CN101970639A - 产生环状化合物的微生物 - Google Patents
产生环状化合物的微生物 Download PDFInfo
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- CN101970639A CN101970639A CN200980108901XA CN200980108901A CN101970639A CN 101970639 A CN101970639 A CN 101970639A CN 200980108901X A CN200980108901X A CN 200980108901XA CN 200980108901 A CN200980108901 A CN 200980108901A CN 101970639 A CN101970639 A CN 101970639A
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Abstract
本发明提供一种微生物,该微生物产生可用作抗真菌剂、特别是可用作如霉菌性鼻窦炎等深部真菌疾病的治疗剂的化合物。作为对具有抗真菌作用的化合物进行探索研究的一个环节,对天然存在的微生物进行了深入研究,结果发现了真菌桃色枝顶孢(Acremonium persicinum),其产生具有良好的抗真菌活性、并且可用作药物、特别是可用作抗真菌剂的化合物,从而完成了本发明。
Description
技术领域
本发明涉及一种真菌桃色枝顶孢,该真菌产生可用作药物组合物(例如,用于治疗真菌疾病、特别是深部真菌疾病的药物组合物)的有效成分的环状化合物。
背景技术
一般认为,给患者长期施用抗生素时,虽然可以除去目标病原菌,但是抵抗抗生素的真菌会增生,从而造成深部真菌疾病(此处,将存活的真菌异常增殖的现象称为所谓的菌交替现象(microbial substitution)),或者,高龄患者、术后患者、或施用了抗癌剂或免疫抑制剂后的患者,由于身体防御功能被抑制因而容易感染真菌,从而真菌增殖,造成深部真菌疾病。
作为治疗深部真菌疾病的药物,有这样的抗真菌剂:1)核酸碱基类药物氟胞嘧啶,其作用机制是阻碍真菌的DNA合成、以及2)多马霉素类药物双性霉素B、咪唑类药物咪康唑、以及***类药物氟康唑(fluconazole),它们的作用机制是阻碍真菌的细胞膜合成。
然而,虽然已知如下所示的由3个鸟氨酸构成的环状六胜肽(hexapeptide)—铁色素(Ferrichrome)(非专利文献1),但是在该文献中没有记载铁色素具有抗真菌活性。
非专利文献1:Journal of American Chemical Society,102卷,pp.4224-4231,1980年
发明内容
本发明要解决的问题
本发明提供一种微生物,该微生物产生可用作药物组合物(例如,用于治疗真菌疾病、特别是深部真菌疾病的药物组合物)的有效成分的化合物。
解决问题所采用的手段
作为对具有抗真菌作用的化合物进行探索研究的一个环节,本发明人对天然存在的微生物进行了深入研究,结果发现,被称为真菌桃色枝顶孢MF-347833的菌株能够产生具有优异的抗真菌作用的化合物。进而详细地研究了该菌株的培养液,成功地从该菌株的培养液中分离出具有优异的抗真菌作用的环状化合物,从而完成了本发明。
即,本发明涉及产生式(I)所示化合物或其盐的真菌桃色枝顶孢。
发明效果
真菌桃色枝顶孢能够产生可成为真菌疾病、特别是深部真菌疾病等的预防剂和/或治疗剂的式(I)所示化合物或其盐。
附图简单说明
图1是化合物A的1H-NMR谱图。(测定溶剂为d6-DMSO)
图2是化合物A的13C-NMR谱图。(测定溶剂为d6-DMSO)
图3是化合物B的1H-NMR谱图。(测定溶剂为d6-DMSO)
