CN106810526A - A kind of vitamin D of cumarin modification2Derivative and its preparation method and application - Google Patents
A kind of vitamin D of cumarin modification2Derivative and its preparation method and application Download PDFInfo
- Publication number
- CN106810526A CN106810526A CN201510849428.8A CN201510849428A CN106810526A CN 106810526 A CN106810526 A CN 106810526A CN 201510849428 A CN201510849428 A CN 201510849428A CN 106810526 A CN106810526 A CN 106810526A
- Authority
- CN
- China
- Prior art keywords
- vitamin
- derivative
- compound
- modified
- synthetic method
- 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
Links
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 150000003710 vitamin D derivatives Chemical class 0.000 title claims description 14
- 229930003316 Vitamin D Natural products 0.000 title claims description 12
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 title claims description 12
- 235000019166 vitamin D Nutrition 0.000 title claims description 12
- 239000011710 vitamin D Substances 0.000 title claims description 12
- 229940046008 vitamin d Drugs 0.000 title claims description 12
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 title claims 4
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 title claims 4
- 238000002360 preparation method Methods 0.000 title abstract description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 26
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000000007 visual effect Effects 0.000 claims abstract description 7
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims abstract description 7
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 6
- 238000001514 detection method Methods 0.000 claims abstract description 6
- 230000007246 mechanism Effects 0.000 claims abstract description 5
- 239000011653 vitamin D2 Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 238000010189 synthetic method Methods 0.000 claims description 6
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 claims description 4
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical compound [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 claims 1
- 150000002466 imines Chemical class 0.000 claims 1
- 230000002045 lasting effect Effects 0.000 claims 1
- 238000010926 purge Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 150000003703 vitamin D2 derivatives Chemical class 0.000 abstract description 14
- 229960000956 coumarin Drugs 0.000 abstract description 11
- 235000001671 coumarin Nutrition 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 abstract description 3
- 229960002061 ergocalciferol Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 235000001892 vitamin D2 Nutrition 0.000 abstract description 3
- 238000005741 Steglich esterification reaction Methods 0.000 abstract description 2
- 239000012141 concentrate Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 102000009310 vitamin D receptors Human genes 0.000 description 3
- 108050000156 vitamin D receptors Proteins 0.000 description 3
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 2
- 229960002882 calcipotriol Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1011—Condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Plasma & Fusion (AREA)
- Molecular Biology (AREA)
- Optics & Photonics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种香豆素修饰的维生素D2衍生物及其制备方法和应用。本发明采用7-N,N-二乙氨基香豆素-3-羧酸与维生素D2通过Steglich酯化反应合成香豆素修饰的维生素D2衍生物，首先将化合物II溶于非质子溶剂中，加入二环己基碳二亚胺、4-二甲基氨基吡啶及维生素D2，持续搅拌反应，反应结束后经浓缩、提纯得到目标产物。本发明合成原料易得、反应条件温和，操作简单，合成的维生素D2衍生物具有良好的紫外吸收和荧光性能，在维生素D2抑癌作用机制的可视化检测方面具有潜在的应用价值。
The invention discloses a coumarin - modified vitamin D2 derivative, a preparation method and application thereof. The present invention uses 7-N, N-diethylaminocoumarin-3-carboxylic acid and vitamin D2 to synthesize coumarin - modified vitamin D2 derivatives through Steglich esterification, first dissolving compound II in an aprotic solvent , add dicyclohexylcarbodiimide, 4-dimethylaminopyridine and vitamin D 2 , continue to stir the reaction, after the reaction is completed, concentrate and purify to obtain the target product. The invention has easy-to - obtain synthetic raw materials, mild reaction conditions and simple operation, and the synthesized vitamin D2 derivative has good ultraviolet absorption and fluorescence properties, and has potential application value in the visual detection of the vitamin D2 tumor suppressor mechanism.
