CN1152881C - 从海洋放线菌中得到的新吲哚并咔唑生物碱及其组合物和用途 - Google Patents
从海洋放线菌中得到的新吲哚并咔唑生物碱及其组合物和用途 Download PDFInfo
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- CN1152881C CN1152881C CNB008121583A CN00812158A CN1152881C CN 1152881 C CN1152881 C CN 1152881C CN B008121583 A CNB008121583 A CN B008121583A CN 00812158 A CN00812158 A CN 00812158A CN 1152881 C CN1152881 C CN 1152881C
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- 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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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本发明提供式(1)的化合物和其可药用盐,其中R1是氢原子、含1到6个碳原子的烷基或含1个到6个碳原子的烷氧基;R2是氢原子、含1到6个碳原子的烷基或含1个到6个碳原子的烷氧基。本发明也涉及一种获得这种化合物的方法、含有这种化合物的组合物和它们的治疗用途。这种化合物显示出极佳的抗哺乳动物癌细胞系的活性。
Description
发明领域
已经从产生斯太罗斯泼林(staurosporine)的放线菌(CLCO-002)的肉汤培养基中分离出新吲哚并咔唑生物碱。其通过在菌株的控制条件下需氧发酵,并分离和纯化其产物来生产。该化合物和发酵肉汤被证明具有抗几种癌细胞系的明显活性。
发明背景
蛋白质激酶C(PKC)的同功酶在信号转导和细胞调节中起着关键的作用(Y.Nishizuka,1988)。据观察肿块促进佛波醇酯对PKC活性有刺激作用(Y.Nishizuka,1984),推测该酶的抑制剂对癌的化学治疗起到有效的作用。PKC抑制剂已经被作为可能治疗癌症的药物被广泛的研究。因此,本发明的目的是提供一种新的抗癌试剂;这些化合物是含有抗多种癌细胞系活性的生物碱。
然而,本发明的另一个目的是提供药物组合物,供需要使用该活性化合物治疗的患者用药。
微生物产品由于当代已经建立了很好的工业生产,引起了人们的关注。因此,本发明的另一个目标是从发酵的肉汤中生产活性化合物并分离、提纯。
发明概述
本发明提供式(1)的化合物。
其中:
R1是氢原子,含1到6个碳原子的烷基或含1到6个碳原子的烷氧基;
R2是氢原子,含1到6个碳原子的烷基或含1到6个碳原子的烷氧基;和可药用的盐。
式(1)中R1和R2的定义中,烷基和烷氧基的烷基部分是直链或支链烷基,含1到6个碳原子诸如甲基、乙烷基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基和己基。
优选R1和R2独立地代表氢原子或含1到4个碳原子的烷基,特别是氢原子、甲基或乙基。
在本发明特别优选的实施方案中,本发明涉及4’-N-甲基-5’-羟斯太罗斯泼林(IB-97224)和5’-羟斯太罗斯泼林(IB-97225),化学结构为:IB-97224(R2=Me)IB-97225(R2=H)
本发明也描述了获得式(1)或可药用的盐的方法。这个方法包括培养能够产生式(1)化合物的微生物菌株,从培养肉汤中回收这种化合物,和可选地将所回收的化合物成盐。
产生IB-97224和IB-97225化合物的特别优选方法包括在水性营养培养基中和可同化的碳氮源和盐一起在可控浸没需氧条件下培养能够产生IB-97224和IB-97225化合物的微生物菌株。IB-97224和IB-97225化合物从培养的肉汤中回收。
优选的培养物是菌株CLCO-002,它的化学、生物化学和形态特性表明它属于放线菌。按照本发明其他的放线菌菌株也可以在本方法中使用。
如上所述,式(1)化合物特别是IB-97224和IB97225已经发现有很好的抗鼠和人类瘤细胞系的活性,包括P-388D,HT-29,A-549和SK-MEL-28。
因此,本发明也提供一种治疗或预防哺乳动物恶性肿瘤的方法,包括给需要这样治疗的哺乳动物一定的有效量的如上说明的式(1)的化合物或可药用的盐。
本发明更进一步涉及如上述定义的式(1)的化合物或可药用的盐在用于制备用于治疗或预防哺乳动物恶性肿瘤的药物中的用途。
