CN109134597B - 茶氨酰氨基酸苄酯修饰的姜黄素,其合成,活性和应用 - Google Patents
茶氨酰氨基酸苄酯修饰的姜黄素,其合成,活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮,涉及它们的制备方法,涉及它们的抗肿瘤生长活性,涉及它们的抗炎活性,因而本发明涉及它们在制备抗肿瘤药物和抗炎药物中的应用。本发明属于生物医药领域。
背景技术
恶性肿瘤是严重危害人类健康的全球性问题。肿瘤患者发现病患时大多已是临床中晚期,治疗方法以放化疗为主,化疗是恶性肿瘤处于中晚期时的主要治疗手段。然而,炎症会进一步恶化肿瘤患者的预后。由于现有抗肿瘤药物没有抗炎作用,所以肿瘤化疗的临床疗效不理想。发明具有抗炎活性的抗肿瘤药物是临床的迫切需求。此前,发明人曾公开1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰氨基酸苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮具有明显的抑制肿瘤细胞增殖的活性。后来发明人又公开抗黏附肽修饰的姜黄素在1μmol/kg剂量下可抑制S180小鼠肿瘤生长和抑制ICR小鼠的炎症。可是最低有效剂量为1μmol/kg。为了降低最低有效剂量,发明人对姜黄素的酚羟基展开了各种修饰。经过3年探索,发现用茶氨酰-AA-OBzl(AA选自L-Ala残基、L-Glu残基、Gly残基、L-Ile残基、L-Met残基和L-Thr残基)修饰的姜黄素不仅可使抗肿瘤生长的最低有效剂量降至0.1μmol/kg,而且抗炎的最低有效剂量低至0.1μmol/kg。抗肿瘤生长的有效剂量降低10倍表明,这种结构修饰有突出的技术效果。根据这些发现,发明人提出了本发明。
发明内容
本发明的第一个内容是提供下式的1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(式中AA选自L-Ala残基、L-Glu残基、Gly残基、L-Ile残基、L-Met残基和L-Thr残基)
本发明的第二个内容是提供1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(式中AA选自L-Ala残基、L-Glu残基、Gly残基、L-Ile残基、L-Met残基和L-Thr残基)的合成方法,该方法包括:
(1)制备6-(4-羟基-3-甲氧苯基)-5,6-己烯-2,4-二酮(1);
(2)制备2-(4-甲酰基-2-甲氧基苯氧基)-乙酸苄酯(2);
(3)以步骤(1)和步骤(2)的产物为反应原料制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(3);
(4)将1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮皂化,得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(4);
(5)化合物4和L-茶氨酸苄酯偶联得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5);
(6)将化合物5皂化得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6);
(7)化合物6和L-氨基酸苄酯偶联得到权利要求1的1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7);
(8)化合物7皂化得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(AA选自L-Ala残基、L-Glu残基、L-Gly残基、L-Ile残基、L-Met残基和L-Thr残基)。
本发明的第三个内容是评价1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮对S180小鼠肿瘤生长的抑制应用。
本发明的第四个内容是评价1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮对ICR小鼠炎症的抑制作用。
附图说明
图1 1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮的合成路线.7a中AA为L-Ala残基;7b中AA为L-Glu残基;7c中AA为L-Gly残基;7d中AA为L-Ile残基;7e中AA为L-Met残基;7f中AA为L-Thr残基;i)三氧化二硼(B2O3),乙酰丙酮,硼酸三正丁酯,正丁胺,氯化氢水溶液(1M);ii)碳酸钾,溴乙酸苄酯;iii)三氧化二硼(B2O3),硼酸三正丁酯,正丁胺,10%乙酸水溶液;iv)氢氧化钠水溶液(2M),丙酮;v)二环己基碳二亚胺(DCC),1-羟基苯并三唑(HOBt),N-甲基吗啉(NMM),四氢呋喃(THF)。
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6-(4-羟基-3-甲氧苯基)-5,6-己烯-2,4-二酮(1)
