CN1320127A - 新的含三(噁唑)的细胞毒性大环内酯化合物 - Google Patents
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- A—HUMAN NECESSITIES
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Abstract
给出了两种新的含三(噁唑)的细胞毒性大环内酯化合物,HA-1和TH-2。这些化合物通过化学修饰海洋天然产物制得。根据NMR数据确定了这些化合物的结构。
Description
本发明涉及通过化学修饰海洋天然产物得到的新的含三(噁唑)的细胞毒性大环内酯化合物。
发明背景
海洋生物、特别是软珊瑚、海绵和被囊动物可以提供多种次级代谢物并且具有不同程度的生物学活性(参考文献1)。这些代谢物的一个重要家族是含三(噁唑)的细胞毒性大环内酯化合物家族;于1986年首先报道了三种含三(噁唑)的大环内酯化合物的结构:Ulapualide A和B(参考文献2)和Kabiramide C(参考文献3)。
此后,又公开了30多种含三(噁唑)的大环内酯化合物(参考文献4)。
发明概述
本发明涉及式(Ⅰ)的新的含三(噁唑)的细胞毒性大环内酯化合物:其中X表示低级烷基;R1和R2表示氢或低级烷基;R3a表示氢,R3b表示或或R3a和R3b合在一起表示氧;R4表示氢、低级烷氧基或低级烷基;R5表示氢、氨基甲酰基或低级链烷酰基;R6a表示氢,R6b表示羟基,或者R6a和R6b合在一起表示氧;R7表示氢、低级烷基或羟基甲基;R8表示低级烷氧基或低级烷基;Y1表示氢或甲基,Y2表示氢,或者Y1和Y2合在一起表示双键。
在式(Ⅰ)基团的定义中,低级烷基和低级链烷酰基或低级烷氧基的低级烷基部分是指含有1-6个碳原子的直链或支链烷基,例如甲基、低级烷基部分是指含有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。
HA-1和TH-2分别通过化学修饰已知的Kabiramide B和C制得。
HA-1和TH-2具有抗肿瘤活性。具体地讲,HA-1和TH-2对于从人实体瘤如人肺癌、人结肠癌和人黑素瘤等衍生的细胞系具有抗肿瘤活性,它们对其它肿瘤细胞系如白血病和淋巴瘤也具有活性。这些化合物,HA-1和TH-2,对实体瘤具有体外抗肿瘤选择性。
本发明还涉及对患有对式(Ⅰ)化合物敏感的恶性肿瘤的哺乳动物进行治疗的方法,该方法包括,向感染的个体施用治疗有效量的式(Ⅰ)化合物或其药物组合物。
本发明还提供含有作为活性成分的式(Ⅰ)化合物的药物组合物及其制备方法。
另一方面,本发明涉及制备化合物HA-1和TH-2的方法,该方法包括,分别对Kabiramide B和C进行化学修饰。
药物组合物的例子包括适于口服、局部或胃肠外给药的任何固体(片剂、丸剂、胶囊、颗粒剂等)或液体(溶液、混悬液或乳液)制剂,它们可以含有纯的化合物或同时含有任何载体或其它的药理学活性化合物。当进行胃肠外给药时,这些组合物必需是无菌的。
含有式(Ⅰ)化合物的药物组合物的适宜剂量取决于药物制剂、给药方式、具体部位、所治疗患者以及肿瘤。其它因素如年龄、体重、性别、饮食、给药时间、排泄速率、患者的病情、药物联用、疾病的反应敏感性和严重程度也应考虑。给药可以在最大耐受剂量范围内连续地或周期性地进行。抗肿瘤活性
将细胞在Eagle’s最低基本培养液中保持在对数生长期,所述培养液含有Eagle’s平衡盐、2.0mM L-谷氨酰胺、非基础氨基酸,不含碳酸氢钠(EMEM/neaa);用10%胎牛血清(FCS)、10-2M碳酸氢钠和0.1g/l青霉素-G+硫酸链霉素补充。
采用Bergeron等所述方法(参考文献5)的改良形式进行筛选,以确定并比较这些化合物的抗肿瘤活性。所采用的抗肿瘤细胞为P-388(来自DBA/2小鼠的淋巴瘤悬浮培养物)、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)。
将P-388细胞用1ml含有给定药物浓度的MEM 5FCS等份液以每孔1×104细胞接种到16mm孔中。接种另外一组不含药物的培养物作为对照生长以确保细胞保持在生长的指数期。所有测定均一式两份地进行。于37℃、10%CO2下在98%潮湿气氛中温育3天后,通过将含药物孔中的生长与对照孔中的生长相比较确定IC50的近似值。
