CN101491511B - Hirsutanols A在制备抗肿瘤药物中的应用 - Google Patents
Hirsutanols A在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了Hirsutanols A在制备抗肿瘤药物中的应用。本发明研究发现化合物Hirsutanols A对多种肿瘤细胞系显示出强效的细胞毒性,如:对人鼻咽癌细胞株CNE2和SUNE1,人乳腺癌细胞MCF-7、MDA-MB-435和MDA-MB-453,人肝癌细胞HEP3B的IC50值分别为:4.06、3.44、10.14、9.86、4.30和2.61μg/mL。表明Hirsutanols A可用于制备抗肿瘤药物,可与其他药物制成抗肿瘤药物组合物,可与药学可以接受的辅料制成注射剂、片剂、丸剂、胶囊剂、溶液、悬浮剂和乳剂等剂型;其给药途径可为经口服、静脉、肌肉或皮肤给药。
Description
技术领域
本发明涉及化合物Hirsutanols A的新用途。
背景技术
海洋微生物,资源极其丰富。由于海洋环境十分独特,如:高盐、高压、低营养、无光照、海洋微生物适应了海洋独特的生活环境,必然造就了其独特的代谢途径和遗传背景。研究发现海洋微生物能产生化学结构独特的、具各种生理活性的代谢产物,其中很多是陆源微生物所不能产生的、是海洋微生物所独有的。海洋微生物可实现大规模化的发酵培养,活性代谢产物的制备、药物研发不存在资源问题,海洋微生物已被认为是发现海洋新药的最重要资源。目前已有多个海洋微生物代谢产物作为药物已进入了临床前或临床试验。
海洋微生物的研究,主要集中于海洋细菌、蓝细菌、放线菌、真菌。由于各种原因,国际上对海洋真菌的化学研究起步比较晚,其真正兴起开始于上世纪90年代中期。被研究的海洋真菌主要分离于海绵、海藻、被囊动物、软体动物的体表或体内,以及海洋漂浮木、海洋底泥。已发现了数百个结构新颖的海洋真菌代谢产物,其结构类型多种多样,但主要为生物碱类、萜类、大环内酯类化合物。据初步统计,近80%的化合物被报道具有生物活性,如:抗肿瘤、抗心血管病、抗菌、酶抑制剂等。(李厚金,海洋真菌的代谢产物,见林永成主编《海洋微生物及其代谢产物》第七章,p224-293,2003年化学工业出版社;Natural ProductsReports,2004,21,143-163.)。
海洋真菌的药用研究最成功的例子是头孢菌素的研制。在1945年7月,Brotzu G.在地中海撒丁岛海域分到的一株真菌即顶头孢霉(Cephalospoiunacremonium),并且发现该菌的培养液能抑制革兰氏阳性和阴性细菌的生长。后来对培养液活性成分进行提取、分离,得到多种抗菌素,如:头孢菌素Cephalosporin C,Cephalosporin P1,P2,P3,P4,P5以及青霉素Penicillin N。六十多年过去了,头孢菌素仍在临床上广泛使用。从真菌筛选,到半合成结构改造,目前产品品种已达200多种,产量占世界抗生素产量的60%以上,头孢菌素与青霉素相比具有抗菌谱较广,耐青霉素酶,疗效高、毒性低,过敏反应少等优点。
尽管珊瑚的化学成分及药用研究近半个世纪来一直都是国际研究的热点,但来源于珊瑚的海洋真菌的研究仍是非常稀少,仅有的几例报道也可见该研究方向的潜力。例如:在1999年,McDonald L.A.报道了从一个未鉴定的软珊瑚中分离到一株未经鉴定的真菌,从该真菌的代谢产物中分离得到spiroxins A-E,其中spiroxinA对25种不同肿瘤细胞系的平均ICs0为0.09μg/mL,并且具有独特的DNA断裂作用机制(Tetrahedron Lett.,1999,40,2489.)。
