CN105294825B - 1-(乙基氨基酸苄酯)-β-咔啉-3-羧酸苄酯的纳米结构、制备、活性及应用 - Google Patents
1-(乙基氨基酸苄酯)-β-咔啉-3-羧酸苄酯的纳米结构、制备、活性及应用 Download PDFInfo
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Abstract
本发明公开了1‑(乙基‑Val‑AA‑OBzl)‑β‑咔啉‑3‑羧酸苄酯和L‑Lys残基及制备方法,公开了它们的纳米结构,公开了它们抑制肿瘤细胞增殖的活性,进一步公开了它们抑制S180小鼠肿瘤生长的活性,阐明了它们在制备抗肿瘤药物中的应用。
Description
技术领域
本发明涉及1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯和L-Lys残基,涉及它们的制备方法,涉及它们的纳米结构,涉及它们的体外肿瘤细胞增殖抑制活性,进一步涉及它们对荷S180小鼠肿瘤生长的抑制作用.因而本发明涉及它们在制备抗肿瘤药物中的应用.本发明属于生物医药领域。
技术背景
近年来,鉴于全球癌症发病率和死亡率急剧上升,癌症已经成为了一个世界问题。我国的癌症患者人数处于世界前列,癌症患者人数不断增加,对抗肿瘤药的需求也不断增加。目前临床应用的抗肿瘤药物存在许多局限性,随着科技的进步以及科学的发展,寻找安全有效的抗肿瘤新药是药物研究的热点之一。
癌症是一组可影响身体任何部位的多种疾病的通称。使用的其它术语为恶性肿瘤和赘生物。据世界卫生组织统计,癌症是世界上的头号死因之一,尤其是在发展中国家。而全世界癌症死亡人数预计将继续上升,到2030年将超过1310万。因此,开发新的高效,低毒,毒副作用小的抗肿瘤药物一直是新药研亢的重要课题之一。
随着对肿瘤特性和发病本质的认识,最近几年抗肿瘤药物不断从传统的细胞毒药物向发展非细胞毒药物过渡。β-咔啉是天然来源的细胞毒性抗肿瘤化合物。发明人认识到,β-咔啉抗肿瘤的细胞毒性本质是与肿瘤细胞DNA之间的嵌插。这种形式的扦插可造成细胞毒性。发明人曾经发现,β-咔啉可以***肿瘤细胞DNA之间的双螺旋碱基之间。在进一步的研究中,发明人认识到,β-咔啉的抗肿瘤活性来自嵌插。发明人还认识到,在β-咔啉的1位引入二肽生成β-咔啉-3-羧酸苄酯及衍生物可增强β-咔啉与肿瘤细胞的作用,增强抗肿瘤活性。根据这些认识,发明人提出1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯。与发明人前期的发明1-(乙基-AA-OBzl)-β-咔啉-3-羧酸苄酯相比,本发明的突出创造性在于,保留了β-咔啉与肿瘤细胞DNA之间的嵌插作用,在低剂量下显示高抗肿瘤活性。于是,1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯显示了良好的抑制肿瘤细胞增殖作用和抗肿瘤活性。
发明的内容
本发明的第一个内容是提供下式的1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯.式中AA代表Gly,L-Ala,L-Phe,L-Val,L-Asp(OBzl),L-Trp,L-Ile,L-Leu,L-Thr,L-Ser,L-Met,L-Pro,L-Asn,L-Gln,L-Cys(pMeOBzl),L-Arg(NG-NO2)和L-Lys残基。
本发明的第二个内容是提供1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯的制备方法,该方法包括:
(1)将L-色氨酸苄酯在三氟醋酸的催化下与1,1,3,3-四甲氧基丙烷进行Pictet-Spengler缩合,得到1-(2,2-二甲氧乙基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯;
(2)将1-(2,2-二甲氧乙基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯在四氢呋喃中,用高锰酸钾水溶液氧化得到1-(2,2-二甲氧乙基)-β-咔啉3-羧酸苄酯;
(3)在冰醋酸、浓盐酸、混合液中1-(2,2-二甲氧乙基)-β-咔啉3-羧酸苄酯水解为1-乙醛基-β-咔啉3-羧酸苄酯;
(4)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Ala-OBzl偶联得到1-(乙基-Val-Ala-OBzl)-β-咔啉-3-羧酸苄酯;
(5)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Phe-OBzl偶联得到1-(乙基-Val-Phe-OBzl)-β-咔啉-3-羧酸苄酯;
(6)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Trp-OBzl偶联得到1-(乙基-Val-Trp-OBzl)-β-咔啉-3-羧酸苄酯;
(7)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Val-OBzl偶联得到1-(乙基-Val-Val-OBzl)-β-咔啉-3-羧酸苄酯;
(8)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Asp(OBzl)-OBzl偶联得到1-(乙基-Val-Asp(OBzl)-OBzl)-β-咔啉-3-羧酸苄酯;
(9)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Ile-OBzl偶联得到1-(乙基-Val-Ile-OBzl)-β-咔啉-3-羧酸苄酯;
(10)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Leu-OBzl偶联得到1-(乙基-Val-Leu-OBzl)-β-咔啉-3-羧酸苄酯;
(11)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Gly-OBzl偶联得到1-(乙基-Val-Gly-OBzl)-β-咔啉-3-羧酸苄酯;
(12)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Thr-OBzl偶联得到1-(乙基-Val-Thr-OBzl)-β-咔啉-3-羧酸苄酯;
(13)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Ser-OBzl偶联得到1-(乙基-Val-Ser-OBzl)-β-咔啉-3-羧酸苄酯;
(14)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Met-OBzl偶联得到1-(乙基-Val-Met-OBzl)-β-咔啉-3-羧酸苄酯;
(15)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Pro-OBzl偶联得到1-(乙基-Val-Pro-OBzl)-β-咔啉-3-羧酸苄酯;