Description
技术领域technical field
本发明涉及一种香豆素修饰的维生素D2衍生物，具体地说，涉及一种具有7-N,N-二乙氨基香豆素结构的维生素D2衍生物和制备方法，及其在维生素D抑癌机制的可视化检测中的应用，属于医药化学技术领域。The present invention relates to a coumarin - modified vitamin D2 derivative, in particular to a vitamin D2 derivative with a 7 -N,N-diethylaminocoumarin structure and a preparation method thereof, and its use in The invention relates to an application in the visual detection of vitamin D tumor suppressor mechanism, which belongs to the technical field of medicinal chemistry.
背景技术Background technique
维生素D及其衍生物能够介导细胞凋亡，用其处理一些动物肿瘤模型，可以发现癌细胞数量显著减少，显示出维生素D及其衍生物在治疗肿瘤方面有潜在的应用价值。如维生素D3在体内的代谢物卡泊三醇具有抑制角质形成细胞过度增殖并诱导角质形成细胞分化的功能，维生素D2的衍生物卡泊三醇在癌症方面也显示出了良好的生理活性。维生素D的许多生物学功能都是通过维生素D受体(VDR)介导调节靶基因转录来实现的，维生素D衍生物作为激素信号分子在靶细胞与VDR结合形成激素-受体复合物，从而对结构基因的表达产生调节作用。由于维生素D本身不具有大的荧光基团，因而不便对其作用机制进行可视化监测。香豆素具有荧光效率高、斯托克斯位移大等优点，广泛应用于探针的合成中。Vitamin D and its derivatives can mediate cell apoptosis. Using it to treat some animal tumor models, it can be found that the number of cancer cells is significantly reduced, showing that vitamin D and its derivatives have potential application value in the treatment of tumors. For example, the metabolite calcipotriol of vitamin D3 in the body has the function of inhibiting the excessive proliferation of keratinocytes and inducing the differentiation of keratinocytes, and the derivative of vitamin D2, calcipotriol , also shows good physiological activity in cancer . Many biological functions of vitamin D are realized by regulating the transcription of target genes mediated by vitamin D receptor (VDR). Vitamin D derivatives, as hormone signaling molecules, combine with VDR in target cells to form hormone-receptor complexes, thereby Regulates the expression of structural genes. Since vitamin D itself does not have a large fluorescent group, visual monitoring of its mechanism of action is inconvenient. Coumarin has the advantages of high fluorescence efficiency and large Stokes shift, and is widely used in the synthesis of probes.
发明内容Contents of the invention
本发明的目的在于提供一种香豆素修饰的维生素D2衍生物、制备方法及其在维生素D抑癌机制的可视化检测中的应用。The object of the present invention is to provide a coumarin - modified vitamin D2 derivative, a preparation method and its application in the visual detection of vitamin D tumor suppressor mechanism.
实现本发明目的的技术方案是：一种香豆素修饰的维生素D2衍生物，其结构式如I所示：The technical scheme that realizes the object of the present invention is: a kind of coumarin-modified vitamin D 2 derivatives, its structural formula is as shown in I:
一种上述香豆素修饰的维生素D2衍生物的合成方法，包括如下步骤：A synthetic method of the above-mentioned coumarin - modified vitamin D derivatives, comprising the steps of:
首先将化合物II溶于非质子溶剂中，加入二环己基碳二亚胺(DCC)、4-二甲基氨基吡啶(DMAP)及维生素D2(VD2)，混合均匀，然后持续搅拌下于20～70℃下反应，反应结束后经浓缩、提纯得到目标化合物，其中，化合物II的结构式如下：First dissolve compound II in an aprotic solvent, add dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) and vitamin D 2 (VD 2 ), mix well, and then place under constant stirring React at 20-70°C. After the reaction, concentrate and purify to obtain the target compound, wherein the structural formula of compound II is as follows:
优选地，所述的非质子溶剂选自二氯甲烷、甲苯、乙酸乙酯、苯或1,4-二氧六环。Preferably, the aprotic solvent is selected from dichloromethane, toluene, ethyl acetate, benzene or 1,4-dioxane.
优选地，所述的化合物II与DCC、DMAP及VD2的摩尔比为2～4:2～4:0.1～0.4:1。Preferably, the molar ratio of compound II to DCC, DMAP and VD 2 is 2-4:2-4:0.1-0.4:1.
