CN1390218A - 新的活性海洋生物碱类物质 - Google Patents
新的活性海洋生物碱类物质 Download PDFInfo
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- CN1390218A CN1390218A CN00815559A CN00815559A CN1390218A CN 1390218 A CN1390218 A CN 1390218A CN 00815559 A CN00815559 A CN 00815559A CN 00815559 A CN00815559 A CN 00815559A CN 1390218 A CN1390218 A CN 1390218A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
通式(I)的新的抗肿瘤生物碱类,其中R1为氢、烷基或酰基,R2为氢或酰基,所述生物碱类包括其中R1为氢且R2为乙酰基的胶汝霉素,其从软体动物Jorunna funebris中萃取得到。
Description
本发明涉及新的活性生物碱类,特别是涉及从软体动物Jorunnafunebris中分离得到的生物碱类。
海洋生物特别是软珊瑚、海绵动物和被囊动物提供许多次级代谢物,其不同程度地显示出生物学活性(Faulkner,D.J.Nat.Prod.Reports.,1999,16:155-198,以及其中所引用的参考文献)。
发明概述
本发明提供具有下列式(I)的生物碱类:其中R1选自氢、低级烷基和低级酰基,R2选自氢和低级酰基。在式(I)基团的定义中,低级烷基和低级酰基中的低级烷基部分通常为具有1-6个碳原子的直链或支链烷基,例如甲基、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。
胶汝霉素(Jorumycin)显示抗肿瘤活性。具体地说,胶汝霉素对于人实体瘤细胞系显示抗肿瘤活性,其中所述的人实体瘤例如人肺癌、人结肠癌和人黑素瘤等,其对于其它肿瘤细胞系例如白血病和淋巴瘤也具有活性。
本发明还提供治疗患有恶性肿瘤的哺乳动物的方法,所述恶性肿瘤对式(I)化合物是敏感的,所述方法包含给药治疗有效量的式(I)化合物或其可药用组合物。
本发明还提供含有式(I)化合物作为活性成分的药物组合物和该组合物的制备方法。
本发明还提供式(I)化合物在制备用于治疗或预防肿瘤的药物中的应用。
更具体地说,本发明涉及胶汝霉素(在式(I)化合物中R1=H并且R2=Ac),其从软体动物Jorunna funebris中提取并分离得到。胶汝霉素的结构式为:
本发明提供不含有其它在软体动物中存在的化合物的胶汝霉素,以及基本上纯的胶汝霉素。本发明另一方面提供制备化合物胶汝霉素(在式(I)中,R1=H并且R2=Ac)的方法,所述方法包含从软体动物Jorunna funebris中提取和分离。
本发明优选的实施方案
药物组合物的例子包括任何适合口服、局部、胃肠外或其它途径给药的固体制剂(片剂、丸剂、胶囊和粒剂等)或液体制剂(溶液剂、混悬剂或乳剂),它们可以含有纯的化合物或者与任意载体或其它药理学活性化合物结合。当胃肠外给药时,这些组合物可能需要进行消毒。
含有式(I)化合物的药物组合物的正确剂量可以根据下列因素进行改变:药物剂型、应用方式和用药部位、所需治疗的宿主和肿瘤。另外还应该考虑其它因素例如年龄、体重、性别、饮食、给药时间、排泄速率、宿主的健康状况、结合的药物、反应敏感性和疾病的严重程度。在最大耐受剂量范围内可以连续给药或周期性给药。抗肿瘤活性
把细胞置于Eagle’s最低必需培养基中维持在对数生长期,其中所述Eagle’s最低必需培养基含有Earle’s平衡盐、2.0mM L-谷氨酰胺、非必需氨基酸,不含碳酸氢钠(EMEM/neaa);补充10%胎牛血清(FCS)、10-2M碳酸氢钠和0.1g/l青霉素-G+硫酸链霉素。
