CN103450199B - 茶氨酸修饰的咔啉酰氨基酸苄酯、其制备、抗肿瘤活性和应用 - Google Patents
茶氨酸修饰的咔啉酰氨基酸苄酯、其制备、抗肿瘤活性和应用 Download PDFInfo
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Abstract
本发明涉及茶氨酸修饰的咔啉酰氨基酸苄酯、其制备、抗肿瘤活性和应用,公开了通式I代表的17种化合物(式中AA选自L-Leu,L-Glu,L-Val,L-Trp,L-Pro,L-Tyr,L-Met,L-Phe,L-Ala,L-Gly,L-Asn,L-Asp,L-Ile,L-Lys,L-Ser,L-Theanine残基,或AA-OBzl共同代表OBzl)、公开了它们的制备合成方法、本发明进一步公开了它们体内外的抗肿瘤活性、因而本发明公开了它们作为抗肿瘤药物的临床应用前景。
Description
发明领域
本发明涉及通式I代表的17种化合物(式中AA选自L-Leu,L-Glu,L-Val,L-Trp,L-Pro,L-Tyr,L-Met,L-Phe,L-Ala,L-Gly,L-Asn,L-Asp,L-Ile,L-Lys,L-Ser,L-Theanine残基,或AA-OBzl共同代表OBzl)、涉及它们的制备合成方法、进一步涉及它们体内外的抗肿瘤活性、因而本发明涉及它们作为抗肿瘤药物的临床应用前景。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,近20年来,我国肿瘤死亡率上升了29.42%。在35至59岁的中壮年人群中,肿瘤已列居各类死因之首。有数据显示:我国肿瘤发病率约为200/10万人,每年新发病例约220万人以上,在治患者约600万人以上。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。由于临床应用的抗肿瘤药物大都存在疗效不理想和毒性高的局限性,所以寻找新的抗肿瘤药物一直是新药研究的热点之一。
β-咔啉类衍生物具有广泛的生物活性。例如它们能抑制拓扑异构酶、细胞周期蛋白依赖性激酶(CDK)和DNA的合成。又例如它们能嵌入DNA双链中。这些作用使β-咔啉类衍生物具有强的抗肿瘤活性。在β-咔啉类衍生物的结构修饰中,发明人发现[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸是一种新的抗肿瘤先导结构。在进一步的结构修饰中,发明人认识到往[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸的羧基引入天然氨基酸苄酯能产生更为优秀的抗肿瘤活性。按照这些发现与认识,发明人提出与[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰氨基酸苄酯的抗肿瘤相关的发明。
发明内容
本发明的第一个内容是提供通式I代表的17种化合物,式中AA选自L-Leu,L-Glu,L-Val,L-Trp,L-Pro,L-Tyr,L-Met,L-Phe,L-Ala,L-Gly,L-Asn,L-Asp,L-Ile,L-Lys,L-Ser,L-Theanine残基,或AA-OBzl共同代表OBzl。
本发明的第二个内容是提供通式I代表的17种化合物的制备方法,该方法可用图1描述,包括L-色氨酸在稀硫酸催化下与甲醛进行Pictet-Spengler缩合生成3S-1,2,3,4-四氢-β-咔啉-3-羧酸;缩合生成的3S-1,2,3,4-四氢-β-咔啉-3-羧酸的仲胺基用Boc保护;保护生成的3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸与茶氨酸苄酯偶联,生成3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-甲酰-茶氨酸苄酯;3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-甲酰-茶氨酸苄酯用4N的氯化氢乙酸乙酯(4N HCl/EtOAc)脱Boc并在三乙胺、甲醇中和丙酮缩存在下环化为[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸苄酯;[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸苄酯以Pd/C为催化剂氢解脱除苄基生成[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸;[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸与16种氨基酸苄酯偶联得到本发明的16种新化合物。
本发明的第三个内容是用MTT法评价通式I代表的17种化合物抗K562、HL60、A549、HepG2和HT-29五株肿瘤细胞增殖的活性。
本发明的第四个内容是评价通式I代表的17种化合物对荷S180小鼠肿瘤增长的抑制作用。
本发明的第五个内容是阐述通式I代表的17种化合物作为抗肿瘤药物的临床应用前景。
附图说明
