酸放入250ml圆底烧瓶中,与50ml苄醇及20g多聚磷酸混合之后90摄氏度反应8小时,薄层监测原料基本消失时停反应,降温,将反应混合液倒入放有500ml水和700ml乙醚的混合液中,搅拌12小时,减压过滤并用水和乙醚洗涤得到9g(50.1%)标题化合物,为淡黄色固体。ESI-MS(m/e)294[M+H]+。
实施例4制备氨基酸苄酯
将0.1mol氨基酸放入250ml圆底烧瓶中与40ml苄醇、100ml环己烷及9g对甲苯磺酸混合并回流8小时,薄层监测原料基本消失时停反应,降温,将反应混合液倒入适量乙醚中搅拌,减压过滤,滤液用乙醚洗涤,得到标题化合物,为无色固体。
实施例5制备2-Boc-β-咔啉-3-甲酰色氨酸苄酯
在100ml茄瓶中0.005mol 2-Boc-β-咔啉-3-羧酸用60ml无水THF溶解,冰浴下加入0.005mol DCC,0.005mol HOBt,反应约30分钟后,加入0.004mol色氨酸苄酯并用NMM调节pH至9,TLC监测原料消失后终止反应,过滤,滤液减压浓缩至干。得到的残余物用100ml乙酸乙酯溶解、置于250ml分液漏斗中、依次用饱和碳酸氢钠水溶液洗(30mL×3)、饱和氯化钠水溶液洗(30mL×3)、5%硫酸氢钾水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)、饱和碳酸氢钠水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)。合并的乙酸乙酯层用无水硫酸钠干燥、过滤、滤液减压浓缩至干,得到2.76g(93.1%)标题化合物,为无色固体。ESI-MS(m/e)593[M+H]+。
实施例6制备2-Boc-β-咔啉-3-甲酰色氨酸
将2-Boc-β-咔啉-3-甲酰色氨酸苄酯用20ml乙醇溶解在100ml茄瓶中,冰浴下滴加10ml4N/NaOH水溶液,TLC监测原料消失时停反应。将反应混合物减压浓缩至干,残留物用饱和硫酸氢钾调节pH 2,用乙酸乙酯萃取4次,酯层合并后用无水硫酸钠干燥,过滤,滤液减压浓缩至干,得到2-Boc-β-咔啉-3-甲酰色氨酸。ESI-MS(m/e)503[M+H]+
实施例7制备22种2-Boc-β-咔啉-3-甲酰色氨酰氨基酸苄酯的通法
在100ml茄瓶中0.004mol 2-Boc-β-咔啉-3-甲酰色氨酸用40ml无水THF溶解,冰浴下加入0.004mol DCC和0.004mol HOBt反应约30分钟后,加入0.0044mol氨基酸苄酯,用NMM调节pH 9,TLC监测原料消失后终止反应。反应化合物过滤,滤液减压浓缩至干。得到的残余物用100ml乙酸乙酯溶解、置于250ml分液漏斗中、依次用饱和碳酸氢钠水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)、5%硫酸氢钾水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)、饱和碳酸氢钠水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)。合并的乙酸乙酯层用无水硫酸钠干燥、过滤、滤液减压浓缩至干,得到22种2-Boc-β-咔啉-3-甲酰色氨酰氨基酸苄酯,为无色固体。
实施例8制备22种β-咔啉-3-甲酰色氨酰氨基酸苄酯
0.003mol 2-Boc-β-咔啉-3-甲酰色氨酰氨基酸苄酯用尽量少的无水乙酸乙酯溶解在100ml茄瓶中,冰浴下滴加10ml 4N/氯化氢-乙酸乙酯溶液,TLC监测反应,待原料点消失后终止反应,加入80ml石油醚,有大量固体析出,静置液体层,反复3次后用乙醚替换石油醚重复操作,乙醚洗过3次的固体减压过滤,得到22种β-咔啉-3-甲酰色氨酰氨基酸苄酯。
实施例9β-咔啉-3-甲酰色氨酰苯丙氨酸苄酯(Ia)的数据
1.976g(四步反应总收率64%),为无色固体。ESI-MS(m/e)639[M+H]+。1H NMR(DMSO):δ/ppm=10.78(m,2H),8.79(m,1H),8.49(m,1H),8.30(s,1H),7.15(m,20H),5.68(m,2H),5.14(m,1H),4.75(m,1H),4.60(q,J=7.5Hz,1H),4.35(q,J=7.5Hz,1H),3.16(m,3H),3.08(m,2H),2.95(m,1H),2.06(m,1H);13CNMR(DMSO)δ/ppm=171.42,170.82,169.75,161.40,158.30,144.53,138.75,136.76,133.45,132.94,130.89,129.02,128.69,128.45,128.00,127.82,126.94,126.52,126.20,125.32,123.93,122.84,121.66,120.88,119.80,118.92,113.66,111.90,110.19,110.03,75.23,64.88,55.62,54.34,41.25,36.08,34.23,24.02,20.05。
