CN103819456A - 一组格尔德霉素衍生物及其应用 - Google Patents

一组格尔德霉素衍生物及其应用 Download PDF

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CN103819456A
CN103819456A CN201410048284.1A CN201410048284A CN103819456A CN 103819456 A CN103819456 A CN 103819456A CN 201410048284 A CN201410048284 A CN 201410048284A CN 103819456 A CN103819456 A CN 103819456A
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methylamino
aag
piperidin
geldanamycin
carboxyl
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CN103819456B (zh
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施国伟
王继峰
林志远
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FIFTH PEOPLE'S HOSPITAL OF SHANGHAI FUDAN UNIVERSITY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

本发明涉及一组格尔德霉素衍生物，所述的格尔德霉素衍生物是关于17-（(1-取代芳酰基哌啶-4-基)甲胺基）-17-去甲氧基格尔德霉素。本发明还提供了17-((1-(3,5,6-三甲基吡嗪-2-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素和17-((1-(2-羟基苯甲酰基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素在制备抗前列腺癌药物中的应用。本发明公开的化合物对前列腺癌相关肿瘤细胞具有显著的抑制作用，但对人正常组织来源的脐静脉上皮细胞、正常前列腺上皮细胞和人正常肝细胞毒性小，具有较好的成药性。

Description

一组格尔德霉素衍生物及其应用
技术领域
本发明涉及有机化合物合成技术领域，具体地说，是关于一组17-（(1-取代芳酰基哌啶-4-基)甲胺基）-17-去甲氧基格尔德霉素及其在制备抗前列腺癌药物方面的应用。
背景技术
格尔德霉素（Geldanamycin, GA）最早在1970年从吸水链霉菌（Streptomyces hygroscopicus）发酵液中分离得到，该化合物具有抗菌、抗原虫、抗炎、抗肿瘤和抗病毒等生物活性。GA生物活性的发挥多与热休克蛋白90（Heat shock protein 90, Hsp90）相关，它通过竞争性结合Hsp90 N末端ATP/ADP结构域，改变Hsp90构象，从而抑制Hsp90分子伴侣功能。Hsp90失活后，依赖Hsp90的众多信号转导系统的成员（包括多种癌基因产物和细胞周期调控蛋白，如Her2、Raf、AKT、CDK4等）被泛素化降解，从而产生抑制增殖、诱导细胞凋亡等一系列效应。
GA抗肿瘤作用是近年来关注的热点之一，其具有广谱的抗肿瘤作用。经检索，利用在GA分子17-位通过4-氨甲基哌啶连接引入不同的取代基，从而获得针对前列腺癌细胞具有细胞杀伤活性、细胞增殖抑制活性，同时能够维持或增加其原有抗肿瘤活性的专利及文献还未见报道。
发明内容
本发明的目的是针对现有技术中的不足，提供一组格尔德霉素衍生物。
本发明的再一的目的是，提供格尔德霉素衍生物应用。
为实现上述目的，本发明采取的技术方案是：
一组格尔德霉素衍生物，所述衍生物是一组17-位单取代格尔德霉素衍生物，其结构通式如式（Ⅰ）所示：
Figure 740425DEST_PATH_IMAGE001
式（Ⅰ）
其中：
X为N或者CH；Y为N或者CH；Z为N或者CH；Q为N或者CH；T为N或者CH；
R为甲基、甲氧基、羟基、羧基、氨基、卤素，
ArCO为2-吡啶甲酰基、烟酰基、异烟酰基、2,4-嘧啶甲酰基、3,5-嘧啶甲酰基、3,5,6-三甲基吡嗪甲酰基、2-羟基苯甲酰基、3-羟基苯甲酰基、4-羟基苯甲酰基。
所述的格尔德霉素衍生物是：
17-（(1-吡啶基哌啶-4-基)甲胺基）-17-去甲氧基格尔德霉素的合成（3a）、17-((1-烟酰基哌啶-4-基)甲胺基)- 17-去甲氧基格尔德霉素 (3b)、17-((1-异烟酰基哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3c)、17-((1-(嘧啶-4-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素（3d）、17-((1-(嘧啶-5-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3e)、17-((1-(3,5,6-三甲基吡嗪-2-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3f)和17-((1-(2-羟基苯甲酰基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3g)。
为实现上述第二个目的，本发明采取的技术方案是：
格尔德霉素衍生物在制备抗前列腺癌药物中的应用。
所述的格尔德霉素衍生物是17-((1-(3,5,6-三甲基吡嗪-2-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3f)和17-((1-(2-羟基苯甲酰基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3g)。
所述的前列腺癌是指激素非依赖性前列腺癌。
所述的前列腺癌是指激素依赖性前列腺癌。
本发明所述格尔德霉素衍生物的制备可以通过以下通用方法实现。
首先4-氨甲基哌啶在卤代烷烃类溶剂中，与格尔德霉素反应，得到中间体2，然后2与取代的芳基甲酸缩合生成目标产物3。

