CN1304309A - 半合成海鞘素 - Google Patents
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Abstract
本发明涉及几种新型半合成海鞘素,称之Et757、Boc-Et 729、Iso-Et 743、Et 875和Et l560。并报导了这些化合物的物理性质、其制备方法以及生物活性。
Description
发明背背
海鞘素(本文简称为Et或Et’s)是从海生有被膜陀螺状海鞘(Ecteinascidia turbinata)分离出的超强抗肿瘤剂。具体来说Et’s729、743和722已证明过在体内的效果,包括抗P388鼠白血病、B16黑色素瘤、Lewis肺癌、以及几种人肿瘤在鼠体内的异种移植模式的活性。对Et 729和Et 743由NCI和目前的实验所评价的活性表明,在用B16黑色素瘤感染后,Et 729给出的60天存活率为10分之8。由于这些令人鼓午的结果,人们继续不断地研究其它的海鞘素化合物。
本发明概述
发现上述新的海鞘素化合物有与已知的海鞘素化合物相似的抗肿瘤活性的特征,因此它们能用作治疗化合物,例如用来治疗哺乳动物肿瘤,包括黑色素瘤、肺癌等。所用剂量和给药途径,可视患者的需要和活性成分的具体活性而异。这些因素的确定是有实践经验的医生的常识。
附图简述
图1A和1B表示在魔弹(MB)中的Et 757的LRFAB质谱,参见Rinehart等人“生物化学和生物物理研究通报”1984,124,350。
图2A和2B表示MB中Et 757的串联FABMS/MS谱。
图3表示CD3OD中Et 757的1HNMR(500 MHz)谱。
图4A和4B表示MB中Et 729的LRFAB质谱。
图5A和5B表示MB中Boc-Et 729的串联FABMS/MS质谱。
图6表示MB中Iso-Et 743的LRFAB质谱。
图7A和7B表示MB中Iso-Et 743的串联FABMS/MS谱。
图8表示CD3OD中Iso-Et 743的1HNMR(500 MHz)谱。
图9表示CD3OD中Iso-Et 743的扩展HMBC(750 MHz)谱。
图10A和10B表示MB中Et 875的LRFAB质谱。
图11A和11B表示MB中Et 875的串联FABMS/MS质谱。
图12表示MB中Et 1560的LRFAB质谱。
参考实施方案详述本发明
如前述,很多生物活性海鞘素化合物从陀螺状海鞘样品中分离出,例如公开在US 5089273、和5256663中的海鞘素729、743、745、759A、759B和770,这些公开内容均引入本文作为参考。也例如公开在US 5149804中的海鞘素736和722,再参见US 5478932和5654426这些也引入本文作为参考。
本发明下面进一步以实施例举例说明,以有助于对本发明的理解,但这并不构成对本发明的限制。除非另有说明,所有百分数均以重量计,所有温度均以摄氏度表示。实施例1-半合成Et 757
Et 729(9.2mg,0.012mmol,1eq),二异丙胺(12.9μL,0.074mmol,6eq)和CH3CN(300μL)的溶液中加入CH3I(1.5μL,0.024mmol,2eq),所得溶液于60℃搅拌24小时。氮气流中将反应混合物浓缩至干。使用含0.02M Nacl的75%MeOH/H2O作为流动相,采用反相HPLC(Phenomenex/Ultracarb-ODS,2ml/min)提纯残留物,得到Et757(2.2mg,24%)和Et 743(2.3mg,25%),以及预甲基化产物的复合混合物。使用含0.02M Nacl的60%MeOH/H2O作为流动相,以HPLC(Ultracarb-ODS)进一步提纯Et 757,得到纯的Et 757(1.4mg,15%)。HRFABMS,由C40H44N3O10S[M+H-H2O]-m/z计算值为758.2747,实验值758.2765,见图1和图2;1HNMR见图3。实施例2-半合成Iso-Et 743步骤A-Boc-Et 729
Et 729(12.5mg,0.017mmol, 1eq)、二异丙基乙胺(1.5μL,0.07mmol,4eq)和CH3CN(300μL)的溶液中,加入二碳酸二叔丁酯(3.6mg,0.017mmol,1.0eq),所得溶液在室温下搅拌9小时。氮气流中将反应混合物浓缩至干。用快速色谱将残留物提纯(梯度洗脱液:100%CHCl3→90%CHCl3/MeOH),得到Boc-Et 729(11.6mg,91%,Rf在90%CHCl3/MeOH中为0.53);HRFABMS,从C43H48N3O12S[M+H]-m/z计算值为830.2958,实验值为830.2942,见图4和5。步骤B-I50-Et 743
含Boc-Et 729(11.6mg,0.014mmol,1eq)、二异丙基乙胺(7.1μL,0.041mmol,3eq)、500μL CH3CN和磁搅拌器的反应烧瓶中加入CH3I(2.1mg,0.015mmole,1.1eq),将所得溶液60℃搅拌24小时。氮气流中将反应混合物浓缩至于,然后加入700μLTFA/CH2Cl2/H2O(4∶1∶1)。该混合物于室温下搅拌30分钟后,于氮气流中溶液至干。用60%MeOH/H2O(含0.02M NaCl)作为流动相,以反相HPLC(Alltech-C18,2ml/min)将残留物提纯,得到Iso-Et 743(1.9 mg,28%,以回收的Et 729为基础计)。HRFABMS,由C39H42N3O10S[M+H-H2O]+m/z得计算值为744.2591,实验值744.2619,见图6和7;1HNMR和HMBC分别见图8和9。实施例3-半合成Et 875