实施例10β-咔啉-3-甲酰色氨酰丙氨酸苄酯(Ib)的数据
1.645g(四步反应总收率62%),为无色固体。ESI-MS(m/e)564[M+H]+。1H NMR(DMSO)δ/ppm=10.85(m,2H),8.56(m,1H),8.33(m,2H),7.10(m,15H),5.52(m,2H),5.01(m,1H),4.52(m,2H),4.35(m,2H),3.12(m,1H),3.02(m,1H),2.98(m,1H),2.88(m,1H),1.45(m,3H);13CNMR(DMSO)δ/ppm=171.10,170.13,169.71,169.43,141.25,136.86,136.42,131.26,129.18,127.72,127.00,126.82,122.82,122.20,121.95,120.98,119.14,111.25,110.24,107.22,67.22,65.35,56.23,49.42,37.33,34.10,22.42,21.31。
实施例11β-咔啉-3-甲酰色氨酰甘氨酸苄酯(Ic)的数据
1.625g(四步反应总收率66%),为无色固体。ESI-MS(m/e)550[M+H]+。1H NMR(DMSO)δ/ppm=10.87(m,J=7.5Hz,1H),8.56(m,J=7.5Hz,1H),8.36(m,3H),7.24(m,15H),5.63(d,J=6.5Hz,2H),5.00(d,J=13.5Hz,1H),4.87(m,J=6.5Hz,1H),4.78(m,J=11.0Hz,2H),4.56(m,J=3.5Hz,2H),4.35(m,1H),3.02(m,J=6.0Hz,2H),2.79(m,J=6.5Hz,1H);13CNMR(DMSO):δ/ppm=172.41,171.85,170.53,169.21,137.80,137.51,135.22,133.22,128.76,127.35,126.27,124.40,123.40,122.54,121.88,119.07,112.24,111.32,70.25,67.55,66.35,57.25,56.57,35.25,33.54,23.03。
实施例12β-咔啉-3-甲酰色氨酰硝基精氨酸苄酯(Id)的数据
2.224g(四步反应总收率54%),为无色固体。ESI-MS(m/e)694[M+H]+。1H NMR(DMSO):δ/ppm=10.78(m,2H),8.75(m,1H),8.41(m,4H),8.21(m,1H),7.32(t,J=9.0Hz,1H),7.10(m,14H),5.63(m,2H),5.00(m,2H),4.65(m,1H),4.60(m,1H),4.35(m,1H),4.24(m,1H),3.15(m,2H),3.07(m,2H),2.96(m,1H),1.68(m,4H);13CNMR(DMSO)δ/ppm=171.32,170.85,170.52,166.35,142.57,137.59,136.82,131.25,131.11,129.10,128.44,128.13,127.52,126.64,126.10,125.76,124.32,124.24,121.31,121.02,118.68,114.25,113.52,112.63,112.04,109.25,69.15,64.98,55.24,52.42,36.22,35.68,34.52,31.30,23.42,22.36。
实施例13β-咔啉-3-甲酰色氨酰天冬酰胺苄酯(Ie)的数据
1.391g(四步反应总收率52%),为无色固体。ESI+-MS(m/e)607[M+H]+。1H NMR(DMSO):δ/ppm=10.74(m,2H),8.64(m,1H),8.42(m,1H),7.25(m,16H),5.54(m,2H),4.89(m,1H),4.74(m,2H),4.69(m,1H),4.52(m,1H),4.40(q,J=7.5Hz,1H),3.35(m,1H),3.08(m,2H),2.65(m,2H),1.04(t,J=7.0Hz,1H),0.86(m,1H);13CNMR(DMSO):δ/ppm=173.42,172.42,172.26,170.12,138.42,138.28,132.10,131.84,130.46,129.32,128.03,127.10,126.36,124.8,123.62,122.46,121.27,121.03,112.57,111.56,110.75,110.57,73.14,66.75,64.58,50.21,42.26,34.75,34.42,24.57。
实施例14β-咔啉-3-甲酰色氨酰异亮氨酸苄酯(If)的数据
