CN102241674A - 1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯的合成和抗肿瘤活性评价 - Google Patents
1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯的合成和抗肿瘤活性评价 Download PDFInfo
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Abstract
本发明公开了一类1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯化合物,及其合成方法,还公开了它们对K562、HepG2、HL60、SH-Sy5y和S180五株肿瘤细胞增殖的抑制活性、进一步公开了它们在移植性小鼠S180肉瘤模型中的体内抗肿瘤活性。因而本发明公开了1,1-二甲基-β-咔啉羧酸衍生物作为抗肿瘤药物的临床应用前景。
Description
技术领域
本发明涉及一类1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯及其合成方法,还涉及其对K562、HepG2、HL60、SH-Sy5y和S180五株肿瘤细胞增殖的抑制活性、在移植性小鼠S180肉瘤模型中的体内抗肿瘤活性和作为抗肿瘤剂的临床应用前景。本发明属于生物医药领域。
背景技术
恶性肿瘤是多发性疾病,对人类健康造成了严重危害。西方国家的恶性肿瘤的死亡率略低于血管疾病,居疾病死因第二位。我国城市地区的恶性肿瘤的死亡率大约是1.3/1000,其中男性恶性肿瘤病人的死亡率大约为1.6/1000、女性恶性肿瘤病人的死亡率大约为1/1000,居疾病死因第一位。我国农村地区的恶性肿瘤的死亡率大约为1.05/10000,其中男性恶性肿瘤病人的死亡率大约为1.3/1000、女性恶性肿瘤病人的死亡率大约为0.8/1000,居疾病死因第二位。
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多种类型恶性肿瘤的主要手段。因此,寻找新的化学治疗药物是人类与恶性肿瘤抗争中的重要任务。
β-咔啉对多种人肿瘤细胞具有细胞毒。β-咔啉不仅能够抑制细胞周期蛋白依赖性激酶、IγB激酶复合物(IγK)和DNA的合成,而且能嵌入DNA双螺旋中抑制拓扑异构酶I和II,引起DNA损伤。β-咔啉的DNA嵌入能力还可以稳定DNA双螺旋结构,抑制DNA复制。这些作用使得β-咔啉成为抗肿瘤药物的重要先导结构。2007年发明人曾经披露图1左边的四环咔啉除了具有抑制肿瘤耐药活性之外还有一定的抗肿瘤活性(Jiawang Liu,Guohui Cui,Ming Zhao,Chunying Cui,Jingfang Ju,Shiqi Peng,Dual-acting agents thatpossess reversing resistance and anticancer activities:Design,synthesis,MES-SA/Dx5 cellassay and SAR of 2,2-dimethyl-3-[1’-substi-tutedacetylo-xybenzyl]-4-oxoimidazo[3’,5’:2,3]tetrahydro-β-carbolines,Bioorg.Med.Chem.2007,15,7773-7778)。发明人进一步认识到,将图1左边的四环咔啉简化为右边的三环咔啉,可以更加方便地嵌入DNA双螺旋,因而会有比较好的抗肿瘤作用。按照这种设想,形成了本发明。
发明内容
本发明的目的在于提供如通式1所示的化合物,即1,1-二甲基-β-咔啉-3-羧酸
本发明还提供一类1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯化合物,具有如下通式:
其中,R选自H、CH3、CH2CH(CH3)2、CH(CH3)CH2CH3、CH2C6H5、CH2OH、吲哚-5-基-CH2、CH2CH2CO2Bzl、CH(OH)CH3、CH(CH3)2、环丁胺-2-基、(CH2)4NH2、(CH2)3NHC(NH)NHNO2、咪唑-4-基-CH2、CH2CO2Bzl、CH2CH2CONH2、CH2CONH2、CH2CH2SCH3、CH2C6H4OH-p或CH2S(叔丁基)。
