CN116462616A - 炔酰胺类化合物及其应用 - Google Patents
炔酰胺类化合物及其应用 Download PDFInfo
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- CN116462616A CN116462616A CN202210028975.XA CN202210028975A CN116462616A CN 116462616 A CN116462616 A CN 116462616A CN 202210028975 A CN202210028975 A CN 202210028975A CN 116462616 A CN116462616 A CN 116462616A
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- ethynyl
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2475—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aralkylamines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
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Abstract
本发明提供了一种具有式(Ⅰ)所示结构的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体,及其应用。具体提供了所述炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在选择性修饰蛋白质氨基酸残基中的应用,优选地,所述氨基酸为天冬氨酸、谷氨酸和/或半胱氨酸。还提供了所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在制备激酶抑制剂中的应用,所述激酶为EGFR、ALDH1、GAPDH、MEK2、ECH1、GAPDH和/或ALDH1。还提供了所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗肿瘤的药物中的应用。
Description
技术领域
本发明涉及化学生物学分子探针技术领域以及化学医药技术领域,具体涉及一类炔酰胺类化合物及其应用。
背景技术
应用化学工具对蛋白质进行共价修饰是鉴定、定量和调节这些生物分子的有效方法。小分子化合物是研究蛋白质功能的强大工具,可通过形成共价键对蛋白质的功能进行调控,为一些疾病的治疗提供益处,如增强和持续药物的抑制作用。然而,大多数人类蛋白质因缺乏小分子配体而无法备用于药物设计。蛋白质特定位点的选择性修饰是解决上述问题的有效途径之一。目前最为广泛的选择性修饰为基于半胱氨酸及赖氨酸残基修饰的小分子研究,而对于占蛋白质中的残基比例高达12.2%的天冬氨酸(ASP)和谷氨酸(GLu)的选择性修饰研究却很少。而利用酸性氨基酸共价弹头设计合成共价抑制剂并在抗肿瘤细胞增殖方面应用的研究也是寥寥无几。因此针对酸性氨基酸进行小分子共价弹头的设计及开发对化学蛋白质组学应用和共价抑制剂的开发至关重要。
发明内容
针对上述问题,本发明提供了一类可选择性修饰氨基酸残基并有效抗肿瘤细胞增殖的炔酰胺类化合物,所述修饰的氨基酸为天冬氨酸、谷氨酸和/或半胱氨酸。
具体包括如下技术方案。
具有式(Ⅰ)所示结构的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在选择性修饰蛋白质氨基酸残基中的应用,
其中,R选自:磺酰基、酰基或者磷酰基;
R1选自:取代或者未取代的烷基、取代或者未取代的芳基,或者R1、R和与其相连的氮原子以及R3共同形成取代或者未取代的杂环;
R2选自:H、取代或者未取代的芳基;
R3选自:取代或者未取代的烷基、取代或者未取代的芳基;
R4选自:取代或者未取代的烷基、取代或者未取代的芳基,或者R3、R和R4共同形成取代或者未取代的杂环;并且,当R为磺酰基和/或酰基时,R4没有。
在其中一些实施例中,所述氨基酸为天冬氨酸、谷氨酸和/或半胱氨酸。
在其中一些实施例中,R1选自:R5取代或者未取代的C1-C12烷基、R5取代或者未取代的C6-C18芳基,或者R1、R和与其相连的氮原子以及R3共同形成R5取代或者未取代的5-10元杂环;
R5选自:H、乙炔基、C6-C10芳基、R6取代的C6-C10芳基;
R6选自:C3-C6炔氧基、乙炔基。
在其中一些实施例中,R1选自:R5取代或者未取代的C1-C6烷基、R5取代或者未取代的C6-C10芳基,或者R1、R和与其相连的氮原子以及R3共同形成R5取代或者未取代的5-9元杂环。
在其中一些实施例中,R5选自:H、乙炔基、苯基、R6取代的苯基;R6选自:炔丙氧基、乙炔基。
在其中一些实施例中,R1选自:甲基、乙基、丙基、炔丙氧基苯基取代的甲基、炔丙氧基苯基取代的乙基、3-乙炔基丙基、2-乙炔基乙基、炔丙基,或者R1、R和与其相连的氮原子以及R3共同形成如下基团:
在其中一些实施例中,R2选自:H、R7取代或者未取代的C6-C10芳基;R7选自:H、乙炔基、苯基、R6取代的苯基;R6选自:炔丙氧基、乙炔基。
在其中一些实施例中,R2选自:H、苯基、4-乙炔基苯基。
在其中一些实施例中,R3选自:R8取代或者未取代的C1-C12烷基、R8取代或者未取代的C6-C18芳基;
R4选自:R8取代或者未取代的C1-C12烷基、R8取代或者未取代的C6-C18芳基,或者R3、R和R4共同形成R8取代或者未取代的5-10元杂环;
R8选自:H、乙炔基、C1-C12烷基、-OR9取代的C1-C2烷基、-NR9R10取代的C1-C2烷基、-OR9、C6-C10芳基、-C(=O)O R10、-C(=O)NR9R10;
R9选自:R11取代或者未取代的C1-C2烷基、R11取代或者未取代的芳基、R11取代或者未取代的杂芳基;
R10选自:C1-C6烷基;
R11选自:H、乙炔基、卤素、苯基、C1-C6烷基、R12取代或者未取代的苯氧基、-N(R10)2;
R12选自:H、乙炔基、C1-C6烷基、卤素。
在其中一些实施例中,R3选自:R8取代或者未取代的C1-C6烷基、R8取代或者未取代的C6-C10芳基;
R4选自:R8取代或者未取代的C1-C6烷基、R8取代或者未取代的C6-C10芳基,或者R3、R和R4共同形成R8取代或者未取代的5-7元杂环。
在其中一些实施例中,R8选自:H、乙炔基、C1-C6烷基、-CH2-OR9、-CH2-NR9R10、-OR9、C6-C10芳基、-C(=O)O R10、-C(=O)NR9R10;
R9选自:苯甲基、R11取代或者未取代的C6-C10芳基、R11取代或者未取代的5-10元杂芳基;
R10选自:C1-C3烷基;
R11选自:H、乙炔基、卤素、C1-C6烷基、乙炔基取代的苯氧基、苯氧基、-N(R10)2。
在其中一些实施例中,R8选自:H、乙炔基、C1-C3烷基、-CH2-OR9、-CH2-NR9CH3、苯氧基、苯基、-C(=O)O CH3、-C(=O)NR9CH3;
R9选自:苯甲基、R11取代或者未取代的C6-C10芳基、R11取代或者未取代的5-10元杂芳基;
R11选自:H、乙炔基、卤素、C1-C3烷基、乙炔基取代的苯氧基、苯氧基、二甲胺基。
在其中一些实施例中,所述炔酰胺类化合物具有如下式(II)所示结构:
其中,R1选自:C1-C3烷基;R2为H;
R3选自:R8取代或者未取代的C6-C10芳基;
R8选自:H、乙炔基、-CH2-OR9、-CH2-NR9CH3、苯氧基、苯基、-C(=O)O CH3、-C(=O)NR9CH3;
R9选自:苯甲基、R11取代或者未取代的C6-C10芳基、R11取代或者未取代的5-10元杂芳基;
R11选自:H、乙炔基、卤素、乙炔基取代的苯氧基、苯氧基、二甲胺基。
在其中一些实施例中,所述炔酰胺类化合物选自如下化合物:
所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在制备激酶抑制剂中的应用,所述激酶为EGFR、ALDH1、GAPDH、MEK2、ECH1、GAPDH和/或ALDH1。
所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗肿瘤的药物中的应用。
在其中一些实施例中,所述肿瘤为肝癌(HepG2)、结肠癌(HT-29、HCT15、LOVO)、乳腺癌(MDA-MB-231)、结直肠腺癌(NCI-H716)、急性早幼粒白血病(HL60)、淋巴瘤(U937)和/或肺癌(H3255)。