1.497g(四步反应总收率52%),为无色固体。ESI-MS(m/e)606[M+H]+。1H NMR(DMSO):δ/ppm=10.78(m,2H),8.82(m,1H),8.31(m,2H),7.24(m,15H),5.78(m,2H),5.02(m,1H),4.85(m,2H),4.70(m,1H),4.42(m,2H),3.21(m,1H),3.14(m,2H),3.02(m,1H),1.98(m,1H),1.48(m,1H),1.02(t,J=7.5Hz,3H),0.87(m,3H);13CNMR(DMSO):δ/ppm=175.82,171.52,170.72,170.15,137.45,137.25,135.78,132.34,128.58,128.04,127.74,127.54,127.41,127.26,122.68,122.19,120.38,118.31,111.82,110.47,70.72,65.45,55.48,51.64,44.42,35.72,34.52,23.48,22.84,22.14,22.02。
实施例15β-咔啉-3-甲酰色氨酰蛋氨酸苄酯(Ig)的数据
1.482g(四步反应总收率47%),为无色固体。ESI-MS(m/e)624[M+H]+。1H NMR(DMSO):δ/ppm=10.78(m,2H),8.75(m,1H),8.52(m,2H),7.26(m,15H),5.71(m,2H),5.14(m,1H),4.75(m,2H),4.67(m,1H),4.45(m,1H),4.35(m,1H),3.14(m,2H),3.07(m,2H),2.74(m,1H),2.14(s,3H),1.15(m,1H),1.09(t,J=7.0Hz,1H);13CNMR(DMS0):δ/ppm=171.75,171.32,170.47,169.47,140.56,135.70,135.65,131.75,130.50,128.64,127.44,127.12,127.01,124.20,123.35,121.10,118.41,111.87,111.12,110.31,109.75,69.49,65.84,54.89,50.85,35.48,33.76,30.47,29.67,21.45,17.24。
实施例16β-咔啉-3-甲酰色氨酰丝氨酸苄酯(Ih)的数据
1.49g(四步反应总收率52%),为无色固体。ESI-MS(m/e)580[M+H]+。1H NMR(DMSO):δ/ppm=10.78(m,J=5.5Hz,1H),10.68(m,J=10.0Hz,1H),8.67(m,J=7.2Hz,1H),8.28(m,J1=8.5Hz,2H),7.19(m,15H),5.60(m,J=6.3Hz,1H),5.25(m,J=8.5Hz,1H),4.75(m,J=11.0Hz,2H),4.70(m,J=15.0Hz,1H),4.38(m,J=15.0Hz,1H),4.27(m,J=6.4Hz,1H),3.74(m,J=6.8Hz,2H),3.30(m,J=7.5Hz,3H);13CNMR(DMSO):δ/ppm=172.68,170.57,169.68,168.87,143.87,138.05,137.45,133.46,132.78,128.78,128.25,128.02,127.51,124.65,124.21,124.12,123.31,122.64,122.01,113.40,113.11,112.85,112.45,70.47,65.28,64.79,57.54,56.48,35.34,33.85,23.57。
实施例17β-咔啉-3-甲酰色氨酰酪氨酸苄酯(Ii)的数据
1.425g(四步反应总收率46%),无色固体。ESI-MS(m/e)654[M+H]+。1H NMR(DMSO)δ/ppm=10.84(m,2H),9.38(d,J=5.5Hz,1H),8.64(m,1H),8.32(m,2H),7.25(m,19H),5.74(m,3H),5.01(m,1H),4.75(m,2H),4.48(q,J=7.2Hz,1H),4.53(m,1H),3.21(m,1H),3.10(m,2H);13CNMR(DMSO)δ/ppm=171.45,170.81,170.45,169.73,155.72,142.45,137.75,136.85,133.52,132.58,129.25,129.11,128.52,127.24,127.14,123.68,122.71,121.58,120.24,119.07,115.45,112.72,111.28,109.45,68.75,65.97,55.57,54.46,43.37,35.75,33.74,22.78。
实施例18β-咔啉-3-甲酰色氨酰苏氨酸苄酯(Ij)的数据
