CN1298410A - 用于将棘白菌素类肽类转化成其c4－高酪氨酸单脱氧类似物的方法 - Google Patents
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Abstract
本发明涉及一种用于将棘白菌素类肽类转化成其C4－高酪氨酸单脱氧类似物、特别是将牟伦多菌素转化成脱氧牟伦多菌素的方法,该方法由单一步骤组成,所述的步骤是在没有预先对相同易得的C5—0m(鸟氨酸)羟基进行保护/脱保护的中性条件下选择性地将带有C4－htyr(高酪氨酸)羟基的棘白菌素类还原成其单脱氧类似物并从粗反应混合物中纯化所述的单脱氧化合物。
Description
本发明涉及一种用于将通式Ⅰ的棘白菌素类肽类转化成通式Ⅰ的其C4-高酪氨酸单脱氧类似物的方法；
在通式Ⅰ的棘白菌素类肽类中W、X、Y、Z、R和R’如下所定义：
W X Y Z R R’1．棘白菌素B OH OH OH OH CH3 亚麻酰基2．肺炎球菌素 A0OH OH OH OH CH2-CONH2 10,12-二甲(Pneumocandin A0) 基-肉豆蔻酰
基3．肺炎球菌素 A1OH OH OH OH CH2-CONH2“(Pneumocandin A1)4．肺炎球菌素 A2H OH H H CH2-CONH2“(Pneumocandin A2)5．肺炎球菌素 B0OH OH OH OH CH2-CONH2“(Pneumocandin B0)6．肺炎球菌素 B2OH OH H H CH2-CONH2“(Pneumocandin B2)7．肺炎球菌素 C0OH OH OH OH CH2-CONH2“(Pneumocandin C0)8．脱氧牟伦多菌素 OH OH OH OH H 12-甲基-十
四酰基
在通式Ⅰ的其C4-高酪氨酸单脱氧类似物中W、X、Y、Z、R和R’如下所定义：
W X Y Z R R’1．脱氧棘白菌素B(棘白菌素C) OH H OH OH CH3 麻酰基2．脱氧肺炎球菌素 A0OH H OH OH CH2- 10,12-(Deoxypneumocandin A0) CO-NH2甲基-肉豆
蔻酰基3．脱氧肺炎球菌素 A1H H OH OH CH2-“(Deoxypneumocandin A1) CONH24．脱氧肺炎球菌素 A2OH H H H CH2-“(Deoxypneumocandin A2) CONH25．脱氧肺炎球菌素 B0OH H OH OH CH2-“(Deoxypneumocandin B0) CONH26．脱氧肺炎球菌素 B2OH H H H CH2-“(Deoxypneumocandin B2) CONH27．脱氧肺炎球菌素 C0OH H OH OH CH2-“(Deoxypneumocandin C0) CONH28．脱氧牟伦多菌素 OH H OH OH H 12-甲基-
十四酰基
本发明特别涉及一种用于将牟伦多菌素(通式Ⅱ的化合物)
转化成脱氧牟伦多菌素(通式Ⅲ的化合物)的方法；
1,3-β-葡聚糖合成抑制剂是对白色假丝酵母其且也对卡氏肺囊虫有效的抗真菌剂，所述的卡氏肺囊虫是一种可导致HIV病人和其它他无免疫应答宿主中的经常性致死肺炎的机会生物体。在所有1,3-β-葡聚糖合成抑制剂的结构种类中，仅棘白菌素类明显受到关注[参见：《药物化学杂志》(J.Med.Chem.)35,198-200(1992)]。棘白菌素类肽类是带有亲脂侧链的环状六肽类。
已经报导了几种在酸性条件下将棘白菌素转化成相应的脱氧类似物的方法[参见：《四面体通讯》(Tetrahedron Letts)33,4529-4532(1992)；于1994年4月4日提交的美国专利申请222157]。上述方法包括通过使用预先对相同易得的C5-Om(鸟氨酸)羟基进行保护/脱保护而选择性地将带有C4-htyr(高酪氨酸)羟基的棘白菌素类还原成其单脱氧类似物的步骤。
具有抗真菌特性的牟伦多菌素[《抗菌素杂志》(J.Antibiotics)40,275-280和281-289(1987)]和脱氧牟伦多菌素[印度专利IN169830；《抗菌素杂志》(J.Antibiotics)45,618-623(1992)]分离自萨氏曲霉(Aspergillus sydowii)(Bainier和Sartory)Thom和Church var.Nov.Mulundensis Roy(培养基号HIL Y-30462)。发现脱氧牟伦多菌素具有比牟伦多菌素更好的抗真菌活性。然而，在发酵期间脱氧牟伦多菌素的产量比牟伦多菌素的产量低200倍。