已经进行了筛选方法来确定和比较这些化合物的抗肿瘤活性,所采用的方法为Bergeron等记载的改良方法(Raymond J Bergeron,Paul F Cavanaugh,Jr,Steven J Kline,Robert G Hughes,Jr,GaryT Elliot和Carl W Porter。亚精胺儿茶酚酰胺铁螯合剂的抗肿瘤和抗疱疹活性。Biochem.Bioph.Res.Comm.1984,121:848-854)。所应用的抗肿瘤细胞为P-388(DBA/2小鼠淋巴瘤的悬浮培养物)、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(人黑素瘤的单层培养物)。
以1×104个细胞/孔的浓度把P-388细胞置于16mm孔中培养,各个孔含有1ml等份的含有指示浓度药物的MEM 5FCS。把不含药物的独立培养物作为对照生长组培养从而使细胞处于指数生长期。所有测定以一式双份进行。在37℃温度、10%CO2和98%湿气环境中培养3天后,把药物组孔中的生长与对照组孔中的生长进行比较确定大约的IC50值。
以2×104个细胞/孔的浓度把A-549、HT-29和MEL-28细胞置于16mm孔中培养,各个孔含有1ml等份的含有指示浓度药物的MEM10FCS。把不含药物的独立培养物作为对照生长组培养从而使细胞处于指数生长期。所有测定以一式双份进行。在37℃温度、10%CO2和98%湿气环境中培养3天后,用0.1%结晶紫将这些孔染色。把药物组孔中的生长与对照组孔中的生长进行比较确定大约的IC50值。
结果列于下表:
抗肿瘤活性
IC50(μM) | ||||
P-388 | A-549 | HT-29 | MEL-28 | |
胶汝霉素 | 0.02 | 0.02 | 0.02 | 0.02 |
胶汝霉素对于还显示抗格兰氏阳性菌(葡萄球菌属及其它属细菌)的活性。提取和分离
从1998年4月Mandapam(印度)收集的软体动物Jorunnafunebris(Molusca:Nudibranchia:Doridina:Kentrodorididae)中分离得到胶汝霉素。该产品以nudibranch的粘液和外膜提取物的形式存在。在通常的方法中,用丙酮提取冷冻的生物学样品(粘液或动物体)。减压除去有机溶剂后,将残余物分配于水(15ml)和乙酸乙酯中。用乙酸乙酯(共34毫升)提取水相3次。减压除去有机溶剂得到油状残余物,将其经Sephadex LH-20色谱分离,然后用SiO2-TLC洗脱提取物组份(CHC13/甲醇95∶5,Rf=0.4)。用连续SiO2色谱(氯仿/甲醇)和HPLC(Sherisorb S5W分析柱,等度洗脱:正己烷/CHC13/TEA 90:10:10,检测器:
Waters R401差示折光计)获得最终纯化的胶汝霉素。该产品溶于CHC13、二氯甲烷和甲醇,其在酸和碱介质中高度不稳定。
胶汝霉素:(C27H30N2O9);[α]Dz-57°(c0.05 CHCl3);IP(液体膜)3310,1731,1700cm-1;UV(MeOH)268nm(ε=15000);1H-NMR(CDCl3)δ1.25(m,1H),1.75(s,3H),1.93(s,3H),1.96(s,3H),2.24(d,1H,J=20.1Hz),2.26(s,3H),2.65(dd,1H,J=20.1和7.3Hz),2.84(dd,1H,J=16.7和2.1Hz)3.16(bdt,1H,J=12.0,2.7和2.7Hz).3.18(bs,1H),3.82(dd,1H,J=11.2和3.5Hz),3.90(bs,1H),3.98(s,3H),4.00(bs,3H),4.36(bm,1H),4.40(bs,1H),4.42(dd,1H,J=11.2和3.7Hz);13C-NMR(CDCl3)δ185.8(s),181.3(s),170.0(s),155.7(s),155.0(s),141.9(s),141.7(s),137.2(s),128.8(s),128.4(s),113.8(s),109.4(s),83.0(d),65.2(t),61.0(d),57.7(d),56.1(d),54.4(d),52.6(d),41.3(q),25.5(t),20.7(q),20.6(t),8.8(q),8.7(q);ESMS(m/z)526(20,M+),508(100,M-H2O),494(10,M-32);HRESMS(m/z)508.189(Δ+5mmu).