本发明也涉及含有式(1)的化合物或可药用的盐作为活性成分以及可药用的载体或稀释剂的药物制品。
药物组合物的例子包括含有合适成分的任何固体(药片、药丸、胶囊、颗粒等等)或液体(溶液、悬浮液或乳状液),适用于口服、局部或非肠道使用,它们可以含有这种纯化合物或和载体或其他药物活性化合物相结合。当非肠道用药时这些组合物必需是无菌的。
药物组合物的正确的剂量按照具体的制剂,使用的模式、具体的位置、患者和细菌或被医治的肿瘤的不同进行调整。其他的因素象年龄、体重、性别、饮食、给药时间、排泄速度、患者的状况、药物组合、反应敏感性和疾病的严重程度应加以考虑。在最大的容忍剂量内能够连续或周期性的用药。
发明详述
生产有机体
用于生产新的化合物的微生物优选放线菌菌株,特别是放线菌菌株CLCO-002,保存在西班牙的西班牙典型培养物保藏中心,Universityof Valencia,保藏编号是CECT-3347。这项保藏符合布达佩斯条约的规定,在本申请授权时公众即可获得该保藏物。
生物体从加那利群岛的水中收集的无定形的海绵状物质中分离获得。
所有的培养在27℃下进行并记录21天的试验数据
有机生物体的描述如下:
形态
本项研究所用的培养基是ISP培养基No2、4、5和6(Shirlingand Gotlieb,1966),ATCC培养基No 172(美国典型培养物保藏中心目录,1989),Czapek琼脂(Atlas,1993),Bennet琼脂(Atlas,1993),1.5%水琼脂(Luedemann)。所有的培养基用50%的人造海水补充。在28℃生长21天后进行研究。观察到若干橙色阴影。非气生型菌丝形成。随后菌丝分支,观察到不溶性的色素。
生理学特征
用ISP-9(Shirling & Gotlieb,1966)研究碳氮的利用。由于在规定培养基中CLCO-002的生长速率低,碳和氮的利用试验表明有残余生长,因此未能获得清晰的试验结果。采用含提高NaCl浓度的ATTCs 172培养基测量NaCl抗性。盐的最适浓度是1%。用7%的盐没有观察到生长。
细胞的化学成分
氨基酸:用Hasegawa等(1983)的方法测量二氨基庚二酸。菌株CLCO-002的整个细胞水解产物中出现内消旋二氨基庚二酸的异构体。
脂肪酸:
采用Van der Auwera等(1986)的方法确定FAMEs。FAME成分以及与
其他类似菌株的成分比较在表1进行描述。
尽管保存的生物体是优选的,但本发明不限制或局限于这种特殊的菌株或生物体。本发明人的目的是包括在本发明范围内的其他的生物体、菌株和突变体。
表1
TABLE 1
菌株CLCO-002和其他放线菌菌株的FAME组成。组成的单位是总脂肪酸含量的百分数。13∶0 i-14∶0 14∶0 i-15∶0 a-15∶0 15∶0 i-16∶1 i-16∶0 16∶1 16∶0 i-17∶0 i-17∶0 a-17∶0 17∶1 17∶0 i-18∶1 i-18∶0 cia-18∶1 18∶0CLCO-002 <1 <1 <1 16.91 3.94 6.71 <1 31.83 <1 <1 3.73 <1 <1 24.3 3.31 <1 <1 4.13 <1STALBUS <1 6.52 <1 9.88 22.92 <1 5.50 25.29 <1 3.75 1.28 3.38 8.60 <1 <1 <1 1.09 <1 <1SPAMETH 1.21 10.34 <1 1.86 <1 4.30 <1 15.51 5.63. 8.62 1.08. <1 <1 24.02 9.43 7.11 <1 4.60 1.04SPVIRIDO <1 4.04 1.10 18.94 2.71 4.89 <1 26.44 <1 4.43 <1 2.60 1.58 11.36 8.58 7.48 <1 <1 1.16AMCITRE <1 <1 3.18 <1 <1 1.03 <1 6.37 12.62 40 <1 <1 <1 <1 1.16 <1 <1 4.25 2.82APBRAZL <1 3.15 <1 15.46 18.91 2.76 <1 19.07 2.15 1.79 <1 2.39 9.64 11.18 2.82 <1 <1 3.38 1.06AMPDIGIT<1 11.57 <1 11.21 9.96 <1 2.87 34.23 <1 1.08 <1 1.28 5.08 4.39 1.64 <1 1.76 7.60 1.54AMYORIE <1 3.40 2.37 19.94 4.66 1.17 <1 11.85 5.59 18.41 <1 2.99 4.44 3.09 2.73 <1 <1 6.21 3.04MNCHALC <1 1.68 <1 8.91 2.29 1.53 1.15 38.23 <1 1.88 1.49 2.32 2.25 5.43 6.95 14.58 1.31 1.28 2.68MNECHCA <1 1.17 <1 6.97 1.24 2.81 <1 30.88 <1 2.29 1.63 4.11 1.68 12.15 4.90 7.23 <1 10.05 1.69MNFUSCA <1 <1 <1 26.56 6.53 <1 <1 30.88 <1 <1 7.30 11.8913.25 2.90 3.37 3.59 <1 2.33 1.94SACCAER <1 306 1.35 14.41 8.62 1.04 5.68 20.07 13.84 6.16 4.55 2.20 5.31 2.02 <1 <1 <1 <1 1.43NOAFRI 1.51 5.43 3.35 4.62 <1 7.46 3.09 22.18 2.69 5.15 2.35 <1 <1 8.15 4.75 17.03<1 <1 1.23MTSALMO <1 1.12 1.28 6.75 <1 7.83 7.53 21.58 1.21 1.97 1.01 <1 1.07 11.58 5.53 17.34<1 <1 <1MTRUBRA <1 1.40 1.38 4.12 <1 3.41 7.27 25.00 2.63 3.89 2.17 1.08 <1 6.84 4.97 15.441.25 <1 1.61MTROSEO2.03 3.65 5.14 33.86 <1 9.03 3.02. 12.31 3.46 6.95 1.17 <1 <1 13.51 4.46 18.67 <1 1.77 <1AMROSEO <1 2.19 1.24 6.73 1.09 6.94 1.43 22.21 2.21 3.61. 2.74 1.03 <1 10.97 4.33 17.84 <1 <1 <1MTFERU 1.03 1.91 1.19 1.94 <1 6.43 4.12 21.50 2.32 2.34 <1 <1 <1 23.51 5.71 12 15 1.27 1.43 <1
CLCO-002=菌株CLCO-002;AMCITRE=Actinomadura citrea DSM
43461;AMPDIGIT=Ampullariella digitata ATCC 15349;AMROSEO
=Actinomadura roseoviolacea DSM 43144;AMYORIE=
Amycolatopsis orientais DSM 40040:<#s>APBRAZIL=
Actinoplanes braziliensis ATCC25844;MNCHALC =
Micromonospora chalcea ATCC 31395;MNECHCA =
Micromonosporaechinospora calichinensis NRRL 15839;MNFUSCA
=Micromonosporafusca NRRL B-3298;MTFERRU=Microtetraspora
ferruginea DSM 43553;MTROSEO=Microtetraspora roseola
ATCC33579;MTRUBRA=Microtetraspora rubra ATCC 27031;
MTSALMO=Microtetraspora salmoneaATCC 33580;NOAFRI=
Nocardiopsis africana DSM 43748;SACCAER=Saccharothrix
aerocolonigenes NRRL B-3298;SPAMETH=Streptosporangium
amethystogenes DSM 43179;SPVIRIDO=Streptosporangium
viridogriseum ATCC 25242;STALBUS=Streptomyces albus DSM40313
发酵
菌株CLCO-002,在适当的培养基中在受控条件下培养可产生化合物IB-97224和IB-97225。该菌株在有氧和中温条件下于液体培养基中培养,优选在22℃至35℃,pH在6.0到8.0之间。有许多种液体培养基可以用于培养有机物,有用的培养基含有可同化的碳源如淀粉,糊精,糖蜜,甘油,葡萄糖等,可同化的氮源如蛋白质类,蛋白水解产物,脱脂的谷类,玉米浆等,和有用的无阴离子和阳离子如钠,镁,钾,铵,硫酸盐,氯化物,磷酸盐,碳酸盐等。微量元素也可以被添加到其中。通风可以将空气补充到发酵培养基中。搅拌是以机械转子提供的。常规的发酵罐非常适合培养该微生物。为了增加生产和避免泡沫形成,发酵过程中可能需要添加营养和pH控制及消泡剂。