本发明还提供了一种防治肿瘤病的药用组合物,所述防治肿瘤病的药用组合物由活性成分和药学上可接受的载体或者辅料制备得到,所述活性成分包括所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体。
本发明提供了一种可选择性修饰氨基酸残基的炔酰胺类化合物,该类炔酰胺类化合物可以选择性修饰天冬氨酸、谷氨酸和半胱氨酸的残基,可以作为分子探针化合物选择性修饰蛋白质氨基酸的残基,可通过形成共价键对蛋白质的功能进行调控,同时可以和亲和药效团组合成共价抑制剂,为一些疾病的治疗提供益处,尤其可以有效抑制肿瘤细胞的增殖,用于制备抗肿瘤药物。
附图说明
图1为化合物对纯蛋白氨基酸残基的共价修饰结果。
图2为化合物对肿瘤细胞的蛋白氨基酸残基的共价修饰结果。
图3为化合物对纯蛋白酸性氨基酸残基的选择性修饰结果。
图4为化合物对细胞的酸性氨基酸残基的选择性修饰结果。
图5为化合物YN-4对不同激酶的抑制活性结果。
图6为化合物YN-1和化合物YN-4的靶标确证的蛋白组学实验结果。
图7为下拉和蛋白质免疫印迹实验结果。
图8为化合物YN-4对H3255肿瘤细胞的克隆形成增殖抑制结果。
图9为化合物YN-4对H3255细胞的EGFR激酶以及其下游通路蛋白磷酸化抑制作用。
具体实施方式
本发明所述化合物中,当任何变量(例如R10等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。术语“杂环”为饱和或部分不饱和的单环或多环环状取代基,其中一个或多个环原子选自N、O、P(O)或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,杂环取代基的连接可通过碳原子或通过杂原子实现。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
本发明包括式Ⅰ-II化合物的游离形式,也包括其药学上可接受的盐及立体异构体。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式Ⅰ-II化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
在一个实施方案中,本发明提供了一种利用具有式Ⅰ-II所示结构的化合物及其药学上可接受的盐治疗人或其它哺乳动物的肿瘤疾病。
在一个实施方案中,本申请的化合物及其药学可接受的盐可以用于治疗或控制肝癌、结肠癌、乳腺癌、结直肠腺癌、急性早幼粒白血病、淋巴瘤和/或肺癌。
药物组合物
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体或者辅料。
本发明所述的“活性成分”是指本发明所述的式I-II化合物或者其药学上可接受的盐或者其立体异构体。
本发明所述的“活性成分”和药物组合物可用作蛋白激酶抑制剂,可用于制备预防和/或治疗肿瘤和的药物。
“安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体或者辅料”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
药学上可以接受的载体或者辅料部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在另一优选例中,本发明式I-II化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中,本发明式I-II化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:
(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;
(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;
(c)保湿剂,例如,甘油;
(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;
(e)缓溶剂,例如石蜡;
(f)吸收加速剂,例如,季胺化合物;
(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;
(h)吸附剂,例如,高岭土;和
(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他治疗药物(如降糖药)联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
联合用药
式I-II化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式和剂量保持不变,而同时或随后服用式I-II化合物。当式I-II化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I-II化合物的药用组合物。药物联用也包括在重叠的时间段服用式I-II化合物与其它一种或几种已知药物。当式I-II化合物与其它一种或几种药物进行药物联用时,式I-II化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式I-II化合物进行药物联用的药物或活性成分包括但不局限为:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体、JAK抑制剂等。
在一个实施方案中,可以与式I-II化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
下列实施例中所用试剂均可购买得到。
以下实施例所合成的化合物及其简称如下:
实施例1
第一步,在干燥的圆底烧瓶中加入4-溴-N-甲基苯磺酰胺(248.9mg,1.0mmol)、PdCl2(PPh3)2(10%mmol)、CuI(20mol%),然后在N2保护下加入超干THF(5ml)和Et3N(157.7mg,1.55mmol)。室温搅拌30min后,缓慢加入TMS乙炔,在室温下搅拌24h。用薄层色谱法监测反应过程,直至反应完成,用5ml乙酸乙酯稀释混合物,通过硅藻土过滤。滤液减压蒸发,粗产物经硅胶柱层析纯化,得到化合物2(221.9mg,产率83%)。1H NMR(400MHz,CDCl3)δ7.76(d,J=8.6Hz,2H),7.56(d,J=8.6Hz,2H),4.36(dd,J=10.6,5.3Hz,1H),2.63(d,J=5.4Hz,3H),0.23(s,9H).13C NMR(101MHz,CDCl3)δ138.4,132.7,128.1,127.3,103.3,98.8,29.5.
第二步,化合物2溶解在甲醇中,在N2保护下加入无水K2CO3(103.7mg,1.5eq)。反应混合物在室温下搅拌5h。反应完成后,通过硅藻土进行过滤,滤液在减压下蒸发。硅胶柱层析纯化得到化合物3(94.7mg,收率97%)。1H NMR(400MHz,CDCl3)δ7.85-7.79(m,2H),7.64-7.60(m,2H),4.58(d,J=4.9Hz,1H),3.26(s,1H),2.67(d,J=5.4Hz,3H).13C NMR(101MHz,CDCl3)δ139.0,132.9,129.0,127.4,82.2,80.9,29.5.
第三步,化合物3(47mg,0.24mmol)和60%NaH(300mg,1.5mmol)加到配有搅拌子的Schlenk管中。用注射器向试管中加入2mLDMSO,即时搅拌反应混合物15min,加热至70℃,缓慢加入1,1-二氯乙烯(58.2mg,0.6mmol)。混合物在70℃下再搅拌24小时,然后冷却到室温。然后用冷水淬灭,用二氯甲烷萃取三次。复合有机层在无水硫酸钠上干燥,在真空下蒸发。随后进行硅胶柱层析纯化,得到所需产品YN-1,为淡黄色固体(40.0mg,产率76%)。1H NMR(400MHz,CDCl3)δ7.87(d,J=8.5Hz,2H),7.67(d,J=8.5Hz,2H),3.31(s,1H),3.09(s,3H),2.70(s,1H).13C NMR(101MHz,CDCl3)δ136.1,133.0,128.3,127.9,81.9,81.7,77.5,58.0,39.2.HRMS(ESI)calcd.for C11H9NO2S 220.0427[M+H]+,found 220.0436.
合成YN-5的方法和上述的方法类似。YN-5,(淡黄色固体,产率91%)。1H NMR(400MHz,CDCl3)δ7.80(d,J=8.3Hz,2H),7.37(d,J=8.0Hz,2H),3.06(s,3H),2.68(s,1H),2.46(s,3H).13C NMR(101MHz,CDCl3)δ145.1,133.4,130.0,128.077.8,57.7,39.1,21.9.