本发明的另一目的是提供一种制备所述的1,1-二甲基-β-咔啉-3-羧酸的方法,是将L-色氨酸在稀盐酸催化下与丙酮进行Pictet-Spengler缩合反应得到。
优选的条件是在冰浴下将5g L-色氨酸与100ml丙酮混合,往得到的悬浮液中加入5ml浓盐酸和2.5ml水,冰浴下搅拌10分钟后室温搅拌36小时,TLC监测原料斑点消失,浓缩反应液,加入乙醚析出黄色油状物,滴加少量丙酮后,析出大量无色固体即得。
本发明进一步提供一种制备所述1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯化合物的方法,如图2所示,具体包括如下步骤:
1)按前述方法制备得到1,1-二甲基-β-咔啉-3-羧酸;
2)1,1-二甲基-β-咔啉-3-羧酸与氨基酸苄酯或其衍生物偶联生成1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯。
其中所述氨基酸苄酯或其衍生物是指氨基酸苄酯或双苄酯的盐、保护基保护的氨基酸苄酯或双苄酯,所述盐是指氨基酸苄酯或双苄酯与对甲苯磺酸、磷酸或盐酸形成的盐,所述保护基包括叔丁氧羰基等常见氨基酸保护基团。
本发明优选的氨基酸苄酯或其衍生物选自甘氨酸苄酯、丙氨酸苄酯、亮氨酸苄酯、异亮氨酸苄酯、苯丙氨酸苄酯、丝氨酸苄酯、色氨酸苄酯、谷氨酸双苄酯、苏氨酸苄酯、缬氨酸苄酯、脯氨酸苄酯、叔丁氧羰基赖氨酸苄酯、硝基精氨酸苄酯、组氨酸苄酯、天冬氨酸双苄酯、谷酰胺苄酯、天冬酰胺苄酯、蛋氨酸苄酯、酪氨酸苄酯、叔丁 基半胱氨酸苄酯,或上述化合物与对甲苯磺酸、磷酸或盐酸形成的盐。所述氨基酸优选L-构型的氨基酸。
其中所述偶联是在N,N-二环己基碳二亚胺(DCC),1-羟基苯并三唑(HOBt)、N-甲基吗啉(NMM)、无水四氢呋喃(THF)存在下进行反应。
优选的条件是在冰浴下往20ml无水四氢呋喃中加入0.74mmol 1.1-二甲基-β-咔啉-3-羧酸、0.74mmol N-羟基苯并三氮唑,5分钟后滴加5ml无水THF溶解的0.74mmol二环己基羰二亚胺,得到反应液I;将0.53mmol氨基酸苄酯或其衍生物加入到10ml无水THF中,调pH值8-9之间,得到反应液II;20分钟后将II反应液滴加到反应液I中,室温反应15分钟后补加10ml无水二氯甲烷,并保持反应液pH值8-9。
其中所述调节pH值是用N-甲基吗啉。
本发明的又一目的是提供所述1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯化合物在制备抗肿瘤药物中的应用。本发明采用四噻唑蓝(MTT)法评价了化合物2a-t的体外抑制肿瘤细胞繁殖的活性,选取K562、HepG2、HL60、SH-Sy5y和S180五株细胞,得出2a-t抑制它们繁殖的IC50值,并在移植性小鼠S180肉瘤模型上评价它们的体内抗肿瘤活性。
附图说明
图1为现有技术中的四环咔啉简化为本发明的三环咔啉示意图。
图2为本发明化合物的合成路线;其中,i)稀盐酸、丙酮;ii)DCC、HOBt、NMM、氨基酸苄酯。
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1.1-二甲基-β-咔啉-3-羧酸(1)
冰浴下将5g(24.5mmol)L-色氨酸与100ml丙酮混合,往得到的悬浮液中加入5ml浓盐酸和2.5ml水,冰浴下搅拌10分钟后室温搅拌36小时,TLC监测原料斑点消失,浓缩反应液,加入乙醚析出黄色油状物,滴加少量丙酮后,析出大量无色固体,过滤得到产品6.6g,产率为96%。Rf=0.25(氯仿∶甲醇,5∶1)。Mp:232-233℃。 (c=0.7,甲醇)。ESI(m/e)243[M-H]-。IR(KBr):3606,3471,3260,2986,2775,1733,1589,1391,1207,752。1H NMR(300MHz,DMSO-d6)δ/ppm=11.53(s,1H),7.49(d,J=7.8Hz,1H),7.35(d,J=7.8Hz,1H),7.12(t,J=7.2Hz,1H),7.02(t,J=7.2Hz,1H),4.62 (d,J=7.2Hz,1H),3.29(m,1H),3.05(m,1H),1.86(s,1H),1.72(s,1H)。13C NMR(75MHz,DMSO-d6)δ/ppm=170.69,136.73,135.51,125.96,122.28,119.51,118.7,111.84,103.6,57.03,51.89,25.98,25.65,22.76.
