CN107759652A - Containing cholesteric coumarin derivatives and its synthesis and application - Google Patents
Containing cholesteric coumarin derivatives and its synthesis and application Download PDFInfo
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- CN107759652A CN107759652A CN201710764590.9A CN201710764590A CN107759652A CN 107759652 A CN107759652 A CN 107759652A CN 201710764590 A CN201710764590 A CN 201710764590A CN 107759652 A CN107759652 A CN 107759652A
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- coumarin
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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- 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
- C09K19/00—Liquid crystal materials
- C09K19/04—Liquid crystal materials characterised by the chemical structure of the liquid crystal components, e.g. by a specific unit
- C09K19/36—Steroidal liquid crystal compounds
Abstract
The invention discloses synthesis and application of the one kind containing cholesteric coumarin derivatives, belongs to biological organic synthesis field.Cholesterine after modification is introduced cumarin, new drug of the research and development with anticancer effect by the present invention.It is of the present invention to contain cholesteric coumarin derivatives, it is that different coumarin derivatives is synthesized with 5 different substituted salicylic aldehydes, studies the structure-activity relationship of drug molecule；Cumarin and cholesterine are had to the new target compound containing cholesteric naphthalimide analog derivative of active anticancer by acylation reaction or the generation of DCC methods esterification.
Description
Technical field
The present invention relates to containing cholesteric coumarin derivatives and its synthesis and application, belong to biological organic synthesis neck
Domain.
Background technology
Coumarin kind compound refers to that bioactivity is extensive using benzo a- pyranone structure as the compound of female ring, such as anti-
HIV, inoxidizability, antibacterium is antiviral, anticoagulation, treating tuberculosis, antitumor etc..Warfarin sodium, it is to be related to anti-cancer field earliest
Coumarin drugs, can significant anti-V2 cancer cells.Cumarin has strong cyclic voltammetry method ability, and exists in molecule
The conjugated degree that C=C, C=O double bond add molecule makes it have larger conjugated system, and it is firm that lactone structure enhances molecule
Property so that coumarin derivatives have fluorescence, and light quantum stability and photoluminescence quantum efficiencies are all higher, make it
There is extensive potential application in various fields such as food, fuel, spices, medicine, agricultural chemicals, photoelectric material, Supramolecular Recognitions.Courage
The formation of sterol and cell membrane, cholic acid, vitamin D is closely bound up, great to animal body effect, and some cholesterin derivatives
With antitumor, active anticancer.There is a hydroxy functional group, esterification modification has obtained many derivatives on cholesterine.Hydroxyl
The soluble derivative of steroid has strong antitumaous effect to mouse Krebs II.Mohamed Ramadan El Sayed
Aly et al. has synthesized cholesterine triazole derivative and has shown obvious antifungal activity and cytotoxicity.
The content of the invention
The present invention provides a kind of synthesis and application containing cholesteric coumarin derivatives.Cholesterine after modification is drawn
Enter cumarin, new drug of the research and development with anticancer effect.
Of the present invention to contain cholesteric coumarin derivatives, (1) synthesizes different cumarins with different salicylides
Derivative, study the structure-activity relationship of drug molecule.(2) cumarin and cholesterine are passed through into acylation reaction or DCC method esterifications
New target compound containing cholesteric naphthalimide analog derivative of the generation with active anticancer.
Technical scheme is used by the present invention solves above-mentioned technical problem：Containing cholesteric coumarin derivatives, its
Chemical molecular general structure C is as follows：
In formula C:
R is selected from H atom, N, TMSDEA N diethylamine base, methyl, methoxyl group.
