CN109134598A - 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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- CN109134598A CN109134598A CN201710458701.3A CN201710458701A CN109134598A CN 109134598 A CN109134598 A CN 109134598A CN 201710458701 A CN201710458701 A CN 201710458701A CN 109134598 A CN109134598 A CN 109134598A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
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- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了下式的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(式中AA选自L‑Lys残基、L‑Asn残基、L‑Pro残基、L‑Gln残基、L‑Ser残基和L‑Thr残基),公开了它们的制备方法、公开了它们的抗肿瘤生长活性,以及公开了它们的抗炎活性,因而本发明公开了它们在制备抗肿瘤药物和抗炎药物中的应用。
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-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(式中AA选自L-Lys残基、L-Asn残基、L-Pro残基、L-Gln残基、L-Ser残基和L-Thr残基)。涉及它们的制备方法、涉及它们的抗肿瘤生长活性,以及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,化疗过程中炎症可协助肿瘤生长而严重影响化疗效果。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。发明具有抗炎作用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-Lys残基、L-Asn残基、L-Pro残基、L-Gln残基、L-Ser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也低至0.1μmol/kg。抗肿瘤生长的有效剂量降低10倍及兼有抗炎作用表明,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-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(式中AA选自L-Lys残基、L-Asn残基、L-Pro残基、L-Gln残基、L-Ser残基、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-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(AA选自L-Lys残基、L-Asn残基、L-Pro残基、L-Gln残基、L-Ser残基、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。
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-OBzl-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-OBzl-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为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.7a中AA为L-Lys残基;7b中AA为L-Asn残基;7c中AA为L-Pro残基;7d中AA为L-Gln残基;7e中AA为L-Ser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-Lys-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7a)
冰浴下将1.3g(2.23mmol)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),1g(2.68mmol)HCl·Lys(Boc)-OBzl和0.36g(2.68mmol)N-羟基苯并三唑(HOBt)用20mL无水四氢呋喃溶解。之后,往里滴加0.98g(4.78mmol)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),得到的黄色固体先在冰浴下用10mL无水乙酸乙酯溶解,然后加10mL氯化氢的乙酸乙酯溶液(4M)并搅拌4h。TLC(二氯甲烷/甲醇=50/1)显示反应结束,减压浓缩,残留物用无水乙酸乙酯溶解,减压浓缩。该操作重复三次。残留物用无水乙醚充分悬浮,去乙醚,得到306mg(16%)标题化合物,为黄色固体。Mp191-193℃;(c=0.1,甲醇);ESI/MS(m/e):801[M+H]+1;1H NMR(300MHz,DMSO-d6):δ/ppm=9.72(s,1H),8.59(d,J=7.8Hz,1H),8.11(d,J=8.1Hz,1H),7.80(m,3H),7.57(d,J=14.7Hz,2H),7.37(m,7H),7.23(d,J=8.4Hz,1H),7.18(d,J=8.1Hz,1H),6.96(d,J=8.4Hz,1H),6.83(m,3H),6.10(s,1H),5.14(s,2H),4.61(s,2H),4.41(m,1H),4.28(m,1H),3.87(s,3H),3.84(s,3H),3.04(dq,J1=6.0Hz,J2=7.2Hz,2H),2.72(m,2H),2.29-1.24(m,10H),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-Asn-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7b)
冰浴下将4.12g(7.08mmol)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),2.20g(8.50mmol)HCl·Asn-OBzl和1.15g(8.50mmol)N-羟基苯并三唑(HOBt)用50mL无水四氢呋喃溶解。之后,往里滴加1.75g(8.50mmol)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(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=60/1),得到1.18g(21%)标题化合物,为黄色固体。Mp 186-187℃;(c=0.1,甲醇);ESI-MS(m/e):787[M+H]+;IR(cm-1):3417,3281,3077,2936,1735,1664,1641,1586,1548,1509,1450,1421,1269,1139,1031,964;1H NMR(300MHz,DMSO-d6):δ/ppm=8.55(d,J=6.9Hz,1H),8.09(d,J=8.1Hz,1H),7.75(t,J=6.3Hz,1H),7.55(m,2H),7.39(m,8H),7.23(d,J=7.8Hz,1H),7.18(d,J=7.8Hz,1H),6.98(m,2H),6.82(m,3H),6.10(s,1H),5.11(s,2H),4.72(m,1H),4.62(s,2H),4.40(m,1H),3.87(s,3H),3.85(s,3H),3.05(qd,J1=7.2Hz,J2=6.3Hz,2H),2.58(m,2H),2.08(m,2H),1.95(m,1H),1.74(m,1H),0.99(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-Pro-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7c)