图4是化合物B的13C-NMR谱图。(测定溶剂为d6-DMSO)
本发明的最佳实施方案
以下详细地说明本发明。
生产式(I)所示化合物或其盐的微生物的菌学性质如下所示。
(1)生产菌的来源
(2)生产菌的形态学性质
观察在马铃薯葡萄糖琼脂培养基上的形态,从而来判断形态特征。在马铃薯葡萄糖琼脂培养基(Difco公司制造的2010)上生长旺盛,于25℃下2周后直径扩展至39-41mm,亦发现形成了分生孢子。菌落表面为羊毛状(floccose),菌落周围则为波浪状(undulate)。虽然自中央部位向周围部位产生了数条放射状的沟,但是该沟难以自表面确认。菌落为白色(white,1A1),但中央部位为稍浅的白黄色(yellowish white,4A2)。在菌落的背面可确认自中央部位向周围部位产生了呈放射状的沟。整体颜色为象牙色(Ivory,4A3),但菌落的中央部位为浅棕色(mustard brown,5E6)。于30℃下2周后菌落的直径为约24mm,在5℃和37℃下未发现有生长情形。
另外,在玉米粥琼脂培养基(Difco公司制造的0386)上生长旺盛,于25℃下2周后扩展至直径为39-40mm。菌落表面为毡状(felty)。菌落周围则为波浪状(undulate)且菌落中未产生沟。菌落为白色(white,1A1)。菌落背面亦为白色(white,1A1)。于30℃下培养2周后菌落的直径为14mm。菌落表面未产生沟。在5℃和37℃下未发现有生长情形。
营养菌丝的粗细为1.8-2.7μm,未观察到厚膜孢子。分生孢子梗无分枝,无色,且单生于一根营养菌丝、或生于成束的松散的分生孢子束。分生孢子梗表面存在多个小的疣状突起,分生孢子梗的根部生有隔膜。分生孢子形成样式为瓶梗型(phialidic),自分生孢子梗的根部至瓶梗(phialide)的前端的长度为33-40μm。分生孢子为无色、椭圆形,大小为3.7-4.5×2.8-3.2μm(平均为4×3μm)。稍具粘性,瓶梗的前端形成为分生孢子块。用光学显微镜(400倍)可见分生孢子的表面平滑,但是用电子显微镜(9000倍)观察则可确认呈粗糙的凹凸形状。
上述形态特征暗示了本菌可能属于枝顶孢属。因此,与Cephalosporium-artige Schimmelpilze(Hyphomycetes)/Walter Gams(1971)进行比较研究,结果发现,与粘鞭霉节(Gliomastix)的桃色枝顶孢(Acremonium persicinum)的形态特征非常一致。此外,对本菌的28SrDNA和18SrDNA进行同源性检索的结果表明,本菌包含在粘鞭霉节的桃色枝顶孢的进化枝(clade)中,因此,不管是形态方面还是基因方面都不存在矛盾之处。由此,将本菌鉴定为桃色枝顶孢(Acremonium persicinum),并称为桃色枝顶孢MF-347833株。
(3)培养特性
培养特性根据市售的培养基、以及用记载于文献中的组成而调制的培养基来判定。分别购买Difco公司的2010马铃薯葡萄糖琼脂培养基、Difco公司的0109沙氏葡萄糖琼脂培养基、Difco公司的0739Emerson YpSs琼脂培养基、Difco公司的0386玉米粥琼脂培养基、Difco公司的0552燕麦粥琼脂培养基。麦芽提取物琼脂培养基、Czapek液状琼脂培养基、MY20琼脂培养基的组成遵循JCM目录(Nakase,T.第6版,第617页,Japan Collection of Microorganisms,the Institute of Physical and Chemical Research,Saitama,1995)。
[表1]
桃色枝顶孢MF-347833株的培养特性