图1.[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(甲基丙基)-乙酰氨基酸苄酯的合成路线.i)稀硫酸、甲醛;ii)(Boc)2O、DMF、Et3N;iii)DCC、HOBt、NMM、无水THF;iv)4NHCl/EtOAc、甲醇、丙酮、Et3N;v)H2、Pd/C、甲醇;vi)DCC、HOBt、NMM、无水THF、氨基酸苄酯.6a中AA为L-Leu残基;6b中AA为L-Glu(OBzl)残基;6c中AA为L-Val残基;6d中AA为L-Trp残基;6e中AA为L-Pro残基;6f中AA为L-Tyr残基;6g中AA为L-Met残基;6h中AA为L-Phe残基;6i中AA为L-Ala残基;6j中AA为L-Gly残基;6k中AA为L-Asn残基;6l中AA为L-Asp(OBzl)残基;6m中AA为L-Ile残基;6n中AA为L-Lys残基;6o中AA为L-Ser残基;6p中AA为L-Theanine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3S-1,2,3,4-四氢-β-咔啉-3-羧酸(1)
将200mL水置于250mL的圆底烧瓶中,缓慢加入0.1mL浓硫酸。往得到的稀硫酸溶液中加入2.52g(12.4mmol)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5mL浓度为37-40%的甲醛溶液。反应混合物室温搅拌6小时,薄层层析监测到L-色氨酸消失,终止反应。反应溶液通过缓慢滴加浓氨水调pH至6,静置半小时。减压滤出的生成的沉淀,沉淀用水及丙酮反复淋洗3次,将滤出的无色固体平铺于培养皿,置于通风橱中吹干后得到2.64g(98%)标题化合物,为无色粉末。ESI-MS(m/e)215[M-H]-.
实施例2制备3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸(2)
100mL茄瓶中加入20mL DMF,搅拌下加入2.033g(9.41mmol)3S-1,2,3,4-四氢-β-咔啉-3-羧酸(1),得白色浑浊混悬液。在冰浴和搅拌下往该混悬液中加入2.752g(12.6mmol)二碳酸二叔丁酯(Boc2O),然后加三乙胺将pH值调至10。反应混合物室温搅拌48小时,薄层层析监测至1消失,终止反应。将反应液减压浓缩至干。得到的油状物用100mL乙酸乙酯溶解,然后用KHSO4水溶液(5%)洗涤(10mL×3)。分出合并的乙酸乙酯层,加入无水硫酸钠干燥,过滤,滤液减压浓缩至干,析出无色固体。得到的无色固体与氯仿悬浮,过滤,得到2.230g(75%)标题化合物,为无色粉末。ESI-MS(m/e)315[M-H]-。
实施例3制备3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-甲酰-茶氨酸苄酯(3)
冰浴下向250mL茄瓶中加入2.084g(6.59mmol)3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸(2),1.651g(5.50mmol)HCl·Theanine-OBzl,0.758g(6.59mmol)N-羟基苯并三氮唑(HOBt)和50mL无水四氢呋喃(THF),搅拌溶解,得到反应液I。将1.358g(6.59mmol)二环己基羰二亚胺(DCC)溶于10mL无水THF,得到反应液II。冰浴下将反应液II缓缓滴加至反应液I中,充分搅拌5分钟,用N-甲基吗啉(NMM)调pH至8。反应混合物0℃搅拌6小时后滤除二环己基脲(DCU),滤液减压浓缩至干。得到的残余物用150mL乙酸乙酯溶解之后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。得到的淡黄色油状物用少量乙醚溶解。得到的溶液减压浓缩至固化。该操作反复3次。得到的固体经柱层析纯化,得到4.552g(81%)标题化合物,为淡黄色粉末。Rf=0.55(二氯甲烷∶甲醇=20∶1)。ESI-MS(m/e)463[M+H]+;1H-NMR(DMSO-d6,300MHz):δ=7.87(t,J=5.1Hz,1H),7.43(d,J=7.5Hz,1H),7.37-7.25(m,6H),7.06-6.95(m,2H),5.21-5.08(m,2H),4.26(s,1H),3.95(d,J=7.1Hz,1H),3.77(d,J=7.1Hz,1H),3.46(dd,J=4.2Hz,J=10.2Hz,1H),3.11-3.02(m,2H),2.93(s,1H),2.44-2.37(m,2H),2.26-2.18(m,3H),1.42(s,9H),1.01(t,J=6.9Hz,3H)。
实施例4制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸苄酯(4)
将3.000g(5.33mmol)3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-甲酰-茶氨酸苄酯(3)置于100mL茄形瓶中,加入10mL乙酸乙酯溶解。冰浴下往得到的溶液中缓慢滴入30mL氯化氢的乙酸乙酯溶液(4N)。反应混合物0℃搅拌2小时,减压浓缩至干。残留物加入乙酸乙酯充分搅拌,再减压浓缩至干。该操作重复3次。得到的残留物加入乙醚充分搅拌,减压浓缩至干。该存在重复3次。得到的红色粉末溶于60mL THF和20mL丙酮的混合溶剂中,用三乙胺调整pH值至9、避光反应7天,薄层层析监测至N-Boc-S-咔啉酰-茶氨酸苄酯变淡至无变化,终止反应。反应混合物减压浓缩至干、残留物用200mL乙酸乙酯溶解、溶液用饱和氯化钠水溶液洗(30mL×8)。乙酸乙酯层用无水硫酸钠干燥、过滤、滤液减压浓缩至干。残留物经柱层析纯化得到267mg(10%)标题化合物,为淡黄色粉末。Rf=0.23(二氯甲烷∶甲醇=30∶1).ESI-MS(m/e)503[M+H]+.Mp 129-133℃.(c=0.06,CH3OH).1H-NMR(DMSO-d6,300MHz):δ=7.87(t,J=5.1Hz,1H),7.43(d,J=7.5Hz,1H),7.37-7.25(m,6H),7.06-6.95(m,2H),5.21-5.08(m,2H),4.26(s,1H),3.95(d,J=7.1Hz,1H),3.77(d,J=7.1Hz,1H),3.46(dd,J=4.2Hz,J=10.2Hz,1H),3.11-3.02(m,2H),2.88(dd,J=3.6Hz,J=14.7Hz,1H),2.44-2.37(m,2H),2.26-2.18(m,3H),1.34(d,J=8.4Hz,6H),1.01(t,J=6.9Hz,3H)。