将45.0mL(437.7mmol)乙酰丙酮,21.0g(301.6mmol)氧化硼和150.0mL无水乙酸乙酯于60℃回流1h。然后,往里加22.5g(148.0mmol)香草醛和41mL(293.0mmol)硼酸三丁酯。反应混合物70℃搅拌30min。于30min内继续往里加15mL(205.1mmol)正丁胺与135mL乙酸乙酯中的溶液。混合物于100℃搅拌3h后冷却至室温,并往里滴加150mL盐酸(1M)。混合物于50℃搅拌30min,静置,充分分层,水层用乙酸乙酯萃取3次。合并的乙酸乙酯层用饱和NaCl溶液洗至中性,无水硫酸钠干燥,过滤,滤液减压浓缩至干,残留物用硅胶柱层析纯化(石油醚/乙酸乙酯=4/1)得到10.05g(29%)目标化合物,为黄色固体。ESI-MS(m/e):235[M+H]+;1H NMR(300MHz,DMSO-d6):δ/ppm=15.74(s,1H),9.64(s,1H),7.50(d,J=15.9Hz,1H),7.30(s,1H),7.12(d,J=8.1Hz,1H),6.82(d,J=8.1Hz,1H),6.64(d,J=15.9Hz,1H),5.84(s,1H),5.14(s,2H),3.83(s,3H),2.12(s,3H)。
实施例2制备3-甲氧基-4-(氧基-2-乙酰苄酯基)苯甲醛(2)
将10g(65.8mmol)香草醛溶于100mL无水四氢呋喃。向该溶液分批加入10.9g(79.0mmol)碳酸钾并搅拌3h。然后向溶液中滴加9.3mL溴乙酸苄酯,室温搅拌48h,TLC监(石油醚/乙酸乙酯=3/1)显示反应结束。反应混合物过滤,滤液减压浓缩,残余物用100mL乙醚磨洗静置12h后倒掉乙醚,10mL乙醚磨洗3次,去乙醚,得到15.4g(78%)标题化合物,为无色固体。ESI-MS(m/e):301[M+H]+;1H NMR(300MHz,DMSO-d6):δ/ppm=9.86(s,1H),7.50(dd,J1=8.4Hz,J2=1.8Hz,1H),7.44(d,J=1.8Hz,1H),7.39(s,5H),7.11(d,J=8.4Hz,1H),5.21(s,2H),5.03(s,2H),3.84(s,3H)。
实施例3制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(3)
将5.55g(23.7mmol)6-(4-羟基-3-甲氧苯基)-5,6-己烯-2,4-二酮(1),0.83g(11.9mmol)氧化硼和100mL乙酸乙酯的悬浮液于70℃回流1h。之后,减压浓缩。残留物用100mL无水DMF溶解。往得到的溶液中加10.67g(35.6mmol)3-甲氧基-4-(氧基-2-乙酰苄酯基)苯甲醛(2)和11.15mL(41.0mmol)硼酸三丁酯。得到的溶液于80℃搅拌30min。之后,往里分4次滴加0.98mL(6.4mmol)正丁胺,用时1h,得到的溶液于80℃继续搅拌3h。之后,往里加200mL预热至60℃的10%乙酸水溶液。得到的溶液于80℃继续搅拌1h。反应混合物冷却至室温,过滤,滤饼用柱层析纯化(石油醚/乙酸乙酯=3/1),得到6.63g(53%)标题化合物,为黄色固体。ESI-MS(m/e):517[M+H]+;1H NMR(300MHz,DMSO-d6):δ/ppm=9.69(s,1H),8.51(d,J=7.5Hz,1H),7.80(t,J=5.7Hz,1H),7.59(d,J=3.0Hz,1H),7.54(d,J=3.0Hz,1H),7.37(m,7H),7.16(m,1H),6.89(m,4H),6.09(s,1H),5.14(s,2H),4.62(s,2H),4.37(m,1H),3.87(s,3H),3.84(s,3H),3.04(qd,J1=7.2Hz,J2=5.7Hz,2H),2.15(m,2H),2.05(m,1H),1.90(m,1H),0.98(t,J=7.2Hz,3H)。
实施例4制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(4)
将5g(9.7mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(3)用丙酮溶解。室温下往里加NaOH水溶液(2M),调节反应液pH为13并搅拌6h。TLC(石油醚/乙酸乙酯=3/1)显示反应完成。反应混合物用饱和KHSO4水溶液将pH调到7,减压浓缩,残余物用饱和KHSO4水溶液调pH到2。之后,用乙酸乙酯萃取3次。合并乙酸乙酯层,用饱和NaCl溶液洗至中性,用无水硫酸钠干燥。过滤,滤液减压浓缩,残留物用无水乙醚磨洗,得到2.64g(64%)标题化合物,为红色固体。ESI-MS(m/e):425[M-H]-;1H NMR(300MHz,DMSO-d6):δ/ppm=9.55(s,1H),7.57(m,2H),7.37(m,2H),7.20(m,2H),6.79(m,4H),6.06(s,1H),4.74(s,2H),3.85(s,6H)。
实施例5制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5)