通过优选的有机体生产这些化合物必需的步骤是:
从冷冻或冻干的菌丝体开始。原始的细胞在含有如上所述的成分的培养基的摇瓶中于中温和好氧的条件下培养获得菌丝体,这个过程可能需要重复几次,收集的材料作为种子接种一个或几个含有合适培养基的发酵罐,需要时这些发酵罐也可以用作种子,必要时,这一步骤可以重复几次,或者它们可以用于生产阶段,这取决于所需的发酵液体积。生产阶段可以持续从几天到超过一个星期,这取决于菌株、接种阶段、温度和其他的条件。一旦发酵达到了最高的产率,就可以收集用于分离这种新的化合物。
生产阶段的培养基可以不同于接种所使用的培养基。表2列出了能够用于接种和生产这些新化合物的典型培养基。
表2
接种培养基 (g/L) 生产培养基 (g/L)葡萄糖 5 葡萄糖 5淀粉 20 糊精 20牛肉膏 3 大豆粉 3酵母膏 5 酵母膏 5蛋白胨 5 蛋白胨 1CaCO3 4 CaCO3 4NaCl 4 NaCl 5 |
Na2SO4 1 Na2SO4 2.5KCl 0.5 KCl 0.5MgCl2 2 MgCl2 0.5K2HPO4 0.5 K2HPO4 0.5(NH4)2SO4 0.5加入水定容至1000ml |
这些化合物的生产能够采用通过HPLC或其他足够敏感的方法对整个肉汤的抗A-549或任何其他敏感细胞的分析进行监测。
分离IB-97224和IB-97225
生物碱IB-97224和IB-97225能够采用合适的溶剂混合物如CHCl3∶CH3OH∶H2O通过萃取的方法从这些菌丝体分离。在底层活性被浓缩。合并两次重复萃取获得的萃取物并真空干燥。
从粗活性萃取物分离和纯化IB-97224和IB-97225可以采用合适的常规层析技术的组合。
分馏可以通过馏分的抗癌活性或通过用浓硫酸中的香草醛显色的TLC或采用光电二极管探测器的分析HPLC进行指导。HPLC在室温下进行(Waters RCM 8x10,8C18 10μm柱),使用乙腈-磷酸氢钠0.025M pH=3(75∶25)作为流动相,流速2ml/min,在290nm作图。目标化合物的保留时间为3.92和3.29分钟,分别对应于IB-97224和IB-97225。
下面给出的光谱数据能够确定这些化合物是IB-97224和IB-97225。不同的原子采用如下的系统编号。采用下列缩写:红外光谱:w:弱;m:中;s:强;br:宽核磁共振光谱:s:单;d:双;t:三;dd:双双
4’-N-甲基-5’-羟基斯太罗斯泼林(IB-97224)(R2=Me)IR(KBr)vmax/cm-1:3406(s,br),3070(m),2925(s),2852(m),1915(w,br),1664(s),1583(s),1450(m),1415(m),1391(s),1351(s),1319(s),1281(s),1249(s),1236(m),1223(m),1181(m),1150(m),1117(s),1103(s),1066(s),1018(m),988(m),887(w),835(w),816(w),742(s),698(w),664(w),636(w),609(w)。
1H NMR(300MHz,CDCl3),δ/ppm:9.43(1H,d,J 7.7Hz,C4
H),
7.90(1H,d,J7.7Hz,C8
H),7.76(1H,d,J7.7Hz,C11
H),
7.64(1H,d,J7.7Hz,C1
H),7.53(1H,t,J7.7Hz,C2
H),
7.45(1H,t,J7.7Hz,C10
H),7.38(1H,t,J7.7Hz,C3
H),
7.34(1H,t,J7.7Hz,C9
H),6.52(1H,s,C6’
H),6.50(1H,s,N6
H),4.99(1H,s,C7
H),4.43(1H,d,J9.9Hz,C5’
H),3.95(1H,s,C3
H),3.02(1H,d,J9.9Hz.C4’
H),2.48(3H.s.CH3),2.37 (6H,s,N4’(CH3)2),2.03(3H,s,CH3O)。
13C NMR(75 MHz,CDCl3),173.65(C5),137.86(C11a),137.12(C13a),131.94(C7a),130.64(C12a),126.79(C12b),126.13(C4),125.46(C2),124.94(C10),124.54(C7c),123.22(C4a),121.49(C8),120.43(C9),119.98(C3),118.89(C4c),115.86(C4b),114.14(C7b), 111.46(C11),108.97(C1),94.92(C2’),91.54(C6’),79.30(C3’),69.50(C5’),66.75(C4’),58.36(CH3O),45.79(C7),41.67(N4’(CH3)2),28.00(CH3)。UV(75:25CH3CN/0.025 M Na2HPO4 pH 3),λmax/nm:370,354,334,320,291,242,206。