实施例2
第一步,将PPh3(2.1g,4.0mmol)和CBr4(1.3g,8.0mmol)的DCM(10mL)溶液在0℃下加入4-炔基苯甲醛(260.3mg,2.0mmol)的DCM(10mL)溶液中。在常温条件下搅拌,直至TLC检测反应完成,反应混合物经过滤、浓缩、柱层析纯化得到化合物5(520.5mg,产率91%)。
第二步,在N2保护下向10ml试管中加入对甲苯磺酰胺(185.2mg,1.0mmol)、化合物5(314.6mg,1.1mmol)、CsCO3(1.96g,6.0mmol)、N,N'-二甲基乙二胺(88.2mg,1.0mmol)和CuI(34.2mg,0.18mmol),然后加入干燥脱气的DMF(5ml)。将混合物加热至70℃搅拌24h,用乙酸乙酯过滤洗涤。溶剂蒸发后,经柱层析纯化得到YN-2为白色固体(275.3mg,得率89%)。1HNMR(400MHz,CDCl3)δ7.85(d,J=8.3Hz,2H),7.41(dd,J=11.3,8.3Hz,4H),7.35–7.25(m,2H),3.18(s,3H),3.17(s,1H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ145.2,133.4,132.2,131.2,130.1128.0,123.5,121.5,86.1,83.5,78.9,69.0,39.5,21.9.HRMS(ESI)calcd.forC18H15NO2S 310.0756[M+H]+,found 310.0722.
合成YN-6的方法和上述的方法类似。YN-6,(白色固体,产率89%)。1H NMR(400MHz,CDCl3)δ7.84(d,J=8.3Hz,2H),7.43–7.34(m,4H),7.31–7.27(m,3H),3.15(s,3H),2.46(s,3H).13C NMR(101MHz,CDCl3)δ145.0,133.3,131.58,130.0,128.5,128.0,122.8,84.1,69.2,39.5,21.9.
实施例3
第一步,N,4-二甲基苯磺酰胺(555.7mg,3.0mmol)、NBS(356.0mg,2.0mmol)和AIBN(492.6mg,3.0mmol)的混合物在乙腈(10mL)中加热回流7h。然后将混合物过滤浓缩,得到化合物7。粗产品在下一步中使用,没有进一步的净化。
第二步,在5.0mL的DMF溶剂中加入化合物7(264.1mg,1.0mmol),K2CO3(276.4mg,2mmol)和对羟基苯炔(177.2mg,1.5mmol)。将混合物在80℃下搅拌4h,反应完成后加入10.0mL水。混合物用乙酸乙酯萃取,有机层用盐水洗涤,用无水硫酸钠干燥。溶剂蒸发后,用柱层析纯化,得到化合物8(283.3mg,产率94%)。
第三步,在N2保护下加入1,10-邻菲罗啉一水(36.0mg,0.2mmol)、化合物8(301.4mg,1.0mmol)、K2CO3(276.4mg,2.0mmol)、CuSO4·5H2O(21.2mg,0.1mmol)和2-溴乙炔基三异丙基硅烷(522.2mg,2.0mmol)。85℃搅拌12h,过滤后用乙醚洗涤。溶剂蒸发后,用柱层析纯化,得到粗产品。然后用THF(10mL)溶解产物,加入TBAF(2.0eq),室温搅拌2h,用水(10.0mL)淬灭反应混合物,用乙醚(3×10.0mL)提取。结合的有机层用盐水洗涤,用Na2SO4干燥,真空浓缩,得到YN-3,为白色固体(211.5mg,产率65%)。1H NMR(400MHz,CDCl3)δ7.97(d,J=8.5Hz,2H),7.67(d,J=8.6Hz,2H),7.48(d,J=8.9Hz,2H),7.28(s,2H),6.94(d,J=8.9Hz,2H),5.19(s,2H),3.12(s,3H),3.04(s,1H),2.73(s,1H),1.58(s,2H).13C NMR(400MHz,CDCl3)δ158.5,143.0,135.7,133.8,128.2,127.7,115.1,114.8,83.3,77.4,77.3,77.3,77.0,76.8,76.3,68.9,57.7,38.9.HRMS(ESI)calcd.for C18H15NO3S 326.0845[M+H]+,found 326.0843.
合成YN-7/8/9/10/11/12/13/14/15/16/17/18的方法和上述的方法类似。
YN-7(白色固体,产率47%),1H NMR(400MHz,DMSO-d6)δ8.04–7.97(m,2H),7.99–7.92(m,2H),7.81–7.75(m,2H),7.58–7.49(m,2H),7.51–7.43(m,1H),3.82(d,J=1.5Hz,1H),3.08(d,J=1.6Hz,3H).
YN-8(白色固体,产率34%),1H NMR(300MHz,DMSO-d6)δ7.87–7.80(m,2H),7.51–7.45(m,2H),7.21–7.13(m,2H),6.73–6.66(m,2H),4.71(s,2H),3.76(s,1H),3.05(s,3H),3.02(s,3H).
YN-9(黄色固体,产率55%),1H NMR(400MHz,DMSO-d6)δ7.90–7.84(m,2H),7.53–7.46(m,2H),7.32–7.27(m,1H),7.23–7.16(m,4H),3.80(s,1H),3.02(s,3H).
YN-10(白色固体,产率73%),1H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.0Hz,1H),8.26(dd,J=14.0,8.4Hz,2H),8.12(d,J=8.1Hz,1H),7.88(dd,J=8.7,2.0Hz,1H),7.79(ddd,J=8.3,6.8,1.4Hz,1H),7.73(ddd,J=8.2,6.9,1.4Hz,1H),3.79(s,1H),3.10(s,3H).
YN-11(白色固体,产率82%),1H NMR(400MHz,DMSO-d6)δ8.64(dd,J=8.5,1.2Hz,1H),8.39(d,J=8.1Hz,1H),8.26(dd,J=7.4,1.3Hz,1H),8.20–8.13(m,1H),7.81–7.69(m,3H),3.84(s,1H),3.09(s,3H).
YN-12(白色固体,产率69%),1H NMR(400MHz,DMSO-d6)δ8.04–7.97(m,2H),7.99–7.92(m,2H),7.81–7.75(m,2H),7.58–7.49(m,2H),7.51–7.43(m,1H),3.82(d,J=1.5Hz,1H),3.08(d,J=1.6Hz,3H).
YN-13(白色固体,产率46%),1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.00(d,J=8.9Hz,1H),7.95–7.91(m,2H),7.85(d,J=2.6Hz,1H),7.83–7.79(m,2H),7.26(dd,J=8.9,2.6Hz,1H),5.36(s,2H),3.79(s,1H),3.05(s,3H).
YN-14(黄色油状物,产率22%),1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.97–7.91(m,2H),7.72–7.67(m,2H),7.33(dt,J=8.8,0.7Hz,1H),7.21(t,J=2.8Hz,1H),7.16(d,J=2.4Hz,1H),6.95(dd,J=8.8,2.5Hz,1H),6.49(ddd,J=3.1,2.0,0.9Hz,1H),5.21(s,2H),3.09(s,3H),2.70(s,1H).
YN-15(白色固体,产率62%),1H NMR(400MHz,DMSO-d6)δ7.91–7.87(m,2H),7.77–7.71(m,2H),6.94–6.86(m,2H),6.75–6.68(m,2H),5.16(s,2H),3.80(s,1H),3.04(s,3H),2.79(s,6H).