将冰醋酸(5μL28%AcOH/CH3CN溶液,4eq)加入到Et 743(0.9mg,0.001mmol,1eq)、哌啶(5μL2%哌啶/CH3CN溶液,0.001mmol,1eg)、丙二酸二甲酯(5μL3%丙二酸二甲酯/CH3CN溶液0.001mmol,1eq)、和压碎的活化4分子筛(约0.5mg)在CH3CN的混合物中,所得悬浮液于室温下搅拌24小时。将反应物过滤,将滤液浓缩至干。用快速色谱将残留物提纯(梯变洗脱液:100%CHCl3→90%CHCl3/MeOH),得到Et875(180μg,20%,90%CHCl3/MeOH中Rf为0.53);HRFABMS,由C44H50N3O14S[M+H]+m/z得计算值876.3013,实验值876.2986,见图10和11。实施例4-半合成Et 1560(Et 729的二聚物)
含Et729(2.4mg,0.0032mmol,2eq)、二异丙胺(2μL)和CH3CN(75μL)和磁搅拌器的反应烧瓶中加入α,α’-二溴-对二甲苯(34μL12.5μg/μlα,α’-二溴-对二甲苯/CH3CN溶液,0.0016mmol,1eq),将所得溶液于60℃搅拌1小时。氮气流中将反应混合物浓缩至干,用快速色谱提纯残留物(梯度洗脱液:100%CHCl3→90%CHCl3/MeOH),得到Et 1560(300μg,12%,90%CHCl3/MeOH中Rf为0.53);HRFABMS,由C84H85N6O20S2[M+H-2H2O]-m/z得计算值1561.5260,实验值1561.5221、见图12。
生物活性
如上所述,海鞘素是高度官能化二或三(四氢异喹啉)生物碱,于体内有很强抗肿瘤活性。这些化合物主要从红树属有被膜陀螺海鞘中作为天然产物分离出,这些生物在加勒比海和墨西哥湾生长。大量提取的主要产物Et 743目前已在治疗人类固体肿瘤方面进行第一阶段临床试验。例如参见Kuffel等人,“美国癌症研究协会报告”,38:596(1997);Moore等人上述报告,38:314(1997);Mirsalis等人上述报告,38:309(1997);Reid等人,“癌症化学疗法和药物疗法”,38:329-334(1996);Faircloth等人,“欧洲癌症杂志”,32A、补编1,PP S5(1996);Garcia-Rocha等人,“不列颠癌症杂志”,73:875-883(1996);Eckhardt等人,“美国癌症研究协会报告”,37:409(1996);以及Hendriks等人,“美国癌症研究协会报告”,37:389(1996)。
鉴于天然海鞘素异乎寻常的抗肿瘤性能,本发明研究了本文制备的半合成类似物的抗肿瘤活性。表Ⅰ列出了新的Et化合物与两种天然产物Et 743和Et 729活性相比较的体外细胞毒性活性。
表Ⅰ化合物名称 对L1210鼠白血病的细胞毒性
IC50 IC50(Et 743)/IC50Et 729 0.05 10Et 743 0.5 1Et 757 0.01 50Iso-Et 743 0.03 17Boc-Et 729 5.0 0.1Et 1560 2.0 0.25Et 875 0.5 1
如上表中所示的体外数据,本发明新化合物与两种天然海鞘素化合物相比,其细胞毒性要好最高10倍之多。因此,预期该化合物将作为药物组合物对哺乳动物体内治疗,尤其是治疗人类肿瘤是很有效的。
参考文献
摘引下面的出版物作为其它背景资料,为使完全了解本发明,将所有这些文献引入本文作为参考:
1.Rinchart,K.L.等人,“天然产物杂志”53:771-791(1990)。
2.Wright,A.E.等人,“有机化学杂志”55:4508-4512(1990)
3.Sakai等人,“自然科学方法(美国)”89:11456-11460(1992)
4.Rinehart等人,“有机化学杂志”55:4512-4515(1990)
本发明已加以详细描述,包括以优选实施方案进行介绍。但应明确,根据本发明所公开的内容,本领域技术人员可对本发明作出修改和/或改进,这些将落入本发明的精神和范围之中。
Claims (15)
1.结构如下的化合物Et 757:
4.结构如下的化合物Et 875:
5.结构如下的化合物Et 1560:
6.含有化合物Et 757和药用稀释剂、载体或赋形剂的药物组合物。
7.含有化合物Boc-Et 729和药用稀释剂、载体或赋形剂的药物组合物。
8.含有化合物Iso-Et 743和药用稀释剂、载体或赋形剂的药物组合物。
9.含有化合物Et 875和药用稀释剂,载体或赋形剂的药物组合物。
10.含有化合物Et 1560和药用稀释剂,载体或赋形剂的药物组合物。
11.治疗罹患哺乳动物肿瘤的患者的方法,所述肿瘤选自哺乳动物白血病,哺乳动物黑色素瘤、和哺乳动物肺癌,所述方法包括给所述患者施用抗肿瘤有效量基本上纯的、本文称之为Et 757的化合物,和药用载体、稀释剂或赋形剂。
12.治疗罹患哺乳动物肿瘤的患者的方法,所述肿瘤选自哺乳动物白血病,哺乳动物黑色素瘤、和哺乳动物肺癌,所述方法包括给所述患者施用抗肿瘤有效量基本上纯的、本文称之为Boc-Et 729的化合物,和药用载体、稀释剂或赋形剂。