实施例2 制备1,1-二甲基-β-咔啉-3-甲酰基甘氨酸苄酯(2a)
冰浴下往20ml无水四氢呋喃(THF)中加入181mg(0.74mmol)1.1-二甲基-β-咔啉-3-羧酸(1)、100mg(0.74mmol)N-羟基苯并三氮唑(HOBt),5分钟后滴加5ml无水THF溶解的153mg(0.74mmol)二环己基羰二亚胺(DCC),得到反应液I。将178mg(0.53mmol)甘氨酸苄酯对甲苯磺酸盐加入到10ml无水THF中,用N-甲基吗啉调pH值8-9之间,得到反应液II。20分钟后将II反应液滴加到反应液I中,室温反应15分钟后补加10ml无水二氯甲烷,并滴加N-甲基吗啉保持反应液pH值8-9。TLC监测原料斑点消失、滤出二环己基脲(DCU)、减压浓缩、残留物用15ml乙酸乙酯溶解,依次用5%NaHCO3溶液、饱和NaCl溶液、5%KHSO4溶液、饱和NaCl溶液、饱和NaHCO3溶液和饱和NaCl溶液各洗三次至中性,有机相用无水Na2SO4干燥、过滤、减压除去溶液、残留物经柱层析纯化、得到175mg(85%)标题化合物,为淡黄色固体。Rf=0.25(石油醚∶丙酮,2∶1)。Mp:81-83℃。 (c=0.75,甲醇)。ESI(m/e)392[M+H]+。IR(KBr):3403,3303,3031,2967,2927,2360,1744,1663,1517,1456,1192,743,699。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.34(t,J=6.0Hz,1H),7.35(m,7H),6.98(m,2H),5.17(s,2H),3.99(m,2H),3.65(d,J=7.8Hz,1H),2.88(m,1H),2.26(s,1H),1.47(s,1H),1.38(s,1H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.98,170.26,141.65,141.51,136.38,136.13,135.97,128.90,128.57,128.43,127.12,120.99,118.73,118.02,111.26,105.64,66.34,55.37,53.43,51.13,29.59,28.65,26.14。
实施例3制备1,1-二甲基-β-咔啉-3-甲酰基丙氨酸苄酯(2b)
按照制备化合物2a的操作,由170mg(0.7mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和175mg(0.5mmol)L-丙氨酸苄酯对甲苯磺酸盐制得80mg(40%)2b,为无色固体。Rf=0.25(石油醚∶丙酮,2∶1)。Mp:235-236℃。 (c=0.6,甲醇)。ESI(m/e)406[M+H]+。IR(KBr):3362,3264,3067,3020,2965,2919,2368,1718,1665,1544,1456,1286,1206,1174,1045,751,700。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.31(d,J=6.9Hz,1H),7.34(m,7H),7.03(t,J=6.4Hz,1H),6.95(t,J=7.2Hz,1H),5.17(s,2H),4.44(m,1H),3.65(m,1H),2.83(dd,J=4.2Hz,J=4.2Hz,1H),2.12(m,1H),1.47(s,3H),1.39(m,6H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.38,172.86,141.86, 136.48,136.15,128.89,128.52,128.26,127.19,120.96,118.73,117.95,111.32,105.58,66.43,53.34,51.07,48.04,29.68,28.81,26.34,17.49。
实施例4制备1,1-二甲基-β-咔啉-3-甲酰基亮氨酸苄酯(2c)
按照制备化合物2a的操作,由170mg(0.7mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和197mg(0.5mmol)L-亮氨酸苄酯对甲苯磺酸盐制得156mg(70%)2c,为无色固体。Rf=0.35(石油醚∶丙酮,3∶1)。Mp:72-73℃。 (c=0.5,甲醇)。ESI(m/e)448[M+H]+。IR(KBr):3307,3068,3025,2960,2919,2358,1740,1661,1516,1456,1382,1302,1252,1189,1155,742,697。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.23(d,J=7.5Hz,1H),7.35(m,7H),7.02(t,J=7.2Hz,1H),6.94(t,J=6.9Hz,1H),5.16(m,2H),4.44(m,1H),3.65(m,1H),2.82(dd,J=4.2Hz,J=4.2Hz,1H),2.12(d,J=11.4Hz,1H),1.62(m,3H),1.46(s,3H),1.36(s,3H),0.90(m,6H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.64,172.76,141.47,136.40,135.94,128.91,128.58,128.38,127.08,120.98,118.74,117.95,111.27,105.45,66.47,53.23,50.89,50.63,31.16,29.59,28.83,26.43,24.68,23.18,21.92。
实施例5制备1,1-二甲基-β-咔啉-3-甲酰基异亮氨酸苄酯(2d)