南海扭曲肉芝软珊瑚Sarcophyton tortuosum,能产生多个具有独特的双十四元大环的四萜化合物,如:methyl sartortuoate,methyl isosartortuoate和methyltortuoate A-C,在多种肿瘤细胞株的细胞毒筛选实验中,这些四萜化合物也显示了中等强度的细胞毒活性(Journal ofAsian Natural Products Research,2007,9(3),267-271;Journal ofNatural Products,2004,67(11),1915-1918;Journal oftheAmerican Chemical Society,1986,108(1),177-178.)。我们对采自海南三亚西岛海域的软珊瑚Sarcophyton tortuosum的内生微生物进行了分离培养,已纯化得到数十株内生真菌,这些微生物均可稳定培养、保藏,其中一株新的内生真菌Chondrostereum sp.nov.,在培养液中分离发现系列Hirsutane类倍半萜化合物。
Hirsutane类倍半萜,结构独特,由三个五元环骈合合成,主要发现于真菌的代谢产物。1998年,Crews等报道从海绵Haliclona sp.中分离的一株种属未鉴定的真菌在玉米粉(Difco’s corn meal)海水培养基中能产生hirsutane类倍半萜化合物hirsutanols A-C和ent-gloeosteretriol。陆源真菌Coriolus consors ATCC 66132在葡萄糖(coriolus glucose broth,CGB)海水培养基能产生具有同样骨架的hirsutanolD。化合物Hirsutanols A和ent-gloeosteretriol有弱的抗枯草杆菌Bacillus subtilis活性(Tetrahedron,1998,54,7335-7342.)。(3aS,3bR,6S)-3,3a,3b,4,5,6-六氢-3b,6-二羟基-3a,5,5-三甲基-3-亚甲基-2H-环戊二烯并[a]戊搭稀-2-酮{化合物英文名:(3aS,3bR,6S)-3,3a,3b,4,5,6-hexahydro-3b,6-dihydroxy-3a,5,5-trimethyl-3-methylene-2H-cyclopenta[a]pentalen-2-one,又名Hirsutanols A,以下简称为化合物A}是新的内生真菌Chondrostereum sp.nov.的一个主要代谢产物。Hirsutanols A的抗肿瘤活性未见报道。
发明内容
本发明的目的在于提供一种海洋真菌代谢产物Hirsutanols A在制备抗肿瘤药物中的应用。
本发明所述的化合物Hirsutanols A的中文名为:(3aS,3bR,6S)-3,3a,3b,4,5,6-六氢-3b,6-二羟基-3a,5,5-三甲基-3-亚甲基-2H-环戊二烯并[a]戊搭稀-2-酮;英文名为:(3aS,3bR,6S)-3,3a,3b,4,5,6-hexahydro-3b,6-dihydroxy-3a,5,5-trimethyl-3-methylene-2H-cyclopenta[a]pentalen-2-one,又名Hirsutanols A,以下简称为化合物A,是新的内生真菌Chondrostereum sp.nov.的一个主要代谢产物。
化合物A的结构式为:
本发明的化合物A可以从真菌,例如南海海洋软珊瑚Sarcophyton tortuosum的内生真菌Chondrostereum sp.nov.的培养液中提取分离而得到。
本发明化合物A由真菌Chondrostereum sp.nov.发酵制备方法包括以下步骤:
a.海洋真菌Chondrostereum sp.nov.的种子培养:
选用PDA(potato dextro se agar)培养基,其培养基组成为:马铃薯200g,葡萄糖20g,琼脂20g,海水1L;制成试管斜面,挑取菌株接入斜面,25-28℃培养5-7天;
b.海洋真菌Chondrostereum sp.nov.的发酵培养:
发酵培养基成分配比按重量比为:葡萄糖5-35,酵母提取物0.5-1.5,蛋白胨1-10,粗海盐30-50,水1000;将斜面中培养好的菌株挑入发酵培养基,于室温25-30℃静置2040天;