将A-549、HT-29和MEL-28细胞用1ml含有给定药物浓度的MEM10FCS等份液以每孔2×104细胞接种到16mm孔中。接种另外一组不含药物的培养物作为对照生长以确保细胞保持在生长的指数期。所有测定均一式两份地进行。于37℃、10%CO2下在98%潮湿气氛中温育3天后,将孔用0.1%结晶紫染色。通过将含药物孔中的生长与对照孔中的生长相比较确定IC50的近似值。
在下表中给出了用细胞系P-388、A-549、HT-29和MEL-28进行的HA-1和TH-2体外细胞毒性试验的结果:
化合物 | IC50(μM) |
P-388 A-549 HT-29 MEL-28 | |
HA-1TH-2 | 0.010 0.001 0.001 0.0010.011 0.002 0.002 0.002 |
以上结果表明,带有末端醛甲基的化合物HA-1和TH-2对A-549、HT-29和MEL-28等实体瘤具有体外抗肿瘤选择性。已知的Kabiramide B和C的分离
于1997年5月从Sichang岛采集未鉴定的黑色海绵(湿重,13.2kg)。将其二氯甲烷部分(67g)首先通过硅胶真空快速色谱(VFC,分步洗脱)分离,然后通过Sephadex(二氯甲烷-甲醇,1-1)分离,最后通过反相HPLC(甲醇-水-乙酸乙酯,3-2-1)分离得到Kabiramide B(参考文献6)(24.0mg)和Kabiramide C(参考文献3)(35.0mg)。
将Kabiramide B(24.0mg)在10ml酸性二氧六环水溶液(0.5N HCl-二氧六环,2-3)中于50℃处理2小时制备化合物HA-1。将粗产物在反相HPLC上分离得到6.4mg(28%)玻璃样的化合物HA-1和7.1mg(30%)回收的Kabiramide B。
HA-1的NMR数据为:
所有化学位移均是相对于TMS(δ=0ppm)。1H NMR(CDCl3):δ9.75(1H,t,J=2.5Hz),8.10(1H,s),8.04(1H,s),7.59(1H,s),7.29(1H,m),6.33(1H,d,J=16.0Hz),5.18(1H,dt,J=2.0,10.0Hz),5.02(1H,dd,J=8.0,12.0Hz),4.85(1H,s),4.15(1H,m),3.84(1H,m),3.45(3H,s),3.37(3H,s),3.30(3H,s),3.27(1H,dd,J=4.0,7.5Hz),3.07(1H,m),2.73(1H,m),2.62(1H,m),2.57(1H,m),2.53(2H,m),2.45(1H,m),2.43(2H,m),2.36(1H,dd,J=2.0,8.0Hz),2.25(1H,m),2.09(1H,m),1.85(3H,m),1.75(1H,m),1.72(3H,m),1.46(2H,m),1.35(1H,m),1.05(3H,d,J=7.0Hz),1.02(3H,d,J=7.0Hz),1.01(3H,d,J=7.0Hz),0.97(3H,d,J=7.0Hz),0.93(3H,d,J=7.0Hz),0.83(3H,d,J=7.0Hz).13C NMR(CDCl3):δ213.3s,201.8d,172.0s,163.9s,157.7s,156.5s,155.4s,145.5d,141.7s,137.2d,136.9d,135.7d,131.1s,129.8s,115.1d,87.5d,82.2d,78.2d,74.4d,73.5d,70.4d,68.2d,60.6q,57.9q,57.6q,48.7t,46.1t,45.3t,43.4t,42.8t,42.7d,41.7t,37.8t,37.3d,34.7d,34.6t,31.0d,25.3t,25.1d,18.3q(2C),15.6q,13.4q,10.6q,9.2q.IR(CHCl3)3470,3015,1720,1650,1460,1315,1215,915,665cm-1.TH-2的合成