按照制备化合物2a的操作,由342mg(1.4mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和395mg(1.0mmol)L-异亮氨酸苄酯对甲苯磺酸盐制得290mg(65%)2d,为浅黄色固体。Rf=0.35(石油醚∶丙酮,3∶1)。Mp:69-70℃。 (c=0.6,甲醇)。ESI(m/e)448[M+H]+。IR(KBr):3310,3056,3026,2965,2931,2876,2356,1739,1662,1515,1457,1380,1301,1255,1191,1146,742,697。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.14(d,J=8.1Hz,1H),7.37(m,7H),6.96(m,2H),5.17(m,2H),4.37(m,1H),3.72(dd,J=4.8Hz,J=3.9Hz,1H),2.84(dd,J=3.9Hz,J=4.2Hz,1H),1.86(m,1H),1.46(s,3H),1.36(s,3H),1.26(d,J=5.4Hz,1H),1.19(d,J=5.4Hz,1H),1.12(d,J=7.2Hz,1H),0.87(m,7H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.66,171.72,141.53,136.32,135.94,128.90,128.63,128.59,127.10,120.97,118.73,117.96,111.27,105.55,66.45,56.55,53.20,50.94,29.55,28.83,26.35,25.24,15.90,11.67。
实施例6 制备1,1-二甲基-β-咔啉-3-甲酰基苯丙氨酸苄酯(2e)
按照制备化合物2a的操作,由481mg(1.97mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和702mg(1.6mmol)L-苯丙氨酸苄酯对甲苯磺酸盐制得323mg(42%)2e,为无色固体。Rf=0.15(石油醚∶丙酮,3∶1)。Mp:142-143℃。 (c=0.75,甲醇)。ESI(m/e)482[M+H]+。IR(KBr):3318,3032,2973,2930,2831,2361,1725,1668,1516, 1456,1268,1196,746,708,695。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.29(d,J=7.5Hz,1H),7.35(m,12H),6.99(m,1H),5.12(s,2H),4.63(m,1H),3.59(d,J=10.8Hz,1H),3.10(m,2H),2.80(dd,J=4.2Hz,J=4.2Hz,1H),2.40(m,1H),2.05(d,J=8.1Hz,1H),1.44(s,1H),1.33(s,1H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.40,171.72,141.42,137.37,136.18,135.97,129.72,128.86,128.79,128.56,128.45,127.15,127.08,121.00,118.76,117.96,111.29,105.51,66.57,53.75,53.28,51.03,37.17,33.81,29.59,28.70,26.19,24.93。
实施例7制备1,1-二甲基-β-咔啉-3-甲酰基丝氨酸苄酯(2f)
按照制备化合物2a的操作,由1.54g(4.2mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.1g(3mmol)L-丝氨酸苄酯对甲苯磺酸盐制得556mg(42%)2f,为无色固体。Rf=0.25(石油醚∶丙酮,1∶1)。Mp:206-207℃。 (c=0.75,甲醇)。ESI(m/e)422[M+H]+。IR(KBr):3547,3349,3256,2965,2926,2355,1716,1663,1545,1458,1293,1210,1049,987,753,696。1H NMR(300MHz,DMSO-d6):δ/ppm=10.79(s,1H),8.23(d,J=7.8Hz,1H),7.35(m,7H),7.02(t,J=7.2Hz,1H),6.94(t,J=7.5Hz,1H),5.19(m,2H),4.51(m,1H),3.83(m,1H),3.71(m,2H),2.88(dd,J=3.9Hz,J=3.9Hz,1H),2.28(d,J=12.0Hz,1H),1.47(s,3H),1.37(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.53,170.88,141.55,136.43,136.01,128.87,128.46,128.12,127.16,120.99,118.74,118.01,111.27,105.76,66.49,61.60,54.84,53.34,51.15,33.81,29.62,28.66,26.00,24.92。
实施例8制备1,1-二甲基-β-咔啉-3-甲酰基色氨酸苄酯(2g)
按照制备化合物2a的操作,由1.7g(7mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.96g(5mmol)L-色氨酸苄酯磷酸盐制得2.49g(96%)2g,为无色固体。Rf=0.25(石油醚∶丙酮,2∶1)。Mp:106-107℃。 (c=0.6,甲醇)。ESI(m/e)521[M+H]+。IR(KBr):3415,3306,2975,2926,2357,1747,1707,1661,1509,1456,1256,1188,752,740,705。1H NMR(300MHz,DMSO-d6):δ/ppm=10.95(s,1H),10.79(s,1H),8.26(d,J=7.5Hz,1H),7.56(d,J=7.8Hz,1H),7.35(m,5H),7.27(m,3H),7.18(s,1H),7.03(m,4H),5.09(s,2H),4.71(m,1H),3.63(s,1H),3.23(m,2H),2.86(dd,J=3.6Hz,J=3.9Hz1H),1.99(s,2H),1.43(s,3H),1.33(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.37,172.06,136.63,136.25,136.15,128.84,128.50,128.32,127.72,127.18,124.39,121.49,120.99,118.99,118.74,118.62,118.00,111.96,111.32,109.52,105.68,66.53,60.22,53.44,53.37,51.19,29.61,28.65,27.59,26.10,21.22,14.55。
实施例9制备1,1-二甲基-β-咔啉-3-甲酰基谷氨酸双苄酯(2h)