c.将上述培养好的发酵液过滤,滤除菌体,收集发酵液;
d.发酵液用乙酸乙酯提取,合并提取液,浓缩得到总提取物;
e.用乙酸乙酯溶解提取物,溶解物在硅胶柱中进行色谱分离,以石油醚-乙酸乙酯-甲醇梯度淋洗;
f.收集石油醚-乙酸乙酯(1∶3)得到的洗脱组分,用乙酸乙酯重结晶3次,纯化得到白色无晶形固体,即为所需的化合物A。
与现有技术相比,本发明具有如下有益效果:本发明研究发现化合物A对多种肿瘤细胞系显示出强效的细胞毒性,如:对人鼻咽癌细胞株CNE2和SUNE1,人乳腺癌细胞MCF-7、MDA-MB-435和MDA-MB-453,人肝癌细胞HEP3B的IC50值分别为:4.06、3.44、10.14、9.86、4.30和2.61μg/mL。表明化合物A可用于制备抗肿瘤药物,可与其他药物制成抗肿瘤药物组合物,可与药学可以接受的辅料制成注射剂、片剂、丸剂、胶囊剂、溶液、悬浮剂和乳剂等剂型;其给药途径可为经口服、静脉、肌肉或皮肤给药。
具体实施方式
下面结合实施例对本发明作进一步说明。
实施例1:化合物A的制备
a.海洋真菌Chondrostereum sp.nov.的种子培养:
菌种以PDA为培养基,组成为:马铃薯200g,葡萄糖20g,琼脂20g,水1L。制成试管斜面,挑取菌株接入斜面,25-28℃培养7天后于4℃保存。
b.海洋真菌Chondrostereum sp.nov.的发酵培养:
发酵培养基组成为:葡萄糖10g,酵母提取物1g,蛋白胨2g,粗海盐30g,水1L;将斜面中培养好的菌株挑入发酵培养基,于室温25-28℃静置培养30天;
c.将上述培养好的发酵液过滤,滤除菌体,收集培养液;
d.培养液用体积比为1∶1的乙酸乙酯萃取3次,合并提取液,40℃水浴旋转蒸发浓缩得到总提取物;
e.用乙酸乙酯溶解提取物,溶解物在硅胶柱中进行色谱分离,以石油醚-乙酸乙酯-甲醇梯度淋洗;
f.收集由石油醚-乙酸乙酯(1∶3)洗脱得到的组分,蒸除溶剂后,再加乙酸乙酯进行重结晶,纯化得到白色无晶形固体化合物A。
化合物A的试验数据:
元素分析(w%,C15H18O3):C 73.18,H 7.39,O 19.43,N 0.000;计算值:C73.15,H 7.37,O 19.49。IR/cm-1(KBr):3401,2966,1678,1642,1590,1455,1366,1284,1155,1131,1031,879。HR EI-MS:m/z 246.1336[M]+。晶体数据:从乙酸乙酯中结晶。正交晶系,空间群P2(1)2(1)2(1),a=8.2584(2),b=8.9021(2),c=19.3724(4),V 1424.20(6) 3,Z 6。晶体大小0.40×0.20×0.20mm。化合物A的NMR实验数据如表1所示。
化合物A的结构与碳的位置编号
表1化合物A的NMR数据(1H,500MHz,13C,125MHz;DMSO-d6,TMS)
实施例2:化合物A的抗肿瘤活性试验
a.细胞株:鼻咽癌细胞株CNE2、SUNE1;乳腺癌细胞株MCF-7、MDA-MB-453、MDA-MB-435;肝癌细胞株HEP3B。
b.取对数生长的上述肿瘤细胞株加入96孔板中,每孔200μL含有3000-8000个细胞。
c.再加入药物,设7个药物浓度梯度,分别为0、0.39、0.78、1.56、3.12、6.25、12.5、25μg/mL,另设DMSO溶剂对照组。
d.每组设4个平行孔,置37℃培养72小时。实验终止前4小时加入10μL5mg/mL MTT液,再培养4小时,弃去培养液,加入0.1mL DMSO。
e.待结晶溶解后在酶联检测仪上双波长(570nm,655nm)检测每孔的OD值。按下列公式求出生长抑制率,再按BLISS法计算机程序求出半数抑制率〔ICs0值〕,实验结果见表2。
细胞生长抑制率=(1-用药组平均OD值/对照组孔OD值)×100%
表2化合物A的细胞毒性试验结果
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