13.治疗罹患哺乳动物肿瘤的患者的方法,所述肿瘤选自哺乳动物白血病,哺乳动物黑色素瘤、和哺乳动物肺癌,所述方法包括给所述患者施用抗肿瘤有效量基本上纯的、本文称之为Iso-Et 743的化合物,和药用载体、稀释剂或赋形剂。
14.治疗罹患哺乳动物肿瘤的患者的方法,所述肿瘤选自哺乳动物白血病,哺乳动物黑色素瘤、和哺乳动物肺癌,所述方法包括给所述患者施用抗肿瘤有效量基本上纯的、本文称之为Et 875的化合物,和药用载体、稀释剂或赋形剂。
15.治疗罹患哺乳动物肿瘤的患者的方法,所述肿瘤选自哺乳动物白血病,哺乳动物黑色素瘤、和哺乳动物肺癌,所述方法包括给所述患者施用抗肿瘤有效量基本上纯的、本文称之为Et 1560的化合物,和药用载体、稀释剂或赋形剂。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100355775C (zh) * | 2006-01-20 | 2007-12-19 | 南方医科大学 | 一种海鞘多肽及其制备方法 |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5985876A (en) * | 1997-04-15 | 1999-11-16 | Univ Illinois | Nucleophile substituted ecteinascidins and N-oxide ecteinascidins |
WO1999058125A1 (en) * | 1998-05-11 | 1999-11-18 | Pharma Mar, S.A. | Metabolites of ecteinascidin 743 |
MY164077A (en) * | 1999-05-13 | 2017-11-30 | Pharma Mar Sa | Compositions and uses of et743 for treating cancer |
MY130271A (en) | 1999-05-14 | 2007-06-29 | Pharma Mar Sa | Hemisynthetic method and new compounds |
US6686470B2 (en) | 2000-01-19 | 2004-02-03 | The Trustees Of Columbia University In The City Of New York | Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof |
US7919493B2 (en) * | 2000-04-12 | 2011-04-05 | Pharma Mar, S.A. | Anititumoral ecteinascidin derivatives |
MXPA02011319A (es) * | 2000-05-15 | 2003-06-06 | Pharma Mar Sa | Analogos antitumorales de ecteinascidina 743. |
CA2447553A1 (en) * | 2000-11-03 | 2002-05-23 | President And Fellows Of Harvard College | Saframycins, analogues and uses thereof |
AU1249902A (en) * | 2000-11-06 | 2002-05-15 | Pharma Mar Sa | Effective antitumour treatments |
GB0117402D0 (en) * | 2001-07-17 | 2001-09-05 | Pharma Mar Sa | New antitumoral derivatives of et-743 |
GB0119243D0 (en) * | 2001-08-07 | 2001-10-03 | Pharma Mar Sa | Antitumoral analogs of ET-743 |
GB0202544D0 (en) | 2002-02-04 | 2002-03-20 | Pharma Mar Sa | The synthesis of naturally occuring ecteinascidins and related compounds |
GB0312407D0 (en) * | 2003-05-29 | 2003-07-02 | Pharma Mar Sau | Treatment |
GB0324201D0 (en) * | 2003-10-15 | 2003-11-19 | Pharma Mar Sau | Improved antitumoral combinations |
EP1689404B9 (en) | 2003-11-13 | 2009-04-22 | Pharma Mar, S.A.U. | Combination of et-743 with 5-fluorouracil pro-drugs for the treatment of cancer |
GB0326486D0 (en) * | 2003-11-14 | 2003-12-17 | Pharma Mar Sau | Combination treatment |