(16)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Lys(Nω-Fmoc)-OBzl偶联得到1-(乙基-Va1-Lys(Nω-Fmoc)-OBzl)-β-咔啉-3-羧酸苄酯;将1-(乙基-Val-Lys(Nω-Fmoc)-OBzl)-β-咔啉-3-羧酸苄酯在无水二氯甲烷中,冰浴下滴加六氢吡啶得到1-(乙基-Val-Lys-OBzl)-β-咔啉-3-羧酸苄酯;
(17)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Arg(NG-NO2)-OBzl偶联得到1-(乙基-Val-Arg(NG-NO2)-OBzl)-β-咔啉-3-羧酸苄酯;
(18)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Asn-OBzl偶联得到1-(乙基-Val-Asn-OBzl)-β-咔啉-3-羧酸苄酯;
(19)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Gln-OBzl偶联得到1-(乙基-Val-Gln-OBzl)-β-咔啉-3-羧酸苄酯;
(20)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Cys(pMeOBzl)-OBzl偶联得到1-(乙基-Val-Cys(pMeOBzl)-OBzl)-β-咔啉-3-羧酸苄酯。
本发明的第三个内容是评价1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯抑制肿瘤细胞增殖的作用。
本发明的第四个内容是评价1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯抑制荷S180小鼠肿瘤生长的作用。
本发明的第五个内容是测定1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯的纳米结构。
附图说明
图1化合物5a-q的合成路线图.i)化合物1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯的合成路线图.i)多聚磷酸,苯甲醇;ii)三氟醋酸,1,1,3,3-四甲氧基丙烷;iii)高锰酸钾,四氢呋喃,水;iv)溶浓盐酸,冰醋酸,水;V)N-甲基吗啉,无水硫酸镁,氰基硼氢化钠,Val-AA-OBzl.5a中AA=Ala残基,5b中AA=Phe残基,5c中AA=Trp残基,5d中AA=Val残基,5e中AA=Asp(OBzl)残基,5f中AA=Ile残基,5g中AA=Leu残基,5h中AA=Gly残基,5i中AA=Thr残基,5j中AA=Ser残基,5k中AA=Met残基,51中AA=Pro,5m中AA=Lys残基,5n中AA=Arg(NG-NO2)残基,5o中AA=Asn残基,5p中AA=Gln残基,5q中AA=Cys(pMeOBzl)残基。
图2化合物5a-q在pH7.4环境中,浓度为6×10-7M浓度下的透射电镜照片。
具体实施方式
为了进一步阐述本发明,下面给出一些列实施例.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-(2,2-二甲氧乙基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯
先将5gL-色氨酸苄酯用饱和NaHCO3水溶液洗,用70mL乙酸乙酯萃取,共萃取3次,酯相用饱和氯化钠溶液洗至中性,无水硫酸钠干燥,过滤至250mL的圆底烧瓶中,滤液减压浓缩至干得4g无色固体。在100mL的圆底烧瓶中,先将4mL1,1,3,3-四甲氧基丙烷溶于40mL二氯甲烷溶剂中,再加入4mL三氟醋酸,活化45min,在冰浴下,将刚刚得到的4g无色固体加入到反应瓶中.反应52小时,TLC(石油醚/丙酮=4/1)显示反应完成,用饱和NaHCO3水溶液中和反应液中的酸,然后用70mL二氯甲烷萃取,共萃取3次。二氯甲烷层用饱和氯化钠水溶液洗至中性,二氯甲烷相用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶湿法柱层析纯化,得到3.5g(51%)标题化合物,为黄色油状物。ESl-MS(m/e)395[M+H]+。
实施例2制备1-(2,2-二甲氧乙基)-β-咔啉3-羧酸苄酯
将5g(12.7mmol)1-(2,2-二甲氧乙基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯,与150mL四氢呋喃加入到250mL的茄瓶中,冰浴搅拌,分批加入5g(31.6mmol)高锰酸钾的水溶液,室温反应5小时,TLC(石油醚/丙酮=4/1)显示反应完成,过滤,并加入四氢呋喃冲洗滤饼,滤液减压浓缩,再将残余水相用70mL二氯甲烷提取,共提取3次,合并的二氯甲烷相,用饱和食盐水洗涤3次,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶湿法柱层析纯化,再用石油醚-丙酮重结晶得到3g(60%)标题化合物,为无色固体。ESI/MS(m/e)391[M+H]+。
实施例3制备1-乙醛基-β-咔啉3-羧酸苄酯
先加入72mL冰醋酸使344mg(1mmol)1-(2,2-二甲氧乙基)-β-咔啉3-羧酸苄酯完全溶解,再依次加入9mL浓盐酸和9mL水。搅拌4h,TLC显示原料斑点消失,反应化合物加入大量冰水混合物,搅拌使大量固体析出,过滤并用90mL冰水冲洗滤饼。收集滤饼,充分干燥,备下一步反应使用。
实施例4制备1-(乙基-Val-Ala-OBzl)-β-咔啉-3-羧酸苄酯(5a)
冰浴下,往377mg(1.2mmol)HCl·Val-Ala-OBzl与20ml无水四氢呋喃的溶液中滴加N-甲基吗啉调节溶液pH值至8,往溶液中加344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯20mL二氯甲烷的悬浮液,搅拌10分钟后加入200mg无水硫酸镁搅拌15分钟.往反应混合物中加63mg(1mmol)氰基硼氢化钠,室温搅拌14h,TLC(CHCl3/MeOH=28/1)显示反应完成.反应混合物过滤,滤液减压浓缩,剩余物加入饱和NaHCO3水溶液溶解,得到的溶液用50ml乙酸乙酯液萃取,共萃取3次.乙酸乙酯层用饱和氯化钠溶液洗至中性,收集的乙酸乙酯相用无水硫酸钠干燥,过滤,滤液减压浓缩,得到的糖浆状物先后经硅胶柱层析(二氯甲烷/甲醇=65/1)及制备薄层层析(二氯甲烷/甲醇=26/1)纯化,得到117mg(19%)标题化合物,为淡黄色油状物.ESI-MS(m/e)608.4[M+H]+; IR(KBr):3412.08,2960.73,2889.37,1647.21,1496.76,1456.26,1448.54,1373.32,1373.32,1348.24,1340.53,1251.80,1209.37,1151.50,1138.00,1097.50,1047.35,997.20,962.48,875.68,854.47,833.25,790.81,696.30,669.30cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.58(s,1H),8.73(s,1H),8.14(d,J=7.8Hz,1H),7.83(d,J=8.1Hz,1H),7.61~7.26(m,14H),5.51(s,2H),5.29(d,J=12.3Hz,1H),5.18(d,J=12.3Hz,1H),4.81(m,1H),3.51(m,1H),3.41(m,1H),3.17(d,J=6.9Hz,1H),3.15(d,J=6.9Hz,1H),3.05(d,J=4.8Hz,1H),2.14(m,1H),1.46(d,J=7.2Hz,3H),1.03(d,J=6.9Hz,3H),0.97(d,J=6.9Hz,3H)。