实施例5制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5)
将100mg(0.199mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸苄酯(4)溶于15mL甲醇,搅拌下加入15mg Pd/C,通氢气2小时。薄层层析监测至4消失,停止反应,小心滤除Pd/C,滤液减压浓缩至干。得到74mg(90%)标题化合物,为淡黄色粉末。Rf=0.20(二氯甲烷∶甲醇∶冰醋酸=20∶1∶0.1)。ESI-MS(m/e)411[M-H]-。
实施例6制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(甲基丙基)-乙酰亮氨酸苄酯(6a)
按照实施例3的方法从286mg(0.69mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),80mg(0.69mmol)HOBt,327mg(0.69mmol)Tos·Leu-OBzl和143mg(0.68mmol)DCC得到256mg(60%)标题化合物。Rf=0.27(二氯甲烷∶甲醇=20∶1)。ESI-MS(m/e)616[M+H]+.Mp 100-101℃.(c=0.06,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.86(s,1H),8.01(d,J=7.8Hz,1H),7.79(s,1H),7.44(d,J=7.5Hz,1H),7.30(s,6H),7.07-6.95(m,2H),5.10(s,2H),4.39(s,1H),3.97-3.93(m,2H),3.71(d,J=7.5Hz,1H),3.48(dd,J=3.6Hz,J=9.9Hz,1H),3.06(t,J=6.6Hz,2H),2.95-2.91(m,2H),2.43-2.13(m,4H),1.65-1.59(m,3H),1.30(s,6H),1.02(t,J=7.2Hz,3H),0.90-0.84(m,6H).
实施例7制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰谷氨酸苄酯(6b)
按照实施例3的方法从200mg(0.49mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),290mg(0.58mmol)Tos·Glu-OBzl,65mg(0.49mmol)HOBt和99mg(0.49mmol)DCC得到191mg(55%)标题化合物。Rf=0.33(氯仿∶甲醇=20∶1)。ESI-MS(m/e)722[M+H]+.Mp 59-60℃.(c=0.06,CH3OH).1H-NMR(CDCl3,300MHz)δ=8.27(d,J=8.1Hz,1H),7.91(s,1H),7.50(d,J=7.2Hz,1H),7.28-7.14(m,8H),5.85(s,1H),5.14-5.11(m,4H),4.67-4.55(m,1H),3.95-3.77(m,3H),3.54(dd,J=4.2Hz,J=10.8Hz,1H),3.37-3.22(m,2H),3.14(dd,J=3.9Hz,J=14.7Hz,1H),2.50-2.03(m,8H),1.68(s,1H),1.39(d,J=7.8Hz,6H),1.24(t,J=7.2Hz,3H)。
实施例8制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰缬氨酸苄酯(6c)
按照实施例3的方法从210mg(0.42mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),190mg(0.50mmol)Tos·Val-OBzl,48mg(0.42mmol)HOBt和86mg(0.42mmol)DCC得到220mg(61%)标题化合物。Rf=0.53(氯仿∶甲醇=20∶1)。ESI-MS(m/e)602[M+H]+.Mp 105-107℃.(c=0.06,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.87(s,1H),7.82(d,J=5.7Hz,1H),7.43-7.25(m,7H),7.05-6.98(m,2H),5.22-5.10(m,2H),4.31(s,1H),4.17-4.10(m,1H),3.99-3.94(m,2H),3.77(d,J=8.1Hz,1H),3.67(d,J=3Hz,1H),3.55-3.43(m,1H),3.16(s,1H),3.07(t,J=6.9Hz,3H),3.02-2.92(m,2H),2.16-2.10(m,5H),1.38-1.31(m,6H),1.01(t,J=7.2Hz,3H),0.88-0.78(m,6H).