从接种于各琼脂培养基开始、于25℃下培养14天后,观察真菌MF-347833株。色调的记载参照了文献Methuen Handbook of Colour(Kornerup,A和J.H.Wanscher,第3版,第252页,Methuen,London,1987)。关于生长温度,在马铃薯葡萄糖琼脂培养基(Difco公司制造的2010)上进行判定。
另外,本菌株有时会发生人工或天然的变异,除了由自然界分离出的微生物之外,本发明中所使用的真菌桃色枝顶孢MF-347833株也包含用紫外线、放射线、化学药物等人工变异株及其天然变异株。
式(I)所示的化合物有时候也与碱形成盐。作为这样的盐,具体可以列举与无机碱(例如钠、钾、镁、钙等)或与有机碱(例如甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等)形成的盐。此外,所述盐还包括所谓的络合物盐和螯合化合物。作为形成这样的盐的金属,可以列举二价或三价金属,例如可以列举铁、铝等。
以下,在本说明书中,有时会
将式(I)所示化合物的游离体记载为化合物A、
将式(I)所示化合物的铝盐记载为化合物B、
将式(I)所示化合物的铁盐记载为化合物C。
式(I)所示的化合物可存在几何异构体。在本说明书中,虽然仅记载了式(I)所示化合物的异构体的一种形态,但是其它的异构体、异构体分离后得到的物质、或这些异构体的混合物也包括在本发明内。
另外,式(I)所示化合物中有时具有不对称碳原子,可以存在基于这些不对称碳原子的光学异构体。式(I)所示化合物的光学异构体分离后得到的物质、或它们的混合物也都包含在本发明内。
此外,本发明还包括式(I)所示化合物或其盐的各种水合物、溶剂合物以及多晶态物质。而且,本发明还包括用各种放射性同位素或非放射性同位素标记后的化合物。
(生产方法)
通常,只要按照一般微生物的培养方法来培养本发明微生物,就可以得到式(I)所示的化合物或其盐。
作为培养基,可以使用合成培养基、半合成培养基或天然培养基,只要是含有真菌桃色枝顶孢MF-347833株可利用的营养源的培养基即可。关于培养基的组成,例如,作为碳源,可以使用L-***糖、D-木糖、D-葡萄糖、D-果糖、蔗糖、肌醇、L-鼠李糖、棉籽糖、D-甘露糖醇、甘露糖、蜜二糖、乳糖、D-半乳糖、麦芽糖、海藻糖、水杨苷、黄嘌呤、甲壳质、淀粉、葡萄糖、糊精、甘油、植物油等;作为氮源,可以使用肉提取物、蛋白胨、蛋白粉(gluten meal)、棉籽粉、大豆粉、花生粉、鱼粉、玉米浆、干燥酵母、酵母提取物、氯化铵、硫酸铵、硝酸铵、尿酸,此外,还可以使用其它的有机氮源或无机氮源。另外,根据需要,可以添加钠、钾、镁、钙、锌、钴等的硫酸盐、硝酸盐、碳酸盐、磷酸盐等作为金属盐。此外,根据需要,还可以添加蛋氨酸、半胱氨酸、胱氨酸、硫代硫酸盐、油酸甲酯、猪油、硅油、表面活性剂等促进生成物质或消泡剂。
作为培养条件,一般在好氧条件下进行培养是有利的,培养温度在8.9~31.2℃的范围内,优选为26.0~27.6℃左右。培养时间可根据培养基的组成、温度条件来适当地设定,但是通常为1~30天左右,优选为2~7天左右。
采用通常的从微生物的培养物中纯化分离生理活性物质的方法,可以从培养物中纯化分离出式(I)所示化合物或其盐。即,用适当的有机溶剂自培养物进行萃取,再对该萃取物进行纯化而分离出有效物质。即,以抗真菌活性为指标,采用通常的用于制备生理活性物质的方法而进行分离、纯化,其中所述方法利用了在适当的溶剂中的溶解性以及溶解度的差别等。根据需要,这些方法可单独使用、或者以任意顺序进行组合、重复而使用。此外,作为纯化方法,可以使用这样的方法:其中,直接使用培养物、或者经离心分离或过滤而去除菌体之后,利用在适当的溶剂中的溶解性以及溶解度的差别、从溶液中析出的速度的差别、对各种吸附剂的吸附亲和性的差别、在2种液相间的分配的差别等。具体可以列举(例如)这样的方法:使培养液与适当的载体接触后以吸附该化合物,接着以适当的溶剂进行洗脱,从而纯化该化合物。根据需要,这些方法可单独使用、或者以任意顺序进行组合、重复而使用。