实施例5制备1-(乙基-Val-Phe-OBzl)-β-咔啉-3-羧酸苄酯(5b)
按照实施例4的方法,由425mg(1.2mmol)HCl·Val-Phe-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得177mg(26%)标题化合物,为淡黄色油状物.ESI-MS(m/e)715.3[M+MeOH]+=IR(KBr):3743.83,3089.96,3030.17,2960.73,2852.72,1734.01,1716.65,1647.21,1624.06,1597.06,1496.76,1456.26,1448.54,1436.97,1379.10,1348.24,1301.95,1253.73,1215.15,1176.58,1155.36,1134.14,1107.14,1085.92,1026.13,987.55,956.69,875.68,738.74,698.26,684.73cm-1;1H NMR(300MHz,CDCl3)δ/ppm:9.67(s,1H),8.78(s,1H),8.17(d,J=7.8Hz,1H),7.57~7.53(m,5H),7.44~7.22(m,15H),5.99(s,1H),5.82(s,1H),5.50(s,2H),4.25(m,3H),3.90(s,1H),3.50(d,J=3.00Hz,1H),3.44(d,J=3.00Hz,1H),3.43(d,J=3.00Hz,1H),2.91(m,1H),2.36(m,1H),1.03(d,J=7.2Hz,3H),0.86(d,J=6.9Hz,3H)。
实施例6制备1-(乙基-Val-Trp-OBzl)-β-咔啉-3-羧酸苄酯(5c)
按照实施例4的方法,由515mg(1.2mmol)HCl·Val-Trp-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得63mg(9%)标题化合物,为淡黄色油状物.ESI-MS(m/e)723.4[M+H]+;IR(KBr):3323.35,3062.96,3035.96,2958.80,2924.09,2854.65,1718.58,1649.14,1597.06,1554.63,1521.84,1489.05,1456.26,1379.10,1348.24,1249.87,1213.23,1176.58,1153.43,1136.07,1101.35,1002.98,966.34,908.47,786.96,742.59,723.31,696.30cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.39(br s,1H),8.80(s,1H),8.77(s,1H),8.13(d,J=7.8Hz,1H),7.71(d,J=9.0Hz,1H),7.53~7.49(m,4H),7.45~7.22(m,11H),7.07(m,2H),6.94(m,1H),5.51(s,2H),5.13(m,2H),5.08(m,1H),3.32(m,2H),3.01(m,2H),2.84(m,3H),1.93(m,1H),1.85(s,1H),0.86(d,J=6.0Hz,3H);0.84(d,J=6.0Hz,3H)。
实施例7制备1-(乙基-Val-Val-OBzl)-β-咔啉-3-羧酸苄酯(5d)
按照实施例4的方法,由411mg(1.2mmol)HCl·Val-Val-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得134mg(21%)标题化合物,为淡黄色油状物.ESI-MS(m/e)636.0[M+H]+;IR(KBr):3736.12,3574.10,3527.80,3406.29,3379.39,3360.00,3346.50,3334.92,3267.41,3207.62,2362.80,2345.44,1724.36,1680.00,1653.00,1602.85,1558.44,1516.05,1506.41,1448.54,1375.25,1348.24,1253.73,1215.15,1136.07,1122.57,983.70,808.17,754.17,644.22cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.37(br s,1H),8.78(s,1H),8.18(d,J=15.0Hz,1H),7.87(d,J=9.3Hz,1H),7.56~7.54(m,4H),7.45~7.22(m,10H),5.53(s,2H),5.37(d,J=12.3Hz,1H),5.24(d,J=12.3Hz,1H),4.76(q,J=9.6Hz,1H),3.49(m,2H),3.19(d,J=11.7Hz,1H),3.16(d,J=6.6Hz,1H),3.02(d,J=3.3Hz,1H),2.31(m,1H),2.11(m,1H),1.04(d,J=7.5Hz,3H),1.02(d,J=4.2Hz,3H),0.99(d,J=3.3Hz,3H),0.92(d,J=6.9Hz,3H)。
实施例8制备1-(乙基-Val-Asp(OBzl)-OBzl)-β-咔啉-3-羧酸苄酯(5e)
按照实施例4的方法,由538mg(1.2mmol)HCl·Val-Asp(OBzl)-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得74mg(10%)标题化合物.ESI-MS(m/e)742.6[M+H]+;IR(KBr):3225.28,3269.34,3089.96,3064.89,3034.03,2958.80,2873.94,2640.55,1992.47,1951.96,1942.32,1861.31,1732.08,1645.28,1625.99,1597.06,1566.20,1558.48,1498.69,1456.26,1411.89,1379.10,1348.24,1251.80,1213.23,1166.93,1157.29,1136.07,1105.21,1082.07,1047.35,1028.06,968.27,910.40,825.53,806.25,786.96,738.74,696.30,677.01cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.23(br s,1H),8.78(s,1H),8.31(d,J=9.3Hz,1H),8.17(d,J=7.8Hz,1H),7.57~7.19(m,19H),5.53(s,2H),5.26(d,J=12.3Hz,1H),5.18(d,J=9.3Hz,1H),5.11(d,J=6.9Hz,1H),5.02(d,J=6.6Hz,1H),5.10(m,2H),3.48(m,1H),3.36(m,1H),3.27(dd,J=4.2Hz,J=4.2Hz,1H),3.06(m,1H),2.95(d,J=8.1Hz,1H),2.87(d,J=4.5Hz,1H),2.06(m,1H),1.85(m,1H),0.98(d,J=6.9Hz,3H),0.81(d,J=6.9Hz,3H)。