实施例9制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰色氨酸苄酯(6d)
按照实施例3的方法从210mg(0.42mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),190mg(0.50mmol)HCl·Trp-OBzl,48mg(0.42mmol)HOBt和86mg(0.42mmol)DCC得到220mg(61%)标题化合物。Rf=0.53(氯仿∶甲醇=20∶1)。ESI-MS(m/e)689[M+H]+.Mp 77-78℃.(c=0.06,CH3OH).1H-NMR(CDCl3,300MHz)δ=8.04(s,1H),7.88(s,1H),7.64(d,J=6.0Hz,1H),7.34-7.31(m,5H),7.19-7.14(m,7H),5.01(s,2H),4.51(s,1H),4.07-3.75(m,5H),3.11-3.02(m,2H),2.91-2.85(m,1H),2.03-1.95(m,2H),1.93-1.81(m,3H),1.35(d,J=8.4Hz,6H),1.01(t,J=6.9Hz,3H)。
实施例10制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰脯氨酸苄酯(6e)
按照实施例3的方法从200mg(0.49mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),174mg(0.58mmol)HCl·Pro-OBzl,65mg(0.49mmol)HOBt和100mg(0.49mmol)DCC得到89mg(30%)标题化合物。Rf=0.53(氯仿∶甲醇=20∶1)。ESI-MS(m/e)600[M+H]+.Mp 108-109℃.(c=0.05,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.85(s,1H),7.82-7.78(m,1H),7.44-7.32(m,7H),7.06-6.99(m,2H),5.15(d,J=6.3Hz,2H),4.74-4.70(m,1H),4.38(t,J=4.8Hz,1H),3.95-3.90(m,1H),3.75-3.60(m,2H),3.49-3.43(m,2H),3.08-2.89(m,4H),2.83-1.82(m,8H),1.38(s,3H),1.20(s,3H),1.03-0.99(m,3H)。
实施例11制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰酪氨酸苄酯(6f)
按照实施例3的方法从180mg(0.44mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),232mg(0.52mmol)Tos·Tyr-OBzl,60mg(0.44mmol)HOBt和90mg(0.44mmol)DCC得到134mg(46%)标题化合物。Rf=0.23(氯仿∶甲醇=20∶1)。ESI-MS(m/e)664[M-H]-.Mp 114-116℃.(c=0.06,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.85(s,1H),9.20(s,1H),7.94(d,J=7.8Hz,1H),7.75(s,1H),7.46(d,J=7.5Hz,1H),7.36-7.27(m,6H),7.07-6.93(m,3H),6.62(d,J=8.1Hz,2H),5.06(s,2H),4.59-4.54(m,1H),3.93-3.84(m,2H),3.73(d,J=9.0Hz,1H),3.44(dd,J=3.0Hz,J=9.6Hz,1H),3.11-2.83(m,6H),2.37-2.32(m,1H),2.27-2.23(m,1H),2.12-2.08(m,2H),1.21(d,J=12.6Hz,6H),1.01(t,J=7.2Hz,3H)。
实施例12制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰蛋氨酸苄酯(6g)
按照实施例3的方法从200mg(0.49mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),293mg(0.59mmol)Tos·Met-OBzl,65mg(0.49mmol)HOBt和100mg(0.49mmol)DCC得到175mg(57%)标题化合物。Rf=0.44(氯仿∶甲醇=20∶1)。ESI-MS(m/e)634[M+H]+.Mp 87-88℃.(c=0.06,CH3OH).1H-NMR(CDCl3,300MHz)δ=8.19(d,J=7.8Hz,1H),7.96(s,1H),7.54(d,J=7.8Hz,1H),7.39-7.30(m,3H),7.26-7.16(m,4H),5.81(s,1H),5.13(d,J=4.5Hz,2H),4.75-4.68(m,1H),3.99-3.73(m,3H),3.53(dd,J=4.2Hz,J=10.5Hz,1H),3.37-3.26(m,3H),2.78-2.69(m,2H),2.52(t,J=7.2Hz,2H),2.36-2.29(m,4H),1.71(s,1H),1.40(d,J=9.0Hz,6H),1.18(t,J=7.2Hz,3H)。