冰浴下将2g(4.7mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(4),1.69g(5.6mmol)盐酸茶氨酸苄酯和0.761g(5.64mmol)N-羟基苯并三唑(HOBt)用50mL无水四氢呋喃溶解。向溶液中滴入由1.16g(5.63mmol)二环己基羰二亚胺(DCC)和10mL无水四氢呋喃的溶液。反应液用N-甲基吗啉调pH到8,室温搅拌12h。TLC(石油醚/乙酸乙酯=3/1)显示反应完成。反应液减压浓缩至干,残余物用150mL乙酸乙酯溶解。过滤、滤液依次用饱和碳酸氢钠水溶液洗3次,饱和氯化钠水溶液洗3次,饱和硫酸氢钾水溶液洗3次,饱和氯化钠水溶液洗3次,饱和碳酸氢钠水溶液洗3次及饱和氯化钠水溶液洗3次。合并的乙酸乙酯层用无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用柱层析(二氯甲烷/甲醇=80/1)纯化,得到2.24g(71%)标题化合物,为黄色固体。ESI-MS(m/e):673[M+H]+;1HNMR(300MHz,DMSO-d6):δ/ppm=9.69(s,1H),8.51(d,J=7.5Hz,1H),7.80(t,J=5.7Hz,1H),7.59(d,J=3.0Hz,1H),7.54(d,J=3.0Hz,1H),7.37(m,7H),7.16(m,1H),6.89(m,4H),6.09(s,1H),5.14(s,2H),4.62(s,2H),4.37(m,1H),3.87(s,3H),3.84(s,3H),3.04(qd,J1=7.2Hz,J2=5.7Hz,2H),2.15(m,2H),2.05(m,1H),1.90(m,1H),0.98(t,J=7.2Hz,3H)。
实施例6制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6)
将2.24g(3.3mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5)用丙酮溶解,室温下向溶液中滴加NaOH水溶液(2M)至反应液pH为13,搅拌6h,TLC(石油醚/乙酸乙酯=3/1)显示反应完成。用饱和KHSO4水溶液将反应液pH调到7,减压浓缩,残余物用饱和KHSO4水溶液调pH到2。之后,用乙酸乙酯萃取3次,合并的乙酸乙酯层用饱和NaCl水溶液洗至中性,用无水硫酸钠干燥,过滤,滤液减压浓缩得到1.07g(55%)标题化合物,为红色糖浆。ESI-MS(m/e):581[M-H]-;1H NMR(300MHz,DMSO-d6):δ/ppm=9.42(s,1H),8.1(m,1H),7.77(m,1H),7.57(m,1H),7.37(m,1H),7.24(m,2H),7.10(m,2H),6.96(d,J=5.1Hz,1H),6.79(m,3H),6.06(s,1H),4.57(s,2H),4.20(m,1H),3.82(s,6H),3.01(m,2H),2.09(m,3H),1.77(m,1H),0.95(t,J=4.5Hz,3H)。
实施例7制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Asp(OBzl)-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7a)
冰浴下将2.83g(6.32mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6),1.63g(7.58mmol)HCl·Ala-OBzl和1.02g(7.58mmol)N-羟基苯并三唑(HOBt)用20mL无水四氢呋喃溶解。之后,往里滴加1.56g(7.58mmol)二环己基羰二亚胺(DCC)和5mL无水四氢呋喃的溶液。反应液用N-甲基吗啉(NMM)调pH为8,室温搅拌12h,TLC(二氯甲烷/甲醇=50/1)显示反应结束。反应液减压浓缩至干,残余物用150mL二氯甲烷溶解,抽滤、滤液依次用饱和碳酸氢钠水溶液洗3次,饱和氯化钠水溶液洗3次,饱和硫酸氢钾水溶液洗3次,饱和氯化钠水溶液洗3次,饱和碳酸氢钠水溶液洗3次及饱和氯化钠水溶液洗3次。合并的二氯甲烷层用无水硫酸钠干燥,过滤,滤液减压浓缩至干。残留物用柱层析纯化(二氯甲烷/甲醇=50/1),得到1.64g(35%)标题化合物,为黄色固体。Mp 152-153℃; (c=0.1,甲醇);ESI-MS(m/e):744[M+H]+;IR(cm-1):3284,3068,2973,2931,2851,1736,1641,1626,1584,1540,1508,1449,1374,1337,1267,1211,1135,1030,964,696;1HNMR(300MHz,DMSO-d6):δ/ppm=9.70(s,1H),8.59(d,J=6.9Hz,1H),8.1(d,J=7.8Hz,1H),7.77(t,J=6.0Hz,1H),7.57(d,J=15.6Hz,2H),7.37(m,7H),7.24(d,J=8.1Hz,1H),7.17(d,J=8.1Hz,1H),6.97(d,J=8.4Hz,1H),6.89(m,3H),6.10(s,1H),5.13(s,2H),4.61(s,2H),4.37(m,2H),3.87(s,3H),3.84(s,3H),3.04(qd,J1=7.2Hz,J2=6.0Hz,2H),2.09(m,2H),1.95(m,1H),1.77(m,1H),1.31(d,J=7.2Hz,3H),0.99(t,J=7.2Hz,3H)。