实施例9制备1-(乙基-Val-Ile-OBzl)-β-咔啉-3-羧酸苄酯(5f)
按照实施例4的方法,由450mg(1.2mmol)HCl·Val-Ile-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得174mg(27%)标题化合物,为淡黄色油状物.ESI-MS(m/e)650.5[M+H]+;IR(KBr):3558.67,3450.65,2964.59,2927.94,2885.51,1951.96,1909.53,1847.81,1716.65,1647.21,1595.13,1456.26,1373.32,1348.24,1336.27,1300.02,1251.80,1215.15,1172.72,1155.36,1138.00,1089.78,1080.14,1026.13,952.84,852.54,792.74,725.23,696.30cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.36(br s,1H),8.75(s,1H),8.15(d,J=7.8Hz,1H),7.87(d,J=8.7Hz,1H),7.57~7.50(m,4H),7.46~7.32(m,7H),7.28~7.22(m,3H),5.52(s,2H),5.37(d,J=12.0Hz,1H),5.22(d,J=12.6Hz,1H),4.78(q,J=9.0Hz,1H),3.50(m,2H),3.10(m,2H),2.15(m,2H),2.03(m,1H),1.39(m,1H),1.19(m,1H),1.05(d,J=5.1Hz,3H),0.95(d,J=3.9Hz,3H),0.92(d,J=4.2Hz,3H),0.87(d,J=7.5Hz,3H)。
实施例10制备1-(乙基-Val-Leu-OBzl)-β-咔啉-3-羧酸苄酯(5g)
按照实施例4的方法,由450mg(1.2mmol)HCl·Val-Leu-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得199mg(31%)标题化合物,为淡黄色油状物.ESI-MS(m/e)650.4[M+H]+;IR(KBr):3568.31,3315.63,3072.60,3035.96,2960.73,2870.08,1890.24,1865.17,1830.45,1772.58,1718.58,1701.22,1597.06,1490.97,1458.18,1446.61,1436.97,1419.61,1436.97,1419.61,1375.25,1348.24,1301.95,1251.80,1209.37,1151.50,1139.93,1103.28,1083.99,904.61,844.82,788.89,746.45,721.38,590.22cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.39(br s,1H),8.78(s,1H),8.16(d,J=8.1Hz,1H),7.63(d,J=6.3Hz,1H),7.56~7.51(m,4H),7.45~7.28(m,11H),5.53(s,2H),5.32(d,J=12.3Hz,1H),5.23(d,J=12.3Hz,1H),4.82(m,1H),3.52(m,1H),3.39(m,1H),3.16(d,J=6.9Hz,1H),3.14(d,J=7.2Hz,1H),3.01(d,J=3.9Hz,1H),2.10(m,1H),1.67(m,2H),1.57(m,1H),1.02(d,J=7.2Hz,3H),1.00(d,J=9.0Hz,3H),0.94(d,J=5.7Hz,3H),0.94(d,J=5.7Hz,3H)。
实施例11制备1-(乙基-Val-Gly-OBzl)-β-咔啉-3-羧酸苄酯(5h)
按照实施例4的方法,由360mg(1.2mmol)HCl·Val-Gly-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得89mg(15%)标题化合物,为淡黄色油状物.ESI-MS(m/e)594.4[M+H]+;IR(KBr):3336.85,3269.34,3217.27,3091.89,3034.03,2958.80,2933.73,2870.08,1953.89,1909.53,1857.45,1718.58,1647.21,1624.06,1597.06,1570.06,1498.69,1456.26,1436.97,1375.25,1348.24,1300.02,1251.80,1213.23,1188.15,1155.36,1138.00,1105.21,1083.99,1029.99,964.41,950.91,943.19,904.61,893.04,810.10,788.89,725.23,696.30,669.30cm-1;1HNMR(300MHz,CDCl3)δ/ppm:10.73(s,1H),8.77(s,1H),8.16(d,J=7.8Hz.1H),7.83(m,1H),7.56~7.51(m,3H),7.42~7.28(m,9H),5.50(s,2H),5.20(s,2H),4.38(dd,J=7.5Hz,J=7.8Hz,1H),3.96(dd,J=4.5Hz,J=4.5Hz,1H),3.41(m,1H),3.31(m,1H),3.16(m,1H),3.06(m,1H),3.01(d,J=5.1Hz.1H),2.33(br s,2H),2.03(m,1H),1.01(d,J=10.2Hz,3H),0.95(d,J=6.6Hz,3H)。
实施例12制备1-(乙基-Val-Thr-OBzl)-β-咔啉-3-羧酸苄酯(5i)