实施例13制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰苯丙氨酸苄酯(6h)
按照实施例3的方法从220mg(0.53mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),287mg(0.64mmol)HCl·Phe-OBzl,72mg(0.53mmol)HOBt和110mg(0.53mmol)DCC得到190mg(55%)标题化合物。Rf=0.44(氯仿∶甲醇=20∶1)。ESI-MS(m/e)650[M+H]+.Mp 124-125℃.(c=0.05,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.877(s,1H),8.37(d,J=6.9Hz,1H),7.82-7.60(m,1H),7.45-7.23(m,12H),7.01-6.94(m,2H),5.13(d,J=7.2Hz,2H),4.41-4.27(m,1H),3.93(s,2H),3.78-3.74(m,2H),3.50-3.41(m,1H),3.17-3.02(m,3H),2.93(d,J=9.0Hz,1H),2.28-2.12(m,4H),1.37-1.35(m,2H),1.32-1.22(m,7H),1.03(t,J=6.0Hz,3H)。
实施例14制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰丙氨酸苄酯(6i)
按照实施例3的方法从200mg(0.49mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),203mg(0.58mmol)Tos·Ala-OBzl,65mg(0.49mmol)HOBt和100mg(0.49mmol)DCC得到172mg(65%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)596[M+Na]+.Mp 93-94℃.(c=0.06,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.87(s,1H),8.35(d,J=6.9Hz,1H),7.74-7.60(m,1H),7.44-7.30(m,7H),7.12-6.94(m,2H),5.13(d,J=7.2Hz,2H),4.41-4.27(m,1H),3.93(s,2H),3.78-3.64(m,2H),3.50-3.41(m,1H),3.16-3.04(m,3H),2.95-2.90(m,1H),2.28-1.99(m,4H),1.37-1.35(m,2H),1.30(s,7H),1.01(t,J=6.9Hz,3H)。
实施例15制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰甘氨酸苄酯(6j)
按照实施例3的方法从150mg(0.36mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),148mg(0.58mmol)Tos·Gly-OBzl,49mg(0.36mmol)HOBt和74mg(0.36mmol)DCC得到101mg(50%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)560[M+H]+.Mp 86-87℃.(c=0.06,CH3OH).1H-NMR(CDCl3,300MHz)δ=8.24(s,1H),7.87(s,1H),7.53(d,J=7.2Hz,1Hz),7.35(s,5H),7.19-7.11(m,2H),5.18(d,J=6.9Hz,2H),4.17-3.87(m,5H),3.51(s,1H),2.98-2.90(m,2H),2.78-2.22(m,4H),1.46-1.45(m,3H),1.39(s,1H),1.36(s,2H),1.19-1.15(m,3H).
实施例16制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰谷酰胺氨酸苄酯(6k)
按照实施例3的方法从150mg(0.36mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),148mg(0.58mmol)HCl·Asn-OBzl,49mg(0.36mmol)HOBt和74mg(0.36mmol)DCC得到101mg(50%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)639[M+Na]+.Mp 131-132℃.(c=0.06,CH3OH).1H-NMR(CDCl3,300MHz)δ=8.29(s,1H),7.94(s,2H),7.75(s,1H),7.52(d,J=6.0Hz,2H),7.35(d,J=6.0Hz,2H),7.21-7.13(m,5H),5.44(s,2H),5.12(s,1H),4.86(s,1H),4.01(d,J=6.0Hz,1H),3.90(d,J=6.0Hz,1H),3.56(dd,J=6.0Hz,J=3.0Hz,1H),2.93-2.77(m,5H),2.41-2.23(m,5H),1.35(d,J=8.4Hz,6H),1.01(t,J=6.9Hz,3H).