只要在营养培养基中培养本发明微生物,就可通过常规方法从培养物中得到式(I)所示的化合物或其盐。在式(I)所示化合物或其盐的制备中所使用的微生物,可使用任意的微生物,只要该微生物是具有生产式(I)所示化合物或其盐的能力的枝顶孢属微生物即可。
使用本领域中通常使用的赋形剂(即,药用赋形剂或药用载体等),根据常规方法,可以制备含有1种或2种以上的式(I)所示化合物或其盐作为有效成分的药物组合物。
可以采用经口给药的剂型(例如片剂、丸剂、胶囊剂、颗粒剂、散剂、液体制剂等),或者采用非经口给药的剂型(例如关节内、静脉内、肌肉内等的注射剂、栓剂、滴眼剂、眼软膏、经皮用的液体制剂、软膏剂、经皮用的贴剂、经粘膜的液体制剂、经粘膜的贴剂、吸入剂等)来进行给药。
作为用于经口给药的固体组合物,可以采用片剂、散剂、颗粒剂等。在这样的固体组合物中,将1种或2种以上的有效成分与至少一种惰性赋形剂(例如乳糖、甘露醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮和/或硅酸铝镁等)混合。按照常规方法,在组合物中也可以含有惰性添加剂,例如硬脂酸镁等润滑剂、羧甲基淀粉钠等崩解剂、稳定剂、溶解助剂。根据需要,片剂或丸剂也可以用糖衣或者胃溶性或肠溶性物质的膜进行包衣。
用于经口给药的液体组合物包括可药用的乳剂、溶液剂、混悬剂、糖浆剂或酏剂等,并且含有常用的惰性稀释剂,例如纯化水或乙醇。除了惰性稀释剂以外,该液体组合物中也可以含有诸如增溶剂、润湿剂、混悬剂之类的助剂、甜味剂、矫味剂、芳香剂、防腐剂。
用于非经口给药的注射剂包括无菌的水性或非水性的溶液剂、混悬剂或乳剂。作为水性的溶剂,例如包括注射用蒸馏水或生理盐水。作为非水性的溶剂,例如有丙二醇、聚乙二醇或橄榄油等植物油、乙醇等醇类、或聚山梨醇酯80(药典名)等。这样的组合物中还可以含有等渗剂、防腐剂、润湿剂、乳化剂、分散剂、稳定剂、或溶解助剂。它们例如可以通过可截留细菌的过滤器进行过滤、加入杀菌剂、或者进行照射而被灭菌。此外,也可以将这些组合物制成无菌的固体组合物,在使用之前用无菌水或无菌的注射用溶剂进行溶解或混悬后使用。
作为外用剂,包括软膏剂、硬膏剂、霜剂、凝胶剂、贴剂、喷雾剂、洗液、滴眼剂、眼软膏等。这种外用剂包含常用的软膏基剂、洗剂基剂、水性或非水性的液体制剂、混悬剂、乳剂等。例如,作为软膏基剂或洗剂基剂,可以列举聚乙二醇、丙二醇、白凡士林、白蜂蜡、聚氧乙烯氢化蓖麻油、单硬脂酸甘油酯、十八烷醇、十六烷醇、聚桂醇、失水山梨醇倍半油酸酯等。
吸入剂或经鼻剂等经粘膜剂,可以以固体、液体或半固体的状态使用,并且可以按照以往公知的方法来制备这些经粘膜剂。还可以适当地添加(例如)公知的赋形剂、还有pH调节剂、防腐剂、表面活性剂、润滑剂、稳定剂或增稠剂等。给药时可以使用合适的吸入或吹送用装置。例如,可以使用计量给药吸入装置等公知的装置或喷雾器,将化合物单独地或作为配方后的混合物粉末来给药、或者可以将化合物与可药用的载体组合后,作为溶液或混悬液来给药。干燥粉末吸入器等可用于一次给药或多次给药,并且可以使用干燥粉末或含有粉末的胶囊。或者,也可以采用加压气溶胶喷雾等形式,通过使用适当的抛射剂(例如,氯氟烷烃、氢氟烷烃或二氧化碳等适当的气体)来给药。
通常在经口给药时,合适的1天的给药量按体重约为0.01~100mg/kg,优选为0.1~10mg/kg,并将该剂量一次服用或者分2~4次服用。静脉内给药时,合适的1天的给药量按体重约为0.01~100mg/kg,并将该剂量一日分为一次至多次给药。应考虑症状、年龄、性别等,根据不同的情况,而适当地选择给药量。
式(I)所示化合物或其盐可以与疾病的各种治疗剂或预防剂并用,所述疾病为前述的式(I)所示化合物或其盐对其显示出有效性的那些疾病。并用该药剂时,可以同时给药,或者分别且连续地、或按所希望的时间间隔给药。同时给药时的制剂可以是配合剂,也可以是分别制成的制剂。