按照实施例4的方法,由411mg(1.2mmol)HCl·Val-Thr-OBzl和344mg(1mmol)l-乙醛基-β-咔啉-3-羧酸苄酯得72mg(11%)标题化合物,为淡黄色油状物.ESI-MS(m/e)638.4[M+H]+;IR(KBr):3348.42,3078.39,3034.03,2962.66,2933.73,2873.94,1768.72,1718.58,1647.21,1627.92,1597.06,1500.62,1456.26,1375.25,1348.24,1321.24,1301.95,1251.80,1213.23,1155.36,1139.93,1103.28,1082.07,1028.06,1012.63,968.27,914.26,896.90,883.40,825.53,742.59,698.23,663.51cm-1;1HNMR(300MHz,CDCl3)δ/ppm:10.50(s,1H),8.47(s,1H,),8.23(d,J=9.0Hz,1H),7.95(d,J=6.0Hz,1H),7.51~7.49(m,2H),7.45~7.31(m,5H),7.28~7.21(m,7H),5.46(s,2H),5.19(d,J=12.0Hz,1H),5.08(d,J=12.0Hz,1H),4.63(m,2H),3.72(m,1H),3.40(m,1H),3.31(m,1H),2.99(m,3H),2.09(m,1H),1.31(d,J=6.0Hz,3H),1.00(d,J=6.0Hz,3H),0.98(d,J=6.0Hz,3H)。
实施例13制备1-(乙基-Val-Ser-OBzl)-β-咔啉-3-羧酸苄酯(5j)
按照实施例4的方法,由397mg(1.2mmol)HCl·Val-Ser-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得122mg(18%)标题化合物,为淡黄色油状物.ESI-MS(m/e)624.4[M+H]+;IR(KBr):3439.08,2974.23,2883.58,1830.45,1776.44,1743.65,1705.07,1653.00,1647.21,1600.92,1560.41,1508.33,1458.18,1436.97,1375.25,1348.24,1340.53,1247.94,1209.37,1155.36,1136.07,883.40,731.02,700.16cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.89(s,1H),8.43(s,1H),8.39(d,J=6.0Hz,1H),7.96(d,J=6.3Hz,1H),7.55~7.17(m,15H),5.44(s,2H),5.18(d,J=12.0Hz,1H),5.10(d,J=12.0Hz,1H),4.80(m,1H),4.28(dd,J=6.0Hz,J=3.0Hz,1H),4.03(dd,J=3.0Hz,J=3.0Hz,1H),3.35(m,1H),3.22(m,1H),3.02(m,1H),2.94(d,J=6.0Hz,1H),2.87(m,1H),2.02(m,1H),0.99(d,J=3.0Hz,3H),0.97(d,J=3.0Hz,3H)。
实施例14制备1-(乙基-Val-Met-OBzl)-β-咔啉-3-羧酸苄酯(5k)
按照实施例4的方法,由470mg(1.2mmol)HCl·Val-Met-OBzl和344mg(1mmol)1-乙醛基β-咔啉-3-羧酸苄酯得122mg(19%)标题化合物,为淡黄色油状物.ESI-MS(m/e)668.5[M+H]+;IR(KBr):3331.08,3091.89,3034.03,2958.80,2916.37,2873.94,1992.47,1942.32,1869.02,1734.01,1718.58,1705.07,1647.21,1624.06,1597.06,1521.84,1498.69,1456.26,1436.97,1419.61,1375.25,1348.24,1300.02,1251.80,1213.23,1203.58,1166.93,1155.36,1134.14,1103.28,1082.07,1060.85,1026.13,968.27,956.69,902.69,823.60,786.96,736.81,696.30,619.15cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.58(s,1H),8.87(s,1H),8.13(d,J=6.0Hz,1H),7.96(d,J=6.0Hz,1H),7.63~7.21(m,12H),5.53(s,2H),5.30(d,J=12.0Hz,1H),5.19(d,J=12.0Hz,1H),4.93(m,1H),3.47(m,1H),3.32(m,1H),3.11(m,2H),3.09(m,1H),2.94(m,2H),2.50(d,J=9.0Hz,1H),2.47(d,J=9.0Hz,1H),2.15(m,2H),2.10~1.90(m,5H),0.98(d,J=9.0Hz,3H),0.94(d,J=6.0Hz,3H)。
实施例15制备1-(乙基-Val-Pro-OBzl)-β-咔啉-3-羧酸苄酯(5l)
按照实施例4的方法,由409mg(1.2mmol)HCl·Val-Pro-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得139mg(22%)标题化合物,为淡黄色油状物.ESI-MS(m/e)634.4[M+H]+;CH3OH);IR(KBr):3462.22,3228.84,2960.73,2879.72,1768.72,1739.79,1718.58,1701.22,1676.14,1618.28,1560.41,1541.12,1498.69,1458.18,1419.61,1379.10,1348.24,1305.81,1253.73,1211.30,1170.79,1138.00,1105.21,966.34,900.76,742.59,696.30cm-1;1H NMR(300MHz,CDCl3)δ/ppm:12.46(s,1H),8.70(s,1H),8.14(d,J=6.0Hz,1H),7.59~7.07(m,15H),5.52(s,2H),5.24(d,J=12.0Hz,1H),5.18(d,J=12.0Hz,1H),4.70(q,J=3.0Hz,J=3.0Hz,1H),3.62(m,3H),3.44(m,2H),3.25(m,1H),2.97(m,1H),2.23(m,2H),2.02(m,2H),1.23(d,J=9.0Hz,3H),1.20(d,J=6.0Hz,3H)。
实施例16制备1-(乙基-Val-Lys-OBzl)-β-咔啉-3-羧酸苄酯(5m)
按照实施例4的方法,由752mg(1.2mmol)HCl·Val-Lys(Fmoc)-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得179mg(20%)1-(乙基-Val-Lys(ωN-Fmoc)-OBzl)-β-咔啉-3-羧酸苄酯,为白色固体.ESI-MS(m/e)887.6[M+H]+; IR(KBr):3427.51,3313.71,3064.89,3032.10,2956.87,2929.87,2866.22,1772.58,1753.29,1739.79,1718.58,1649.14,1618.28,1541.12,1473.62,1346.31,1332.81,1303.88,1267.23,1246.02,1213.23,1201.65,1180.44,1139.93,1105.21,1039.63,1020.34,974.05,950.91,900.76,883.40,846.75,823.60,777.31,756.10,734.88,700.16cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.36(s,1H),8.77(s,1H),8.16(d,J=9Hz,1H),7.79~7.73(m,3H),7.62~7.49(m,6H),7.43~7.27(m,10H),5.52(s,2H),5.33(d,J=12.0Hz,1H),5.20(d,J=15.0Hz,1H),4.77(m,1H),4.40(m,2H),4.20(m,1H),3.48(m,2H),3.38(m,1H),3.13(m,4H),3.01(m,1H),2.09(m,1H),1.88(m,2H),1.78(m,2H),1.49(m,2H),1.35(m,3H),1.01(d,J=6.0Hz,3H),0.97(d,J=6.0Hz,3H)。
