CN1258534C - 由海绵分离的包括Asmarine A和B的细胞毒性生物碱衍生物 - Google Patents
由海绵分离的包括Asmarine A和B的细胞毒性生物碱衍生物 Download PDFInfo
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Abstract
从海绵Raspailia物种分离了新型细胞毒性生物碱Asmarine A和B。已经在NMR数据的基础上建立了这些化合物的结构并通过X-射线分析予以证实。同时还要求对化合物(I)或(II)的权益进行保护,其中R1代表氢原子或低级烷基或低级链烷酰基;R2代表氢原子或低级烷基;R3或者是含有一个或多个异戊二烯单位的烷基或环烷基团,或者是一个单萜或倍半萜烯或二萜基团;R4或R5代表氢原子或低级烷基;R6代表低级烷基;X代表F或Cl或Br或I。
Description
技术领域
本发明涉及从海绵Raspailia物种分离的新型细胞毒性生物碱Asmarine A和B。
背景技术
海洋生物,特别是软珊瑚、海绵和被囊动物,产生许多次级代谢物并显示不同水平的生物活性(参考资料1)。这些代谢物中的一个家族是二萜生物碱家族;1984年(参考资料2)报道了四个Agelasines。的结构:
我们已经从海绵Raspailia物种分离出与该agelasine家族有关的新型细胞毒性二萜生物碱。
发明内容
本发明提供了或者具有结构式(I),或者具有结构式(II)的新型二萜生物碱:
其中R1代表氢原子或低级烷基或低级链烷酰基;R2代表甲基;R3由倍半萜基团取代的甲基;R4和R5代表氢原子或低级烷基;R6代表低级烷基;X代表F或Cl或Br或I。
在结构式(I)和(II)的基团的定义中,所述低级烷基以及低级链烷酰基的低级烷基部分是指含有1到6个碳原子的直链或分支烷基基团,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基和己基。
更具体地说,本发明涉及从海绵Raspailia物种提取和分离出的Asmarine A和Asmarine B。Asmarine A的结构如下所示:
所显示的立体化学是相对构型。
Asmarine A和Asmarine B显示出抗肿瘤活性。具体地说,Asmarine A和Asmarine B显示出针对来自人类实体瘤(如人肺癌、人结肠癌和人黑素癌)的细胞系的抗肿瘤活性,并且相似地对其它肿瘤细胞系,如白血病和淋巴瘤有效。
本发明还提供治疗罹患恶性肿瘤的哺乳动物的方法,所述恶性肿瘤对具有结构式(I)或结构式(II)的化合物敏感,该方法包括给予治疗有效量的具有结构式(I)或结构式(II)的化合物,或其药用组合物。
本发明还提供了含有具有结构式(I)或结构式(II)的化合物作为活性成分的药用组合物,以及制备这些药用组合物的方法。
本发明的又一方面是制备化合物Asmarine A和Asmarine B的方法,该方法包括从海绵Raspailia物种的提取和分离。
药用组合物的例子包括任何适合口服给予、局部给予或胃肠外给予而配制的固体(片剂、丸剂、胶囊、颗粒剂等)或液体(溶液、悬浮液或乳液),它们可以仅含有纯化合物或与任何载体或其它药物学上有活性的化合物组合。当胃肠外给予时,这些组合物必须是无菌的。
含有具有结构式(I)或结构式(II)的化合物的药用组合物的正确剂量将根据药物制剂、使用方法以及要治疗的具体部位、宿主和肿瘤而变化。其它因素应该考虑在内,如年龄、体重、性别、食谱、给药时间、排泄率、宿主的疾病状况、联合用药情况、反应敏感性和疾病的严重程度。在最大耐受剂量内,可以持续或定期给药。抗肿瘤活性
在含有Earle’s平衡盐、2.0mM L-谷氨酸、非必需氨基酸、不含碳酸氢钠的Eagle’s极限必需培养基(EMEM/neaa)中,添加10%胎牛血清(FCS)、10-2M碳酸氢钠和0,1g/L青霉素-G+链霉素硫酸盐,维持细胞处于对数生长期。
使用Bergeron等人(参考资料3)描述的方法的修改形式,已经执行了一个筛选程序来确定和比较这些化合物的抗肿瘤活性。所使用的抗肿瘤细胞是P-388(得自DBA/2小鼠的淋巴样肿瘤的悬浮培养物)、A-549(人肺癌的单层培养物)、HT-29(人结肠癌的单层培养物)和MEL-28(人黑素癌的单层培养物)。
将P-388细胞以1×104每孔接种到16mm孔中1ml等分的含有指定浓度药物的MEM 5FCS中。接种另外一组不含药物的培养物作为对照生长,以确保所述细胞维持在指数生长期。所有测定都一式两份进行。在37℃、10%CO2、98%湿度空气中孵育三天后,通过比较有药物的孔中的生长和对照孔中的生长,确定大致的IC50。
将A-549、HT-29以及MEL-28细胞以2×104个细胞每孔接种到16mm孔中1ml等分的含有指定浓度药物的MEM 10FCS中。接种另外一组不含药物的培养物作为对照生长,以确保所述细胞维持在指数生长期。所有测定都一式两份进行。在37℃、10%CO2、98%湿度空气中孵育三天后,用0.1%结晶紫染色这些孔。通过比较有药物的孔中的生长和对照孔中的生长,确定大致的IC50。
使用细胞系P-388、A-549、HT-29以及MEL-28对Asmarine A和Asmarine B的体外细胞毒性测定的结果在下表中给出:
IC50(μM)
P-388 | A-549 | HT-29 | MEL-28 | |
Asmarine AAsmarine B | 1.180.24 | 1.180.12 | 1.180.12 | 1.180.24 |
提取和分离
在一台EIMS质谱仪上记录低分辨率质谱。在一台Bruker ARX-500波谱仪上记录1H和13C-NMR波谱。根据TMS(δ=0ppm)报告所有化学位移。