实施例
以下基于实施例对式(I)所示化合物或其盐的制备方法进行更详细的说明。此外,本发明并不局限于以下实施例记载的化合物。另外,式(I)所示化合物或其盐的制备方法并不仅局限于以下所示的具体实施例的制备方法,也可以通过这些制备方法的组合、或者本领域技术人员已知的方法来制备式(I)所示化合物或其盐。
此外,在实施例、制备例和下述表中,有时使用以下缩写。
[表2]
缩写 | 全名 |
AlK(SO4)2·12H2O | 硫酸铝钾十二水合物 |
CHCl3 | 氯仿 |
FeCl3·6H2O | 氯化铁(Ⅲ)六水合物 |
KCl | 氯化钾 |
KH2PO4 | 磷酸二氢钾 |
MeCN | 乙腈 |
MeOH | 甲醇 |
MgSO4·7H2O | 硫酸镁七水合物 |
NaNO3 | 硝酸钠 |
(NH4)2SO4 | 硫酸铵 |
TFA | 三氟醋酸 |
HR ESI MS | 高分辨率电喷雾法MS |
实施例1
(化合物A的培养生产)
将基础培养基1(参照表3,30mL)注入到三角烧瓶(尺寸:100mL)中,用高压蒸气灭菌器进行灭菌(121℃,30分钟)。将真菌MF-347833株的斜面培养物(斜面培养物)用白金耳勺无菌地植入到基础培养基1上,采用旋转摇荡器,于25℃下振荡培养(220rpm)4天。然后,将生产培养基1(参照表4,100mL)注入到三角烧瓶(尺寸:500mL)中,以高压蒸气灭菌器进行灭菌(121℃,30分钟)。将基础培养物(2mL)以无菌的方式植入到该烧瓶中,采用旋转摇荡器,于25℃下振荡培养(220rpm)7天。用HPLC进行分析的同时进行培养(分析型HPLC1,条件参照表5)。
[表3]
基础培养基1
培养基成分 | 含量(%) |
玉米淀粉 | 2 |
甘油 | 1 |
蔗糖 | 1 |
药用培养基(Pharma media) | 1 |
蛋白粉 | 1 |
吐温80 | 0.2 |
[表4]
生产培养基1
培养基成分 | 含量(%) |
葡萄糖 | 0.5 |
可溶性淀粉(ナカライテスク公司制造) | 1.5 |
酵母提取物(和光纯药工业株式会社制造) | 0.5 |
KCl | 0.02 |
MgSO4·7H2O | 0.02 |
KH2PO4 | 0.1 |
NaNO3 | 0.2 |
[表5]
分析型HPLC1的条件
柱 | Mightysil RP-18 GP 150-4.6(5μm),关东化学株式会社制造 |
流动相 | MeCN∶水=28∶72(v/v)(含0.5%NH4H2PO4) |
流速 | 1mL/分钟 |
检测波长 | 210nm |
保留时间 | 约4.2分钟 |
(化合物A的分离纯化)
向通过上述培养方法而获得的培养物(2.6L)中添加等量的丙酮,搅拌1小时后过滤,得到培养萃取物。向该培养萃取液中加入2倍量的水,使其通过Diaion SP 850柱(尺寸:400mL,三菱化学株式会社制造),用混合溶剂{丙酮∶水=30∶70(v/v),1.9L}进行洗脱。
向该洗脱液中加水(2.1L),使其通过Daisogel SP-120-ODS-B柱(尺寸:350mL,15/30μm,DAISO公司制造),用混合溶剂{MeCN∶水=25∶75(v/v),340mL}进行洗脱。
向该洗脱液中加水(350mL),使其通过OASIS HLB色谱柱(尺寸:6g,Waters公司制造),用MeOH(150mL)进行洗脱。将该洗脱液减压浓缩,添加丙酮后得到沉淀物。将该沉淀物干燥,从而得到黄色粉末(100mg)。
将该黄色粉末(15mg)溶解于少量的MeOH中,以制备型HPLC1进行纯化(条件参照表6)。收集洗脱时间为约22分钟的峰。向该流份中加入等量的水,并使其通过OASIS HLB色谱柱(尺寸:500mg),以水(50mL)进行洗柱后,再以MeOH(50mL)进行洗脱。将该洗脱液减压浓缩,添加丙酮后得到沉淀物。将该沉淀物干燥,从而得到白色粉末的化合物A(13mg)。