我们已经发现：通过广泛深入地研究和实验，可以在中性条件下可以将通式Ⅰ的棘白菌素类肽类转化成相应的C4-htyr高酪氨酸单脱氧类似物、特别是可以将牟伦多菌素转化成脱氧牟伦多菌素。因此，本发明的目的是提供一种将通式Ⅰ的棘白菌素类肽类转化成相应的C4-高酪氨酸类似物、特别是将牟伦多菌素(通式Ⅱ的化合物)转化成脱氧牟伦多菌素(通式Ⅲ的化合物)的方法。
本发明提供了一种用于将通式Ⅰ的棘白菌素类肽类转化成通式Ⅰ的其C4-高酪氨酸单脱氧类似物的方法；
在通式Ⅰ的棘白菌素类肽类中W、X、Y、Z、R和R’如下所定义：
W X Y Z R R’1．棘白菌素B OH OH OH OH CH3 亚麻酰基2．肺炎球菌素 A0OH OH OH OH CH2-CO-NH2 10,12-二(Pneumocandin A0) 甲基-肉
豆蔻酰基3．肺炎球菌素 A1OH OH OH OH CH2-CO-NH2“(Pneumocandin A1)4．肺炎球菌素 A2H OH H H CH2-CO-NH2“(Pneumocandin A2)5．肺炎球菌素 B0OH OH OH OH CH2-CO-NH2“(Pneumocandin B0)6．肺炎球菌素 B2OH OH H H CH2-CONH2“(Pneumocandin B2)7．肺炎球菌素 C0OH OH OH OH CH2-CO-NH2“(Pneumocandin C0)8．牟伦多菌素 OH OH OH OH H 12-甲基-
十四酰基
在通式Ⅰ的其C4-高酪氨酸单脱氧类似物中W、X、Y、Z、R和R’如下所定义：
W X Y Z R R’1．脱氧棘白菌素B(棘白菌素 OH H OH OH CH3 亚麻酰基C)2．脱氧肺炎球菌素 A0OH H OH OH CH2-CO-NH2 10,12-(Deoxypneumocandin A0) 二甲基-
肉豆蔻酰
基3．脱氧肺炎球菌素 A1H H OH OH CH2-CO-NH2“(Deoxypneumocandin A1)4．脱氧肺炎球菌素 A2OH H H H CH2-CO-NH2“(Deoxypneumocandin A2)5．脱氧肺炎球菌素 B0OH H OH OH CH2-CONH2“(Deoxypneumocandin B0)6．脱氧肺炎球菌素 B2OH H H H CH2-CO-NH2“(Deoxypneumocandin B2)7．脱氧肺炎球菌素 C0OH H OH OH CH2-CO-NH2“(Deoxypneumocandin C0)8．脱氧牟伦多菌素 OH H OH OH H 12-甲基
-十四酰
基
本发明特别涉及一种用于将牟伦多菌素(通式Ⅱ的化合物)
转化成脱氧牟伦多菌素(通式Ⅲ的化合物)的方法；
该方法由单一步骤组成，所述的步骤是在没有预先对相同易得的C5-Om(鸟氨酸)羟基进行保护/脱保护的中性条件下选择性地将带有C4-htyr(高酪氨酸)羟基的棘白菌素类还原成其单脱氧类似物并从粗反应混合物中纯化所述的单脱氧化合物。
通过在pH3-9下的诸如甲醇、乙醇或二噁烷这样的溶剂中用阮内镍氢解可以实现经在C4-htyr上的选择性还原而将棘白菌素类转化成其单脱氧类似物的过程。优选的情况是，所述的选择性还原反应通过在pH7和室温下在乙醇中用阮内镍氢解来进行，其中每毫摩尔牟伦多菌素使用的阮内镍比例为6.8ml。
例如，可以按照如下方法从粗反应混合物中纯化本发明的单脱氧化合物：
通过使用正相色谱法(使用氧化铝或硅胶作为固定相和诸如石油醚、乙酸乙酯、二氯甲烷、氯仿、甲醇或其混合物这样的洗脱剂)的分级分离、使用反相色谱法(使用反相硅胶样二甲基十八烷基甲硅烷基硅胶、也称作RP-18或二甲基辛基甲硅烷基硅胶、也称作RP-8作为固定相和诸如水这样的洗脱剂；诸如磷酸盐、乙酸盐、柠檬酸盐(pH2-8)这样的缓冲剂和诸如甲醇、乙腈、丙酮、四氢呋喃或这些溶剂混合物这样的有机溶剂)的分级分离、使用凝胶渗透色谱法-在诸如甲醇、氯仿或乙酸盐或其混合物中使用诸如“Sephadex LH-20”(Pharmacia Chemical Industries，瑞典)、TSKgel Toyopearl HW(Tosohaas,Tosoh Corporation，日本)这样的树脂或在水中使用Sephadex G-10和G-25的分级分离；或者通过逆流色谱法，其中使用两相洗脱剂系统，该系统由两种或多种溶剂诸如水、甲醇、乙醇、异丙醇、正丙醇、四氢呋喃、丙酮、乙腈、二氯甲烷、氯仿、乙酸乙酯、石油醚、苯和甲苯构成。可以重复使用这些技术或可以将不同的技术合并使用。在ITO旋管上使用两相洗脱剂系统的逆流色谱法(液-液色谱法)是纯化本发明化合物的优选方法。