m/z(快原子轰击)497.2(MH+)。5’-羟基斯太罗斯泼林(IB-97225)(R2=H)
IR(KBr)vmax/cm-1:3415(s,br),3070(m),2931(m),2851(m),1991(w,br),1664(s),1583(m),1453(s),1416(m),1392(m),1352(s),1317(s),1280(m),1248(m),1236(m),1225(m),1151(m),1130(m),1118(m),1064(m),1036(m),1017(m),973(w),927(w),896(w),860(w),836(w),814(w),772(m),746(s),651(w),638(w)。
1H NMR 300 MHz,CDCl3),δ/ppm:9.40(1H,d,J 7.4 Hz.C4
H),7.89(1H,d,J 7.4Hz,C8
H),7.85(1H,d,7.4,C11
H),7.53(1H,d.J8.1Hz,C1
H),7.44(2H,t,J 7.4Hz,C2
H & C10
H),7.31(2H,t,J 7.4Hz,C3
H & C9
H),6.49(1H,d,J 1.2Hz,C6’
H),6.43(1H,s,N6
H),4.98(1H,s,C7
H),4.26(1H,dd,J 6.8Hz,1.2 Hz,C5’
H),4.14(1H,d,J 2.8Hz,C3’
H),3.09(1H,dd,J 6.8Hz,2.8Hz,C4’
H),2.71(3H,s,CH3O),2.45(3H,s,CH3),2.17(3H,s,CH3N4’)。
13CNMR(75MHz,CDCl3),8/ppm:173.81(C5),138.86(C11a),137.05(C13a),132.17(C7a),130.50(C12a),126.89(C12b),126.13(C4),125.33(C2),124.67(C10),124.52(C7c),123.24(C4a),121.01(C8),120.32(C9),119.92(C3),118.56(C4c),115.64(C4b),114.19(C7b),113.50(C11),108.10(C1),92.37(C2’),88.38(C6’),80.14(C3’),70.03(C5’),60.11(C4’),59.02(CH3O),45.88(C7),33.68(CH3N4’),28.96(CH3)。
UV(75:25 CH3CN/0.025 M Na2HPO4 pH3),λmax/nm:370,354,334,320,291,242,206。
m/z(快原子轰击)483.2(MH+)。
生物活性
在小鼠白血病P-388DI,人类肺癌A-549,人类结肠癌HT-29和人类黑色素瘤SK-MEL-28的细胞培养物中体外测定了IB-97224和IB-97225的抗癌活性。测定采用了Bergeron,等(1984),和Schroeder等(1981)描述的方法进行。
本发明将参照下述实施例进一步说明,这些实施例是为了理解本发明,而非限制本发明。这里所报告的百分数除非特别指定,都是重量百分数。所有温度用摄氏温度。所有的培养都是在28℃和在摇床上的摇瓶中进行的。所有的培养基和容器都是已灭菌的,所有的培养过程都是无菌的。
实施例1
种子培养物:菌株CLCO-002的肉汤纯培养被冷冻保存在20%的甘油中。
种子:向含有如前所述的100ml种子培养基的250cc摇瓶中接种冰冻培养物或斜面培养物(5%体积)。温育48小时。用10%的第一阶段种子接种含有500毫升相同培养基的2L烧瓶。再温育48小时。
发酵: 用第二阶段培养的2.5L在75L发酵罐中接种50L的生产用的培养基。用400 rpm的搅拌速度和0.5V/V.M通气发酵96小时。
通过对全肉汤的抗A-549分析或采用HPLC来监测第二阶段代谢生产。
分离:收集的10L全肉汤过滤分离生物物质和其他固体。菌丝体被CHCl3∶CH3OH∶H2O(2∶1∶1)溶剂混合物(2.41)萃取两次,在低层浓缩活性物质。有机溶剂真空浓缩、干燥获得3.2g的粗萃取物。萃取物在硅胶凝胶“真空反射”柱上层析。在用正乙烷-乙酸乙酯按1∶1混合洗脱后,这根柱用乙酸乙酯-甲醇梯度展开。洗脱过程通过抗A-539细胞的细胞毒性检测,并用TLC(氯仿-甲醇9∶1)和分析反相HPLC-光电二极管分析进行监测。采用硅胶柱层析进一步提纯活性部分(250mg)并用氯仿-甲醇92∶8和95∶5洗脱活性物质。在C18柱反相上层析分离,并用甲醇-水65∶35洗脱得到12mg的斯太罗斯泼林,4mg的IB-97224和8mg的IB-97225。