Claims (6)

1.一组格尔德霉素衍生物，其特征在于：所述衍生物是一组17-位单取代格尔德霉素衍生物，其结构通式如式（Ⅰ）所示：
Figure 972892DEST_PATH_IMAGE001
式（Ⅰ）
 其中：
X为N或者CH；Y为N或者CH；Z为N或者CH；Q为N或者CH；T为N或者CH；
R为甲基、甲氧基、羟基、羧基、氨基、卤素，
ArCO为2-吡啶甲酰基、烟酰基、异烟酰基、2,4-嘧啶甲酰基、3,5-嘧啶甲酰基、3,5,6-三甲基吡嗪甲酰基、2-羟基苯甲酰基、3-羟基苯甲酰基、4-羟基苯甲酰基。
2.根据权利要求1所述的格尔德霉素衍生物，其特征在于：所述的格尔德霉素衍生物是：
17-（(1-吡啶基哌啶-4-基)甲胺基）-17-去甲氧基格尔德霉素的合成（3a）、17-((1-烟酰基哌啶-4-基)甲胺基)- 17-去甲氧基格尔德霉素 (3b)、17-((1-异烟酰基哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3c)、17-((1-(嘧啶-4-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素（3d）、17-((1-(嘧啶-5-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3e)、17-((1-(3,5,6-三甲基吡嗪-2-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3f)和17-((1-(2-羟基苯甲酰基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3g)。
3.根据权利要求2所述的格尔德霉素衍生物在制备抗前列腺癌药物中的应用。
4.根据权利要求3所述的应用，其特征在于：所述的格尔德霉素衍生物是17-((1-(3,5,6-三甲基吡嗪-2-羧基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3f)和17-((1-(2-羟基苯甲酰基)哌啶-4-基)甲胺基)-17-去甲氧基格尔德霉素(3g)。
5.根据权利要求4所述的应用，其特征在于：所述的前列腺癌是指激素非依赖性前列腺癌。
6.根据权利要求4所述的应用，其特征在于：所述的前列腺癌是指激素依赖性前列腺癌。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1817866A (zh) * 2006-03-21 2006-08-16 中国医学科学院医药生物技术研究所 一组连有核苷碱基的格尔德霉素衍生物
CN101220068A (zh) * 2008-01-18 2008-07-16 中国医学科学院医药生物技术研究所 一组格尔德霉素衍生物及其制备方法
CN102115460A (zh) * 2010-01-05 2011-07-06 杭州华东医药集团生物工程研究所有限公司 格尔德霉素衍生物及其制备方法和用途
CN103450164A (zh) * 2012-05-31 2013-12-18 杭州华东医药集团生物工程研究所有限公司 格尔德霉素衍生物及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1817866A (zh) * 2006-03-21 2006-08-16 中国医学科学院医药生物技术研究所 一组连有核苷碱基的格尔德霉素衍生物
CN101220068A (zh) * 2008-01-18 2008-07-16 中国医学科学院医药生物技术研究所 一组格尔德霉素衍生物及其制备方法
CN102115460A (zh) * 2010-01-05 2011-07-06 杭州华东医药集团生物工程研究所有限公司 格尔德霉素衍生物及其制备方法和用途
CN103450164A (zh) * 2012-05-31 2013-12-18 杭州华东医药集团生物工程研究所有限公司 格尔德霉素衍生物及其制备方法和用途

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