优选地，所述的反应时间为1～8h。Preferably, the reaction time is 1-8 hours.
优选地，所述的提纯采用柱层析法，柱层析纯化过程中采用的硅胶为200-300目，洗脱液为石油醚与乙酸乙酯的体积比为6:1的混合溶液。Preferably, the purification adopts column chromatography, the silica gel used in the column chromatography purification process is 200-300 mesh, and the eluent is a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 6:1.
进一步地，本发明还提供上述香豆素修饰的维生素D2衍生物在维生素D抑癌机制的可视化检测中的应用。Further, the present invention also provides the application of the above-mentioned coumarin - modified vitamin D2 derivatives in the visual detection of vitamin D tumor suppressor mechanism.
本发明合成原料易得、反应条件温和、操作简单，且产率较高，香豆素修饰的维生素D2衍生物既具有抗癌活性又具有良好的紫外吸收和荧光性能，在VD2抑癌作用机制的可视化检测方面具有潜在的应用价值。The synthetic raw material of the present invention is easy to get, the reaction condition is mild, the operation is simple, and the yield is high, and the vitamin D2 derivative modified by coumarin not only has anticancer activity but also has good ultraviolet absorption and fluorescence performance, and suppresses cancer in VD2 The visual detection of the mechanism of action has potential application value.
附图说明Description of drawings
图1为本发明的香豆素修饰的维生素D2衍生物的紫外可见吸收光谱图。Fig. 1 is the ultraviolet-visible absorption spectrogram of the coumarin - modified vitamin D2 derivative of the present invention.
图2为本发明的香豆素修饰的维生素D2衍生物的荧光光谱图。Fig. 2 is a fluorescence spectrogram of the coumarin-modified vitamin D2 derivative of the present invention.
具体实施方式detailed description
本发明的原理为：以维生素D2为原料，通过Steglich酯化反应合成了式I所示的目标化合物——香豆素修饰的维生素D2衍生物。The principle of the present invention is: taking vitamin D2 as a raw material, the target compound represented by formula I—coumarin - modified vitamin D2 derivatives is synthesized through Steglich esterification reaction.
本发明的一种香豆素修饰的维生素D2衍生物的合成路线如下：The synthetic route of a kind of coumarin - modified vitamin D2 derivative of the present invention is as follows:
(a)DCC(二环己基碳二亚胺)，DMAP(4-二甲基氨基吡啶)，非质子溶剂，20～70℃。(a) DCC (dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine), aprotic solvent, 20-70°C.
下面结合实施例和附图对本发明作进一步详细说明。The present invention will be described in further detail below in conjunction with the embodiments and accompanying drawings.
实施例1Example 1
化合物I的合成如下：Compound I was synthesized as follows:
于10mL的单口烧瓶中于5mL二氯甲烷中依次加入化合物II(131mg，0.5mmol)、DCC(103mg，0.5mmol)、DMAP(12mg，0.1mmol)和VD2(99mg，0.25mmol)，于20℃下搅拌反应。TLC监测反应(V乙酸乙酯：V石油醚＝1:2)，反应完全后，减压浓缩。通过柱层析(硅胶200-300目，V乙酸乙酯：V石油醚＝1:6)进行纯化，得到纯品化合物I(87mg，54.5％)。Add compound II (131mg, 0.5mmol), DCC (103mg, 0.5mmol), DMAP (12mg, 0.1mmol) and VD 2 (99mg, 0.25mmol) successively in 5mL dichloromethane in a 10mL single-necked flask, at 20 The reaction was stirred at °C. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1:2). After the reaction was complete, it was concentrated under reduced pressure. Purification by column chromatography (silica gel 200-300 mesh, V ethyl acetate: V petroleum ether = 1:6) gave pure compound I (87 mg, 54.5%).