实施例17制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰天冬氨酸氨酸苄酯(6l)
按照实施例3的方法从180mg(0.44mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),257mg(0.53mmol)Tos·Asp(OBzl)-OBzl,60mg(0.44mmol)HOBt和90mg(0.44mmol)DCC得到171mg(55%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)708[M+H]+.Mp 133-135℃.(c=0.05,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.88(s,1H),8.11(d,J=8.4Hz,1H),7.80(s,1H),7.43-7.29(m,12H),7.07-6.95(m,2H),5.07(s,4H),4.84(d,J=6.6Hz,1H),3.97-3.93(m,2H),3.77(d,J=8.0Hz,1H),3.47(d,J=6.9Hz,1H),3.07(t,J=6.0Hz,2H),2.91(d,J=5.4Hz,3H),2.64-2.60(m,1H),2.34-2.32(m,2H),2.16(s,2H),1.30(s,6H),1.02(t,J=6.9Hz,3H)。
实施例18制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰异亮氨酸氨酸苄酯(6m)
按照实施例3的方法从100mg(0.24mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),113mg(0.29mmol)Tos·Asp-OBzl2,32mg(0.24mmol)HOBt和50mg(0.24mmol)DCC得到101mg(68%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)616[M+H]+.Mp 70-71℃.(c=0.05,CH30H).1H-NMR(DMSO-d6,300MHz)δ=8.05(d,J=8.7Hz,1H),7.985(s,1H),7.52(d,J=7.2Hz,1H),7.36-7.17(m,8H),5.08(d,J=9.6Hz,2H),4.57(d,J=4.5Hz,1H),4.03-3.80(m,3H),5.30(dd,J=4.2Hz,J=9.9Hz,1H),3.41-3.29(m,2H),3.18-3.13(m,1H),2.89-2.83(m,1H),2.75-2.66(m,1H),2.41-2.32(m,2H),2.02(s,2H),1.39(d,J=6.9Hz,6H),1.20-1.15(m,6H),0.98(d,J=6.9Hz,3H),0.92(t,J=7.2Hz,3H)。
实施例19制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰赖氨酸氨酸苄酯(6n)
按照实施例3的方法从120mg(0.29mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),130mg(0.35mmol)HCl·Nω-Boc-Lys-OBzl,39mg(0.29mmol)HOBt和60mg(0.29mmol)DCC得到134mg(61%)固体。从中取50mg(0.15mmol)按照实施例4的方法脱Boc得到38mg(87%)标题化合物,为淡黄色粉末。Rf=0.48(二氯甲烷∶甲醇=20∶1)。ESI-MS(m/e)653[M+Na]+.Mp 75-76℃.(c=0.05,CH3OH).1H-NMR(DMSO-d6,300MHz)δ=10.86(s,1H),8.01(d,J=7.8Hz,1H),7.87(t,J=5.4Hz,1H),7.44(d,J=7.5Hz,1H),7.32-7.25(m,6H),7.06-6.94(m,2H),6.72(s,1H),5.10(s,2H),4.37-4.31(m,1H),3.96-3.91(m,2H),3.77(d,J=12.0Hz,1H),3.40(dd,J=6.6Hz,J=10.5Hz,1H),3.09-2.96(m,2H),2.90-2.84(m,3H),2.56(s,1H),2.43-2.20(m,2H),2.17-2.08(m,2H),1.78-1.62(m,2H),1.37-1.24(m,10H),1.02(t,J=7.2Hz,3H)。
实施例20制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰丝氨酸氨酸苄酯(6o)