实施例8制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Glu-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7b)
采用实施例7的方法,从2.5g(5.87mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6)和3.59g(8.80mmol)HCl·Glu(OBzl)-OBzl得到880mg(17%)标题化合物,为黄色固体。Mp 140-142℃;(c=0.1,甲醇);ESI-MS(m/e):892[M+H]+;IR(cm-1):3284,3066,2937,1731,1665,1639,1585,1543,1508,1449,1422,1390,1336,1265,1215,1162,1135,1032,964,845,799,754,741,696;1HNMR(300MHz,DMSO-d6):δ/ppm=9.69(s,1H),8.56(d,J=8.1Hz,1H),8.12(d,J=8.1Hz,1H),7.76(t,J=5.7Hz,1H),7.57(m,2H),7.36(m,12H),7.20(dd,J1=8.4Hz,J2=1.8Hz,1H),6.98(d,J=8.4Hz,1H),6.85(m,3H),6.11(s,1H),5.13(s,2H),5.08(s,2H),4.61(s,2H),4.40(m,2H),3.87(s,3H),3.85(s,3H),3.06(qd,J1=7.2Hz,J2=5.7Hz,2H),2.45(m,2H),2.09(m,2H),1.94(m,1H),1.80(m,1H),1.01(t,J=7.2Hz,3H)。
实施例9制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Gly-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7c)
采用实例7的方法,从0.17g(0.29mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6)和0.12g(0.60mmol)HCl·Gly-OBzl得到65mg(31%)标题化合物,为黄色固体。Mp 208-209℃;(c=0.1,甲醇);ESI-MS(m/e):730[M+H]+;IR(cm-1):3438,3287,3088,2934,1657,1639,1585,1550,1508,1455,1423,1382,1262,1214,1175,1134,1060,1032,962,753,697;1HNMR(300MHz,DMSO-d6):δ/ppm=9.69(s,1H),8.55(t,J=3.6Hz,1H),8.14(d,J=4.8Hz,1H),7.76(t,J=3.3Hz,1H),7.55(d,J=9.3Hz,2H),7.35(m,7H),7.20(d,J=5.10Hz,1H),7.13(d,J=5.1Hz,1H),6.94(d,J=4.8Hz,1H),6.79(m,3H),6.06(s,1H),5.11(s,2H),4.59(s,2H),4.35(m,1H),3.90(dd,J1=7.2Hz,J2=5.7Hz,2H),3.84(s,3H),3.82(s,3H),3.01(qd,J1=6.9Hz,J2=3.3Hz,2H),2.07(t,J=4.8Hz,2H),1.91(m,1H),1.75(m,1H),0.94(t,J=6.9Hz,3H)。
实施例10制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Ile-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7d)
采用实例7的方法,从3.52g(6.05mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6)和1.87g(7.26mmol)HCl·Ile-OBzl得到1.32g(27.8%)标题化合物,为黄色固体。Mp 160-161℃;(c=0.1,甲醇);ESI-MS(m/e):786[M+H]+;IR(cm-1):3267,3076,2963,2932,2874,1732,1670,1646,1633,1586,1550,1508,1448,1422,1380,1340,1271,1256,1220,1195,1163,1133,1031,964,799,696;1HNMR(300MHz,DMSO-d6):δ/ppm=9.70(s,1H),8.39(d,J=7.8Hz,1H),8.08(d,J=8.1Hz,1H),7.79(t,J=5.4Hz,1H),7.58(d,J=18.3Hz,2H),7.37(m,7H),7.23(d,J=8.4Hz,1H),7.17(d,J=8.1Hz,1H),6.96(d,J=8.4Hz,1H),6.82(m,3H),6.10(s,1H),5.13(m,2H),4.61(s,2H),4.47(m,1H),4.27(m,1H),3.87(s,3H),3.84(s,3H),3.05(qd,J1=7.2Hz,J2=5.4Hz,2H),2.09(m,2H),1.79(m,3H),1.32(m,1H),1.18(m,1H),0.99(t,J=7.2Hz,3H),0.78(m,6H)。
