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 PDF

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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
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vitamin
derivative
compound
cumarin
synthetic method
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方志杰
卢庆光
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Nanjing University of Science and Technology
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Nanjing University of Science and Technology
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic 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
    • C07D311/04Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16Benzo[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
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    • C09K11/00Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N21/643Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems 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
    • G01N21/78Systems 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
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    • C09K2211/00Chemical nature of organic luminescent or tenebrescent compounds
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    • C09K2211/00Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10Non-macromolecular compounds
    • C09K2211/1018Heterocyclic compounds
    • C09K2211/1025Heterocyclic compounds characterised by ligands
    • C09K2211/1088Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom

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Abstract

The invention discloses a kind of vitamin D of cumarin modification2Derivative and its preparation method and application.The present invention uses 7-N, N- lignocaines coumarin-3-carboxy acid and vitamin D2The vitamin D modified by Steglich esterifications synthesizing coumarin2, be dissolved in compound II in aprotic solvent first by derivative, adds dicyclohexylcarbodiimide, 4-dimethylaminopyridine and vitamin D2, continuing stirring reaction, reaction obtains target product after terminating through concentration, purification.Synthesis material of the present invention is easy to get, reaction condition gentle, simple to operate, the vitamin D of synthesis2Derivative has good UV absorption and fluorescence property, in vitamin D2The Visual retrieval aspect of cancer suppressing action mechanism has potential application value.

Description

A kind of vitamin D of cumarin modification2Derivative and its preparation method and application
Technical field
The present invention relates to a kind of vitamin D of cumarin modification2Derivative, specifically, is related to a kind of with 7-N, N- The vitamin D of lignocaine tonka bean camphor structure2Derivative and preparation method, and its in the visual of vitamin D mechanism of tumor suppressor Change the application in detection, belong to technical field of medical chemistry.
Background technology
Vitamin D and its derivative can mediating apoptosis, some animal tumor models are processed with it, it can be found that cancer Cell quantity is substantially reduced, and shows that vitamin D and its derivative have potential application value in terms of tumour is treated.Such as Vitamin D3Metabolin Calcipotriol in vivo has suppression keratinocyte hyper-proliferative and induces cutin to be formed carefully The function of born of the same parents' differentiation, vitamin D2Derivative Calcipotriol good physiologically active is also show in terms of cancer. Many biological functions of vitamin D are all to mediate regulation target gene to transcribe come real by vitamin D receptor (VDR) Existing, vitamin D derivative combines to form hormone-receptor compound as hormone signal molecule in target cell and VDR, So as to the expression to structural gene produces adjustment effect.Because vitamin D does not have big fluorophor in itself, thus not Just visualizing monitor is carried out to its mechanism of action.Cumarin has the advantages that fluorescence efficiency is high, Stokes shift is big, extensively It is general to be applied in the synthesis of probe.
The content of the invention
It is an object of the invention to provide a kind of vitamin D of cumarin modification2Derivative, preparation method and its dimension give birth to Application in the Visual retrieval of plain D mechanism of tumor suppressor.
Realizing the technical scheme of the object of the invention is:A kind of vitamin D of cumarin modification2Derivative, its structural formula as I It is shown:
A kind of vitamin D of above-mentioned cumarin modification2The synthetic method of derivative, comprises the following steps:
Compound II is dissolved in aprotic solvent first, adds dicyclohexylcarbodiimide (DCC), 4- dimethylaminos Yl pyridines (DMAP) and vitamin D2(VD2), it is well mixed, then in reaction at 20~70 DEG C under lasting stirring, Reaction obtains target compound after terminating through concentration, purification, wherein, the structural formula of compound II is as follows:
Preferably, described aprotic solvent is selected from dichloromethane, toluene, ethyl acetate, benzene or Isosorbide-5-Nitrae-dioxane.
Preferably, described compound II and DCC, DMAP and VD2Mol ratio be 2~4:2~4:0.1~0.4:1.
Preferably, the described reaction time is 1~8h.
Preferably, described purification uses column chromatography, and the silica gel used in column chromatography purge process is 200-300 mesh, Eluent is 6 with the volume ratio of ethyl acetate for petroleum ether:1 mixed solution.
Further, the present invention also provides the vitamin D of above-mentioned cumarin modification2Derivative is in vitamin D mechanism of tumor suppressor Visual retrieval in application.
Synthesis material of the present invention is easy to get, reaction condition is gentle, simple to operate, and yield is higher, the dimension life of cumarin modification Plain D2Derivative had not only had active anticancer but also had had good UV absorption and fluorescence property, in VD2Cancer suppressing action mechanism Visual retrieval aspect have potential application value.
Brief description of the drawings
Fig. 1 is the vitamin D of cumarin modification of the invention2The ultraviolet-visible absorption spectroscopy figure of derivative.
Fig. 2 is the vitamin D of cumarin modification of the invention2The fluorescence spectra of derivative.
Specific embodiment
Principle of the invention is:With vitamin D2It is raw material, the mesh shown in Formulas I has been synthesized by Steglich esterifications Mark compound --- the vitamin D of cumarin modification2Derivative.
A kind of vitamin D of cumarin modification of the invention2The synthetic route of derivative is as follows:
(a) DCC (dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine), aprotic solvent, 20~70 DEG C.
The present invention is described in further detail with reference to embodiment and accompanying drawing.
Embodiment 1
The synthesis of compound I is as follows:
Sequentially added in 5mL dichloromethane in the single-necked flask of 10mL compound II (131mg, 0.5mmol), DCC (103mg, 0.5mmol), DMAP (12mg, 0.1mmol) and VD2(99mg, 0.25mmol), in Stirring reaction at 20 DEG C.TLC monitoring reaction (V ethyl acetate:V petroleum ether=1:2) after, reacting completely, depressurize dense Contracting.By column chromatography (silica gel 200-300 mesh, V ethyl acetate:V petroleum ether=1:6) purified, obtained sterling Compound I (87mg, 54.5%).
Nuclear-magnetism characterize data is:1H NMR (500MHz, CDCl3) δ 8.34 (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.
Embodiment 2
The synthesis of compound I is as follows:
Compound II (131mg, 0.5mmol), DCC are sequentially added in 5mL toluene in the single-necked flask of 10mL (103mg, 0.5mmol), DMAP (6mg, 0.05mmol) and VD2(99mg, 0.25mmol), is warming up to 60 DEG C of stirring reactions.TLC monitoring reaction (V ethyl acetate:V petroleum ether=1:2) after, reacting completely, it is concentrated under reduced pressure. By column chromatography (silica gel 200-300 mesh, V ethyl acetate:V petroleum ether=1:6) purified, obtained sterling chemical combination Thing I (76mg, 47.5%).
Embodiment 3
The synthesis of compound I is as follows:
Sequentially added in 5mL ethyl acetate in the single-necked flask of 10mL compound II (197mg, 0.75mmol), DCC (155mg, 0.5mmol), DMAP (12mg, 0.1mmol) and VD2(99mg, 0.25mmol), rises Temperature is to 40 DEG C of stirring reactions.TLC monitoring reaction (V ethyl acetate:V petroleum ether=1:2) after, reacting completely, decompression Concentration.By column chromatography (silica gel 200-300 mesh, V ethyl acetate:V petroleum ether=1:6) purified, obtained pure Product compound I (93mg, 58.1%).
Embodiment 4
The synthesis of compound I is as follows:
Compound II (262mg, 1.0mmol), DCC are sequentially added in 5mL benzene in the single-necked flask of 10mL (103mg, 0.5mmol), DMAP (6mg, 0.05mmol) and VD2(99mg, 0.25mmol), is warming up to 60 DEG C of stirring reactions.TLC monitoring reaction (V ethyl acetate:V petroleum ether=1:2) after, reacting completely, it is concentrated under reduced pressure. By column chromatography (silica gel 200-300 mesh, V ethyl acetate:V petroleum ether=1:6) purified, obtained sterling chemical combination Thing I (78mg, 48.8%).
Embodiment 5
The synthesis of compound I is as follows:
Sequentially added in 5mL Isosorbide-5-Nitraes-dioxane in the single-necked flask of 10mL compound II (262mg, 1.0mmol), DCC (206mg, 1.0mmol), DMAP (9mg, 0.075mmol) and VD2(99mg, 0.25mmol), rises Temperature is to stirring reaction at 70 DEG C.TLC monitoring reaction (V ethyl acetate:V petroleum ether=1:2) after, reacting completely, subtract Pressure concentration.By column chromatography (silica gel 200-300 mesh, V ethyl acetate:V petroleum ether=1:6) purified, obtained Sterling compound I (72mg, 45.0%).
Embodiment 6
The vitamin D of cumarin modification2UV absorption and photoluminescent property
It is 10 to prepare Compound I concentration-5mol·L-1DMSO solution, its ultra-violet absorption spectrum is as shown in figure 1, most Big absorbing wavelength is 422nm.By concentration dilution to 5 × 10-6mol·L-1When, its fluorescence spectrum as shown in Fig. 2 wherein, λex=402nm, λ em=471nm.

