CN104844504A - (e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用 - Google Patents

(e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用 Download PDF

Info

Publication number
CN104844504A
CN104844504A CN201510177098.2A CN201510177098A CN104844504A CN 104844504 A CN104844504 A CN 104844504A CN 201510177098 A CN201510177098 A CN 201510177098A CN 104844504 A CN104844504 A CN 104844504A
Authority
CN
China
Prior art keywords
preparation
resveratrol
trans
ethyl acetate
verakanol derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510177098.2A
Other languages
English (en)
Inventor
任玉杰
金鹭
潘安健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Technology
Original Assignee
Shanghai Institute of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Technology filed Critical Shanghai Institute of Technology
Priority to CN201510177098.2A priority Critical patent/CN104844504A/zh
Publication of CN104844504A publication Critical patent/CN104844504A/zh
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种白藜芦醇衍生物，其结构式如I所示：。本发明还公开了上述的这种白藜芦醇衍生物的制备方法，本发明还公开了上述的这种白藜芦醇衍生物在制备治疗乳腺癌的药物中的应用，该白藜芦醇衍生物对乳腺癌细胞MCF-7的抑制活性IC50-值达到了60.8 μM，具有较强的乳腺癌细胞MCF-7抑制作用。

Description

(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用
技术领域
本发明属于药物化学领域，尤其涉及一种白藜芦醇衍生物，具体来说是一种 (E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用。
背景技术
白藜芦醇广泛存在于多种植物体内，是植物体在紫外线照射、外来病菌入侵等不利条件下产生的一种植物抗毒素，具有众多的药理作用，且具有毒性低，安全范围广的优点。已知白藜芦醇具有抗氧化、降血压、延缓衰老以及抗血栓的作用。近年发现白藜芦醇对多种实验肿瘤有明显的抑制活性，引起了人们的普遍关注。
包括对白血病、结肠癌、乳腺癌、前列腺癌、肝癌和食道癌细胞等多种人类白藜芦醇可以引起细胞周期阻滞，并诱导分化或凋亡。有相关文献报道白藜芦醇对人肺癌A549细胞株的IC50为44.7±0.06μM，对白血病HL60 细胞株IC50为5±0.9μM，对宫颈癌HeLa细胞株的IC50为22.5±0.5μM以及对人乳腺癌MDA-MB-231细胞株IC50为20.5±2.6μM。另有报道白藜芦醇对人大肠癌HT-29细胞有抑制作用，同时，白藜芦醇可以抑制肝癌细胞HepG2及结肠癌SW480细胞系癌细胞，引起前列腺细胞PC-3凋亡。综上所述，白藜芦醇不仅有直接的抑瘤作用，还具有抗诱变及免疫功能增强作用，同时具有低毒的特性。白藜芦醇化学名为 (E)-3,4′,5-三羟基-二苯乙烯。结构如下：
                                                
发明内容
本发明的目的在于提供一种白藜芦醇衍生物及制备方法和应用，所述的这种白藜芦醇衍生物及制备方法和应用解决了现有技术中的药物治疗乳腺癌的效果不佳的技术问题。
本发明提供了一种白藜芦醇衍生物，其结构式如I所示：
。
本发明还提供了上述的这种白藜芦醇衍生物的制备方法，先称取白藜芦醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和4-二甲氨基吡啶，所述的白藜芦醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和4-二甲氨基吡啶的摩尔比为15~20: 10~15: 1~2，将上述物质溶解于二氯甲烷和N,N-二甲基甲酰胺的混合溶液中，所述的白藜芦醇、二氯甲烷和N,N-二甲基甲酰胺的摩尔体积比为15~20mol: 50~70L: 1~2L，再称取2-吡啶甲酸加入反应容器中，于65~75℃反应2~4h，所述的白藜芦醇和2-吡啶甲酸的摩尔比为1~2: 1~2，反应物完全消失后，反应液减压浓缩除去溶剂，再用有机溶剂稀释，分别依次用水和饱和食盐水洗涤，干燥过滤，再用有机相减压浓缩除去溶剂，残余物硅胶柱层析得化合物(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯。
进一步的，所述的硅胶柱层析中的洗脱剂、乙酸乙酯和石油醚混合物的体积比为3：2，所述的乙酸乙酯和石油醚混合物中，乙酸乙酯和石油醚为任意体积比。
进一步的，所述的有机溶剂为乙酸乙酯。
进一步的，采用无水硫酸钠干燥过滤。
上述反应的方程式如下：
 