The present invention provides the above-mentioned preparation method containing cholesteric coumarin derivatives, using the salicylide of 5 substitutions as
Initiation material, react through Knoevenagel to obtain 7-R- Coumarin-3-carboxylic Acid Ethyl Esters, basic hydrolysis, acid with diethyl malonate
Change obtains 7-R- coumarin-3-carboxy acids, and ultimately producing target product has two kinds of approach, approach one：7-R- coumarin-3-carboxy acids after
It is continuous to generate 7-R- cumarin -3- formyl chlorides with thionyl chloride reaction, then obtained with cholesterine by acylation reaction containing cholesteric
The target compound of coumarin derivatives；Approach two：7-R- coumarin-3-carboxy acids are directly occurred with cholesterine by DCC methods
Esterification generates the target compound containing cholesteric coumarin derivatives.
The R is selected from H atom, N, TMSDEA N diethylamine base, methyl, methoxyl group.
The above-mentioned synthetic route containing cholesteric coumarin derivatives is as follows：
The present invention provides the above-mentioned application containing cholesteric naphthalimide analog derivative in cancer cell medicine is suppressed.It is described
JEG-3 for HepG2 (human liver cancer cell), Hela (human cervical carcinoma cell), MCF-7 (human breast cancer cell), A549 (people
Lung carcinoma cell).
With above-mentioned synthesis containing cholesteric naphthalimide analog derivative MTT colorimetric methods to HepG2 (human liver cancer cell),
Hela (human cervical carcinoma cell), MCF-7 (breast cancer cell), A549 (lung carcinoma cell) carry out extracorporeal suppression tumor cell growth and lived
Property measure, the results showed that, such compound to the cancer cells such as liver cancer, cervical carcinoma, breast cancer, lung cancer have suppress growth effect
Fruit.
With MTT colorimetric methods by HepG2 (human liver cancer cell), Hela (human cervical carcinoma cell), MCF-7 (breast cancer cell),
A549 (lung carcinoma cell) is with 5 × 103Individual cells/well is inoculated in 96 orifice plates, and the μ L/ of gradient concentration decoction 200 are added after cultivating 24h
Hole, to each tumor cell line, 5 multiple holes are set, separately set acellular zeroing hole；Tumour cell is in 37 DEG C, 5%CO2Under the conditions of
After cultivating 24h, add 20 μ L MTT liquid to continue after cultivating 4h, supernatant is carefully suctioned out with liquid-transfering gun, add DMSO dissolving knots
Crystalline substance, then survey OD with ELIASA490Value, IC of the measured object to growth of cancer cells is calculated using bandit's formula improved method50Value.
It is of the present invention that there is liquid crystalline phase containing cholesteric coumarin derivatives, available for LCDs.
Brief description of the drawings
Fig. 1 is compound C1 liquid crystal phasor；
Fig. 2 is compound C2 liquid crystal phasor.
Embodiment
By embodiment, the present invention is further illustrated.
Embodiment 1 (approach one)
The synthesis of coumarin-3-carboxylic acid cholesterol ester (C1)
(1) synthesis of intermediate 7-R- Coumarin-3-carboxylic Acid Ethyl Esters:
The synthesis of Coumarin-3-carboxylic Acid Ethyl Ester (intermediate 1):
Clean three-necked flask, 45mL absolute ethyl alcohols make solvent, sequentially add 7.86mL salicylides, 13.50mL malonic acid
Second diester, 0.9mL piperidines, 1-3mL glacial acetic acid, load onto the spherical condensation tube with anhydrous calcium chloride drying tube, are heated to reflux 2-
5h, stop heating, be transferred to beaker after being cooled to room temperature, cooled down in ice-water bath, separate out product sufficient crystallising, then decompression is taken out
Filter, and wash crystal 2~3 times with 50% cooled ethanol solution, obtain white crystal 12.4g, yield 75.6%.It is molten
Point：124.0-125.0℃.
(2) synthesis of intermediate 7-R- coumarin-3-carboxy acids:
The synthesis of coumarin-3-carboxy acid's (intermediate 2):
The 5.0g sodium hydroxides of 4.0g intermediates 5, the 25mL of above-mentioned gained are sequentially added in dry round-bottomed flask
95% absolute ethyl alcohol and 10mL water, oil bath backflow, continue the 20min that flows back after ester all dissolving.