Claims (7)

1. the vitamin D that a kind of cumarin is modified2Derivative, it is characterised in that shown in its structural formula as I:
2. the vitamin D that cumarin as claimed in claim 1 is modified2The synthetic method of derivative, it is characterised in that Comprise the following steps:
Compound II is dissolved in aprotic solvent first, add dicyclohexylcarbodiimide, 4-dimethylaminopyridine and Vitamin D2, it is well mixed, then reacted after terminating through concentrating, purifying in being reacted at 20~70 DEG C under lasting stirring To target compound, wherein, the structural formula of compound II is as follows:
3. synthetic method as claimed in claim 2, it is characterised in that described aprotic solvent be selected from dichloromethane, Toluene, ethyl acetate, benzene or 1,4- dioxane.
4. synthetic method as claimed in claim 2, it is characterised in that described compound II and dicyclohexyl carbon two Imines, 4-dimethylaminopyridine and vitamin D2Mol ratio be 2~4:2~4:0.1~0.4:1.
5. synthetic method as claimed in claim 2, it is characterised in that the described reaction time is 1~8h.
6. synthetic method as claimed in claim 2, it is characterised in that described purification uses column chromatography, column chromatography The silica gel used in purge process is 200-300 mesh, and eluent is 6 with the volume ratio of ethyl acetate for petroleum ether:1 it is mixed Close solution.
7. the vitamin D that cumarin as claimed in claim 1 is modified2Derivative is visual vitamin D mechanism of tumor suppressor Change the application in detection.
CN201510849428.8A 2015-11-27 2015-11-27 A kind of vitamin D of cumarin modification2Derivative and its preparation method and application Pending CN106810526A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101921587A (en) * 2010-07-19 2010-12-22 西安交通大学 A kind of fluorescent probe and preparation method thereof with tumor cell proliferation inhibition activity
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101921587A (en) * 2010-07-19 2010-12-22 西安交通大学 A kind of fluorescent probe and preparation method thereof with tumor cell proliferation inhibition activity
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)

* Cited by examiner, † Cited by third party
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 *

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