实施例11制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Met-OBzl-3-甲氧基苯基)-1.6-庚二烯-3,5-二酮(7e)
采用实施例7的方法,从2.5g(5.87mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6)和3.7g(8.80mmol)HCl·Met-OBzl得到830mg(18%)标题化合物,为黄色固体。Mp 169-170℃;(c=0.1,甲醇);ESI-MS(m/e):804[M+H]+;IR(cm-1):3287,3069,2929,1739,1644,1629,1584,1508,1447,1425,1378,1250,1212,1164,1134,1055,1031,963,816,696;1HNMR(300MHz,DMSO-d6):δ/ppm=9.68(s,1H),8.54(d,J=7.2Hz,1H),8.10(d,J=5.2Hz,1H),7.76(t,J=6.0Hz,1H),7.57(m,2H),7.36(m,7H),7.23(d,J=7.2Hz,1H),7.16(d,J=7.8Hz,1H),6.96(d,J=7.8Hz,1H),6.81(m,3H),6.09(s,1H),5.14(s,2H),4.60(s,2H),4.40(m,2H),3.87(s,3H),3.84(s,3H),3.40(m,2H),3.05(qd,J1=7.2Hz,J2=6.0Hz,2H),2.09(m,2H),1.93(m,6H),1.77(m,1H),0.99(t,J=7.2Hz,3H)。
实施例12制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Thr-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7f)
采用实施例7的方法,从3.31g(5.69mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6)和1.68g(6.83mmol)HCl·Thr-OBzl得到0.95g(22%)标题化合物,为黄色固体。Mp 224-225℃;(c=0.1,甲醇);ESI-MS(m/e):774[M+H]+;IR(cm-1):3404,3289,3079,2936,1748,1658,1630,1585,1537,1512,1453,1441,1423,1375,1339,1276,1259,1165,1138,1125,1090,1034,987,962,694;1HNMR(300MHz,DMSO-d6):δ/ppm=9.69(s,1H),8.29(d,J=8.4Hz,1H),8.10(d,J=8.1Hz,1H),7.77(t,J=5.1Hz,1H),7.57(d,J=15.6Hz,2H),7.37(m,7H),7.23(d,J=8.4Hz,1H),7.17(d,J=8.1Hz,1H),6.97(d,J=8.4Hz,1H),6.89(m,3H),6.09(s,1H),5.13(s,2H),5.08(d,J=5.1Hz,1H),4.61(m,3H),4.37(dd,J1=8.4Hz,J2=3.0Hz,1H),4.20(m,1H),3.87(s,3H),3.84(s,3H),3.05(qd,J1=6.9Hz,J2=5.1Hz,2H),2.09(m,2H),1.95(m,1H),1.77(m,1H),1.06(d,J=6.0Hz,3H),0.97(t,J=7.2Hz,3H)。
实施例13制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Ala-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(8a)