Stop heating, be cooled to room temperature, reaction solution is transferred in conical flask, watery hydrochloric acid is added dropwise, shake, can see in drop
To there is white crystal precipitation, ice-water bath cooling makes crystallization complete.Filter, wash, dry, obtain product about 2.87g, yield
82.5%.Fusing point：190.0-191.0℃.
(3) synthesis of intermediate 7-R- cumarins -3- formyl chlorides:
The synthesis of cumarin -3- formyl chlorides (intermediate 3):
2.87g intermediates 6, the SOCl that 20mL newly steams are added in dry 50mL round-bottomed flasks2, oil bath heating backflow
2h, TLC, which track to reaction, to be terminated, and decompression steams remnants SOCl2, obtain faint yellow solid 3.05g, yield 96.8%.Fusing point：
146.0-147.0℃。
(4) synthesis of end-product 7-R- coumarin-3-carboxylic acids cholesterol ester：
The synthesis of end-product coumarin-3-carboxylic acid cholesterol ester (C1)：
In 25mL two-mouth bottles, 20mL dichloromethane makees solvent, adds 0.50g intermediates 7, and being placed in stirring in ice-water bath makes
Dissolving；0.84g (2.17mmol) cholesterine is added, 1h is stirred, is slow added into 0.3mL triethylamines, at room temperature stirring reaction
12h, TLC are tracked.Solvent removed by evaporation at reduced pressure, column chromatography purification (eluent CH2Cl2), obtain white solid D3 0.80g.Production
Rate：66.5%.
+ESI MS(M+Na):C37H50O4, calculated value：558.3709, measured value：558.3599.
1H NMR(400MHz,CDCl3) δ 8.44 (s, 1H), 7.63-7.56 (m, 2H), δ 7.29 (t, J=7.9Hz, 2H),
5.37 (d, J=3.6Hz, 1H), 4.88-4.78 (m, 1H), 2.44 (d, J=7.8Hz, 2H), 2.01-1.70 (m, 7H), 1.60-
1.39 (m, 7H), 1.35-1.27 (m, 3H), 1.22-1.05 (m, 8H), 1.02 (s, 4H), 0.88 (d, J=6.4Hz, 3H),
0.83 (d, J=6.5Hz, 6H), 0.64 (s, 3H)
13C NMR(126MHz,CDCl3)δ162.34(s),156.65(s),155.14(s),148.08(s),139.43
(s),134.18(s),129.44(s),124.78(s),123.00(s),118.74(s),117.93(s),116.77(s),
75.77 (s), 56.69 (s), 56.15 (s), 50.03 (s), 42.33 (s), 39.63 (d, J=26.6Hz), 38.04 (s),
37.00 (s), 36.64 (s), 36.20 (s), 35.80 (s), 31.90 (d, J=8.7Hz), 28.24 (s), 28.02 (s), 27.75
(s), 24.30 (s), 23.85 (s), 22.71 (d, J=32.0Hz), 21.06 (s), 19.37 (s), 18.74 (s), 11.87 (s)
Compound C1 belongs to liquid crystal molecule, and it is as shown in Figure 1 liquid crystalline phase occur at 225.1-108.4 DEG C.
Embodiment 2 (approach two)
The synthesis of 7- (lignocaine) coumarin-3-carboxylic acid cholesterol esters (C2)
(1) synthesis of 7- (lignocaine) Coumarin-3-carboxylic Acid Ethyl Ester (intermediate 4):
In addition to salicylide is replaced with 4- (lignocaine)-salicylide, other operations obtain with the synthesis of the intermediate 1 of embodiment 1
Intermediate 4, yellow solid, yield 90.8%.Fusing point：220.4-222.3℃.