1.664g(四步反应总收率55%)目标化合物,为无色固体。ESI+-MS(m/e)594[M+H]+。1H NMR(DMSO):δ/ppm=10.85(m,2H),8.75(m,1H),8.34(d,J=7.1Hz,1H),8.25(s,1H),7.22(m,15H),5.87(s,1H),5.71(m,2H),5.25(m,1H),4.72(m,2H),4.38(m,1H),4.31(m,1H),4.01(m,1H),3.32(m,1H),3.18(m,1H),3.05(m,1H),1.22(m,3H),1.14(t,J=7.2Hz,1H);13CNMR(DMSO):δ/ppm=171.52,170.82,170.52,169.47,142.74,139.75,137.85,131.75,131.24,130.27,129.95,128.57,127.47,127.10,122.32,121.42,120.74,119.62,112.94,112.54,111.04,109.81,71.56,71.27,64.35,55.35,38.27,33.58,21.57,19.51。
实施例19β-咔啉-3-甲酰色氨酰亮氨酸苄酯(Ik)的数据
1.598g(四步反应总收率55%),为无色固体。ESI-MS(m/e)606[M+H]+。1H NMR(DMSO)δ/ppm=10.95(m,1H),10.84(m,1H),8.68(m,1H),8.45(s,1H),8.24(s,1H),7.25(m,15H),5.68(d,J=7.0Hz,2H),5.01(m,2H),4.77(m,2H),4.58(m,1H),4.27(m,1H),3.13(m,3H),1.78(m,1H),1.61(m,2H),1.01(d,J=6.5Hz,2H),0.90(m,2H),0.84(d,J=6.5Hz,2H);13CNMR(DMSO):δ/ppm=171.72,171.45,170.75,169.77,143.55,137.38,135.98,132.34,131.35,129.57,128.68,128.24,127.46,124.21,123.03,122.46,121.17,120.28,115.24,111.75,110.65,70.24,66.74,55.72,52.71,45.32,35.53,34.71,24.18,22.75,22.19,21.07。
实施例20β-咔啉-3-甲酰色氨酰色氨酸苄酯(Il)的数据
2.532g(四步反应总收率61%)目标化合物,为无色固体。ESI-MS(m/e)679[M+H]+。1H NMR(DMSO):δ/ppm=10.97(m,3H),8.65(m,1H),8.52(s,1H),8.24(s,1H),7.32(m,J=7.5Hz,4H),7.25(m,20H),5.74(m,2H),5.10(m,1H),4.88(m,1H),4.75(m,2H),4.48(m,1H),4.45(t,J=7.0Hz,1H),3.31(m,1H),3.24(m,1H),3.04(m,1H);13CNMR(DMSO)δ/ppm=172.20,171.31,170.38,141.55,138.48,136.91,136.71,131.74,130.65,129.27,128.34,127.95,127.75,127.58,123.75,123.54,122.14,121.02,120.84,119.47,119.25,112.45,112.25,111.75,111.25,110.85,69.87,64.52,54.42,53.86,35.74,34.82,34.47,32.50。
实施例21β-咔啉-3-甲酰色氨酰缬氨酸苄酯(Im)的数据
1.264g(四步反应总收率51%),为无色固体。ESI-MS(m/e)592[M+H]+。1H NMR(DMSO):δ/ppm=10.89(m,J=3.2Hz,2H),8.85(m,1H),8.35(m,2H),7.20(m,15H),5.45(d,J=7.0Hz,2H),5.01(m,1H),4.84(m,2H),4.52(m,1H),4.32(d,J=13.5Hz,1H),3.21(m,1H),3.14(m,2H),3.04(m,1H),2.17(m,1H),1.07(m,6H);13CNMR(DMSO):δ/ppm=171.74,171.21,169.95,169.71,143.42,137.67,132.85,131.82,131.41,130.72,129.74,129.21,128.74,128.49,125.54,123.25,122.76,121.24,112.85,112.40,112.17,110.42,70.64,64.24,58.52,56.40,36.24,34.25,24.45,19.12。
实施例22β-咔啉-3-甲酰色氨酰苄基组氨酸苄酯(In)的数据