核磁表征数据为：1H NMR(500MHz,CDCl3)δ8.34(s,1H),7.32(d,J＝9.0Hz,1H),6.60(dd,J＝8.9,2.3Hz,1H),6.46(d,J＝2.3Hz,1H),6.25(d,J＝11.3Hz,1H),6.06(d,J＝11.2Hz,1H),5.26–5.13(m,3H),5.08(s,1H),4.86(s,1H),3.45(q,J＝7.1Hz,5H),2.81(dd,J＝3.7,13.4Hz,1H),2.70(dd,J＝13.4,3.7Hz,1H),2.59–2.45(m,2H),2.31–2.24(m,1H),2.12–1.94(m,5H),1.93–1.78(m,3H),1.76–1.60(m,4H),1.60–1.39(m,6H),1.40–1.16(m,13H),1.02(d,J＝6.6Hz,4H),0.97–0.87(m,4H),0.87–0.77(m,8H),0.57(s,3H).13C NMR(126MHz,CDCl3)δ162.21,157.45,157.21,151.85,147.76,143.84,141.30,134.67,133.60,130.99,130.02,121.54,116.59,111.64,108.43,106.67,95.83,71.48,55.53,44.88,44.10,41.87,41.27,39.49,39.40,32.14,31.38,31.09,28.09,26.84,22.59,21.27,20.14,18.98,18.68,16.62,11.48,11.30.NMR characterization data are: 1 H NMR (500MHz, CDCl3) δ8.34 (s, 1H), 7.32 (d, J = 9.0Hz, 1H), 6.60 (dd, J = 8.9, 2.3Hz, 1H), 6.46 ( d,J=2.3Hz,1H),6.25(d,J=11.3Hz,1H),6.06(d,J=11.2Hz,1H),5.26–5.13(m,3H),5.08(s,1H), 4.86(s,1H),3.45(q,J=7.1Hz,5H),2.81(dd,J=3.7,13.4Hz,1H),2.70(dd,J=13.4,3.7Hz,1H),2.59–2.45 (m,2H),2.31–2.24(m,1H),2.12–1.94(m,5H),1.93–1.78(m,3H),1.76–1.60(m,4H),1.60–1.39(m,6H) 13 C NMR (126MHz,CDCl3)δ162.21,157.45,157.21,151.85,147.76,143.84,141.30,134.67,133.60,130.99,130.02,121.54,116.59,111.64,108.43,106.67,95.83,71.48,55.53,44.88,44.10,41.87,41.27 ,39.49,39.40,32.14,31.38,31.09,28.09,26.84,22.59,21.27,20.14,18.98,18.68,16.62,11.48,11.30.
实施例2Example 2
化合物I的合成如下：Compound I was synthesized as follows:
于10mL的单口烧瓶中于5mL甲苯中依次加入化合物II(131mg，0.5mmol)、DCC(103mg，0.5mmol)、DMAP(6mg，0.05mmol)和VD2(99mg，0.25mmol)，升温至60℃搅拌反应。TLC监测反应(V乙酸乙酯：V石油醚＝1:2)，反应完全后，减压浓缩。通过柱层析(硅胶200-300目，V乙酸乙酯：V石油醚＝1:6)进行纯化，得到纯品化合物I(76mg，47.5％)。Add compound II (131mg, 0.5mmol), DCC (103mg, 0.5mmol), DMAP (6mg, 0.05mmol) and VD 2 (99mg, 0.25mmol) sequentially into 5mL toluene in a 10mL single-necked flask, and heat up to 60°C Stir the reaction. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1:2). After the reaction was complete, it was concentrated under reduced pressure. Purification by column chromatography (silica gel 200-300 mesh, V ethyl acetate: V petroleum ether = 1:6) gave pure compound I (76 mg, 47.5%).
实施例3Example 3
化合物I的合成如下：Compound I was synthesized as follows:
于10mL的单口烧瓶中于5mL乙酸乙酯中依次加入化合物II(197mg，0.75mmol)、DCC(155mg，0.5mmol)、DMAP(12mg，0.1mmol)和VD2(99mg，0.25mmol)，升温至40℃搅拌反应。TLC监测反应(V乙酸乙酯：V石油醚＝1:2)，反应完全后，减压浓缩。通过柱层析(硅胶200-300目，V乙酸乙酯：V石油醚＝1:6)进行纯化，得到纯品化合物I(93mg，58.1％)。Add compound II (197mg, 0.75mmol), DCC (155mg, 0.5mmol), DMAP (12mg, 0.1mmol) and VD 2 (99mg, 0.25mmol) successively in 5mL ethyl acetate in a 10mL single-necked flask, and heat up to The reaction was stirred at 40°C. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1:2). After the reaction was complete, it was concentrated under reduced pressure. Purification by column chromatography (silica gel 200-300 mesh, V ethyl acetate: V petroleum ether = 1:6) gave pure compound I (93 mg, 58.1%).