按照制备化合物2a的操作,由683mg(2.8mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和727mg(2mmol)L-谷氨酸双苄酯对甲苯磺酸盐制得608mg(55%)2h,为黄色固体。Rf=0.35(石油醚∶丙酮,2∶1)。Mp:44-45℃。 (c=0.5,甲醇)。ESI(m/e)554[M+H]+。
IR(KBr):3304,3061,2967,2921,2360,1739,1675,1513,1455,1386,1301,1257,1171,966,825,743,698。1H NMR(300MHz,DMSO-d6):δ/ppm=10.79(s,1H),8.28(d,J=7.8Hz,1H),7.32(m,13H),7.02(t,J=7.2Hz,1H),6.94(t,J=7.5Hz,1H),5.16(s,2H),5.10(s,2H),4.46(m,1H),3.64(s,1H),2.83(dd,J=3.9Hz,J=3.9Hz,1H),2.12(m,3H),2.19(m,2H),1.46(s,3H),1.36(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.69,172.56,171.88,141.51,136.56,136.34,135.99,128.94,128.89,128.63,128.57,128.48,128.43,128.35,127.11,120.98,118.74,117.95,111.27,105.21,66.61,66.05,55.13,53.33,51.48,51.00,30.30,29.60,29.33,28.73,26.57,26.32,24.91。
实施例10制备1,1-二甲基-β-咔啉-3-甲酰基苏氨酸苄酯(2i)
按照制备化合物2a的操作,由687mg(2.8mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和762mg(2mmol)L-苏氨酸苄酯对甲苯磺酸盐制得392mg(45%)2i,为无色固体。Rf=0.20(石油醚∶丙酮,2∶1)。Mp:93-94℃。 (c=0.60,甲醇)。ESI(m/e)436[M+H]+。IR(KBr):3331,3056,2971,2930,2825,2361,1740,1658,1517,1456,1381,1301,1259,1196,1004,744,699。1H NMR(300MHz,DMSO-d6):δ/ppm=10.80(s,1H),8.03(d,J=8.7Hz,1H),7.36(m,7H),7.03(t,J=6.9Hz,1H),6.95(t,J=7.2Hz,1H),5.18(m,2H),4.44(dd,J=3.0Hz,J=3.0Hz,1H),4.25(m,1H),3.77(m,1H),2.95(dd,J=4.2Hz,J=4.2Hz,1H),2.41(s,1H),1.49(s,3H),1.39(s,3H),1.15(d,J=6.3Hz,3H)。 13C NMR(75MHz,DMSO-d6):δ/ppm=173.92,171.04,141.79,136.45,136.16,128.46,127.22 120.97,118.73,118.03,111.31,105.93,66.96,66.48,65.39,58.01,53.63,51.38,33.83,29.65,28.66,26.15,24.94,20.87,15.64。
实施例11制备1,1-二甲基-β-咔啉-3-甲酰基缬氨酸苄酯(2j)
按照制备化合物2a的操作,由1.37g(5.6mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.51g(4mmol)L-缬氨酸苄酯对甲苯磺酸盐制得900mg(52%)2j,为无色固体。Rf=0.25(石油醚∶丙酮,2∶1)。Mp:167-168℃。 (c=0.6,甲醇)。ESI(m/e)434[M+H]+。IR(KBr):3385,3274,3031,2967,2928,2369,1736,1708,1663,1530,1460,1271,984,748,697。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.13(d,J=8.1Hz,1H),7.34(m,7H),7.02(t,J=7.2Hz,1H),6.94(t,J=7.2Hz,1H),5.17(m,2H),4.31(t,J=7.2Hz,1H),3.72(t,J=9.0Hz,1H),2.84(dd,J=3.9Hz,J=3.9Hz,1H), 2.22(d,J=11.4Hz,1H),2.11(m,1H),1.46(s,3H),1.36(s,3H),0.91(d,J=6.9Hz,6H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.74,171.77,141.71,141.53,136.33,135.94,128.91,128.64,128.59,127.10,120.97,118.73,117.97,111.27,105.56,66.47,57.59,53.24,50.96,30.55,29.55,28.84,26.35,19.44,18.68。
实施例12制备1,1-二甲基-β-咔啉-3-甲酰基脯氨酸苄酯(2k)
按照制备化合物2a的操作,由1.40g(5.6mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.45g(4mmol)L-脯氨酸苄酯盐酸盐制得637mg(37%)2k,为无色固体。Rf=0.35(石油醚∶丙酮,2∶1)。Mp:236-237℃。 (c=0.6,甲醇)。ESI(m/e)432[M+H]+。IR(KBr):3321,2965,2918,2356,1736,1629,1446,1353,1303,1171,747,703。 1H NMR(300MHz,DMSO-d6):δ/ppm=10.79(s,1H),7.29(m,7H),7.03(m,2H),5.15(m,2H),4.43(t,J=3.9Hz,1H),3.86(m,2H),3.67(d,J=5.1Hz,1H),2.65(m,2H),2.22(m,1H),1.94(m,4H),1.34(m,6H)。13C NMR(75MHz,DMSO-d6):δ/ppm=172.32,171.66,141.41,136.51,136.09,128.94,128.90,128.50,128.37,128.25,127.28,120.97,118.67,118.04,111.27,105.45,66.26,59.10,51.53,51.11,46.83,29.56,29.17,28.71,25.03。