YN-16(白色固体,产率57%),1H NMR(400MHz,Chloroform-d)δ8.30–8.18(m,2H),8.02–7.96(m,2H),3.98(d,J=1.2Hz,3H),3.11(d,J=1.2Hz,3H),2.71(d,J=1.2Hz,1H).
YN-17(白色固体,产率56%),1H NMR(400MHz,DMSO-d6)δ7.71(d,J=7.9Hz,2H),7.55(d,J=8.0Hz,2H),7.23(dd,J=22.2,8.3Hz,5H),3.78(s,1H),3.40(s,3H),2.96(s,3H).
YN-18(白色固体,产率76%),1H NMR(400MHz,DMSO-d6)δ7.85(dd,J=8.3,2.5Hz,2H),7.68(dd,J=8.4,2.5Hz,2H),7.42–7.30(m,4H),7.25(s,1H),3.76(d,J=2.5Hz,1H),3.62(d,J=2.6Hz,2H),3.54(d,J=2.6Hz,2H),3.02(d,J=2.5Hz,3H),2.10(d,J=2.6Hz,3H).
实施例4
第一步,将2-氨基-5-羟基苯甲酸(1.53g,10.0mmol)和甲酰胺(2.25g,50.0mmol)的混合物加热至160℃搅拌1h,冷却至室温后过滤。然后用甲醇冲洗固体,干燥得到化合物9-2(产率为90%).
第二步,化合物9-2(810.7mg,5.0mmol)和乙酰氯(471mg,6.0mmol)的混合物溶于DMF(20mL)中,然后在0℃下加入TEA(6.0mmol)、DMAP(0.5mmol)。加热至室温,再搅拌1h,得到化合物9-3(收率97%)。
第三步,在氩气保护下,粗产物9-3溶于10ml亚硫酰氯中,滴加0.05mL DMF。混合物于甲苯溶液50℃搅拌2小时。在室温下,将溶剂与甲苯共蒸发,以去除过量的亚硫酰氯。然后加入CH2Cl2和H2O,用MgSO4干燥有机层,真空下去除溶剂,柱层析法纯化,得到化合物9-4(收率65%)。1H NMR(400MHz,DMSO)δ8.83(s,1H),7.99(d,J=9.0Hz,1H),7.89(d,J=2.3Hz,1H),7.80–7.70(m,1H),2.34(s,3H).
第四步,在氩气保护下,化合物9-4(1.11g,5.0mmol)溶于NH3(17.8mL,124mmol,7Nin CH3OH)溶液中。将混合物在室温下搅拌1.5-2小时。反应完成后,在真空下除去溶剂。用乙醚对固体进行碾磨,过滤得到化合物9,产率为70%。
第五步,化合物9(180.6mg,1mmol)溶于DMF(5.0mL)中,加入K2CO3(276.3mg,2mmol)和4-(溴乙基)-N-甲基苯磺酰胺(396.2mg,1.5mmol)。50℃下搅拌2h,加入10.0mL水。混合物用乙酸乙酯萃取,有机层用盐水洗涤,用无水硫酸钠干燥。溶剂蒸发后,柱层析法纯化,得到化合物10。
第六步,在5.0mL的DMF的溶液中加入化合物10(363.4mg,1.0mmol),K2CO3(276.4mg,2mmol)和对羟基苯炔(177.2mg,1.5mmol)。50℃下搅拌12h,加入10.0mL水。混合物用乙酸乙酯萃取,有机层用盐水洗涤,用无水硫酸钠干燥。溶剂蒸发后,柱层析法纯化,得到化合物11(271.7mg,产率61%)。
第七步,将(溴乙基)三异丙基硅烷(313.5mg,1.2mmol)和1,10-邻菲罗啉一水(36.0mg,0.2mmol)加入到化合物11(445.5mg,1.0mmol)、K2CO3(276.4mg,2.0mmol)、CuSO4·5H2O(21.2mg,0.1mmol)和甲苯(5mL)的溶液中。120℃搅拌6h,过滤后用乙醚洗涤。溶剂蒸发后,柱层析法纯化,得到化合物12。
第八步,将化合物12溶于10ml THF中,加入2.0eq的TBAF,0℃搅拌0.5h,用水(10.0mL)淬灭,乙醚(3×10.0mL)萃取。有机层用盐水洗涤,用无水Na2SO4干燥,真空浓缩,得到YN-4淡黄色固体(164.3mg,产率35%)。1H NMR(400MHz,CDCl3)δ8.72(s,1H),8.01(dd,J=8.3,1.3Hz,3H),7.76(d,J=8.5Hz,2H),7.71-7.67(m,2H),7.51–7.45(m,2H),7.44–7.41(m,1H),7.33–7.29(m,1H),5.37(s,2H),3.16(s,1H),3.13(s,3H),2.74(s,1H).13C NMR(101MHz,CDCl3)δ165.9,157.1,152.4,152.1,148.0,142.5,135.9,130.0,129.9,129.8,128.3,127.9,126.7,125.6,123.9,122.8,117.0,102.3,82.5,78.4,77.3,69.4,57.8,39.0.HRMS(ESI)calcd.for C26H19N3O4S 470.1169[M+H]+,found 470.1154.
实施例5
第一步,在干燥的圆底烧瓶中加入化合物13(426mg,2.0mmol)、CuSO4(64mg,0.4mmo)、K3PO4(828mg,4mmol)、1,10-邻菲罗啉一水(180mg,1mmol),在N2保护下加入甲苯(10ml),然后缓慢加入TIPS溴乙炔加热至110℃。用薄层色谱法监测反应过程,直至反应完成。冷却至室温,用5ml乙酸乙酯稀释混合物,通过硅藻土过滤。滤液减压蒸发,粗产物经硅胶柱层析纯化,得到化合物14(422mg,产率53.7%)。1H NMR(400MHz,DMSO-d6)δ7.63(d,J=2.1Hz,4H),3.25(s,3H),0.90(s,21H).13C NMR(400MHz,DMSO-d6)δ170.20,133.25,131.54,130.44,125.14,100.58,69.65,37.51,18.76,11.11.
第二步,在干燥的圆底烧瓶中加入14(242mg,0.62mmol)、PPh3(3.2mg,0.0124mmol)、PdCl2(PPh3)2(9mg,0.0124mmol)、CuI(5mg,0.0248mmol)、Et3N(1.5ml),在N2保护下加入超干乙酸乙酯(10ml),然后缓慢加入TIPS乙炔,加热至60℃。用薄层色谱法监测反应过程,直至反应完成。冷却至室温,用5ml乙酸乙酯稀释混合物,通过硅藻土过滤。滤液减压蒸发,粗产物经硅胶柱层析纯化,得到化合物15(175mg,产率57%)。1H NMR(400MHz,CDCl3)δ7.75(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),3.36(s,3H),1.15(s,21H),0.97(s,21H).13C NMR(400MHz,CDCl3)δ170.7,133.0,131.4,128.5,126.4,106.3,99.8,93.2,70.3,37.8,18.7,18.5,11.3,11.2.