[表6]
制备型HPLC1条件
柱 | Symmetry 7μm C18柱,19×300mm,Waters公司制造 |
流动相 | MeCN∶水=27∶73(v/v)(含0.05%TFA) |
流速 | 7mL/分钟 |
(化合物A的物理化学性质)
通过上述方法纯化分离后的化合物A具有以下物理化学性质。
[表7]
化合物A的物理化学性质
根据物理化学性质,化合物A的化学结构确定为下式(II)所示的结构。采用经改良的Marfey法,构成氨基酸的立体结构确定为D-Phe、L-Leu、L-Asn。关于鸟氨酸部分,与类似的天然物铁色素(非专利文献1)相比较,根据氨基酸分析得知3个氨基酸相同,由此推测其为L-鸟氨酸。
实施例2
(化合物B及C的培养生产)
将基础培养基2(参照表8)注入(30mL)到三角烧瓶(尺寸:100mL)中,以高压蒸气灭菌器进行灭菌(121℃,30分钟)。将真菌MF-347833株的斜面培养物(斜面培养物)以白金耳勺无菌地植菌到该培养基上,采用旋转摇荡器,于25℃下振荡培养(220rpm)4天。
接下来,将相同组成的基础培养基(160mL)分注至三角烧瓶(尺寸:500mL)中,以高压蒸气灭菌器进行灭菌(121℃,30分钟)。将基础培养物(3.2mL)以无菌的方式植菌到该基础培养基上,采用旋转摇荡器,于25℃下振荡培养(220rpm)3天。
接着,预先调制生产培养基2(参照表9),将该生产培养基2(20L)注入到发酵罐(尺寸:30L)中,灭菌(121℃,30分钟)后,以无菌的方式将基础培养物(480mL)植入。在通气量为20L/分钟、搅拌速度为200rpm的培养条件下,于25℃培养7天。用HPLC进行分析的同时进行培养(分析型HPLC2,条件参照表11)。
另外,也可以使用生产培养基3来代替生产培养基2,并在相同的培养条件下进行生产。
[表8]
基础培养基2
培养基成分 | 含量(%) |
玉米淀粉 | 2 |
甘油 | 1 |
蔗糖 | 1 |
药用培养基 | 1 |
蛋白粉 | 1 |
吐温80 | 0.2 |
[表9]
生产培养基2
培养基成分 | 含量(%) |
葡萄糖 | 0.5 |
可溶性淀粉(ナカライテスク公司制造) | 1.5 |
酵母提取物(和光纯药工业株式会社制造) | 0.5 |
Adekanol LG-109(ADEKA公司制造) | 0.05 |
Silicone KM-70(信越化学工业株式会社制造) | 0.05 |
KCl | 0.02 |
MgSO4·7H2O | 0.02 |
KH2PO4 | 0.1 |
NaNO3 | 0.2 |
[表10]
生产培养基3
培养基成分 | 含量(%) |
蔗糖 | 4 |
干燥酵母(Asahi Food and Healthcare公司制造) | 1.5 |
(NH4)2SO4 | 0.5 |
碳酸钙 | 0.5 |
[表11]
分析型HPLC2的条件
(化合物B及化合物C的分离纯化)
向通过上述培养方法而获得的培养物(生产培养基2:90L)中添加等量的丙酮,搅拌1小时后过滤而得到培养提取物。向该提取液中加入等量的水,使其通过Diaion SP 850柱(10L,三菱化学株式会社制造),以混合溶剂{丙酮∶水=40∶60(v/v),40L}进行洗脱。
向该洗脱液中加入等量的水,使其通过Daisogel SP-120-ODS-B柱(15/30μm,尺寸:2L,DAISO公司制造),以混合溶剂{MeCN∶水=25∶75(v/v),7L}进行洗脱。
向该洗脱液中加入等量的水,使其再次通过DaisogelSP-120-ODS-B柱(尺寸:2L),以混合溶剂{MeCN∶水=27.5∶72.5(含0.05%TFA)(v/v)}洗脱。