实施例4Example 4
化合物I的合成如下：Compound I was synthesized as follows:
于10mL的单口烧瓶中于5mL苯中依次加入化合物II(262mg，1.0mmol)、DCC(103mg，0.5mmol)、DMAP(6mg，0.05mmol)和VD2(99mg，0.25mmol)，升温至60℃搅拌反应。TLC监测反应(V乙酸乙酯：V石油醚＝1:2)，反应完全后，减压浓缩。通过柱层析(硅胶200-300目，V乙酸乙酯：V石油醚＝1:6)进行纯化，得到纯品化合物I(78mg，48.8％)。Add compound II (262mg, 1.0mmol), DCC (103mg, 0.5mmol), DMAP (6mg, 0.05mmol) and VD 2 (99mg, 0.25mmol) sequentially into 5mL benzene in a 10mL single-necked flask, and heat up to 60°C Stir the reaction. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1:2). After the reaction was complete, it was concentrated under reduced pressure. Purification by column chromatography (silica gel 200-300 mesh, V ethyl acetate: V petroleum ether = 1:6) gave pure compound I (78 mg, 48.8%).
实施例5Example 5
化合物I的合成如下：Compound I was synthesized as follows:
于10mL的单口烧瓶中于5mL 1,4-二氧六环中依次加入化合物II(262mg，1.0mmol)、DCC(206mg，1.0mmol)、DMAP(9mg，0.075mmol)和VD2(99mg，0.25mmol)，升温至70℃下搅拌反应。TLC监测反应(V乙酸乙酯：V石油醚＝1:2)，反应完全后，减压浓缩。通过柱层析(硅胶200-300目，V乙酸乙酯：V石油醚＝1:6)进行纯化，得到纯品化合物I(72mg，45.0％)。Add compound II (262mg, 1.0mmol), DCC (206mg, 1.0mmol), DMAP (9mg, 0.075mmol) and VD 2 (99mg, 0.25 mmol), the temperature was raised to 70°C and the reaction was stirred. The reaction was monitored by TLC (V ethyl acetate: V petroleum ether = 1:2). After the reaction was complete, it was concentrated under reduced pressure. Purification by column chromatography (silica gel 200-300 mesh, V ethyl acetate: V petroleum ether = 1:6) gave pure compound I (72 mg, 45.0%).
实施例6Example 6
香豆素修饰的维生素D2的紫外吸收及荧光性质UV absorption and fluorescence properties of coumarin-modified vitamin D 2
配制化合物I浓度为10-5mol·L-1的DMSO溶液，其紫外吸收光谱如图1所示，最大吸收波长为422nm。将浓度稀释至5×10-6mol·L-1时，其荧光光谱如图2所示，其中，λex＝402nm，λem＝471nm。A DMSO solution with a concentration of 10 -5 mol·L -1 of Compound I was prepared, and its ultraviolet absorption spectrum is shown in Figure 1 , with a maximum absorption wavelength of 422nm. When the concentration is diluted to 5×10 -6 mol·L -1 , its fluorescence spectrum is shown in Figure 2, where λ ex =402nm, λem =471nm.