将57mg(0.064mmol)1-(乙基-Val-Lys(N-Fmoc)-OBzl)-β-咔啉-3-羧酸苄酯用25mL无水二氯甲烷在100mL的茄瓶中溶解,冰浴下滴加六氢吡啶5mL,冰浴反应2小时后TLC(CHCl3/MeOH=8/1)反应完成.石油醚反复磨洗,用制备薄层层析进行纯化(二氯甲烷/甲醇=10/1,两次展开),得标题化合物6mg(14%),为淡黄色油状物.ESI-MS(m/e)665.6[M+H]+;IR(KBr):3435.22,2960.73,2924.09,2873.94,1734.01,1718.58,1597.06,1456.26,1448.54,1375.25,1348.24,1305.81,1251.80,1203.58,1193.94,1155.36,1141.86,1083.99,1002.98,985.62,937.40,908.47,848.68,823.60,765.74,756.10cm-1;1H NMR(300MHz,CDCl3)δ/ppm:11.69(br s,1H),8.13(br s,1H),7.81(br s,1H),7.55~7.28(m,12H),7.15(m,1H),5.33(m,2H),5.19(d,J=12.0Hz,1H),5.10(d,J=12.0Hz,1H),4.66(m,1H),3.50(m,2H),3.11(m,4H),2.09(m,1H),1.99~1.85(m,5H),1.64(m,4H),1.28(s,2H),0.95(d,J=3.0Hz,3H),0.94(d,J=6.0Hz,3H)。
实施例17制备1-(乙基-Val-Arg(NG-NO2)-OBzl)-β-咔啉-3-羧酸苄酯(5n)
按照实施例4的方法,由533.4mg(1.2mmol)HCl·Val-Arg(NG-NO2)-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得59mg(8%)标题化合物,为淡黄色油状物.ESI-MS(m/e)737.9[M+H]+;IR(KBr):3408.22,2958.80,2931.80,2872.01,1735.93,1718.58,1676.14,1637.56,1577.77,1560.41,1541.12,1458.18,1375.25,1336.67,1247.94,1213.23,1182.36,1151.50,1136.07,1101.35,1074.35,1055.06,1028.06,1012.63,974.05,939.33,9000.76,848.68,837.11,785.03,738.40,696.30,634.58cm-1;1H NMR(300MHz,CDCl3)δ/ppm:10.49(br s,1H),8.72(s,1H),8.11(d,J=9.0Hz,2H),7.86(br s,2H),7.65~7.28(m,13H),5.47(s,2H),5.23(d,J=12.0Hz,1H),5.10(d,J=12.0Hz,1H),4.66(m,1H),3.42(m,1H),3.28(m,1H),3.22(m,2H),3.05~2.89(m,3H),2.41(m,2H),1.98(m,2H),1.80~1.45(m,3H),0.91(d,J=6.0Hz,3H),0.86(d,J=6.0Hz,3H)。
实施例18制备1-(乙基-Val-Asn-OBzl)-β-咔啉-3-羧酸苄酯(5o)
按照实施例4的方法,由429mg(1.2mmol)HCl·Val-Asn-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得30mg(5%)标题化合物,为淡黄色油状物.ESI-MS(m/e)649.9[M+H]+;IR(KBr):3334.92,3226.91,3066.82,3034.03,2960.73,2870.08,1718.58,1676.14,1662.64,1647.21,1624.06,1600.92,1570.06,1560.41,1500.62,1456.26,1379.10,1348.24,1307.74,1249.87,1215.15,1157.29,1139.93,1103.28,1039.63,1028.06,914.26,894.97,742.59,696.30,619.15,605.65,540.07cm-1;1HNMR(300MHz,CDCl3)δ/ppm:10.49(s,1H),8.66(d,J=9.0Hz,1H),8.50(s,1H),8.03(d,J=6.0Hz,1H),7.57(d,2H),7.85~7.36(m,4H),7.36~7.26(m,3H),7.15~7.05(m,3H),6.87(d,2H),6.28(s,1H),5.83(s,1H),5.52(dd,J=15.0Hz,J=12.0Hz,2H),4.92(m,1H),4.88(dd,J=12.0Hz,J=12.0Hz,2H),3.50(m,1H),3.33(m,1H),3.21(dd,J=6.0Hz,J=6.0Hz,1H),2.93(m,1H),2.81(d,J=6.0Hz,3H),2.76(d,J=3.0Hz,3H),2.15(m,1H),1.71(m,1H),1.00(d,J=6.0Hz,3H),0.92(d,J=6.0Hz,3H)。
实施例19制备1-(乙基-Val-Gln-OBzl)-β-咔啉-3-羧酸苄酯(5p)