第三步,化合15(145mg,0.3mmol)溶解在THF(10ml)中,冰浴,加入TBAF(1M inTHF)(164μl,0.6mmol),用薄层色谱法监测反应过程,直至反应完成。然后用冷水淬灭,用二氯甲烷萃取三次。复合有机层水洗三次,用无水硫酸钠干燥,在真空下蒸发。随后进行硅胶柱层析纯化,得到所需产品YN-19,为白色固体(40mg,产率72.9%)。1H NMR(400MHz,CDCl3)δ7.75(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),3.34(s,3H),3.19(s,1H),2.79(s,1H).13CNMR(400MHz,CDCl3)δ170.7,133.4,131.8,128.9,125.5,83.0,79.7,77.4,60.5,37.6.HRMS(ESI)calcd.for C12H9NO 184.0684[M+H]+,found 184.0757.
实施例6
第一步,在干燥的圆底烧瓶中加入2-氨基-1-(4-溴苯基)乙醇(300.0mg,1.39mmol),然后在N2保护下加入超干DCM(5ml)和Et3N(310.0mg,3.05mmol)。室温搅拌10min后,缓慢分次加入双(三氟醚)碳酸甲酯(110.0mg,555.0mmol),在冰水浴下搅拌8h。用薄层色谱法监测反应过程,直至反应完成,用20ml×3乙酸乙酯萃取,有机相经饱和食盐水洗涤和无水硫酸钠干燥,减压蒸馏后得化合物17的粗品310mg,直接进行下一步反应。
第二步,化合物17粗品200mg,在N2保护下加入无水CuSO4(26.4mg,0.2eq),K3PO4(350.8mg,2.0eq),1,10-邻菲罗啉一水(74.4mg,0.5eq)和5ml甲苯室温搅拌10min后再向体系中滴加(2-溴乙炔基)三异丙基硅烷(260.0mg,1.2eq)。反应混合物回流搅拌4h。用薄层色谱法监测反应过程,直至反应完成,用20ml×3乙酸乙酯萃取,有机相经饱和食盐水洗涤和无水硫酸钠干燥,减压蒸馏除去溶剂后以PE:EA=7:1为洗脱条件进行硅胶柱层析纯化得到化合物18(272.6mg,产率78%)。1H NMR(400MHz,CDCl3)δ7.59(d,J=8.5Hz,2H),7.26(d,J=8.4Hz,2H),5.06(dd,J=8.7,7.4Hz,1H),4.75(t,J=8.9Hz,1H),4.25(dd,J=9.0,7.4Hz,1H),0.94(d,J=2.2Hz,21H)。
第三步,化合物18(140.0mg,0.33mmol),碘化亚铜(1.3mg,0.006mmol),三苯基磷(1.8mg,0.006mmol),三苯基磷二氯化钯(4.7mg,0.006mmol)在N2保护下加入无水乙酸乙酯3ml,搅拌下依次加入TEA(495.8mg,4.9mmol)和三异丙基硅基乙炔(90.7mg,0.3mmol),室温搅拌10min后反应体系在50℃回流搅拌6h。用薄层色谱法监测反应过程,直至反应完成,用20ml×3乙酸乙酯萃取,有机相经饱和食盐水洗涤和无水硫酸钠干燥,减压蒸馏除去溶剂得化合物19粗品160mg,直接进行下一步反应。
第四步,取化合物19粗品50mg,在N2保护下加入无水四氢呋喃3ml,冰水浴搅拌10min,随后加入四丁基氟化铵的四氢呋喃溶液(4M,57μl),冰水浴下继续搅拌10min。用薄层色谱法监测反应过程,直至反应完成,用10ml×3乙酸乙酯萃取,有机相经饱和食盐水洗涤和无水硫酸钠干燥,减压蒸馏除去溶剂后以PE:EA=3:1为洗脱条件进行硅胶柱层析纯化得到化合物YN-20,为白色固体(15.6mg,产率65%)。1H NMR(400MHz,CDCl3)δ7.60(d,J=8.2Hz,2H),7.37–7.33(m,2H),5.12–5.07(m,1H),4.80–4.75(m,1H),4.28–4.23(m,1H),3.17(s,1H),2.76(s,1H)。HRMS(ESI)calcd.for C13H9NO2212.0633[M+H]+,found 212.0706.
实施例7
第一步,在干燥的圆底烧瓶中加入化合物20(904mg,4mmol)、PdCl2(PPh3)2(56mg,0.08mmol)、CuI(30mg,0.16mmol)、Et3N(860μl,6.2mmol),在N2保护下加入超干THF(20ml),加热至70℃,然后缓慢加入TMS乙炔(706μl,5mmol)。用薄层色谱法监测反应过程,直至反应完成。冷却至室温,用5ml乙酸乙酯稀释混合物,通过硅藻土过滤。滤液减压蒸发,粗产物经硅胶柱层析纯化,得到化合物21(900mg,产率92.6%)。1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.88–7.79(m,3H),0.27(s,9H).13C NMR(400MHz,DMSO-d6)δ169.0,168.8,137.8,133.6,132.7,128.2,126.0,123.8,103.85,0.27,0.2.
第二步,在干燥的圆底烧瓶中加入化合物21(243mg,1mmol)、Na2CO3(212mg,2mmol)、Cu(OAc)2(40mg,0.2mmol)、和4A分子筛(400mg)。在反应瓶中加入吡啶(161μL,2mmol)-甲苯(10mL)溶液,然后用3个体积的O2清扫。将反应瓶置于油浴中搅拌1h(70℃),将乙炔基三甲基硅烷(216μL,1.2mmol)溶于干甲苯(1mL)中,然后缓慢加入至反应体系。反应混合物搅拌4h。反应混合物经硅藻土过滤、减压浓缩、硅胶柱层析纯化,得到化合物22(100mg,产率29.5%)。1H NMR(400MHz,DMSO-d6)δ7.94–7.92(m,3H),0.27(s,9H),0.25(s,9H).13C NMR(400MHz,DMSO-d6)δ164.9,164.8,138.6,132.1,130.9,129.2,127.0,124.8,103.4,100.6,86.6,82.4,0.3,0.1.
第三步,在单颈圆底瓶中加入磁性搅拌棒,将化合物22(50mg,0.147mmol)溶于2mL超干THF中。冰浴冷却到4℃。然后将醋酸(16μl,0.294mmol)加入反应溶液中,搅拌5分钟。然后将TBAF(1M in THF)(48μl,0.354mmol)在30分钟内滴加到反应体系中。反应继续在4℃下搅拌,直到薄层色谱法分析判断原料完全消耗为止。然后将反应瓶恢复到室温,然后转移到分液漏斗中,用冷水淬灭,二氯甲烷萃取三次。无水硫酸钠干燥,在真空下蒸发。随后进行硅胶柱层析纯化,得到所需产品YN-21,为淡黄色固体(17mg,产率59.3%)。1H NMR(400MHz,DMSO-d6)δ8.03–7.94(m,3H),4.72(s,1H),4.59(s,1H).13C NMR(400MHz,DMSO-d6)δ165.2,165.1,138.9,132.1,131.1,128.9,127.1,124.8,86.4,82.2,70.9,67.7.HRMS(ESI)calcd.for C12H5NO2196.0320[M+H]+,found 196.0393.