其它的式(I)化合物可以容易通过化学合成或半合成制备得到。
Claims (6)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9921477.7 | 1999-09-10 | ||
GBGB9921477.7A GB9921477D0 (en) | 1999-09-10 | 1999-09-10 | New active marine alkaloids |
Publications (1)
Publication Number | Publication Date |
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CN1390218A true CN1390218A (zh) | 2003-01-08 |
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Application Number | Title | Priority Date | Filing Date |
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CN00815559A Pending CN1390218A (zh) | 1999-09-10 | 2000-09-11 | 新的活性海洋生物碱类物质 |
Country Status (15)
Country | Link |
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EP (1) | EP1210346B1 (zh) |
JP (1) | JP2003509424A (zh) |
CN (1) | CN1390218A (zh) |
AT (1) | ATE244242T1 (zh) |
AU (1) | AU7028500A (zh) |
BR (1) | BR0014176A (zh) |
CA (1) | CA2384656A1 (zh) |
DE (1) | DE60003697T2 (zh) |
DK (1) | DK1210346T3 (zh) |
ES (1) | ES2200922T3 (zh) |
GB (1) | GB9921477D0 (zh) |
IL (1) | IL148590A0 (zh) |
MX (1) | MXPA02002615A (zh) |
PT (1) | PT1210346E (zh) |
WO (1) | WO2001019824A2 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100358516C (zh) * | 2004-12-07 | 2008-01-02 | 中国科学院大连化学物理研究所 | 一种多皱软磺酸在抗hiv-1病毒的药物中的应用 |
CN104755084A (zh) * | 2012-08-29 | 2015-07-01 | 南加州大学 | 抑制缺氧诱导型转录因子复合体的活性的组合物和方法及其治疗肿瘤的用途 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2447553A1 (en) | 2000-11-03 | 2002-05-23 | President And Fellows Of Harvard College | Saframycins, analogues and uses thereof |
US7183054B2 (en) | 2003-06-03 | 2007-02-27 | President And Fellows Of Harvard College | Assay for identifying biological targets of polynucleotide-binding compounds |
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Publication number | Priority date | Publication date | Assignee | Title |
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EP0262085A1 (de) * | 1986-08-15 | 1988-03-30 | Gesellschaft für Biotechnologische Forschung mbH (GBF) | Antibiotika aus Myxococcus |
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1999
- 1999-09-10 GB GBGB9921477.7A patent/GB9921477D0/en not_active Ceased
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- 2000-09-11 AT AT00958872T patent/ATE244242T1/de not_active IP Right Cessation
- 2000-09-11 EP EP00958872A patent/EP1210346B1/en not_active Expired - Lifetime
- 2000-09-11 DE DE60003697T patent/DE60003697T2/de not_active Expired - Fee Related
- 2000-09-11 DK DK00958872T patent/DK1210346T3/da active
- 2000-09-11 WO PCT/GB2000/003489 patent/WO2001019824A2/en active IP Right Grant
- 2000-09-11 CA CA002384656A patent/CA2384656A1/en not_active Abandoned
- 2000-09-11 ES ES00958872T patent/ES2200922T3/es not_active Expired - Lifetime
- 2000-09-11 AU AU70285/00A patent/AU7028500A/en not_active Abandoned
- 2000-09-11 BR BR0014176-3A patent/BR0014176A/pt not_active IP Right Cessation
- 2000-09-11 PT PT00958872T patent/PT1210346E/pt unknown
- 2000-09-11 IL IL14859000A patent/IL148590A0/xx unknown
- 2000-09-11 CN CN00815559A patent/CN1390218A/zh active Pending
- 2000-09-11 JP JP2001523401A patent/JP2003509424A/ja not_active Withdrawn
- 2000-09-11 MX MXPA02002615A patent/MXPA02002615A/es unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100358516C (zh) * | 2004-12-07 | 2008-01-02 | 中国科学院大连化学物理研究所 | 一种多皱软磺酸在抗hiv-1病毒的药物中的应用 |
CN104755084A (zh) * | 2012-08-29 | 2015-07-01 | 南加州大学 | 抑制缺氧诱导型转录因子复合体的活性的组合物和方法及其治疗肿瘤的用途 |
CN104755084B (zh) * | 2012-08-29 | 2018-04-03 | 南加州大学 | 抑制缺氧诱导型转录因子复合体的活性的组合物和方法及其治疗肿瘤的用途 |
Also Published As
Publication number | Publication date |
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DK1210346T3 (da) | 2003-10-06 |
WO2001019824A3 (en) | 2001-09-27 |
JP2003509424A (ja) | 2003-03-11 |
IL148590A0 (en) | 2002-09-12 |
ES2200922T3 (es) | 2004-03-16 |
ATE244242T1 (de) | 2003-07-15 |
MXPA02002615A (es) | 2002-10-23 |
PT1210346E (pt) | 2003-09-30 |
EP1210346A2 (en) | 2002-06-05 |
CA2384656A1 (en) | 2001-03-22 |
DE60003697T2 (de) | 2004-06-17 |
BR0014176A (pt) | 2002-05-07 |
AU7028500A (en) | 2001-04-17 |
GB9921477D0 (en) | 1999-11-17 |
DE60003697D1 (de) | 2003-08-07 |
WO2001019824A2 (en) | 2001-03-22 |
EP1210346B1 (en) | 2003-07-02 |
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