下列实施例用来解释本发明而不用来限定本发明的范围。
实施例1
在室温下将溶于乙醇(8ml)的牟伦多菌素(220mg,2.2mM)与乙醇(30ml)中的W-2阮内镍(pH)一起搅拌3小时。在稳定15分钟后，滗析上清液溶液并用3×30ml乙醇洗涤阮内镍、同时进行搅拌并过滤。通过在35℃和60-70mm/Hg的减压条件下蒸馏而浓缩合并的乙醇溶液，从而获得160mg(75％)的粗脱氧牟伦多菌素、为一种淡绿色固体。
通过在一种上行法的ITO旋管上的液-液色谱法来纯化所述的粗产物，其中使用上层的CH2Cl2∶MeOH∶n-PrOH∶H2O作为固定相和下层作为流动相。将所述的旋管(15+25+215ml)以串联方式连接并维持流速为0.6ml/分钟、活塞冲程为60且压力为0.5巴。通过对白色假丝酵母和黑曲霉的生物活性并通过分析型高效液相色谱法(HPLC)[柱：(10×0.4cm+3×0.4cm)ODS-Hypersil，10μ；流动相：50∶50 CH3CN∶H2O；流速：1ml/分钟；波长：220nm]的两者结合来监测脱氧牟伦多菌素的纯化。将含有脱氧牟伦多菌素的级分(各4.5ml)合并、通过在35℃和60-70mm/Hg的减压条件下蒸馏而浓缩并冻干至产生纯脱氧牟伦多菌素[65mg(30％产率)]。此外，回收了在上述纯化脱氧牟伦多菌素过程中未反应的牟伦多菌素，其产率为10％。半合成的脱氧牟伦多菌素在所有方面均与天然分离的化合物相同并将理化数据列在表1中。
表1外观： 白色粉末熔点： 170-172℃[α]D： -36.6℃(c 0.25，MeOH)HPLC RT： 4.42分钟FAB-MS(快原子：轰击质量) 1014.7(M+Na)+ 1NMR(300MHz,：CD3OD) 附图113C NMR(75MHz,：CD3OD) 附图2
Claims (4)
1．一种用于将通式Ⅰ的棘白菌素类肽类转化成其通式Ⅰ的C4-高酪氨酸单脱氧类似物的方法；
在通式Ⅰ的棘白菌素类肽类中W、X、Y、Z、R和R’如下所定义：
W X Y Z R R’1．棘白菌素B OH OH OH OH CH3 亚麻酰基2．肺炎球菌素 A0OH OH OH OH CH2-CO-NH2 10,12-二(Pneumocandin A0) 甲基-肉豆
蔻酰基3．肺炎球菌素 A1OH OH OH OH CH2-CO-NH2 “(Pneumocandin A1)4．肺炎球菌素 A2H OH H H CH2-CONH2“(Pneumocandin A2)5．肺炎球菌素 B0OH OH OH OH CH2-CO-NH2“(Pneumocandin B0)6．肺炎球菌素 B2OH OH H H CH2-CO-NH2“(Pneumocandin B2)7．肺炎球菌素 C0OH OH OH OH CH2-CO-NH2“(Pneumocandin C0)8．牟伦多菌素 OH OH OH OH H 12-甲基-
十四酰基
在通式Ⅰ的其C4-高酪氨酸单脱氧类似物中W、X、Y、Z、R和R’如下所定义：
W X Y Z R R’1．脱氧棘白菌素B(棘白菌 OH H OH OH CH3 亚麻酰基素C)2．脱氧肺炎球菌素 A0OH H OH OH CH2-CO-NH2 10,12-二(Deoxypneumocandin A0) 甲基-肉豆
蔻酰基3．脱氧肺炎球菌素 A1H H OH OH CH2-CONH2“(Deoxypneumocandin A1)4．脱氧肺炎球菌素 A2OH H H H CH2-CONH2“(Deoxypneumocandin A2)5．脱氧肺炎球菌素 B0OH H OH OH CH2-CONH2“(Deoxypneumocandin B0)6．脱氧肺炎球菌素 B2OH H H H CH2-CONH2“(Deoxypneumocandin B2)7．脱氧肺炎球菌素 C0OH H OH OH CH2-CONH2“(Deoxypneumocandin C0)8．脱氧牟伦多菌素 OH H OH OH H 12-甲基-
十四酰基
该方法由单一步骤组成，所述的步骤是在没有预先对相同易得的C5-Om(鸟氨酸)羟基进行保护/脱保护的中性条件下选择性地将带有C4-htyr(高酪氨酸)羟基的棘白菌素类还原成其单脱氧类似物并从粗反应混合物中纯化所述的单脱氧化合物。
2．一种如权利要求1中所述的方法，其中将牟伦多菌素转化成脱氧牟伦多菌素。