实施例8
第一步:亚磷酸二乙酯(414.3mg,3.0mmol)、NCS(267.1mg,2.0mmol)和AIBN(492.6mg,3.0mmol)的混合物在CCl4(10mL)中加热回流7h。然后将混合物过滤浓缩,得到化合物24。粗产品在下一步中使用,没有进一步的净化。
第二步:在干燥的10ml双颈烧瓶中加入化合物24(738.2mg,4mmol),然后在N2保护下加入超干CH2Cl2(10ml)、Et3N(809.5mg,8mmol),待反应体系降至0℃后,缓慢滴加4-羟基苄胺(541.8mg,4.4mmol)。滴加完毕后恢复室温继续搅拌24h。薄层色谱法监测反应过程直至反应完全,用10ml水淬灭反应,二氯甲烷萃取,有机层用盐水洗涤,无水硫酸钠干燥,蒸干溶剂后使用硅胶柱层析进行纯化,得到化合物25(862.0mg,产率79.4%)。
第三步:将化合物25(850.0mg,3.1mmol)溶解在DMF(10ml)中,在N2保护下加入无水K2CO3(865.2mg,6.2mmol)和3-溴丙炔(559.2mg,4.7mmol)。反应在室温下搅拌5h。至TLC监测反应完全,加水(10ml)淬灭,二氯甲烷萃取3~4次,合并有机层并用盐水洗涤,无水硫酸钠干燥。溶剂蒸发后,用硅胶柱层析纯化,得到化合物26(762.2mg,产率78.6%)。
第四步:在装有搅拌子的Schlenk管中依次加入化合物26(200mg,0.65mmol)、无水硫酸铜(20.75mg,0.13mmol)、1,10-邻菲罗啉一水(58.6mg,0.32mmol)、无水磷酸钾(275.9mg,1.3mmol),然后在N2保护下加入甲苯(3ml)和(溴乙炔基)三异丙基硅烷(219.6mg,0.84mmol)。反应混合物在80℃下反应16h,TLC监测反应进行完全,使用硅藻土过滤,二氯甲烷洗涤,收集滤液,减压蒸发后使用硅胶柱层析纯化得到化合物27(164.1mg,产率51.8%)。
第五步:用超干THF(5ml)溶解化合物27(160mg,0.32mmol),在N2保护下于0℃条件下滴加TBAF(1M in THF,2.0eq),0℃下继续搅拌15min后缓慢升至室温,继续反应2h,待反应完全后,直接蒸发溶剂,柱层析纯化得到产物YN-24,为白色固体(55.0mg,产率50.9%),1H NMR(400MHz,DMSO)δ7.32–7.23(m,2H),6.95(qd,J=5.0,2.5Hz,2H),5.38(td,J=12.4,6.3Hz,1H),4.94(s,1H),3.92–3.81(m,6H),3.77(s,1H),1.17(t,J=7.1Hz,6H).13C NMR(101MHz,DMSO)δ156.2,128.9,115.0,79.8,78.5,73.4,70.9,67.3,61.6,61.6,56.0,55.8,44.2,16.5,16.5.HRMS(ESI)calcd.for C16H20NO4P 321.1130[M+H]+,found 322.1203.
化合物YN-22/23/25/26的合成方法与上述方法类似。
YN-22,(黄色油状物,产率50.9%)。1H NMR(400MHz,DMSO)δ7.31(d,J=8.6Hz,2H),7.00(d,J=8.6Hz,2H),4.97(s,2H),4.32(d,J=9.3Hz,2H),4.25–4.06(m,4H),3.80(s,1H),3.31(d,J=3.5Hz,1H),1.03(s,3H),1.02(s,3H).13C NMR(101MHz,DMSO)δ157.1,130.1,115.1,78.1,78.1,73.6,72.7,71.0,67.3,57.1,57.0,56.0,32.3,32.3,20.9,20.7.
YN-23,(无色油,产率50.8%):1H NMR(400MHz,DMSO)δ4.19-4.07(m,4H),3.39(d,J=3.6Hz,1H),3.26(dd,J=15.0,8.0Hz,2H),2.84(t,J=2.6Hz,1H),2.28–2.20(m,2H),1.84–1.74(m,2H),1.02(d,J=5.8Hz,6H).13C NMR(101MHz,DMSO)δ83.8,78.1,78.0,72.2,32.3,32.3,27.4,20.9,20.6,15.2.HRMS(ESI)calcd.for C12H18NO3P 255.1024[M+H]+,found 256.1097.
YN-25(白色固体,产率78.6%):1H NMR(400MHz,DMSO)δ4.11(d,J=12.0Hz,4H),3.32(d,J=3.6Hz,1H),2.93(d,J=8.3Hz,3H),1.06(s,3H),0.98(s,3H).13C NMR(101MHz,DMSO)δ78.1,78.0,54.6,54.6,37.83,37.8,32.3,32.3,21.0,20.5.HRMS(ESI)calcd.forC8H14NO3P 203.0711[M+H]+,found 204.0784.
YN-26(白色油状物,产率45.45%):HRMS(ESI)calcd.for C7H14NO3P 190.0711[M+H]+,found 192.0784.
实施例9化合物对纯蛋白氨基酸残基的共价修饰。
10.0μM分子探针(即实施例1-8合成的化合物)分别与牛血清蛋白(10μL,1mg/mL)于37℃孵育3h,加入点击化学试剂[TBTA(0.1mmol),抗坏血酸钠(1mmol),CuSO4(1mmol)]及荧光染料TARMA-Azide(0.1mmol),进行点击化学反应,室温反应2h。加入2μL蛋白加样缓冲溶液(5×),并通过聚丙烯酰胺凝胶电泳进行分离。最后,通过多功能激光扫描成像仪Typhoon FLA 9500测试。如图1所示,分子探针YN-1、YN-2、YN-3、YN-4能够共价标记牛血清蛋白。
实施例10化合物对肿瘤细胞的蛋白氨基酸残基的共价修饰。
在37℃,5%CO2下培养人源肝癌细胞HepG2到对数生长期,将细胞均匀地分到6孔板。待24h贴壁后,向6孔板中分别加入50μM分子探针,于37℃孵育3h,去除培养基,用磷酸缓冲液(PBS)洗涤两次。然后,用含有1%的蛋白酶和磷酸酶抑制剂的RIPA细胞裂解液裂解细胞。用BCA蛋白定量试剂盒进行定量蛋白浓度至1mg/mL。取一定量的细胞裂解液,加入点击化学试剂[TBTA(0.1mmol),抗坏血酸钠(1mmol),CuSO4(1mmol)]及荧光染料TARMA-Azide(0.1mmol),进行点击化学反应,室温反应2h。随后,加入冰冻的丙酮溶液析出蛋白并离心去除有机溶剂,得到的蛋白固体加入蛋白加样缓冲液于95℃煮沸10min进行蛋白变性,随后通过聚丙烯酰胺凝胶电泳进行分离。最后,通过多功能激光扫描成像仪Typhoon FLA 9500测试。如图2所示,分子探针YN-1、YN-2、YN-3、YN-4能够在活细胞水平共价标记蛋白。
实施例11化合物对纯蛋白酸性氨基酸残基的选择性修饰。