生物活性:所使用的抗癌细胞是P-388D1(从DBA/2小鼠中得到的淋巴瘤悬浮培养物),A-549(人类大红细胞肺癌单层培养物),HT-29(人类结肠癌的单层培养物),和SK-MEL-28(人类黑色素瘤的单层培养物)。P-388D1细胞以每孔1×104细胞在1ml含有指定浓度药物的MEM 5FCS中接种于16mm的孔中。没有药物的培养物接种作为对照生长,以确保细胞保持在指数生长阶段。所有的检测被重复。在37℃含10%CO2,湿度为98%的气氛中培养三天后,比较有药的孔和没有药的对照生长情况来计算IC50。在1ml的指定浓度药物MEM5FCS中的A-549,HT-29和SK-MEL-28细胞以每孔2×104细胞接种16mm的孔中。没有药物的一组培养基接种作为对照生长,以确保细胞处于指数生长阶段。所有的检测被重复。在37℃含10%CO2,湿度为98%的气氛中培养三天后,各孔用0.1%的结晶紫染色。通过比较有药物的孔和没有药物的对照孔的生长情况来计算IC50。表3是IC50(μM)表示的活性。
表3
细胞系 IC50(μM)
IB-97224 IB-97225
P388D1 0.04 0.02
A-549 0.002 0.002
HT-29 0.004 0.004
SK-MEL-28 0.004 0.002
参考文献
本文引用下述参考资料,它们被引用作为参考。Nishizuka,Y.,Nature 334:661-665,1988Nishizuka,Y.,Nature 308:693-698,1984Shirling B.E.,and Gotlieb D.,Int.J Syst.Bacteriol.16:313-340,1966American Type Culture Catalog 17th edition,1989.Rockville,Maryland.U.S.A.Atlas R.M.,Handbook of Microbiological Media,1993 CRC Inc.Boca Raton,Florida.USALuedemann G.M.Personal CommunicationHasegawa T.,Takizawa M.,and Tanida S.,J. Gen.Appl.Microbiol.29:319-322,1983Van der Auwera P.,Labbe M.,Mayberry W.R.,Ferguson K.P.,and Lambe D.W.Jr.,J.Microbiol.Methods 4:265-275,1986Bergeron et al.,Biochem.Biophys.Res.Comm.,121:848-854,1984Schroeder et al.,J.Med.Chem.,24:1078,1981
Claims (14)
1.式(1)的化合物和其可药用的盐:
其中:
R2是氢原子、含1到6个碳原子的烷基或含1到6个碳原子的烷氧基;
R2是氢原子,含1到6个碳原子的烷基或含1到6个碳原子的烷氧基。
2.权利要求1的化合物,其中R1是氢原子或含1到4个碳原子的烷基。
3.权利要求2的化合物,其中R2是氢原子、甲基或乙基。
4.权利要求3的化合物,其中R2是氢原子。
5.权利要求1的化合物,其中R2是氢原子或含1到4个碳原子的烷基。
6.权利要求5的化合物,其中R2是氢原子、甲基或乙基。
7.权利要求6的化合物,其中R2是氢原子或甲基。
8.权利要求1的化合物,其中
R1是氢原子或含1到4个碳原子的烷基,
R2是氢原子或含1到4个碳原子的烷基。
9.权利要求8的化合物,其中
R1是氢原子、甲基或乙基
R2是氢原子、甲基或乙基。
10.权利要求1的化合物,其中R1是氢原子,R2是甲基。
11.权利要求1的化合物,其中R1和R2都是氢原子。
12.生产权利要求1到11任一项中的式(1)的化合物或其可药用的盐的方法,包括培养放线菌菌株CLCO-002(CECT-3347),从培养肉汤中回收式(1)化合物,和可选地使回收的化合物成盐。
13.含有权利要求1到11任一项中的式(1)化合物或其可药用的盐作为活性成分以及可药用的载体或稀释剂的药物组合物。
14.权利要求1到11任一项的式(1)化合物或其可药用的盐用于制备治疗或预防哺乳动物恶性肿瘤的药物中的用途。
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