实施例13制备1,1-二甲基-β-咔啉-3-甲酰基赖氨酸苄酯(2l)
按照制备化合物2a的操作,由683mg(2.8mmol)h.1-二甲基-β-咔啉-3-羧酸(1)和1.01g(2mmol)叔丁氧羰基保护的L-赖氨酸苄酯制得叔丁氧羰基保护2l,经4N HCl/EA脱除叔丁氧羰基得到462mg(50%)2l,为无色固体。Rf=0.25(二氯甲烷∶甲醇,10∶1)。Mp:174-175℃。 (c=0.55,甲醇)。ESI(m/e)463[M+H]+。IR(KBr):3397,3196,3035,2938,2463,2357,1738,1680,1557,1456,1383,1313,1260,1153,747,699。1H NMR(300MHz,DMSO-d6):δ/ppm=11.44(s,1H),9.99(d,J=11.1Hz,1H),9.66(t,J=11.5Hz,1H),9.39(d,J=7.2Hz,1H),8.12(s,3H),7.35(m,7H),7.13(t,J=7.2Hz,1H),7.04(t,J=7.2Hz,1H),5.19(s,2H),4.61(m,1H),4.32(m,1H),3.29(m,1H),2.86(m,1H),2.78(m,2H),1.81(m,5H),1.69(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=171.67,168.85,136.70,136.55,136.27,136.55,136.27,135.18,128.97,128.69,128.49,125.85,122.31,119.61,118.42,111.90,103.48,66.75,56.67,52.77,52.12,30.17,26.61,26.35,25.43,23.80,22.63。
实施例14制备1,1-二甲基-β-咔啉-3-甲酰基硝基精氨酸苄酯(2m)
按照制备化合物2a的操作,由1.03g(4.2mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.44g(3mmol)硝基保护的L-精氨酸苄酯对甲苯磺酸盐制得162mg(10%)2m,为黄色固体。Rf=0.35(二氯甲烷∶甲醇,10∶1)。Mp:114-115℃。 (c=0.7,甲 醇)。ESI(m/e)536[M+H]+。IR(KBr):3314,2967,2931,2359,1739,1629,1524,1454,1387,1263,1177,745,699。1H NMR(300MHz,DMSO-d6):δ/ppm=10.78(s,1H),8.29(d,J=7.5Hz,1H),7.35(m,7H),7.02(t,J=7.2Hz,1H),6.94(t,J=7.2Hz,1H),5.17(s,2H),4.41(m,1H),3.67(d,J=7.5Hz,1H),3.18(d,J=5.7Hz,1H),2.84(dd,J=3.6Hz,J=3.6Hz 1H),1.82(m,3H),1.59(d,J=6.6Hz,1H),1.47(s,3H),1.37(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.69,172.20,141.60,136.37,136.15,128.90,128.56,128.36,127.15,120.97,118.73,117.95,111.32,105.51,66.55,65.37,56.30,53.41,52.11,51.11,32.55,30.07,29.65,28.81,28.66,26.43,15.63。
实施例15制备1,1-二甲基-β-咔啉-3-甲酰基组氨酸苄酯(2n)
按照制备化合物2a的操作,由902mg(3.7mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.41g(2.4mmol)L-组氨酸苄酯对甲苯磺酸盐制得202mg(18%)2n,为无色固体。Rf=0.30(二氯甲烷∶甲醇,9∶1)。Mp:216-217℃。 (c=0.65,甲醇)。ESI(m/e)472[M+H]+。IR(KBr):3286,3131,2972,2931,2352,1745,1668,1521,1456,1437,1303,1195,1173,1086,830,748,701。1H NMR(300MHz,DMSO-d6):δ/ppm=10.83(s,1H),8.42(d,J=7.2Hz,1H),7.59(s,1H),7.35(m,7H),7.05(t,J=9.9Hz,1H),6.94(t,J=7.2Hz,1H),5.12(s,2H),4.64(m,1H),3.64(dd,J=3.9Hz,J=3.9Hz,1H),3.01(d,J=6.3Hz,2H),2.85(dd,J=3.9Hz,J=3.9Hz,1H),1.47(s,3H),1.36(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.47,171.81,141.57,136.40,136.13,135.50,129.61,128.85,128.48,128.26,127.14,120.99,118.74,117.99,117.15,111.33,105.60,66.42,65.40,53.38,52.81,51.12,29.61,28.72,26.13,15.64。
实施例16制备1,1-二甲基-β-咔啉-3-甲酰基天冬氨酸双苄酯(2o)
按照制备化合物2a的操作,由1.02g(4.2mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.05g(3mmol)L-天冬氨酸双苄酯盐酸盐制得1.16g(72%)2o,为无色固体。Rf=0.30(石油醚∶丙酮,3∶1)。Mp:136-137℃。 (c=0.5,甲醇)。ESI(m/e)540[M+H]+。IR(KBr):3422,3339,3060,3035,2972,2926,2361,1731,1663,1522,1456,1359,1292,1200,740,697。1H NMR(300MHz,DMSO-d6):δ/ppm=10.79(s,1H),8.47(d,J=8.1Hz,1H),7.33(m,2H),6.99(m,2H),5.13(m,4H),4.87(m,1H),3.64(s,1H),2.93(t,J=6.6Hz,1H),2.85(dd,J=4.2Hz,J=3.9Hz 1H),2.17(d,J=10.5Hz,1H),1.46(s,3H),1.36(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.53,170.98,170.54,141.64,136.30,136.21,136.15,128.89,128.53,128.40,128.26,127.15,120.98,118.73,117.96,111.32,105.56,66.83,66.41,53.47,51.16,48.83,36.31,33.82,29.68,28.74,26.27, 24.93。