100μM分子探针YN-1与牛血清蛋白(1mL,1mg/mL)于37℃孵育0.5h,加入点击化学试剂[TBTA(0.1mmol),抗坏血酸钠(1mmol),CuSO4(1mmol)]及DADPS(100μM),进行点击化学反应,室温反应2h。随后,加入预冷的丙酮溶液析出蛋白并离心去除有机溶剂。用1%SDS溶解蛋白样品,超声使之充分溶解,取上清加入亲和素蛋白琼脂Neutravidin agarose resin对蛋白进行富集,在旋转器上室温孵育4h后,离心去除上清液,依次用1%SDS、0.1%SDS及PBS洗涤。将上述亲和素蛋白琼脂溶于500μL 6M尿素的PBS溶液中,加入25μL含100mM DTT的NH4HCO3(25mM)缓冲液,37℃孵育30min,随后加入25μL含400mM IAA的NH4HCO3(25mM)缓冲液,室温避光反应30min,离心去除上清液并用PBS洗涤3次,加入150μL含2M尿素的PBS,150μL含1mM CaCl2的NH4HCO3(50mM)缓冲液,1.5μL胰蛋白酶37℃孵育过夜。离心去除上清液并用双蒸水洗涤3次。加入200μL 10%的甲酸水溶液反应2h,离心并用50%的乙腈水溶液洗涤3次,合并洗脱液并旋干,用C18对肽段进行纯化,所得肽段旋干用于生物质谱分析。如图3所示,分子探针YN-1可选择性修饰酸性氨基酸残基天冬氨酸残基及谷氨酸残基。
实施例12化合物对细胞的酸性氨基酸残基的选择性修饰。
100μM分子探针YN-1与HepG2细胞于37℃孵育8h,加入点击化学试剂[TBTA(0.1mmol),抗坏血酸钠(1mmol),CuSO4(1mmol)]及DADPS(100μM),进行点击化学反应,室温反应2h。随后,加入预冷的丙酮溶液析出蛋白并离心去除有机溶剂。用1%SDS溶解蛋白样品,超声使之充分溶解,取上清加入亲和素蛋白琼脂Neutravidin agarose resin对蛋白进行富集,在旋转器上室温孵育4h后,离心去除上清液,依次用1%SDS、0.1%SDS及PBS洗涤。将上述亲和素蛋白琼脂溶于500μL 6M尿素的PBS溶液中,加入25μL含100mM DTT的NH4HCO3(25mM)缓冲液,37℃孵育30min,随后加入25μL含400mM IAA的NH4HCO3(25mM)缓冲液,室温避光反应30min,离心去除上清液并用PBS洗涤3次,加入150μL含2M尿素的PBS,150μL含1mMCaCl2的NH4HCO3(50mM)缓冲液,3.0μL胰蛋白酶37℃孵育过夜。离心去除上清液并用双蒸水洗涤3次。加入200μL 10%的甲酸水溶液反应2h,离心并用50%的乙腈水溶液洗涤3次,合并洗脱液并旋干,用C18对肽段进行纯化,所得肽段旋干用于生物质谱分析。如图4所示,分子探针YN-1可选择性修饰酸性氨基酸残基天冬氨酸残基及谷氨酸残基。
实施例13 YN-4对不同激酶的抑制活性。
使用Z’-LYTETM荧光共振能量转移(FRET)方法对所有探针进行激酶抑制评价。Z’-LYTETM生化检测采用基于freet的偶联酶格式,并基于磷酸化和非磷酸化肽对蛋白水解裂解的不同敏感性。肽底物被标记为两个荧光体,每一端一个,它们组成一对FRET。在DMSO中将化合物稀释3倍,从5.1×10-9M稀释到1×10-4M。用EnVision阅读器(Perkin Elmer)检测数据。使用Graph Pad Prism 4.0进行曲线拟合和数据表示。如图5所示,其中YN-4对EGFRL858R激酶活性有选择性抑制,其IC50为5.57μM。
实施例14化合物对不同肿瘤细胞的生长抑制活性。
CCK8法检测细胞活力。每孔4000个细胞接种于96孔板中,在培养箱中培养24小时以保持粘附。YN-1~YN-26(0μM~100μM)溶于DMSO中,加入细胞的每孔中,保持DMSO终浓度为0.1%。孵育72h后,每孔加入30μL CCK-8试剂孵育2h。然后,在450nm和650nm波长下,用平板读卡器测定吸光度。确定细胞存活率为VR=(A-A0)/(As-A0)×100%,其中A为实验组吸光度,As为对照组(以DMSO为对照)吸光度,A0为空白组(无细胞)的吸光度。使用GraphpadPris计算IC50值。结果如下表1-表3所示:
表1炔酰胺类化合物对不同的肿瘤细胞的增殖抑制活性
表2炔酰胺类化合物对不同的肿瘤细胞的增殖抑制活性
表3炔酰胺类化合物对不同的肿瘤细胞的增殖抑制活性
实施例15 YN-1/4的靶标确证的蛋白组学实验。
50μM分子探针YN-1和YN-4与HepG2细胞于37℃孵育5h,然后用裂解液将细胞裂解,超声,然后将裂解的轻重细胞等体积等浓度的混合,加入点击化学试剂[TBTA(100μmol),TCEP(1mmol),CuSO4(1mmol)]及Biotin-N3(100μM),进行点击化学反应,室温反应2h。随后,加入预冷的丙酮溶液析出蛋白并离心去除有机溶剂。用1%SDS溶解蛋白样品,超声使之充分溶解,取上清加入亲和素蛋白琼脂Neutravidin agarose resin对蛋白进行富集,在旋转器上室温孵育4h后,离心去除上清液,依次用1%SDS、0.1%SDS及PBS洗涤。将上述亲和素蛋白琼脂溶于500μL 6M尿素的PBS溶液中,加入25μL含100mM DTT的NH4HCO3(25mM)缓冲液,37℃孵育30min,随后加入25μL含400mM IAA的NH4HCO3(25mM)缓冲液,室温避光反应30min,离心去除上清液并用PBS洗涤3次,加入150μL含2M尿素的PBS,150μL含1mM CaCl2的NH4HCO3(50mM)缓冲液,1μL胰蛋白酶(1μg/μl)37℃孵育过夜。加入纯的TFA淬灭反应,用C18对肽段进行纯化,所得肽段旋干用于生物质谱分析,如图6所示,YN-1能有效的鉴定到999个靶蛋白,YN-4可以鉴定到428个靶蛋白,其中有211个靶蛋白重叠。
实施例16下拉蛋白和蛋白质免疫印迹实验。
50μM分子探针YN-1和YN-4与HepG2/H3255细胞于37℃孵育5h,然后用裂解液将细胞裂解,加入点击化学试剂[TBTA(100μmol),TCEP(1mmol),CuSO4(1mmol)]及Biotin-N3(50μM),进行点击化学反应,室温反应2h。随后,加入预冷的丙酮溶液析出蛋白并离心去除有机溶剂。用1%SDS溶解蛋白样品,超声使之充分溶解,取上清加入亲和素蛋白琼脂Neutravidin agarose resin对蛋白进行富集,在旋转器上室温孵育4h后(或4℃过夜),离心去除上清液,依次用1%SDS、0.1%SDS及PBS洗涤。然后95℃煮磁珠30min,接下来进行免疫印迹实验孵育相应的抗体,最后显影得到图7所示的结果,如图7所示,YN-4能靶向结合EGFR、ALDH1和GAPDH;YN-1能靶向结合MEK2、ECH1、GAPDH和ALDH1。
实施例17 YN-4对H3255肿瘤细胞的克隆形成增殖抑制。
H3255细胞以1000细胞/孔的密度植入6孔板。孵育过夜后,分别用不同浓度的YN-4(0、0.11、0.33、1.1、3.3、10μM)处理细胞,复制3个孔。弃去培养基,4%聚甲氧基亚甲基固定细胞,姬姆萨染色液染色30min。洗净培养皿,轻轻风干。用Image J计数克隆聚类,计算细胞形成率,如图8所示,YN-1在1.1μM的浓度下能有效地抑制H3255肿瘤细胞的克隆形成,当YN-4的浓度到达10μM时能几乎完全抑制H3255肿瘤细胞的增殖。