2.253g(四步反应总收率62%),为无色固体。ESI-MS(m/e)720[M+H]+。1H NMR(DMSO):δ/ppm=11.10(m,1H),10.83(m,1H),8.84(m,1H),8.63(m,2H),7.55(m,1H),5.14(m,21H),5.65(m,2H),5.45(m,2H),5.24(m,2H),4.75(m,1H),4.60(m,2H),4.38(m,1H),3.61(m,2H),3.31(m,3H),1.78(m,1H);13CNMR(DMSO):δ/ppm=172.02,171.25,170.87,169.24,145.42,138.52,137.45,135.85,131.82,131.45,130.75,129.87,129.57,128.52,128.33,127.45,126.25,125.75,123.84,122.48,122.14,119.84,119.14,113.24,112.41,110.74,70.80,64.88,59.96,57.42,54.52,37.45,36.27,33.75,23.17。
实施例23β-咔啉-3-甲酰色氨酰脯氨酸苄酯(Io)的数据
0.876g(四步反应总收率28%)目标化合物,为无色固体。ESI+-MS(m/e)590[M+H]+。
1H NMR(DMSO):δ/ppm=10.85(m,2H),10.24(s,1H),8.56(m,1H),7.49(m,1H),7.34(m,4H),7.25(m,3H),7.14(m,4H),6.12(m,3H),5.64(m,2H),5.12(m,1H),4.98(m,2H),4.82(m,1H),4.46(m,2H),3.27(m,2H),3.14(m,2H),3.01(m,2H),2.52(m,2H),1.97(m,1H);13CNMR(DMSO):δ/ppm=171.71,170.86,170.48,138.62,138.38,132.76,129.44,129.01,128.75,127.82,127.36,127.05,124.46,123.87,122.81,120.75,120.47,119.28,112.48,111.57,108.56,70.27,65.75,59.57,56.23,47.38,37.14,35.57,33.11,26.55,23.28。
实施例24β-咔啉-3-甲酰色氨酰谷氨酰胺苄酯(Ip)的数据
1.817g(四步反应总收率57%),为无色固体。ESI-MS(m/e)621[M+H]+。1H NMR(DMSO):δ/ppm=10.96(d,J=15.0Hz,1H),10.45(s,1H),8.74(m,1H),8.48(m,2H),7.25(m,15H),5.70(m,2H),5.12(m,1H),4.75(m,2H),4.68(s,1H),4.46(m,1H),4.34(s,1H),3.27(m,1H),3.14(m,1H),3.02(m,1H),2.41(m,1H),2.37(m,1H),2.25(m,2H);13CNMR(DMSO):δ/ppm=173.15,172.36,171.58,171.35,143.85,138.45,135.75,132.28,129.64,128.75,127.57,127.27,127.12,125.27,124.85,123.27,122.76,122.54,121.75,119.15,113.74,112.41,108.57,71.42,65.55,55.71,54.44,37.82,34.57,33.38,22.84。
实施例25β-咔啉-3-甲酰色氨酰Nω-苄氧羰基赖氨酸苄酯(Iq)的数据
2.340g(四步反应总收率59%)目标化合物,为无色固体。ESI+-MS(m/e)756[M+H]+。
1H NMR(DMSO):δ/ppm=11.02(m,1H),10.85(d,J=6.5Hz,1H),8.77(m,1H),8.36(m,2H),7.49(m,1H),7.41(m,13H),7.10(m,6H),5.68(d,J=7.0Hz,2H),5.20(m,1H),5.10(m,2H),4.87(m,2H),4.69(m,1H),4.51(m,1H),4.42(m,1H),3.28(m,1H),3.21(m,2H),3.14(m,3H),1.97(s,1H),1.34(m,4H);13CNMR(DMSO):δ/ppm=171.62,171.45,170.66,169.75,159.72,142.93,142.74,142.47,137.54,136.27,132.42,131.67,130.57,130.21,129.42,129.10,128.11,128.02,127.55,127.34,127.22,124.11,123.25,122.71,120.25,119.45,113.21,111.24,110.71,69.88,68.24,65.42,56.44,54.21,42.58,36.42,36.27,33.81,30.71,23.48,22.14。