Raspailia物种(Rob Van Soest),(寻常海绵纲异固海绵目Raspailiidea科)是由SCUBA于1997年5月在Dahlak Archipelago,Eritrea潜水到23.5m的深度采集到的。一个参考样品保藏在Tel Aviv大学(ET-388)。将所述海绵当场冰冻起来。使用2倍乙酸乙酯提取冻干的海绵(20gr),蒸发后得到1.2g棕色胶。将此棕色胶通过Kupchon分级分离到四个部分中:己烷、四氯化碳、氯仿和水。CHCl3和CCl4部分是相似的。将这两个部分合并,在sephadex LH-20柱上进行层析,使用MeOH∶CHCl3(1∶1)洗脱后,产生五个组分。使用同样的溶剂系统将组分(3-5)在sephadex LH-20上进一步反复层析,得到作为固体的Asmarine A(100mg),mp=232℃,m/z+=423(C25H37N5O),(100%)188(C8H6N5O+),[α]D 20+55°(c=0.5,CHCl3),IR 3400,2928,1600,1553,1451,1400,1388,900cm-1,该Asmarine A的结构由X-射线分析证实。使用同样的溶剂还分离了作为油状物的Asmarine B(120mg),m/z+=423(C25H37N5O),(100%)188(C8H6N5O+),[α]D 20+60°(c=0.5,CHCl3),IR 3400,2927,1606,1553,1451,1404,1388,900cm-1
Asmarine A和B的NMR数据见于下表:在所有情况下溶剂都是CHCl3,并且根据TMS(δ=0ppm)报告所有化学位移。
δC | δH | |||
C No. | Asmarine A | Asmarine B | Asmarine A | Asmarine B |
1 | 21.82t | 21.17t | 1.70d,1H1.45m,1H | 1.82m,2H |
2 | 28.56t | 24.13t | 1.85brd,1H1.21m,1H | 1.75m,1H1.60m,1H |
3 | 33.20t | 31.65t | 2.25dt,1H2.05dd,1H | 2.45m,1H2.12m,1H |
4 | 160.59s | 153.65s | ||
5 | 40.05s | 39.35s | ||
6 | 37.24t | 38.12t | 1.50m,2H | 2.10t,1H1.20t,1H |
7 | 27.36t | 27.22t | 1.45m,2H | 1.54m,1H1.20m,1H |
8 | 36.68d | 38.12d | 1.37m,1H | 1.35m,1H |
9 | 39.26s | 40.54s | ||
10 | 48.62d | 46.56d | 1.05d,1H | 1.39m,1H |
11 | 31.23t | 31.05t | 1.55dt,1H | 1.59m,1H |
1.25m,1H | 1.30t,1H | |||
12 | 33.01t | 31.55t | 1.95dt,1H1.43m,1H | 1.95dt,1H1.55m,1H |
13 | 64.20s | 64.95s | ||
14 | 36.68t | 36.40t | 2.50dt,1H2.15dd,1H | 2.55m,1H2.25m,1H |
15 | 42.30t | 42.33t | 4.25dt,1H4.20dd,1H | 4.30t,2H |
16 | 21.75q | 23.09q | 1.44s,3H | 1.49s,3H |
17 | 15.93q | 15.84q | 0.70d,3H | 0.74d,3H |
18 | 102.45t | 105.69t | 4.60s,2H | 4.70d,2H |
19 | 20.08q | 32.87q | 1.00s,3H | 1.11s,3H |
20 | 18.28q | 19.85q151.64d | 0.65s,3H | 0.82s,3H |
2’ | 151.68d | 8.50s,1H | 8.50d,1H | |
4’ | 149.00s | 149.57s | ||
5’ | 109.31s | 109.32s | ||
6’ | 158.70s | 158.38s | ||
8’ | 143.10d | 143.32d | 7.95s,1H | 7.95s,1H |
参考资料
1.Faulkner,D.Nat.Prod Rep.1997,14,259-302以及其中的参考资料。
2.Nakamura,H.等人。Tetrahedron Lett 1984,25,2989-2992。
3.Raymond J.Bergeron,Paul F.Cavanaugh,Jr.,Steven J.Kline,RobertG.Hughes,Jr.,Gray T.和Carl W.Porter。亚精胺儿茶酚酰胺catecholamide铁螯合剂的抗肿瘤和抗疱疹活性。Biochem.Bioph.Res.Comm.1984,121,848-85。
Claims (6)
2.依照权利要求1的化合物Asmarine A,具有下面的结构式:
3.依照权利要求1的化合物Asmarine B,具有下面的NMR数据:
4.如权利要求2所定义的Asmarine A或如权利要求3所定义的Asmarine B在制备通过给予患病个体治疗有效量的Asmarine A或Asmarine B或其药用组合物治疗罹患恶性肿瘤的哺乳动物的药物中的用途,所述恶性肿瘤对Asmarine A或Asmarine B敏感。
5.包含如权利要求2所定义的Asmarine A或如权利要求3所定义的Asmarine B作为活性成分的药用组合物。
6.制备如权利要求2所定义的Asmarine A或如权利要求3所定义的Asmarine B的方法,该方法包括从海绵Raspailia物种的提取和分离。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9727301.5 | 1997-12-23 | ||
GBGB9727301.5A GB9727301D0 (en) | 1997-12-23 | 1997-12-23 | Asmarine A and B: New cytotoxic alkaloids |
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CN1336928A CN1336928A (zh) | 2002-02-20 |
CN1258534C true CN1258534C (zh) | 2006-06-07 |
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CNB988136147A Expired - Fee Related CN1258534C (zh) | 1997-12-23 | 1998-12-23 | 由海绵分离的包括Asmarine A和B的细胞毒性生物碱衍生物 |