将500mg(0.67mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Asp(OBzl)-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7a)用丙酮溶解,室温下往里滴加NaOH水溶液(2M)至反应液pH为13并搅拌6h,TLC(二氯甲烷/甲醇=50/1)显示反应完成。用饱和KHSO4水溶液将反应液pH调为7,减压浓缩,残余物用饱和KHSO4水溶液调pH为2,用乙酸乙酯萃取3次,合并的乙酸乙酯层用饱和NaCl溶液洗至中性,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用无水乙醚磨洗,残留物用C18柱层析纯化得到290mg(66%)标题化合物,为黄色固体。Mp 175-177℃;(c=0.1,甲醇);ESI-MS(m/e):742[M-H]-;IR(cm-1):3285,2935,1626,1508,1450,1252,1134,1030,964,843,810,713,666;1HNMR(300MHz,DMSO-d6):δ/ppm=12.60(s,1H),9.70(s,1H),8.40(d,J=6.3Hz,1H),8.07(d,J=6.9Hz,1H),7.77(t,J=6.0Hz,1H),7.60(m,2H),7.37(m,2H),7.24(d,J=7.5Hz,1H),7.17(d,J=7.2Hz,1H),6.98(d,J=8.4Hz,1H),6.89(m,3H),6.10(s,1H),4.61(s,2H),4.40(m,1H),4.21(m,1H),3.88(s,3H),3.85(s,3H),3.04(qd,J1=6.3Hz,J2=6.0Hz,2H),2.10(m,2H),1.93(m,1H),1.76(m,1H),1.28(d,J=6.3Hz,3H),0.99(t,J=6.3Hz,3H)。
实施例14制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Glu-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(8b)
采用实施例13的方法,从500mg(0.56mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Glu-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7b)得到230mg(51%)标题化合物,为黄色固体。Mp 139-140℃;(c=0.1,甲醇);ESI-MS(m/e):710[M-H]-;IR(cm-1):3293,2935,1723,1624,1426,1257,1029,963,844,810,666;1HNMR(300MHz,DMSO-d6):δ/ppm=12.45(s,2H),9.69(s,1H),8.36(d,J=7.5Hz,1H),8.08(d,J=8.1Hz,1H),7.76(t,J=6.0Hz,1H),7.57(m,2H),7.37(m,2H),7.24(d,J=8.1Hz,1H),7.17(d,J=8.1Hz,1H),6.97(d,J=8.1Hz,1H),6.82(m,3H),6.10(s,1H),4.61(s,2H),4.39(m,1H),4.22(m,1H),3.87(s,3H),3.85(s,3H),3.04(qd,J1=6.9Hz,J2=6.0Hz,2H),2.29(t,J=6.9Hz,2H),2.10(m,2H),1.98(m,2H),1.77(m,2H),0.99(t,J=6.9Hz,3H)。
实施例15制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Gly-3-甲氧基苯基)-1,6-庚二烯-3,5-二(8c)
采用实施例13的方法,从500mg(0.69mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Gly-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7c)得到335mg(77%)标题化合物,为黄色固体。Mp 151-153℃;(c=0.1,甲醇);ESI-MS(m/e):638[M-H]-;IR(cm-1):3290,2934,1625,1584,1508,1423,1252,1134,1030,964,845,810,666;1HNMR(300MHz,DMSO-d6):δ/ppm=9.70(s,1H),8.33(t,J=5.4Hz,1H),8.10(d,J=8.1Hz,1H),7.77(t,J=6.0Hz,1H),7.57(m,2H),7.36(m,2H),7.33(s,1H),7.24(d,J=8.1Hz,1H),7.16(d,J=7.8Hz,1H),6.99(d,J=8.4Hz,1H),6.83(m,3H),6.10(s,1H),4.61(s,2H),4.38(m,1H),3.88(s,3H),3.85(s,3H),3.76(t,J=5.4Hz,1H),3.04(qd,J1=6.9Hz,J2=6.0Hz,2H),2.10(m,2H),1.94(m,1H),1.78(m,1H),0.98(t,J=6.9Hz,3H)。
实施例16制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Ile-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(8d)