实施例26β-咔啉-3-甲酰色氨酰对-甲氧基苄基半胱氨酸苄酯(Ir)的数据
2.490g(四步反应总收率67%),为无色固体。ESI-MS(m/e)700M+H]+。1H NMR(DMSO):δ/ppm=10.87(m,2H),8.89(m,1H),8.75(s,2H),7.14(m,19H),5.74(m,2H),5.12(m,2H),4.84(m,2H),4.59(m,1H),4.51(q,J=7.0Hz,1H),3.71(m,2H),3.20(m,1H),3.14(m,1H),3.01(m,1H),2.87(m,2H),2.22(m,3H);13CNMR(DMSO):δ/ppm=171.78,170.84,169.54,145.21,138.57,136.57,131.24,130.84,129.51,128.75,128.32,127.54,127.22,122.66,121.14,120.25,115.14,112.22,111.20,110.64,71.54,66.41,56.51,52.31,45.52,36.54,35.32,24.36,23.20,22.51,22.11。
实施例27β-咔啉-3-甲酰色氨酰-β-丙氨酸苄酯(Is)的数据
1.58g(四步反应总收率59%),为无色固体。ESI-MS(m/e)564[M+H]+。1H NMR(DMSO)δ/ppm=10.86(m,2H),8.57(m,1H),8.28(m,2H),7.10(m,15H),5.56(m,2H),5.04(m,1H),4.47(m,2H),4.41(m,1H),3.59(m,2H),3.14(m,1H),3.01(m,1H),2.88(m,1H),2.85(m,1H),2.82(m,2H);13CNMR(DMSO)δ/ppm=171.02,170.15,169.81,169.67,141.45,136.66,136.32,131.16,129.82,127.22,127.10,126.62,122.47,122.44,121.86,120.99,119.22,111.21,110.34,107.27,67.17,65.47,56.49,49.88,37.33,35.50,34.20,22.37。
实施例28β-咔啉-3-甲酰色氨酰羟脯氨酸苄酯(It)的数据
0.924g(四步反应总收率32%)目标化合物,为无色固体。ESI+-MS(m/e)606[M+H]+。1H NMR(DMSO):δ/ppm=10.82(m,2H),10.26(s,1H),8.54(m,1H),7.25(m,15H),5.54(m,2H),5.11(m,1H),4.95(m,2H),4.80(m,1H),4.51(m,1H),3.31(m,2H),3.25(m,2H),3.00(m,1H),2.54(m,1H),1.96(m,2H),1.64(m,1H);13CNMR(DMSO):δ/ppm=172.21,171.86,170.98,138.62,138.42,132.75,129.25,129.11,128.74,127.52,127.42,127.21,124.22,123.89,122.44,120.89,120.43,119.75,112.25,111.51,108.34,71.21,69.82,65.21,59.47,56.81,47.31,37.56,35.27,33.21,26.57。
实施例29β-咔啉-3-甲酰色氨酰天冬氨酸二苄酯(Iu)的数据
1.52g(四步反应总收率60%),为无色固体。ESI-MS(m/e)564[M+H]+。1H NMR(DMSO)δ/ppm=10.85(m,2H),8.56(m,1H),8.33(m,2H),7.10(m,20H),5.52(m,4H),5.01(m,1H),4.52(m,2H),4.35(m,2H),3.12(m,1H),3.02(m,1H),2.98(m,1H),2.88(m,1H),2.82(m,2H);13CNMR(DMSO)δ/ppm=172.56,171.10,170.13,169.71,169.43,141.25,140.84,136.86,136.42,131.26,129.25,129.18,127.72,127.65,127.54,127.20,127.00,126.82,122.82,122.20,121.95,120.98,119.14,111.25,110.24,107.22,68.10,67.22,65.35,56.23,49.42,38.32,37.33,34.10,22.42。
实施例30β-咔啉-3-甲酰色氨酰谷氨酸二苄酯(Iv)的数据