实施例18 YN-4对H3255细胞的EGFR激酶以及其下游通路蛋白磷酸化抑制作用。
H3255细胞生长到80-90%后去除培养基,用不同浓度的YN-4处理,DMSO不超过1%。孵育3小时后,除去培养基,用PBS洗涤细胞2次,以去除多余的探针。用RIPA缓冲液裂解细胞,离心10分钟(14000rpm,4℃)得到可溶性蛋白溶液。最后用BCA蛋白检测蛋白浓度,然后用PBS稀释。加入1×SDS loading buffer,95℃煮10分钟,然后进行免疫印迹实验孵育相应的抗体,最后显影得到图9所示的结果,如图9所示,YN-4能有效的抑制EGFR的磷酸化水平,同时也能抑制其下游蛋白激酶的磷酸化水平,包括AKT和ERK激酶。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (19)
1.具有式(Ⅰ)所示结构的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在选择性修饰蛋白质氨基酸残基中的应用,
其中,R选自:磺酰基、酰基或者磷酰基;
R1选自:取代或者未取代的烷基、取代或者未取代的芳基,或者R1、R和与其相连的氮原子以及R3共同形成取代或者未取代的杂环;
R2选自:H、取代或者未取代的芳基;
R3选自:取代或者未取代的烷基、取代或者未取代的芳基;
R4选自:取代或者未取代的烷基、取代或者未取代的芳基,或者R3、R和R4共同形成取代或者未取代的杂环;并且,当R为磺酰基和/或酰基时,R4没有。
2.根据权利要求1所述的应用,其特征在于,所述氨基酸为天冬氨酸、谷氨酸和/或半胱氨酸。
3.根据权利要求1所述的应用,其特征在于,R1选自:R5取代或者未取代的C1-C12烷基、R5取代或者未取代的C6-C18芳基,或者R1、R和与其相连的氮原子以及R3共同形成R5取代或者未取代的5-10元杂环;
R5选自:H、乙炔基、C6-C10芳基、R6取代的C6-C10芳基;
R6选自:C3-C6炔氧基、乙炔基。
4.根据权利要求3所述的应用,其特征在于,R1选自:R5取代或者未取代的C1-C6烷基、R5取代或者未取代的C6-C10芳基,或者R1、R和与其相连的氮原子以及R3共同形成R5取代或者未取代的5-9元杂环。
5.根据权利要求3所述的应用,其特征在于,R5选自:H、乙炔基、苯基、R6取代的苯基;R6选自:炔丙氧基、乙炔基。
6.根据权利要求4所述的应用,其特征在于,R1选自:甲基、乙基、丙基、炔丙氧基苯基取代的甲基、炔丙氧基苯基取代的乙基、3-乙炔基丙基、2-乙炔基乙基、炔丙基,或者R1、R和与其相连的氮原子以及R3共同形成如下基团:
7.根据权利要求1所述的应用,其特征在于,R2选自:H、R7取代或者未取代的C6-C10芳基;R7选自:H、乙炔基、苯基、R6取代的苯基;R6选自:炔丙氧基、乙炔基。
8.根据权利要求1所述的应用,其特征在于,R2选自:H、苯基、4-乙炔基苯基。
9.根据权利要求1-8任一项所述的应用,其特征在于,R3选自:R8取代或者未取代的C1-C12烷基、R8取代或者未取代的C6-C18芳基;
R4选自:R8取代或者未取代的C1-C12烷基、R8取代或者未取代的C6-C18芳基,或者R3、R和R4共同形成R8取代或者未取代的5-10元杂环;
R8选自:H、乙炔基、C1-C12烷基、-OR9取代的C1-C2烷基、-NR9R10取代的C1-C2烷基、-OR9、C6-C10芳基、-C(=O)O R10、-C(=O)NR9R10;
R9选自:R11取代或者未取代的C1-C2烷基、R11取代或者未取代的芳基、R11取代或者未取代的杂芳基;
R10选自:C1-C6烷基;
R11选自:H、乙炔基、卤素、苯基、C1-C6烷基、R12取代或者未取代的苯氧基、-N(R10)2;
R12选自:H、乙炔基、C1-C6烷基、卤素。
10.根据权利要求9所述的应用,其特征在于,R3选自:R8取代或者未取代的C1-C6烷基、R8取代或者未取代的C6-C10芳基;
R4选自:R8取代或者未取代的C1-C6烷基、R8取代或者未取代的C6-C10芳基,或者R3、R和R4共同形成R8取代或者未取代的5-7元杂环。
11.根据权利要求9所述的应用,其特征在于,R8选自:H、乙炔基、C1-C6烷基、-CH2-OR9、-CH2-NR9R10、-OR9、C6-C10芳基、-C(=O)O R10、-C(=O)NR9R10;
R9选自:苯甲基、R11取代或者未取代的C6-C10芳基、R11取代或者未取代的5-10元杂芳基;
R10选自:C1-C3烷基;
R11选自:H、乙炔基、卤素、C1-C6烷基、乙炔基取代的苯氧基、苯氧基、-N(R10)2。
12.根据权利要求11所述的应用,其特征在于,R8选自:H、乙炔基、C1-C3烷基、-CH2-OR9、-CH2-NR9CH3、苯氧基、苯基、-C(=O)O CH3、-C(=O)NR9CH3;
R9选自:苯甲基、R11取代或者未取代的C6-C10芳基、R11取代或者未取代的5-10元杂芳基;
R11选自:H、乙炔基、卤素、C1-C3烷基、乙炔基取代的苯氧基、苯氧基、二甲胺基。
13.根据权利要求1所述的应用,其特征在于,所述炔酰胺类化合物具有如下式(II)所示结构:
其中,R1选自:C1-C3烷基;R2为H;
R3选自:R8取代或者未取代的C6-C10芳基;
R8选自:H、乙炔基、-CH2-OR9、-CH2-NR9CH3、苯氧基、苯基、-C(=O)O CH3、-C(=O)NR9CH3;
R9选自:苯甲基、R11取代或者未取代的C6-C10芳基、R11取代或者未取代的5-10元杂芳基;
R11选自:H、乙炔基、卤素、乙炔基取代的苯氧基、苯氧基、二甲胺基。
14.根据权利要求1所述的应用,其特征在于,所述炔酰胺类化合物选自如下化合物:
15.权利要求1-14任一项中所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体。
16.权利要求1-14任一项中所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在制备激酶抑制剂中的应用,所述激酶为EGFR、ALDH1、GAPDH、MEK2、ECH1、GAPDH和/或ALDH1。
17.权利要求1-14任一项中所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗肿瘤的药物中的应用。
18.根据权利要求17所述的应用,所述肿瘤为肝癌、结肠癌、乳腺癌、结直肠腺癌、急性早幼粒白血病、淋巴瘤和/或肺癌。
19.一种防治肿瘤的药用组合物,其特征在于,由活性成分和药学上可接受的载体或者辅料制备得到,所述活性成分包括权利要求1-14任一项中所述的炔酰胺类化合物或者其药学上可接受的盐或者其立体异构体。
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