按照实施例3的方法从100mg(0.24mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),66mg(0.29mmol)HCl·Ser-OBzl,32mg(0.24mmol)HOBt和50mg(0.24mmol)DCC得到83mg(59%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)608[M-H]-.Mp 96-97℃.(c=0.06,CH3OH).1H-NMR(CDCl3,300MHz)δ=7.90(s,1H),7.51(d,J=6.9Hz,1H),7.38-7.11(m,10H),5.32(s,2H),5.18(s,1H),4.64-4.59(m,1H),4.02-3.89(m,5H),3.54(d,J=6.9Hz,1H),3.36-3.27(m,2H),3.12-2.92(m,2H),2.77-2.68(m,2H),2.73(s,1H),2.56-2.25(m,3H),1.36(d,J=8.4Hz,6H),1.00(t,J=7.2Hz,3H)。
实施例21制备[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰茶氨酸氨酸苄酯(6p)
按照实施例3的方法从100mg(0.24mmol)[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸(5),87mg(0.29mmol)HCl·Theanine-OBzl,32mg(0.24mmol)HOBt和50mg(0.24mmol)DCC得到92mg(58%)标题化合物。Rf=0.40(氯仿∶甲醇=20∶1)。ESI-MS(m/e)681[M+Na]+.Mp 92-93℃.(c=0.05,CH3OH).1H-NMR(CDCl3,300MHz)δ=7.99(s,2H),7.52(d,J=7.5Hz,1H),7.39-7.30(m,5H),7.23-7.11(m,2H),5.16(s,2H),4.70-4.63(m,1H),4.03-3.87(m,3H),3.55-3.49(m,1H),3.31-3.20(m,6H),2.79-2.75(m,2H),2.39-1.99(m,7H),1.55(s,1H),1.49(d,J=9.9Hz,2H),1.42(s,1H),1.36-1.28(m,2H),1.19-1.09(m,6H)。
实验例1化合物4和6a-p的抗肿瘤细胞增殖活性评价
本发明的化合物4和6a-p均用含0.25%DMSO的1640培养基配制成所需浓度。K562、HL60、A549、HepG2和HT-29五株肿瘤细胞均购自美国标准菌种收藏所(ATCC)。RPMI-1640培养基于粉购自Gibco公司。每升PBS缓冲液含有8.2g NaCl,0.2g KCl,1.56gNa2HPO4·H2O和0.2g KH2PO4,pH值7.4。胎牛血清购自Hyclone公司,0.25%胰酶溶液购自Hyclone公司,青霉素和链霉素购自solarbio公司。四噻唑蓝(MTT)购自solarbio公司,溶于PBS溶液中,制成5mg/mL的溶液,过滤除菌后使用,避光保存。阿霉素(ADR)购自北京华丰联合技术有限公司,二甲基亚枫(DMSO)购自Hyclone公司。
HepG2细胞选用DMEM培养基,其他细胞选用RPMI-1640培养基。培养液中均含10%灭火的胎牛血清和1×105U/L青霉素和100mg/L链霉素。
对于A549、HepG2和HT-29细胞:将生长状态良好,处于对数生长期的A549、HepG2和HT-29细胞按5×104个/mL的密度接种于96孔板,每孔100μL。37℃下96孔板置于5%CO2培养箱中培养4小时待贴壁。细胞按预设的浓度梯度加入经灭菌处理的化合物4和6a-p的含0.25%DMSO的1640培养基配制成的所需浓度的溶液,每孔25μL,对照孔加入等体积的RPMI-1640,平行6孔。37℃下96孔板置于5%CO2培养箱中培养48小时。之后每孔加入25μL浓度为5mg/mL的MTT溶液,继续培养4小时。小心吸出上清液,每孔加入100μLDMSO溶解紫色残留物(甲瓒),平板振荡10分钟使沉淀全部溶解,于570nm酶标仪上测定O.D.值(吸光度),波长570nm。
按照公式“相对生存率=(D含药-D空白)/(D对照-D空白)×100%”计算每一个样品浓度下的样品对肿瘤细胞的抑制率。
实验平行重复3次,以抑制率对化合物浓度作图,计算本发明化合物4和6a-p的IC50(半数有效抑制浓度)值。
对于K562和HL60细胞:分别将生长状态良好,处于对数生长期的K562和HL60细胞按照4×104个/mL的密度接种于96孔板,每孔100μL。细胞按预设的浓度梯度加入经灭菌处理的化合物4和6a-p的含0.25%DMSO的1640培养基配制成的所需浓度的溶液,每孔25μL,对照孔加入等体积的RPMI-1640,平行6孔。37℃下96孔板置于5%CO2培养箱中培养48小时。之后每孔加入25μL浓度为5mg/mL的MTT溶液,继续培养4小时。离心3分钟(3000rpm/min)。小心吸出上清液,每孔加入100μL DMSO溶解紫色残留物(甲瓒),平板振荡10分钟使沉淀全部溶解,于570nm酶标仪上测定O.D.值(吸光度),波长570nm。
按照公式“相对生存率=(D含药-D空白)/(D对照-D空白)×100%”计算每一个样品浓度下的样品对肿瘤细胞的抑制率。
实验平行重复3次,以抑制率对化合物浓度作图,计算本发明化合物4和6a-p的IC50(半数有效抑制浓度)值。
实验结果列入表1。IC50值表明发明的化合物4和6a-p在体外可抑制肿瘤细胞增殖。
表1化合物4和6a-p抗肿瘤细胞增殖的IC50值
实验例2化合物4和6a-p体内抗肿瘤活性评价