按照实施例4的方法,由446mg(1.2mmol)HCl·Val-Gln-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得25mg(4%)标题化合物,为淡黄色油状物.ESI-MS(m/e)664.0[M+H]+;IR(KBr):3439.08,3288.63,3219.19,3207.62,3192.19,3174.83,3155.54,3088.03,3062.96,3034.03,3010.88,2958.80,2929.87,2893.22,2872.01,2854.65,2819.93,1716.65,1662.64,1600.92,1568.13,1500.62,1456.26,1417.68,1379.10,1348.24,1303.88,1251.80,1213.23,1176.58,1155.36,1136.07,1101.35,1083.99,1028.06,972.12,910.40,852.54,840.96,786.96,738.74,696.30,675.09cm-1;1HNMR(300MHz,CDCl3)δ/ppm:10.83(br s,1H),8.64(s,1H),8.29(d,J=9.0Hz,1H),8.12(d,J=9.0Hz,1H),7.54~7.48(m,4H),7.48~7.20(m,9H),6.22(s,1H),5.97(m,1H),5.49(s,2H),5.19(dd,J=12.0Hz,J=12.0Hz,2H),4.69(m,1H),3.41(m,2H),3.08(d,J=6.0Hz,1H),3.06(d,J=6.0Hz,1H),2.97(d,J=3.0Hz,1H),2.35(m,1H),2.32(m,1H),2.16(m,1H),2.10(m,2H),0.92(d,J=6.0Hz,3H),0.90(d,J=6.0Hz,3H)。
实施例20制备1-(乙基-Val-Cys(pMeOBzl)-OBzl)-β-咔啉-3-羧酸苄酯(5q)
按照实施例4的方法,由560mg(1.2mmol)HCl·Val-Cys(pMeOBzl)-OBzl和344mg(1mmol)1-乙醛基-β-咔啉-3-羧酸苄酯得25mg(3%)标题化合物,为淡黄色油状物.ESI-MS(m/e)760.3[M+H]+;IR(KBr):3439.08,2951.09,2360.87,2345.44,1865.17,1824.66,1772.58,1718.58,1701.22,1653.00,1635.64,1560.41,1541.12,1496.76,1458.18,1375.25,1340.53,1247.94,758.02,727.16,704.02,621.08em-1;1H NMR(300MHz,CDCl3)δ/ppm:10.36(br s,1H),8.78(s,1H),8.17(d,J=9.0Hz,1H),7.92(d,J=9.0Hz,1H),7.60~7.50(m,4H),7.45~7.20(m,12H),7.16(d,J=6.0Hz,1H),6.78(d,J=9.0Hz,1H),5.53(s,2H),5.32(d,J=12.0Hz,1H),5.21(d,J=12.0Hz,1H),5.03(m,1H),3.75(s,2H),3.70(s,1H),3.66(s,1H),3.51(m,1H),3.40(m,1H),3.13(m,2H),2.99(d,J=3.0Hz,1H),2.91(d,J=6.0Hz,2H),2.11(m,1H),1.03(d,J=6.0Hz,3H),0.99(d,J=6.0Hz,3H)。
实验例1测定化合物5a-q对肿瘤细胞增殖的抑制作用
1)本发明的化合物5a-q用含0.1%DMSO的培养基配制成所需浓度。
2)实验用的肿瘤细胞为HL-60(人早幼粒细胞白血病细胞)、A549(肺癌细胞)、Be17402(肝癌细胞)、SH-sy5y(人神经母细胞瘤)、S180(小鼠腹水瘤细胞)、MCF-7(人乳腺癌细胞)。
3)实验方法HL-60,MCF-7,Bel-7402,A549和S180细胞选用RPMI-1640培养基;SH-sy5y细胞选用DMEM培养基.培养基中均含10%经灭活的胎牛血清和1×105U/L青霉素和100mg/L链霉素。
贴壁细胞MCF-7,Bel-7402,A549,SH-sy5y和半贴壁细胞S180的培养:分别将生长状态良好,处于对数生长期的细胞以4×104个/mL的密度接种于96孔板,每孔100μL,置于37℃和5%CO2的细胞孵育箱中培养6小时,然后按预设的浓度梯度加入经灭菌处理的化合物5a-q与含0.1%DMSO的培养基配制成的溶液,每孔25μL,对照组加入等体积的溶解样品的溶媒.继续培养48小时后,每孔加25μL浓度为5mg/mL的MTT溶液,置于37℃和5%CO2的细胞孵育箱中培养4小时.小心除去上清液后每孔加入100μL的DMSO,振荡约10min溶解紫色残留物(甲瓒),立即于酶标仪上检测O.D.(吸光度)值,波长为570nm。
悬浮细胞HL60的培养:分别将生长状态良好,处于对数生长期的细胞以5×104个/mL的密度接种于96孔板,每孔100μL,然后按预设的浓度梯度加入经灭菌处理的化合物5a-q与含0.1%DMSO的培养基配制成的溶液,每孔25μL,对照组加入等体积的溶解样品的溶媒,置于37℃和5%CO2的细胞孵育箱中培养48小时.每孔加入25μL浓度为5mg/mL的MTT溶液,继续置于条件为37℃和5%CO2的细胞孵育箱中培养4小时.3000rpm离心10min,小心吸出上清液,每孔加入100μL DMSO,振荡约10min溶解紫色残留物(甲瓒),立即于酶标仪上检测O.D.(吸光度)值,波长为570nn。
按下式求出各个浓度下化合物5a-q抑制肿瘤细胞增殖的活性:
细胞增殖(%)=(化合物5a-q组平均O.D.值/对照组平均O.D.值)×100%,实验重复3次,以细胞增殖对药物浓度作图,按作图法求出IC50(半数有效抑制浓度)值。
4)结果见表1和表2。结果表明,化合物5a-q对HL-60,MCF-7,Bel-7402,A549和S180和SH-sy5y肿瘤细胞增殖都显示明确的抑制作用。
表1化合物5a-q抑制肿瘤细胞增殖的IC50(均值+SDμM)
表2化合物5a-q抑制肿瘤细胞增殖的IC50(均值+SDμM)
实验例2评价化合物5a-q的体内抗肿瘤活性
1)本发明的化合物5a-q用0.5%羧甲基纤维素钠配制成混悬液.阳性对照阿霉素配制成2μmol/kg生理盐水溶液,阳性对照阿糖胞苷配制成8.2μmol/kg生理盐水溶液.阴性为0.5%羧甲基纤维素钠水溶液。
2)化合物5a-q灌胃给药,剂量为1μmol/kg,连续给药7天,共给药7次;阿霉素腹腔注射,剂量为2μmol/kg,连续给药7天,共给药7次;阿糖胞苷腹腔注射,剂量为8.2μmol/kg,连续7天给药7天,共给药7次;0.5%羧甲基纤维素钠水溶液灌胃给药,剂量为0.2mL/20g,连续7天。
3)实验动物为ICR雄性小鼠(清洁级),体重20±2g,每组12只小鼠。
4)瘤源为小鼠S180肉瘤,购自北京大学医学部动物实验中心,自行传代维持。
5)动物模型与治疗无菌条件下抽取接种生长旺盛的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,并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1.5×107个/mL的细胞悬液,于鼠腋皮下接种,0.2mL/只,制造S180荷瘤小鼠.肿瘤接种24h后,各组小鼠每日按照上面的剂量和给药条件治疗.实验进行至第8天,称小鼠体重,***麻醉,脱颈椎处死小鼠,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%.实验数据采用t检验和方差分析,瘤重以均值+SD g表示.结果见表3。由表3可以看出,在1μmol/kg的口服剂量下,化合物5a-q治疗组小鼠的瘤重明显小于0.5%羧甲基纤维素钠水溶液治疗组小鼠的瘤重,说明它们都有有效的抗肿瘤活性。它们的这个有效剂量(1μmol/kg)比发明人发表的1-(乙基-AA-OBzl)-β-咔啉-3-羧酸苄酯的有效剂量(8.9μmol/kg)低8.9倍。在1μmol/kg的口服剂量下,化合物5e,d治疗组小鼠的瘤重与剂量为8.2μmol/kg的阿糖胞苷治疗小鼠的瘤重相当,说明它的有效剂量比阿糖胞苷的有效剂量低8.2倍。在1μmol/kg的口服剂量下,化合物5e治疗组小鼠的瘤重与剂量为2μmol/kg的阿霉素治疗小鼠的瘤重相当,说明它的有效剂量比阿霉素的有效剂量低2倍。