向该洗脱液中加入等量的水,使其再次通过DaisogelSP-120-ODS-B柱(尺寸:180mL),以MeOH进行洗脱,并将该洗脱液减压浓缩。
将残余物溶解于少量的MeOH中,以制备型HPLC2(条件参照表12)进行纯化。
向洗脱时间为约24~25分钟的流份中加入等量的水,使其通过OASIS HLB色谱柱(尺寸:6g,Waters公司制造),以水(100mL)进行洗柱后,再以MeOH(100mL)进行洗脱。将该洗脱液减压浓缩,替换为水后,冷冻干燥,从而得到粉末状的化合物C(130mg)。将该粉末以溶剂(MeOH、醋酸乙酯、正己烷)进行结晶,从而得到化合物C的橙色结晶。
对洗脱时间为约19~21分钟的流份进行相同的操作而得到粉末,将其溶解于CHCl3中后,以硅胶柱色谱法(球状60N,中性,40-100μm,关东化学株式会社制造,CHCl3∶MeOH=10∶1)进行纯化。将该洗脱液减压浓缩,替换为水后,冷冻干燥,从而得到白色粉末状的化合物B(150mg)。将该白色粉末(109mg)以溶剂(MeOH、醋酸乙酯、正己烷)进行结晶,从而得到无色结晶的化合物B(90.1mg)。
[表12]
制备型HPLC2的条件
(化合物B的物理化学性质)
通过上述方法纯化分离后的化合物B具有以下物理化学性质,由此将该化合物推定为化合物A与铝的比例为1∶1的化合物。
[表13]
化合物B的物理化学性质
(化合物C的物理化学性质)
通过上述方法纯化分离后的化合物C具有以下物理化学性质,根据该物理化学性质以及单晶X射线结构分析,将该化合物确定为化合物A与铁的比例为1∶1的化合物。
[表14]
化合物C的物理化学性质
实施例3
(抗真菌活性测定法)
使用微量液体稀释法(久米光、山崎敏和著,临床与微生物,21卷第5期,573-580页,1994年),测定对于下表所示的检测菌的抗真菌活性。结果,化合物B对各种检测菌的抗菌活性试验的结果示于下表。
[表15]
化合物B的最小有效浓度(MEC)
红色毛癣菌FP596 | 1.25 |
链格孢菌AHU9258 | 0.1 |
由上述试验结果可以确认,式(I)所示化合物或其盐具有抗真菌作用。因此,式(I)所示化合物或其盐可用于治疗真菌疾病,特别是用于治疗深部真菌疾病等,例如霉菌性鼻窦炎等。
因此,由上述结果可以确认,真菌桃色枝顶孢MF-347833株是产生式(I)所示化合物或其盐的微生物,其中式(I)所示化合物或其盐可用于治疗真菌疾病,特别是用于治疗深部真菌疾病等,例如霉菌性鼻窦炎等。
工业实用性
本发明的被称作桃色枝顶孢MF-347833株的微生物产生具有优异的抗真菌作用的式(I)所示化合物或其盐。所得到的式(I)所示化合物或其盐可用作真菌疾病、特别是深部真菌疾病等的预防剂和/或治疗剂。
在上文中,根据特定的实施方案对本发明进行了说明,但是,对于本领域技术人员来说显而易见的改变或改良也包含在本发明的范围内。
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CN102787077A (zh) * | 2012-07-26 | 2012-11-21 | 宁夏大学 | 一株可合成苦参碱的苦豆子内生真菌及其应用和其发酵液的应用 |
WO2013091361A1 (zh) * | 2011-12-21 | 2013-06-27 | 中国科学院南海海洋研究所 | 环七肽及其在制备抗肿瘤药物中的应用 |
CN103205367A (zh) * | 2013-05-10 | 2013-07-17 | 国家***第三海洋研究所 | 桃色顶孢霉s2915及其抗真菌活性蛋白的制备方法 |
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