1.52g(四步反应总收率60%),为无色固体。ESI-MS(m/e)564[M+H]+。1H NMR(DMSO)δ/ppm=10.88(m,2H),8.57(m,1H),8.41(m,2H),7.08(m,20H),5.48(m,4H),4.97(m,1H),4.47(m,2H),4.41(m,2H),3.22(m,2H),3.11(m,2H),2.96(m,1H),2.85(m,1H),2.77(m,2H);13CNMR(DMSO)δ/ppm=172.47,171.20,170.33,169.85,169.47,141.26,140.74,136.85,136.42,131.26,129.27,129.08,127.82,127.76,127.47,127.31,127.10,126.75,122.72,122.30,121.85,120.99,119.22,111.34,110.11,107.24,68.04,67.13,65.34,56.10,49.58,38.87,37.85,34.25,25.86,22.52。
实验例1本发明化合物的抗肿瘤活性实验
1)受试化合物:本发明实施例9-30所制备的化合物(Ia-v);
阳性对照品:阿糖胞苷
2)实验动物:ICR小鼠,雄性,体重20±2g(x±s);每10只小鼠一组,空白及阳性对照各一组。
3)剂量设置
受试化合物及阳性对照设为8.9μmol/kg,均采用腹腔单次给药。
3)药物配制
受试化合物在水中难溶,实验时加入少量的吐温80润湿助溶,逐渐加入0.5%CMC-Na溶液至所需浓度。阳性对照品阿糖胞苷用生理盐水溶解。
4)给药方案
受试化合物每天腹腔给药一次,0.2ml/鼠,连续给药7天,共给药7次。
阴性对照每天一次,0.2ml 0.5%CMC-Na/鼠,连续给药7天,共给药7次。
阳性对照腹腔给药。每天一次腹腔给药一次,0.2ml/鼠,连续给药7天,共给药7次。
5)动物模型
采用体内抗肿瘤腋皮下接种模型:在无菌条件下抽取接种7d,后取生长旺盛S180腹水瘤瘤液,用生理盐水稀释成(1∶2)的液体充分混合,将肿瘤细胞悬液用新鲜配制的0.2%台盼蓝染色,混匀后按白细胞计数方法计数,染蓝色者为死细胞,不染色者为活细胞,按如下公式计算细胞浓度和细胞存活率。
细胞浓度=4大方格内活细胞数/4×104×稀释倍数=细胞数/ml
细胞存活率=活细胞数/(活细胞数+死细胞数)×100%
将存活率大于90%的瘤液用匀浆法制备成1×107个/ml的细胞悬液,于相应宿主腋皮下接种0.2ml/鼠,制成实体瘤动物模型。
6)实体瘤抑瘤率和体重增长的测定
各组连续给药7天后,于第8天脱颈椎处死小鼠,称取体重(处死体重),然后用镊子固定小鼠右腋肿瘤生长部位,剪开皮肤,暴露肿瘤,钝性剥离,称重,按如下公式计算抑瘤率。抑瘤率%=[(阴性对照组平均瘤重-给药组平均瘤重)÷阴性对照组平均瘤重]×100%
7)统计方法
本实验数据统计均采用t检验和方差分析,以(x±SD)表示。
8)实验结果
受试化合物对荷S180肉瘤的体内抗肿瘤活性实验结果如表1所示。在8.9μmol/kg剂量下受试化合物经腹腔连续7天给药以后,对S180小鼠肿瘤有显著的抑制作用。
表1受试化合物的抗肿瘤活性实验结果
给药组别 瘤重(mg) 抑瘤率%
空白对照组 837.2±122.9 -
阳性组 604.5±114.3** 25.8±4.9**
Ia 608.6±50.9** 26.6±7.1**
Ib 577.8±301.46* 33.51±29.6*
Ic 544.30±221.5** 36.6±18.7**
Id 312.6±101.0** 63.2±8.9**
Ie 572.5±316.3* 34.1±31.8*
If 930.5±149.3 -11.4±13.4
Ig 870.3±109.3 -4.6±10.5
Ih 572.8±117.7** 31.9±6.1**
Ii 932.6±121.0 -11.7±7.4
Ij 669.9±99.1* 19.8±5.8*
Ik 641.5±206.9* 24.2±19.0*
Il 782.1±124.1 6.5±6.1
Im 733.1±231.1 11.7±26.7
In 167.4±78.6** 78.2±8.1**
Io 527.0±163.7** 38.0±12.5**
Ip 778.8±133.6 6.9±9.9
Iq 662.0±163.6 21.6±12.8
Ir 519.3±153.2** 38.8±11.2**
Is 691.0±153.9* 17.8±13.2*
It 661.0±186.6* 22.0±14.7*
Iu 594.7±86.5** 28.7±6.3**
Iv 135.6±93.7** 84.6±8.3**
注:与空白对照组比较,*P<0.05;**P<0.01。
实验结果表明,本发明化合物具有确切的抗肿瘤活性,可作为抗肿瘤剂应用。
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