3．一种如权利要求1或2中所述的方法，其中所述的还原反应通过在pH7和室温下在乙醇中用阮内镍氢解来进行。
4．一种如权利要求1-3中所述的方法，其中所述的氢解以每毫摩尔牟伦多菌素使用6.8ml的阮内镍的比例来进行。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101993477A (zh) * | 2009-08-18 | 2011-03-30 | 上海医药工业研究院 | 一种棘白菌素b的脱氧类似物的制备方法 |
| CN102464704A (zh) * | 2010-11-05 | 2012-05-23 | 上海医药工业研究院 | 一种新化合物及其制备方法和用途 |
| WO2023193722A1 (zh) * | 2022-04-07 | 2023-10-12 | 浙江大学 | 棘白菌素类化合物及其制备方法和用途 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9399664B2 (en) * | 2010-03-29 | 2016-07-26 | Biocon Limited | Process for purification of pneumocandin |
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| US5159059A (en) * | 1990-05-29 | 1992-10-27 | Merck & Co., Inc. | Process for reduction of certain cyclohexapeptide compounds |
| US5939384A (en) * | 1991-10-01 | 1999-08-17 | Merck & Co., Inc. | Cyclohexapeptidyl propanolamine compounds |
| US5348940A (en) * | 1991-10-01 | 1994-09-20 | Merck & Co., Inc. | Cyclohexapeptidyl hydroxypropionitrile compounds |
| AU681119B2 (en) * | 1993-05-17 | 1997-08-21 | Fujisawa Pharmaceutical Co., Ltd. | New polypeptide compound and a process for preparation thereof |
| EP0779895B1 (en) * | 1994-08-23 | 1999-11-17 | Merck & Co. Inc. | An improved process for preparing side chain derivatives of cyclohexapeptidyl lipopeptides |
| EP0781141B1 (en) * | 1994-09-16 | 2002-09-04 | Merck & Co. Inc. | Aza cyclohexapeptide compounds |
| CA2205369A1 (en) * | 1994-11-15 | 1996-05-23 | Eli Lilly And Company | Process for performing retro-aldol reaction |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101993477A (zh) * | 2009-08-18 | 2011-03-30 | 上海医药工业研究院 | 一种棘白菌素b的脱氧类似物的制备方法 |
| CN101993477B (zh) * | 2009-08-18 | 2014-03-26 | 上海医药工业研究院 | 一种棘白菌素b的脱氧类似物的制备方法 |
| CN102464704A (zh) * | 2010-11-05 | 2012-05-23 | 上海医药工业研究院 | 一种新化合物及其制备方法和用途 |
| WO2023193722A1 (zh) * | 2022-04-07 | 2023-10-12 | 浙江大学 | 棘白菌素类化合物及其制备方法和用途 |
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