采用实施例13的方法,从500mg(0.64mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Ile-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7d)得到352mg(80%)标题化合物,为黄色固体。Mp 147-149℃;(c=0.1,甲醇);ESI-MS(m/e):694[M-H]-;IR(cm-1):3281,2966,1733,1644,1585,1543,1508,1424,1253,1136,1030,963,844,802,706,604;1HNMR(300MHz,DMSO-d6):δ/ppm=12.66(s,1H),9.68(s,1H),8.18(d,J=8.1Hz,1H),8.06(d,J=7.8Hz,1H),7.78(t,J=5.4Hz,1H),7.56(m,2H),7.37(d,J=18.3Hz,2H),7.24(d,J=7.8Hz,1H),7.17(d,J=8.1Hz,1H),6.98(d,J=8.1Hz,1H),6.88(m,3H),6.10(s,1H),4.61(s,2H),4.47(m,1H),4.19(m,1H),3.87(s,3H),3.84(s,3H),3.05(dq,J1=6.9Hz,J2=5.4Hz,2H),2.11(m,2H),1.92(m,1H),1.78(m,2H),1.40(m,1H),1.21(m,1H),0.99(t,J=6.9Hz,3H),0.87(m,6H)。
实施例17制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Met-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(8e)
采用实施例13的方法,从500mg(0.62mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Met-OBzl-3-甲氧基苯基)-1.6-庚二烯-3,5-二酮(7e)得到223mg(50%)标题化合物,为黄色固体。Mp 162-163℃;(c=0.1,甲醇);ESI-MS(m/e):712[M-H]-;IR(cm-1):3291,3081,2970,2935,1652,1626,1586,1544,1510,1428,1375,1338,1258,1136,1031,963,810;1HNMR(300MHz,DMSO-d6):δ/ppm=12.73(s,1H),9.69(s,1H),8.36(d,J=7.8Hz,1H),8.09(d,J=7.8Hz,1H),7.77(t,J=5.4Hz,1H),7.57(m,2H),7.37(m,2H),7.23(d,J=8.4Hz,1H),7.16(d,J=8.1Hz,1H),6.96(d,J=8.4Hz,1H),6.81(m,3H),6.10(s,1H),4.61(s,2H),4.37(m,2H),3.88(s,3H),3.85(s,3H),3.04(qd,J1=6.9Hz,J2=5.4Hz,2H),2.00(m,9H),0.96(t,J=6.9Hz,3H)。
实施例18制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Thr-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(8f)
采用实施例13的方法,从500mg(0.65mmol)1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Thr-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7f)得到286mg(65%)标题化合物,为黄色固体。Mp 169-170℃;(c=0.1,甲醇);ESI-MS(m/e):682[M-H]-;IR(cm-1):3293,2935,1721,1625,1507,1423,1260,1131,1030,962,844,809,667;1HNMR(300MHz,DMSO-d6):δ/ppm=16.30(s,1H),12.60(s,1H),9.69(s,1H),8.10(d,J=7.8Hz,1H),8.04(d,J=8.4Hz,1H),7.77(t,J=6.3Hz,1H),7.57(m,2H),7.36(d,J=17.1Hz,2H),7.24(d,J=8.4Hz,1H),7.17(d,J=7.8Hz,1H),6.97(d,J=8.1Hz,1H),6.89(m,3H),6.10(s,1H),4.61(s,2H),4.53(m,1H),4.21(m,2H),3.88(s,3H),3.85(s,3H),3.05(qd,J1=7.2Hz,J2=6.3Hz,2H),2.10(m,2H),1.93(m,1H),1.76(m,1H),1.04(d,J=6.3Hz,3H),0.99(t,J=7.2Hz,3H)。
实施例19测定化合物8a-f的抗肿瘤生长活性