本发明还提供了上述的一种白藜芦醇衍生物在制备治疗乳腺癌的药物中的应用。
本发明和已有技术相比，其技术进步是显著的。本发明提供了一种新的白藜芦醇衍生物——(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯化合物，生物活性测定表明它对乳腺癌细胞MCF-7具有较强的抑制作用，对乳腺癌细胞MCF-7的IC50值达到了60.8 μM，是潜在的抗乳腺癌药物的先导化合物。
附图说明
图1显示了本发明浓度与乳腺癌细胞MCF-7抑制率的关系图。
具体实施方式
下面结合具体实施例，进一步阐述本发明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修饰同样落入本发明权利要求所限定的范围。
实施例1
一种(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯化合物的制备方法，具体包括以下步骤：
于适量容积的圆底烧瓶中加入白藜芦醇3.412 g (15mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐1.952 g(10mmol)和4-二甲氨基吡啶0.124 g(1mmol)，溶于50mL二氯甲烷和1mLN,N-二甲基甲酰胺中，再加入2-吡啶甲酸1.859 g (15mmol)，此反应混合物70℃反应3h，薄层析检测反应物完全消失后，反应液减压浓缩除去大部分溶剂，再用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，无水硫酸钠干燥过滤。有机相减压浓缩除去溶剂，残余物硅胶柱层析(洗脱剂：乙酸乙酯/石油醚=3/2)得化合物(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯。
HRMS (ESI) m/z calculated for C24H17N4O5 + [M + H]+: 439.1326
1H NMR (500 MHz, DMSO-d) δ 8.89 (dd, J = 5.0, 1.2 Hz, 2H), 8.24 (dd, J = 8.1, 1.1 Hz, 2H), 7.97 (m, 2H), 7.79 (m, 2H), 7.39 (d, J = 7.5 Hz, 2H), 7.02 (s, 2H), 6.92 (d, J = 15.0 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 15.1 Hz, 1H), 6.76 (d, J = 7.5 Hz, 2H)
实施例2
(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯对乳腺癌细胞MCF-7的抑制作用测定：
MTT比色法：根据细胞生长速率，将处于对数生长期的肿瘤细胞以100μL/孔接种于96孔培养板，贴壁生长24小时再加浓度梯度药物，设5个梯度浓度(0,25, 50, 100,200 μg/ml)，每个浓度设三复孔。肿瘤细胞在37℃、5%CO2条件下培养48h，然后弃去培养液，用PBS冲2~3遍，然后每孔加入100μL含10%MTT的培养液，培养4h，然后吸去培养液。最后加入100μL/孔的二甲基亚砜，在全自动多功能酶标仪检测在OD492nm和630nm波长下测定A值，计算细胞生长抑制率。
实验测得数据见下表，由数据绘制抑制率与浓度关系图，从图1中可得IC50值。
浓度μg/ml A平均值 存活率%
0 0.514667 100
25 0.386 75
50 0.292 56.73575
100 0.171333 33.29016
200 0.003333 0.647668
对乳腺癌细胞MCF-7的抑制活性测试，(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯对乳腺癌细胞MCF-7的IC50值为60.8±1.0 (数值以“平均值±标准偏差”表示，浓度单位μM)，说明该化合物具有较强的乳腺癌细胞MCF-7抑制作用，是抗乳腺癌的潜在药物。

Claims (6)

1.一种白藜芦醇衍生物，其结构式如I所示：
。
2.权利要求1所述的这种白藜芦醇衍生物的制备方法，其特征在于：先称取白藜芦醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和4-二甲氨基吡啶，所述的白藜芦醇、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和4-二甲氨基吡啶的摩尔比为15~20: 10~15: 1~2，将上述物质溶解于二氯甲烷和N,N-二甲基甲酰胺的混合溶液中，所述的白藜芦醇、二氯甲烷和N,N-二甲基甲酰胺的摩尔体积比为15~20mol: 50~70L: 1~2L，再称取2-吡啶甲酸加入反应容器中，于65~75℃反应2~4h，所述的白藜芦醇和2-吡啶甲酸的摩尔比为1~2: 1~2，反应物完全消失后，反应液减压浓缩除去溶剂，再用有机溶剂稀释，分别依次用水和饱和食盐水洗涤，干燥过滤，再用有机相减压浓缩除去溶剂，残余物硅胶柱层析得化合物(E)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯。
3.如权利要求2所述的这种白藜芦醇衍生物的制备方法，其特征在于：所述的硅胶柱层析中的洗脱剂、乙酸乙酯和石油醚混合物的体积比为3：2，所述的乙酸乙酯和石油醚混合物中，乙酸乙酯和石油醚为任意体积比。
4.如权利要求3所述的这种白藜芦醇衍生物的制备方法，其特征在于：所述的有机溶剂为乙酸乙酯。
5.如权利要求2所述的这种白藜芦醇衍生物的制备方法，其特征在于：采用无水硫酸钠干燥过滤。
6.权利要求1所述的这种白藜芦醇衍生物在制备治疗乳腺癌的药物中的应用。
CN201510177098.2A 2015-04-15 2015-04-15 (e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用 Pending CN104844504A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510177098.2A CN104844504A (zh) 2015-04-15 2015-04-15 (e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510177098.2A CN104844504A (zh) 2015-04-15 2015-04-15 (e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用

Publications (1)

Publication Number Publication Date
CN104844504A true CN104844504A (zh) 2015-08-19

Family

ID=53844544

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510177098.2A Pending CN104844504A (zh) 2015-04-15 2015-04-15 (e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用

Country Status (1)