采用实施例8的方法,从4.04g(6.94mmol)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2.01g(8.33mmol)HCl·Pro-OBzl得到1.84g(35%)标题化合物,为黄色固体。Mp 112-113℃;(c=0.1,甲醇);ESI-MS(m/e):770[M+H]+;IR(cm-1):3322,3070,2936,1740,1626,1583,1507,1446,1381,1214,1165,1126,1029,965;1HNMR(300MHz,DMSO-d6):δ/ppm=9.70(s,1H),8.22(d,J=8.1Hz,1H),7.74(t,J=5.7Hz,1H),7.57(m,2H),7.37(m,7H),7.20(dd,J=13.5Hz,J=1.2Hz,1H),7.14(dd,J=13.5Hz,J=1.2Hz,1H),6.96(d,J=9.6Hz,1H),6.82(m,3H),6.09(s,1H),5.14(s,2H),4.61(m,3H),4.41(m,1H),3.87(s,3H),3.84(s,3H),3.67(m,2H),3.04(qd,J1=7.2Hz,J2=5.7Hz,2H),2.19(m,3H),1.92(m,4H),1.89(m,1H),0.99(t,J=7.2Hz,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-Gln-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7d)
采用实施例8的方法,从4.11g(7.07mmol)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2.31g(8.48mmol)HCl·Gln-OBzl得到532mg(9.4%)标题化合物,为黄色固体。Mp 217-219℃;(c=0.1,甲醇);ESI-MS(m/e):801[M+H]+;IR(cm-1):3449,3278,3086,2970,2936,1733,1641,1582,1552,1510,1446,1374,1339,1244,1218,1171,1137,1029,967,696;1H NMR(300MHz,DMSO-d6):δ/ppm=8.61(d,J=6.9Hz,1H),8.13(d,J=8.1Hz,1H),7.80(t,J=6.3Hz,1H),7.55(m,2H),7.37(m,8H),7.23(d,J=7.8Hz,1H),7.15(d,J=7.8Hz,1H),6.98(d,J=8.4Hz,1H),6.86(m,4H),6.06(s,1H),5.13(s,2H),4.62(s,2H),4.42(m,1H),4.40(m,1H),3.87(s,3H),3.84(s,3H),3.05(qd,J1=7.2Hz,J2=6.3Hz,2H),2.00(m,8H),0.99(t,J=7.2Hz,3H)。
实施例11制备1-(4-羟基-3-甲氧基苯基)-7-(4-氧乙酰茶氨酰-Ser-OBzl-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮(7e)
采用实施例8的方法,从2.38g(4.09mmol)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0.95g(4.10mmol)HCl·Ser-OBzl得到742mg(23.9%)标题化合物,为黄色固体。Mp 185-186℃;(c=0.1,甲醇);ESI-MS(m/e):759[M+H]+1;IR(cm-1):3280,3071,2967,2932,1628,1587,1544,1508,1451,1421,1377,1268,1248,1209,1161,1133,1028,963;1H NMR(300MHz,DMSO-d6):δ/ppm=9.67(s,1H),8.50(d,J=7.5Hz,1H),8.07(d,J=8.1Hz,1H),7.74(t,J=5.7Hz,1H),7.57(m,2H),7.37(m,7H),7.24(d,J=7.8Hz,1H),7.17(d,J=8.1Hz,1H),6.97(d,J=8.4Hz,1H),6.89(m,3H),6.10(s,1H),5.15(s,2H),4.60(s,2H),4.49(m,2H),3.87(s,3H),3.84(s,3H),3.69(m,2H),3.40(m,2H),3.04(qd,J1=7.2Hz,J2=5.7Hz,2H),2.10(m,2H),1.94(m,1H),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8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测定化合物7a-f的抗肿瘤生长活性
测定前将阿霉素,化合物6和化合物7a-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7a-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7a-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7a-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.n=10.
实施例14测定化合物7a-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7a-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7a-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7a-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4。在0.1μmol/kg剂量下化合物7a-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)
1.下式的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,
式中AA选自L-Lys残基、L-Asn残基、L-Pro残基、L-Gln残基、L-Ser残基和L-Thr残基。
2.权利要求的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。
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-OBzl-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-OBzl-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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CN111848730A (zh) * | 2019-04-30 | 2020-10-30 | 首都医科大学 | 茶氨酰四氢咪唑并吡啶-6-甲酰极性氨基酸的制备,活性和应用 |
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CN112010749A (zh) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | 3-羟基姜黄素-4-och2co2h锶,其合成,活性和应用 |
CN112094186A (zh) * | 2019-05-30 | 2020-12-18 | 首都医科大学 | 姜黄素-4-och2co2h锶,其合成,活性和应用 |
CN112300245A (zh) * | 2019-07-30 | 2021-02-02 | 首都医科大学 | Rgds和茶氨酸共同修饰的5-氟尿嘧啶,其合成,活性和应用 |
CN112300244A (zh) * | 2019-07-30 | 2021-02-02 | 首都医科大学 | 茶氨酸单独及与rgds共同修饰的5-氟尿嘧啶,其合成,活性和应用 |
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