实施例17制备1,1-二甲基-β-咔啉-3-甲酰基谷酰胺苄酯(2p)
按照制备化合物2a的操作,由1.02g(4.2mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和816mg(3mmol)L-谷酰胺苄酯盐酸盐制得291mg(21%)2p,为黄色固体。Rf=0.40(二氯甲烷∶甲醇,9∶1)。Mp:101-102℃。 (c=0.6,甲醇)。ESI(m/e)463[M+H]+。IR(KBr):3306,3056,2967,2928,2361,1739,1664,1515,1456,1302,1174,744,706。1H NMR(300MHz,DMSO-d6):δ/ppm=10.80(s,1H),8.29(d,J=7.5Hz,1H),7.32(m,9H),7.02(t,J=7.5Hz,1H),6.94(t,J=7.2Hz,1H),6.83(s,1H),5.16(s,2H),4.38(m,1H),3.65(s,1H),2.83(dd,J=3.9Hz,J=3.9Hz,1H),2.19(m,3H),2.05(m,1H),1.88(m,1H),1.46(s,3H),1.36(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.84,173.60,141.47,136.40,136.00,128.90,128.55,128.33,127.11,120.99,118.74,117.96,111.29,105.52,66.50,53.30,52.00,51.02,31.59,29.61,28.74,27.05,26.34。
实施例18制备1,1-二甲基-β-咔啉-3-甲酰基天冬酰胺苄酯(2q)
按照制备化合物2a的操作,由1.10g(4.2mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和774mg(3mmol)L-天冬酰胺苄酯盐酸盐制得322mg(24%)2q,为无色固体。Rf=0.38(二氯甲烷∶甲醇,9∶1)。Mp:163-164℃。 (c=0.55,甲醇)。ESI(m/e)449[M+H]+。IR(KBr):3386,3326,3190,2970,2361,1720,1671,1540,1455,1284,1202,739,694。1H NMR(300MHz,DMSO-d6):δ/ppm=10.77(s,1H),8.34(d,J=7.8Hz,1H),7.33(m,8H),6.97(m,3H),5.14(s,2H),4.76(m,1H),3.65(s,1H),2.86(dd,J=3.6Hz,J=3.3Hz,1H),2.17(s,1H),1.46(s,3H),1.36(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.37,171.67,171.58,141.61,136.49,136.16,128.82,128.40,128.09,127.17,120.97,118.72,117.96,111.32,105.64,66.47,55.37,53.45,51.21,49.06,29.65,28.72,26.18。
实施例19制备1,1-二甲基-β-咔啉-3-甲酰基蛋氨酸苄酯(2r)
按照制备化合物2a的操作,由1.10g(4.2mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.23g(3mmol)L-蛋氨酸苄酯对甲苯磺酸盐制得684mg(49%)2r,为无色固体。Rf=0.20(石油醚∶丙酮,1∶1)。Mp:63-64℃。 (c=0.5,甲醇)。ESI(m/e)466[M+H]+。IR(KBr):3308,3033,2967,2917,2839,2538,1734,1653,1507,1456,1384,1301,1170,739,694。1H NMR(300MHz,DMSO-d6):δ/ppm=10.80(s,1H),8.31(d,J=7.5Hz,1H),7.35(m,7H),7.03(t,J=7.5Hz,1H),6.95(t,J=7.5Hz,1H),5.17(m,2H),4.55(m,1H),3.66(d,J=7.2Hz,1H),2.85(d,J=3.9Hz,1H),2.27(m,1H),2.04(m,5H), 1.47(s,3H),1.37(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.76,172.07,141.67,136.38,136.12,129.28,128.91,128.60,128.43,127.15,120.97,118.74,117.96,111.32,105.54,66.61,53.39,51.38,51.08,31.00,30.07,29.93,29.66,28.82,26.44,14.99。
实施例20制备1,1-二甲基-β-咔啉-3-甲酰基酪氨酸苄酯(2s)
按照制备化合物2a的操作,由854mg(3.5mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.10g(2.5mmol)L-酪氨酸苄酯对甲苯磺酸盐制得695mg(56%)2s,为无色固体。Rf=0.15(石油醚∶丙酮,2∶1)。Mp:189-190℃。 (c=0.55,甲醇)。ESI(m/e)498[M+H]+。IR(KBr):3334,3305,3028,2974,2937,2844,2356,1746,1706,1666,1514,1457,1298,1222,1170,830,755,703。1H NMR(300MHz,DMSO-d6):δ/ppm=10.79(s,1H),9.27(s,1H),8.23(d,J=7.8Hz,1H),7.33(m,7H),6.98(m,4H),6.67(d,J=7.8Hz,2H),5.11(s,2H),4.55(m,1H),3.60(s,1H),2.95(d,J=6.9Hz,1H),2.81(dd,J=3.6Hz,J=3.6Hz,1H),1.44(s,3H),1.34(s,3H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.32,171.80,170.82,156.47,141.45,136.23,136.00,130.67,128.84,128.53,128.42,127.27,127.11,120.99,118.74,117.96,115.49,111.27,105.58,66.49,60.22,53.99,53.31,51.03,36.51,29.59,28.69,26.12,21.21,14.54。