测定前将阿霉素,化合物6和化合物8a-f用生理盐水溶解,用于S180小鼠给药。在无菌环境中取接种于雄性ICR小鼠10天生长旺盛的S180腹水瘤液,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。按细胞浓度=4大方格内活细胞数/4×104×稀释倍数=细胞数/mL计算细胞密度,按细胞存活率=活细胞数/(活细胞数+死细胞数)×100%计算细胞存活率。将存活率大于90%的瘤液用匀浆法制成密度为2.0×107个/mL的细胞悬液。该细胞悬液接种于小鼠右腋皮下(0.2mL/只),制造S180荷瘤小鼠。接种24h后S180荷瘤小鼠每日腹腔注射阿霉素的生理盐水溶液(剂量为2μmol/kg/天g)或腹腔注射化合物6的生理盐水溶液(剂量为1μmol/kg/天)或腹腔注射化合物8a-f的生理盐水溶液(剂量为0.1μmol/kg/天),每组10只。每天给药一次,连续给药12天。最后一次给药的次日乙醚麻醉脱颈椎处死,然后用镊子固定小鼠右腋肿瘤生长部位,剪开皮肤钝性剥离肿瘤并称重。用瘤重(均值±SD g)表示疗效,数据用t检验和方差分析。结果见表1。在0.1μmol/kg剂量下化合物8a-f不仅有效地抑制肿瘤生长,而且活性与剂量比它们大10倍的化合物6没有显著性差异。这些数据表明,本发明有显著的技术效果。
表1化合物8a-f对S180小鼠肿瘤生长的影响
a)与生理盐水比p<0.01,与化合物6比p>0.05;n=10.
实施例20测定化合物8a-f的抗炎活性
因为二甲苯引起的小鼠耳肿胀被公认为急性炎症模型,所以本发明在二甲苯引起的小鼠耳肿胀模型上测定化合物8a-f的治疗作用。因为阿司匹林是治疗急性炎症的阳性药,所以本发明选择阿司匹林为阳性对照药。ICR雄性小鼠(体重22±3g)在22℃环境静息2天,自由饮水和进食。之后,随机分为生理盐水组(剂量为0.2mL/只),阿司匹林组(剂量为1.11mmol/kg),化合物6组(剂量为1μmol/kg)及化合物8a-f组(剂量为0.1μmol/kg),每组10只小鼠。测定时小鼠按所在组或腹腔注射生理盐水,或腹腔注射阿司匹林,或腹腔注射化合物6,或腹腔注射化合物8a-f。给药30min后,往小鼠的左耳廓均匀涂抹30μL二甲苯,2h后小鼠接受乙醚麻醉,断颈处死,剪下左右两耳,用7mm的打孔器在两耳的相同位置取圆形耳片,称重,求出两耳肿胀差值作为肿胀度。即肿胀度=左耳圆片重量–右耳圆片重量。数据见表2。在0.1μmol/kg剂量下化合物8a-f不仅有效地抑制二甲苯引起的小鼠耳肿胀,而且活性与剂量比它们大10倍的化合物6没有显著性差异。这些数据表明,本发明有显著的技术效果。
表2化合物8a-f对二甲苯引起的小鼠耳肿胀的影响
a)与生理盐水比p<0.01,与化合物6比p>0.05;n=10.
Claims (4)
2.权利要求1的1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮的制备方法,该方法包括:
(1)制备6-(4-羟基-3-甲氧苯基)-5,6-己烯-2,4-二酮(1);
(2)制备2-(4-甲酰基-2-甲氧基苯氧基)-乙酸苄酯(2);
(3)以步骤(1)和步骤(2)的产物为反应原料制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(3);
(4)将1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮皂化,得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰乙酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(4);
(5)化合物4和L-茶氨酸苄酯偶联得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸苄酯基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(5);
(6)将化合物5皂化得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酸基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(6);
(7)化合物6和L-氨基酸苄酯偶联得到权利要求1的1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7);
(8)化合物7皂化得到1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮。
3.权利要求1的1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮在制备抗肿瘤生长药物中的应用。
4.权利要求1的1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-AA-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮在制备抗炎药物中的应用。
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