Country Link
CN (1) CN104844504A (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1445216A (zh) * 2003-03-03 2003-10-01 中国科学院广州化学研究所 白藜芦醇烟酸酯及其合成方法
CN102276426A (zh) * 2010-11-04 2011-12-14 上海统益生物科技有限公司 白藜芦醇的一种新型合成方法
CN102816090A (zh) * 2012-09-10 2012-12-12 四川大学 氨基甲酸酯类化合物、其制备方法和用途
WO2013008175A1 (fr) * 2011-07-11 2013-01-17 Centre National De La Recherche Scientifique Procede de preparation du trans-resveratrol et de ses analogues

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1445216A (zh) * 2003-03-03 2003-10-01 中国科学院广州化学研究所 白藜芦醇烟酸酯及其合成方法
CN102276426A (zh) * 2010-11-04 2011-12-14 上海统益生物科技有限公司 白藜芦醇的一种新型合成方法
WO2013008175A1 (fr) * 2011-07-11 2013-01-17 Centre National De La Recherche Scientifique Procede de preparation du trans-resveratrol et de ses analogues
CN102816090A (zh) * 2012-09-10 2012-12-12 四川大学 氨基甲酸酯类化合物、其制备方法和用途

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
WEN YUAN，等: "Synthesis of pterostilbene and resveratrol carbamate derivatives as potential dual cholinesterase inhibitors and neuroprotective agents", 《RES CHEM INTERMED》 *
刘鲁明，等: "《肿瘤科特色治疗技术》", 31 May 2010, 科学技术文献出版社 *
杜成，等: "白藜芦醇衍生物的合成及抑制宫颈癌HeLa 细胞肿瘤活性", 《有机化学》 *
樊慧婷，等: "白藜芦醇烟酸酯与白藜芦醇体内外抗肿瘤作用比较", 《中国新药杂杂志》 *
樊慧婷，等: "白藜芦醇烟酸酯抑制人肝癌细胞HepG2 增殖并诱导细胞的凋亡", 《中国临床药理学与治疗学》 *
陈晓辉，等: "白藜芦醇苯甲酸酯的合成及与DNA相互作用的荧光分析", 《化学试剂》 *

Similar Documents

Publication Publication Date Title
Huang et al. The cytotoxicity of 8-O-4′ neolignans from the seeds of Crataegus pinnatifida
CN103804335B (zh) 一种杨梅素含氮类衍生物及其制备方法和用途
CN102863376B (zh) N-取代甲基-3,5-双取代苄叉基-4-哌啶酮及制备和应用
CN103222970A (zh) 不对称单羰基姜黄素类似物在制备抗肿瘤药物中的应用
CN105418490B (zh) 氮芥基荜茇酰胺类化合物在医药中的用途
CN104016957A (zh) 7-甲基-3-香叶基黄酮和7-甲基-3-异戊烯基黄酮及其制备方法和应用
CN103951602B (zh) 具有抗肿瘤活性的吡咯缩氨基硫脲铜、镍配合物的合成方法
CN104844504A (zh) (e)-5-(羟基苯乙烯基)-1,3-二吡啶-2-甲酸酚酯及制备方法和应用
CN104844505A (zh) (e)-3-羟基-5-(羟基苯乙烯基)吡啶-2-甲酸酚酯及制备方法和应用
CN104844527A (zh) (e)-5-(羟基苯乙烯基)-1,3-二吡嗪-2-甲酸酚酯及制备方法和应用
CN106083646B (zh) 异海松酰腙类化合物及其制备方法与应用
CN104844517A (zh) (e)-3-羟基-5-(羟基苯乙烯基)咪唑乙酸酚酯及在制备方法和应用
CN103864642B (zh) 大黄酸衍生物及其合成方法和用途
CN104788411A (zh) (e)-5-(羟基苯乙烯基)-1,3-二呋喃甲酸酚酯及制备方法和应用
CN102731454A (zh) 去氢木香烃内酯衍生物,其药物组合物及其制备方法和用途
CN109232703A (zh) 含16-(1′-芳香基-1′,2′,3′-三氮唑)亚甲基-雄甾-17-酮衍生物
CN104844560A (zh) (e)-3-羟基-5-(羟基苯乙烯基)噻吩-2-磺酸酚酯及制备方法和应用
CN104844561A (zh) (e)-5-(羟基苯乙烯基)-1,3-二噻吩-2-磺酸酚酯及制备方法和应用
CN104771392A (zh) 一类组蛋白去乙酰化酶抑制剂及应用
CN104098524B (zh) 1-间甲氧基苯甲酰基-3-苯基-1,4-二氢-1,2,4,5-四嗪及制备和应用
CN105418597B (zh) 1,3-二羟基呫吨酮衍生物及其在医药中的用途
CN108997164A (zh) 2-甲基-3-苯基苯甲酰肼及其合成方法
CN105906539B (zh) 莱菔素抗癌衍生化合物及其制备方法
CN104530062B (zh) 一种1,4-萘醌衍生物及其合成方法
CN104341407A (zh) 喹唑啉类化合物及其制备方法和用途

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150819

WD01 Invention patent application deemed withdrawn after publication