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510849428.8A CN106810526A (en) | 2015-11-27 | 2015-11-27 | A kind of vitamin D of cumarin modification2Derivative and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510849428.8A CN106810526A (en) | 2015-11-27 | 2015-11-27 | A kind of vitamin D of cumarin modification2Derivative and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106810526A true CN106810526A (en) | 2017-06-09 |
Family
ID=59102315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510849428.8A Pending CN106810526A (en) | 2015-11-27 | 2015-11-27 | A kind of vitamin D of cumarin modification2Derivative and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106810526A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921587A (en) * | 2010-07-19 | 2010-12-22 | 西安交通大学 | A fluorescent probe with tumor cell proliferation inhibitory activity and preparation method thereof |
| CN102277154A (en) * | 2011-04-21 | 2011-12-14 | 山东大学 | Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof |
| WO2013121284A1 (en) * | 2012-02-14 | 2013-08-22 | Universite De Strasbourg | Iodinated products intended for a use for the medical imaging and their methods of preparation |
| US20140154700A1 (en) * | 2012-11-30 | 2014-06-05 | Zhu Teng | Compositions and Methods for Detecting Vitamin D |
-
2015
- 2015-11-27 CN CN201510849428.8A patent/CN106810526A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921587A (en) * | 2010-07-19 | 2010-12-22 | 西安交通大学 | A fluorescent probe with tumor cell proliferation inhibitory activity and preparation method thereof |
| CN102277154A (en) * | 2011-04-21 | 2011-12-14 | 山东大学 | Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof |
| WO2013121284A1 (en) * | 2012-02-14 | 2013-08-22 | Universite De Strasbourg | Iodinated products intended for a use for the medical imaging and their methods of preparation |
| US20140154700A1 (en) * | 2012-11-30 | 2014-06-05 | Zhu Teng | Compositions and Methods for Detecting Vitamin D |
Non-Patent Citations (2)
| Title |
|---|
| JONATHAN GROTE等: "New methodology for the synthesis of 25-hydroxyvitamin D conjugates", 《TETRAHEDRON LETTERS》 * |
| 闫杰等: "《有机化学反应及其进展研究》", 31 October 2014, 中国水利水电出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107417714A (en) | A kind of highly sensitive fluorescence probe and its synthetic method and application based on BODIPY | |
| CN108047198B (en) | Method for preparing polyaryl substituted naphthalene derivative by reaction of aryl ketone and tolane under catalysis of ruthenium | |
| CN101402655B (en) | Process for producing platinum | |
| CN107266348A (en) | Preparation, structure and the purposes of the indolecarboxaldehyde Schiff base of 4-acetylbiphenyl hydrazone 3 | |
| CN104045680B (en) | Acetylamino acid acyl analog derivative of betulinol and preparation method thereof | |
| CN107445969B (en) | A kind of tricyclic indole derivative and its preparation and application | |
| CN107043345B (en) | 4-acetylbiphenyl hydrazone-indoline -2,3- diketone Schiff base preparation, structure and purposes | |
| CN113603653A (en) | A kind of visible light-promoted synthesis method of seleno-oxazolidine-2.4-dione | |
| CN110746466B (en) | Preparation and application of a chiral platinum complex | |
| CN107118191A (en) | Flavoxate hydrochloride is coupled the preparation method of impurity | |
| CN103450069B (en) | Preparation method of mitiglinide calcium | |
| CN106810526A (en) | A kind of vitamin D of cumarin modification2Derivative and its preparation method and application | |
| CN103145768B (en) | A kind of method preparing ferrocene carboxaldehyde | |
| CN106349125B (en) | Utilize the method for manganese salt selectivity synthesis (E) vinyl sulfone compound | |
| CN113956268B (en) | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method | |
| CN113444107B (en) | Synthetic method and anticancer activity of succinimide spiro-fused sultams compound | |
| WO2014126008A1 (en) | Catalyst and method for producing optically active anti-1,2-nitroalkanol compound | |
| CN111362962B (en) | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof | |
| CN103554007B (en) | Novel 4, 5-substituted-7-methyl formate indole diketone derivative and application thereof in antitumor drugs | |
| CN113582843A (en) | Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester | |
| CN105968013B (en) | A kind of π-copolymer and preparation method thereof | |
| CN105111217B (en) | A kind of synthetic method of iso-indoles dihydroquinazoline derivatives | |
| CN115028568B (en) | Synthesis method of 3-selenoindole compound promoted by visible light | |
| CN112939994B (en) | Method for carrying out reaction of isatin compound and cyclopropenone compound under low catalytic amount | |
| CN117088826B (en) | Synthesis method of polysubstituted oxazole promoted by visible light |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170609 |