实施例21制备1,1-二甲基-β-咔啉-3-甲酰基叔丁基半胱氨酸苄酯(2t)
按照制备化合物2a的操作,由1.35g(5.54mmol)1.1-二甲基-β-咔啉-3-羧酸(1)和1.2g(3.96mmol)叔丁基保护的L-半胱氨酸苄酯制得1.07g(55%)2t,为无色固体。Rf=0.40(石油醚∶丙酮,2∶1)。Mp:74-75℃。 (c=0.5,甲醇)。ESI(m/e)494[M+H]+。IR(KBr):3320,2966,2365,1741,1663,1508,1458,1302,1173,1009,840,743,697。1H NMR(300MHz,DMSO-d6):δ/ppm=10.79(s,1H),8.39(d,J=7.5Hz,1H),7.33(m,7H),7.02(t,J=7.5Hz,1H),6.94(t,J=7.5Hz,1H),5.19(s,2H),4.59(m,1H),3.65(s,1H),2.96(m,2H),2.84(dd,J=3.9Hz,J=3.6Hz,1H),2.17(s,1H),1.46(s,3H),1.36(s,3H),1.29(s,9H)。13C NMR(75MHz,DMSO-d6):δ/ppm=173.58,170.85,141.61,136.26,136.15,128.86,128.56,128.34,127.16,120.98,118.74,117.96,111.32,105.56,66.73,53.43,53.17,51.14,42.89,31.10,29.84,29.68,28.78,26.33。
实验例1化合物2a-t抑制肿瘤细胞增殖实验
本发明的2a-t均用含1%DMSO的PBS配制。共使用了SH-Sy5y(人神经母细胞瘤细胞)、S180(小鼠肉瘤细胞)、K562(慢性粒细胞白血病细胞)、HepG2(肝细胞癌细胞)和HL60(人早幼粒细胞白血病细胞)5株肿瘤细胞。
分别将生长状态良好、处于对数生长期的HepG2、HL60、SH-Sy5y、S180、K562 细胞按照3-5×104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(二甲基亚砜),振荡约15min溶解沉淀。立即于酶标仪上570nm波长下测定O.D.(吸光度)值。每个化合物每个浓度重复测定9次。计算抑瘤率及IC50。结果列入表1。结果表明本发明的化合物对K562、HL60、S180均有明确的抑制作用,化合物对于细胞的毒活性呈现一致的趋势,含有芳香性、亲酯性基团的化合物的细胞毒活性要好于带极性基团的化合物。
表1 2a-t抑制肿瘤细胞增殖的IC50(μM)值
实验例2化合物2a-t在S180小鼠模型上的抗肿瘤活性
测定前将本发明的2a-t加吐温80助溶,溶于生理盐水。无菌条件下取接种于ICR小鼠7-10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2×107/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8.9μmol/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剂量下大部分化合物都有比较好的抗肿瘤活性。
表2.本发明的2a-t的体内抗肿瘤活性
n=12
Claims (10)
3.一种制备权利要求1所述的1,1-二甲基-β-咔啉-3-羧酸的方法,是将L-色氨酸在稀盐酸催化下与丙酮进行Pictet-Spengler缩合反应得到。
4.根据权利要求3所述的方法,是在冰浴下将5gL-色氨酸与100ml丙酮混合,往得到的悬浮液中加入5ml浓盐酸和2.5ml水,冰浴下搅拌10分钟后室温搅拌36小时,TLC监测原料斑点消失,浓缩反应液,加入乙醚析出黄色油状物,滴加少量丙酮后,析出大量无色固体即得。
5.一种制备权利要求2所述的1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯化合物的方法,是将1,1-二甲基-β-咔啉-3-羧酸与氨基酸苄酯或其衍生物偶联生成1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯,其中所述氨基酸苄酯或其衍生物是指氨基酸苄酯或双苄酯的盐、保护基保护的氨基酸苄酯或双苄酯,所述盐是指氨基酸苄酯或双苄酯与对甲苯磺酸、磷酸或盐酸形成的盐,所述保护基包括叔丁氧羰基等常见氨基酸保护基团。
6.根据权利要求5所述的方法,其中所述氨基酸苄酯或其衍生物选自甘氨酸苄酯、丙氨酸苄酯、亮氨酸苄酯、异亮氨酸苄酯、苯丙氨酸苄酯、丝氨酸苄酯、色氨酸苄酯、谷氨酸双苄酯、苏氨酸苄酯、缬氨酸苄酯、脯氨酸苄酯、叔丁氧羰基赖氨酸苄酯、硝基精氨酸苄酯、组氨酸苄酯、天冬氨酸双苄酯、谷酰胺苄酯、天冬酰胺苄酯、蛋氨酸苄酯、酪氨酸苄酯、叔丁基半胱氨酸苄酯,或上述化合物与对甲苯磺酸、磷酸或盐酸形成的盐;所述氨基酸优选L-构型的氨基酸。
7.根据权利要求5所述的方法,所述偶联是在N,N-二环己基碳二亚胺(DCC),1-羟基苯并三唑(HOBt)、N-甲基吗啉(NMM)、无水四氢呋喃(THF)存在下进行反应。
8.根据权利要求7所述的方法,是在冰浴下往20ml无水四氢呋喃中加入0.74mmol1.1-二甲基-β-咔啉-3-羧酸、0.74mmol N-羟基苯并三氮唑,5分钟后滴加5ml无水THF溶解的0.74mmol二环己基羰二亚胺,得到反应液I;将0.53mmol氨基酸苄酯或其衍生物加入到10ml无水THF中,调pH值8-9之间,得到反应液II;20分钟后将II反应液滴加到反应液I中,室温反应15分钟后补加10ml无水二氯甲烷,并保持反应液pH值8-9。
9.根据权利要求8所述的方法,其中所述调节pH值是用N-甲基吗啉。
10.权利要求2所述的1,1-二甲基-β-咔啉-3-甲酰基氨基酸苄酯化合物在制备抗肿瘤药物中的应用。
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