EP1691809A1 (en) * | 2003-11-14 | 2006-08-23 | Pharma Mar, S.A. | Combination therapy comprising the use of et-743 and paclitaxel for treating cancer |
JP2008505862A (ja) * | 2004-07-09 | 2008-02-28 | ファルマ、マール、ソシエダード、アノニマ | 予後分子マーカー |
US20080242670A2 (en) * | 2004-09-29 | 2008-10-02 | Pharma Mar S.A., Sociedad Unipersonal | Anti-Inflammatory Agents |
RS50822B (sr) * | 2004-10-26 | 2010-08-31 | Pharma Mar S.A., Sociedad Unipersonal | Pegilovani lipozomalni doksorubicin u kombinaciji sa ekteinescidinom 743 |
RU2382647C2 (ru) | 2004-10-29 | 2010-02-27 | Фарма Мар С.А., Сосьедад Униперсональ | Композиции, содержащие эктинэсайдин и дисахарид |
GB0522082D0 (en) * | 2005-10-31 | 2005-12-07 | Pharma Mar Sa | Formulations |
JP2011500046A (ja) * | 2007-10-19 | 2011-01-06 | ファルマ・マール・ソシエダード・アノニマ | Et−743治療のための予後分子マーカー |
HUE049389T2 (hu) | 2010-11-12 | 2020-09-28 | Pharma Mar Sa | Kombinált terápia topoizomeráz inhibitorral |
JP2019504061A (ja) * | 2016-02-04 | 2019-02-14 | ジエンス ヘンルイ メデイシンカンパニー リミテッドJiangsu Hengrui Medicine Co.,Ltd. | トラベクテジンの注射可能な胃腸外用医薬組成物及びその製造方法 |
JOP20190254A1 (ar) | 2017-04-27 | 2019-10-27 | Pharma Mar Sa | مركبات مضادة للأورام |
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US5089273A (en) * | 1986-06-09 | 1992-02-18 | Board Of Trustees Of The University Of Illinois | Ecteinascidins 729, 743, 745, 759A, 759B and 770 |
US5256663A (en) * | 1986-06-09 | 1993-10-26 | The Board Of Trustees Of The University Of Illinois | Compositions comprising ecteinascidins and a method of treating herpes simplex virus infections therewith |
US5149804A (en) * | 1990-11-30 | 1992-09-22 | The Board Of Trustees Of The University Of Illinois | Ecteinascidins 736 and 722 |
US5440055A (en) * | 1993-03-12 | 1995-08-08 | Aphios Corporation | Method and apparatus for extracting taxol from source materials |
US5478932A (en) * | 1993-12-02 | 1995-12-26 | The Board Of Trustees Of The University Of Illinois | Ecteinascidins |
US5721362A (en) * | 1996-09-18 | 1998-02-24 | President And Fellows Of Harvard College | Process for producing ecteinascidin compounds |
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CN100355775C (zh) * | 2006-01-20 | 2007-12-19 | 南方医科大学 | 一种海鞘多肽及其制备方法 |
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