将Kabiramide C(35.0mg)在10ml 0.5N HCl-二氧六环(2-3)中的混合物于50℃搅拌2小时。将混合物在乙酸乙酯和水之间进行分配,然后将有机层浓缩。将粗产物在反相HPLC(乙腈-水-乙酸乙酯,6-4-1)上分离得到11.0mg(33%)玻璃样的化合物TH-2和18.3mg(52%)回收的Kabiramide C。TH-2的NMR数据为:所有化学位移均是相对于TMS(δ=0ppm)。1H NMR(CDCl3)δ9.75(1H,t,J=2.3Hz),8.09(1H,s),8.03(1H,s),7.58(1H,d,J=1.0Hz),7.46(1H,ddd,J=16.0,9.5,5.0Hz),6.29(1H,d,J=16.0Hz),5.32(1H,m),5.17(1H,t,J=10.5Hz),4.80(1H,s),3.84(1H,m),3.67(1H,m),3.45(3H,s),3.43(3H,s),3.33(3H,s),3.30(3H,s),3.27(1H,m),3.01(1H,m),2.81(1H,m),2.72(1H,t,J=8.0Hz),2.59(1H,dd.J=14.3,9.7Hz),2.52(1H,m)2.44(1H,m),2.41(1H,m),2.36(1H,m),2.32(1H,m),2.15(1H,m),1.85(1H,m),1.46(1H,m),1.34(1H,m),1.04(3H,d,J=6.7Hz),1.01(3H,d,J=7.0Hz),0.99(3H,d,J=7.0Hz),0.94(3H,d,J=7.0Hz),0.87(3H,d,J=6.4Hz),0.83(3H,d,J=7.0Hz).13C NMR(CDCl3)δ213.4s,201.8d,171.6s,163.2s,157.3s,156.4s,155.4s,142.0d,141.4s,137.1d,136.8d,135.6d,131.1s,129.9s,115.5d,87.4d,82.0d,79.2d,78.3d,74.0d,73.3d,69.3d,60.6q,57.9q,57.6q,57.5q,48.6t,46.0t,45.0t,43.6t,42.9t,41,7t,40.4d,37.3d,34.5d,33.9t,32.9t,30.9d,25.0d(2C),18.2q(2C),15.5q,13.3q,10.7q,8.4q.
参考文献1.Faulkner,D.天然产物报道(Nat.Prod.Rep.)1997,14,259-302以及其中的参考文献。2.Scheuer,P.J.等,美国化学会志(J.Am.Chem.Soc.)1986,108,846-847。3.Fusetani,N.等,美国化学会志(J.Am.Chem.Soc.)1986,108,847-849。4.海洋生物技术(Marine Biotechnology),第一卷,David H.Attaway和Oskar R.Zaborsky编,Plenum Press,New York 1993,211-213以及其中的参考文献。5.Raymond J.Bergeron,Paul F.Cavanaugh,Jr.,Stever J.Kline,Robert G.Hughes,Jr.,Gary T.Elliot和Carl W.Porter。亚精胺儿茶酚胺酰胺(catecholamide)铁螯合剂的的抗肿瘤和抗疱疹活性。生物化学生物物理学研究通讯(Biochem.Bioph.Res.Comm.)1984.121.848-854。6.Fusetani,N.等,有机化学杂志(J.Org.Chem.)1989,54,1360-1363。
Claims (10)
3.权利要求1所述的化合物,该化合物为TH-2,其结构式如下:
4.对患有对权利要求1所定义的式(Ⅰ)化合物敏感的恶性肿瘤的哺乳动物进行治疗的方法,该方法包括,向感染的个体施用治疗有效量的化合物或其药物组合物。
5.对患有对权利要求2所定义的HA-1敏感的恶性肿瘤的哺乳动物进行治疗的方法,该方法包括,向感染的个体施用治疗有效量的HA-1或其药物组合物。
6.对患有对权利要求3所定义的TH-2敏感的恶性肿瘤的哺乳动物进行治疗的方法,该方法包括,向感染的个体施用治疗有效量的TH-2或其药物组合物。
7.含有作为活性成分的权利要求1所定义的式(Ⅰ)化合物的药物制剂。
8.含有作为活性成分的权利要求2所定义的HA-1或权利要求3所定义的TH-2药物制剂。
9.对患有恶性肿瘤的哺乳动物进行治疗的方法,该方法包括,向感染个体施用治疗有效量的权利要求1所定义的式(Ⅰ)化合物和其它抗肿瘤化合物。
10.权利要求2所定义的HA-1或权利要求3所定义的TH-2的制备方法,该方法包括,分别对已知的Kabiramide B和C进行化学修饰。
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