无菌条件下抽取接种7天后生长旺盛的S180腹水瘤瘤液,用生理盐水稀释成(1∶3)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,并按细胞浓度=(4大方格内活细胞数/4)×104稀释倍数=细胞数/mL和细胞存活率=活细胞数/(活细胞数+死细胞数)×100%计算细胞浓度和细胞存活率。
ICR雄性小鼠(清洁级,体重为20±2g,购自北京维通利华实验动物技术有限公司),每12只小鼠一组。将S180活细胞存活率大于90%的瘤液用匀浆法制备成1.5×107个/mL的细胞悬液,于ICR雄性小鼠腋皮下接种(0.2mL/只),造成荷S180实体瘤小鼠并接受治疗。化合物4和6a-p加少量吐温80助溶后逐渐加生理盐水至所需浓度。阳性对照为阿霉素加入生理盐水至所需浓度。它们的给药剂量均为1μmol/kg,每天腹腔注射1次。连续给药7天。空白对照为等体积生理盐水。治疗至第8天,称小鼠体重,脱颈椎处死小鼠,并剖取各组小鼠的肿瘤及各主要脏器称重,最后统计各组药物的抑瘤率。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%。脾指数=脾重(mg)/处死体重(g)。本实验数据统计均采用t检验和方差分析。
实验结果列入表2。治疗小鼠的肿瘤重表明,在0.1μmol/kg剂量下化合物4和6a-p几乎都显示抗肿瘤作用,其中6a和6e的抗肿瘤作用最强。
表2化合物4和6a-p对荷S180小鼠肿瘤重量的影响
n=12;a)与生理盐水及化合物4及化合物6b,d,f,g,i-l,m-p组比较P<0.01,与化合物6c,h,l组比较P<0.05;b)与生理盐水组比较P<0.01;c)与生理盐水及化合物4及化合物6b,d,f,g,i-k,n-p组比较P<0.05.
绝大多数抗肿瘤药物在杀伤肿瘤细胞的同时,也降低免疫功能,引起脾指数大幅度降低。本发明测定的从脾指数表明,与空白对照比较,在1μmol/kg剂量下阿霉素引起脾指数降低50%,而化合物4和6a-p不引起脾指数降低。可见,化合物4和6a-p不降低治疗小鼠的免疫功能。
实验例3化合物6e体内抗肿瘤量效关系
按照试验例2的方法,化合物6e选取高、中、低三个剂量,即0.1μmol/kg、0.01μmol/kg和0.001μmol/kg三个剂量考察化合物的剂量效应依赖关系。结果列入表3。治疗小鼠的肿瘤重表明,6e的抗肿瘤作用显示剂量效应依赖关系。
表3.不同剂量6e对荷S180小鼠肿瘤重量的影响
n=12;a)与生理盐水组和0.001μmol/kg6e组比较P<0.01,与0.01μmol/kg6e组比较P<0.05;b)与生理盐水组和0.001μmol/kg6e组比较P<0.01;c)与生理盐水组比较P>0.05。
Claims (4)
1.通式I代表的化合物,式中AA选自L-Leu,L-Glu,L-Val,L-Trp,L-Pro,L-Tyr,L-Met,L-Phe,L-Ala,L-Gly,L-Asn,L-Asp,L-Ile,L-Lys,L-Ser,L-Theanine残基,或AA-OBzl共同代表OBzl,
2.制备权利要求1的化合物的方法,该方法包括:
1)将L-色氨酸转变为3S-1,2,3,4-四氢-β-咔啉-3-羧酸;
2)将叔丁氧羰基引到3S-1,2,3,4-四氢-β-咔啉-3-羧酸的2位,得到3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸;
3)将茶氨酸苄酯引到3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-羧酸的3位羧基上,得到3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-甲酰-茶氨酸苄酯;
4)将3S-N-Boc-1,2,3,4-四氢-β-咔啉-3-甲酰-茶氨酸苄酯脱去保护基Boc,在三乙胺的催化下与甲醇和丙酮的混合溶剂反应得到[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸苄酯;
5)Pd/C催化下将[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸苄酯脱除苄基得到[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸;
6)将[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酸与16种氨基酸苄酯偶联,得[四氢-β-咔啉并(2,2-二甲基-咪唑-4-酮-3-基)]-2-(乙基丙酰胺)-乙酰氨基酸苄酯。
3.按照权利要求3所述方法,其特征在于步骤6)中所述氨基酸苄酯选自L-Leu-OBzl,L-Glu-OBzl,L-Val-OBzl,L-Trp-OBzl,L-Pro-OBzl,L-Tyr-OBzl,L-Met-OBzl,L-Phe-OBzl,L-Ala-OBzl,L-Gly-OBzl,L-Asn-OBzl,L-Asp-OBzl,L-Ile-OBzl,L-Lys-OBzl,L-Ser-OBzl或L-Theanine-OBzl。
4.权利要求1的通式I的化合物在制备抗肿瘤剂中的用途。
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