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EP (1) | EP1070067B1 (zh) |
JP (1) | JP2001527076A (zh) |
KR (1) | KR100533244B1 (zh) |
CN (1) | CN1258534C (zh) |
AT (1) | ATE290005T1 (zh) |
AU (1) | AU763093B2 (zh) |
BR (1) | BR9814462A (zh) |
CA (1) | CA2316308A1 (zh) |
DE (1) | DE69829223T2 (zh) |
ES (1) | ES2238782T3 (zh) |
GB (1) | GB9727301D0 (zh) |
HU (1) | HUP0100838A3 (zh) |
IL (1) | IL136956A0 (zh) |
PL (1) | PL341475A1 (zh) |
RU (1) | RU2221800C2 (zh) |
WO (1) | WO1999033832A1 (zh) |
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1997
- 1997-12-23 GB GBGB9727301.5A patent/GB9727301D0/en not_active Ceased
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1998
- 1998-12-23 CA CA002316308A patent/CA2316308A1/en not_active Abandoned
- 1998-12-23 KR KR10-2000-7006933A patent/KR100533244B1/ko not_active IP Right Cessation
- 1998-12-23 IL IL13695698A patent/IL136956A0/xx unknown
- 1998-12-23 EP EP98962610A patent/EP1070067B1/en not_active Expired - Lifetime
- 1998-12-23 AU AU17740/99A patent/AU763093B2/en not_active Ceased
- 1998-12-23 HU HU0100838A patent/HUP0100838A3/hu unknown
- 1998-12-23 PL PL98341475A patent/PL341475A1/xx not_active IP Right Cessation
- 1998-12-23 CN CNB988136147A patent/CN1258534C/zh not_active Expired - Fee Related
- 1998-12-23 WO PCT/GB1998/003884 patent/WO1999033832A1/en active IP Right Grant
- 1998-12-23 ES ES98962610T patent/ES2238782T3/es not_active Expired - Lifetime
- 1998-12-23 RU RU2000117270/04A patent/RU2221800C2/ru not_active IP Right Cessation
- 1998-12-23 JP JP2000526512A patent/JP2001527076A/ja not_active Abandoned
- 1998-12-23 DE DE69829223T patent/DE69829223T2/de not_active Expired - Fee Related
- 1998-12-23 AT AT98962610T patent/ATE290005T1/de not_active IP Right Cessation
- 1998-12-23 BR BR9814462-6A patent/BR9814462A/pt not_active Application Discontinuation
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Publication number | Publication date |
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DE69829223D1 (de) | 2005-04-07 |
HUP0100838A3 (en) | 2001-12-28 |
DE69829223T2 (de) | 2006-01-12 |
KR100533244B1 (ko) | 2005-12-05 |
WO1999033832A1 (en) | 1999-07-08 |
GB9727301D0 (en) | 1998-02-25 |
JP2001527076A (ja) | 2001-12-25 |
AU763093B2 (en) | 2003-07-10 |
HUP0100838A2 (hu) | 2001-09-28 |
ATE290005T1 (de) | 2005-03-15 |
IL136956A0 (en) | 2001-06-14 |
CA2316308A1 (en) | 1999-07-08 |
KR20010033447A (ko) | 2001-04-25 |
AU1774099A (en) | 1999-07-19 |
PL341475A1 (en) | 2001-04-23 |
BR9814462A (pt) | 2000-10-10 |
ES2238782T3 (es) | 2005-09-01 |
EP1070067B1 (en) | 2005-03-02 |
RU2221800C2 (ru) | 2004-01-20 |
CN1336928A (zh) | 2002-02-20 |
EP1070067A1 (en) | 2001-01-24 |
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