表3化合物5a-q对S180荷瘤小鼠瘤重的影响(均值+SD g)
n=12;a)与0.5%羧甲基纤维素钠水溶液组比P<0.01;b)与0.5%羧甲基纤维素钠水溶液组比P<0.01,与阿糖胞苷及阿霉素组比较P>0.05,c)与0.5%羧甲基纤维素钠水溶液组比较P<0.01,与阿糖胞苷组比较P>0.05。
实验例3测定化合物5a-q的透射电镜照片
将化合物5a-q按照6×10-7M的浓度配置化合物的pH7.4PBS溶液,均匀的铺在铜网上,在透射电镜(TEM,JEM-1230,JEOL)下观察化合物的自组装性质.得到如图2的照片.结果表明,化合物5a-q在pH7.4PBS溶液中均可形成纳米颗粒,纳米粒径在63-1045nm之间。
Claims (4)
1.下式的1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯,式中AA为Gly,L-Ala,L-Phe,L-Val,L-Asp(OBzl),L-Trp,L-Ile,L-Leu,L-Thr,L-Ser,L-Met,L-Pro,L-Asn,L-Gln,L-Cys(pMeOBzl),L-Arg(NG-NO2)和L-Lys残基,
2.权利要求1的1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯的制备方法,该方法包括:
(1)将L-色氨酸苄酯在三氟醋酸的催化下与1,1,3,3-四甲氧基丙烷进行Pictet-Spengler缩合,得到1-(2,2-二甲氧乙基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯;
(2)将1-(2,2-二甲氧乙基)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯在四氢呋喃中,用高锰酸钾水溶液氧化得到1-(2,2-二甲氧乙基)-β-咔啉- 3-羧酸苄酯;
(3)在冰醋酸、浓盐酸、混合液中1-(2,2-二甲氧乙基)-β-咔啉-3-羧酸苄酯水解为1-乙醛基-β-咔啉- 3-羧酸苄酯;
(4)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Ala-OBzl偶联得到1-(乙基-Val-Ala-OBzl)-β-咔啉-3-羧酸苄酯;
(5)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Phe-OBzl偶联得到1-(乙基-Val-Phe-OBzl)-β-咔啉-3-羧酸苄酯;
(6)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Trp-OBzl偶联得到1-(乙基-Val-Trp-OBzl)-β-咔啉-3-羧酸苄酯;
(7)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Val-OBzl偶联得到1-(乙基-Val-Val-OBzl)-β-咔啉-3-羧酸苄酯;
(8)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Asp(OBzl)-OBzl偶联得到1-(乙基-Val-Asp(OBzl)-OBzl)-β-咔啉-3-羧酸苄酯;
(9)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Ile-OBzl偶联得到1-(乙基-Val-Ile-OBzl)-β-咔啉-3-羧酸苄酯;
(10)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Leu-OBzl偶联得到1-(乙基-Val-Leu-OBzl)-β-咔啉-3-羧酸苄酯;
(11)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Gly-OBzl偶联得到1-(乙基-Val-Gly-OBzl)-β-咔啉-3-羧酸苄酯;
(12)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Thr-OBzl偶联得到1-(乙基-Val-Thr-OBzl)-β-咔啉-3-羧酸苄酯;
(13)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Ser-OBzl偶联得到1-(乙基-Val-Ser-OBzl)-β-咔啉-3-羧酸苄酯;
(14)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Met-OBzl偶联得到1-(乙基-Val-Met-OBzl)-β-咔啉-3-羧酸苄酯;
(15)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Pro-OBzl偶联得到1-(乙基-Val-Pro-OBzl)-β-咔啉-3-羧酸苄酯;
(16)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Lys(Nω-Fmoc)-OBzl偶联得到1-(乙基-Val-Lys(Nω-Fmoc)-OBzl)-β-咔啉-3-羧酸苄酯,将1-(乙基-Val-Lys(Nω-Fmoc)-OBzl)-β-咔啉-3-羧酸苄酯在无水二氯甲烷中,冰浴条件下滴加六氢吡啶得到1-(乙基-Val-Lys-OBzl)-β-咔啉-3-羧酸苄酯;
(17)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Arg(NG-NO2)-OBzl偶联得到1-(乙基-Val-Arg(NG-NO2)-OBzl)-β-咔啉-3-羧酸苄酯;
(18)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Asn-OBzl偶联得到1-(乙基-Val-Asn-OBzl)-β-咔啉-3-羧酸苄酯;
(19)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Gln-OBzl偶联得到1-(乙基-Val-Gln-OBzl)-β-咔啉-3-羧酸苄酯;
(20)将1-乙醛基-β-咔啉-3-羧酸苄酯与HCl·Val-Cys(pMeOBzl)-OBzl偶联得到1-(乙基-Val-Cys(pMeOBzl)-OBzl)-β-咔啉-3-羧酸苄酯。
3.权利要求1的1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯的纳米结构。
4.权利要求1的1-(乙基-Val-AA-OBzl)-β-咔啉-3-羧酸苄酯在制备抗肿瘤药物中的应用。
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