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
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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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- 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
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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
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.
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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 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 |
-
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 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)
| 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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