(2) synthesis of 7- (lignocaine) coumarin-3-carboxylic acid (intermediate 5)：
Except intermediate 1 is replaced with intermediate 4, other operations obtain yellow solid, yield with the synthesis of the intermediate 2 of embodiment 1
80.8%.Fusing point：224.0-224.5℃.
(3) synthesis of end-product 7-R- coumarin-3-carboxylic acids cholesterol ester：
The synthesis of 7- (lignocaine) coumarin-3-carboxylic acid cholesterol esters (C2)：
By 0.71g (1.84mmol) cholesterine and 0.40g (1.53mmol) 7- (lignocaine) coumarin-3-carboxylic acid (in
Mesosome 9) be dissolved in 20mL drying dichloromethane in, stirring at normal temperature 5min, then add 0.02g (0.18mmol) DMAP and
0.38g (1.84mmol) DCC continues that reaction is stirred at room temperature, and TLC is tracked, and is stopped after 16h.Solvent removed by evaporation at reduced pressure, post
Chromatographic purification (eluent CH2Cl2：CH3COOC2H5=20：1).Obtain crocus solid D4 0.44g, yield：45.8%.
+ESI MS(M+H):C41H59NO4, calculated value：629.4444, measured value：629.4498.
1H NMR(400MHz,CDCl3) δ 8.34 (s, 1H), 7.31 (d, J=9.0Hz, 1H), 6.55 (d, J=9.0Hz,
1H), 6.40 (s, 1H), 5.33 (t, J=11.0Hz, 1H), 4.85-4.72 (m, 1H), 3.40 (q, J=6.9Hz, 4H), 2.42
(d, J=7.7Hz, 2H), 1.93 (dt, J=28.8,20.1Hz, 6H), 1.70 (dd, J=23.5,11.4Hz, 2H), 1.56-
1.39 (m, 8H), 1.30 (dd, J=23.5,16.1Hz, 6H), 1.18 (t, J=7.1Hz, 9H), 1.01 (s, 4H), 0.87 (d, J
=6.3Hz, 3H), 0.82 (d, J=6.6Hz, 6H), 0.63 (s, 3H)13C NMR(126MHz,CDCl3)δ163.40(s),
158.32 (d, J=19.7Hz), 152.78 (s), 148.79 (s), 139.79 (s), 130.97 (s), 122.65 (s), 109.39
(d, J=16.8Hz), 107.65 (s), 96.72 (s), 74.74 (s), 56.42 (d, J=70.4Hz), 50.04 (s), 45.07
(s), 42.32 (s), 39.64 (d, J=28.8Hz), 38.21 (s), 37.08 (s), 36.65 (s), 36.19 (s), 35.80 (s),
31.91 (d, J=7.6Hz), 28.24 (s), 28.01 (s), 27.87 (s), 24.29 (s), 23.84 (s), 22.70 (d, J=
32.1Hz),21.05(s),19.39(s),18.73(s),12.45(s),11.86(s).
Compound C2 belongs to liquid crystal molecule, liquid crystalline phase occurs at 180.4-162.5 DEG C as shown in Fig. 2 can be used for liquid crystal
Display screen and e-book display.
Application examples 1：Anti tumor activity in vitro Inhibition test
This chapter experiment from HepG2 (human liver cancer cell), Hela (human cervical carcinoma cell), MCF-7 (breast cancer cell),
Four kinds of cancer cells of A549 (lung carcinoma cell) to target compound C1-C2 test using the corresponding IC of mtt assay calculating50Value.
The compound C1-2 of table 2 is to HepG2, Hela, MCF-7, the IC of A549 cell lines50Value
Tab.2The values of IC50of compounds C1-2against HepG2,Hela,MCF-7,A549
As shown above, compound C1, C2 is to HepG2, Hela, MCF-7, and tetra- kinds of cancer cells of A549 are in micromole's rank
Show good antitumous effect.Compound C1, C2 is best to the inhibition of A549 cell lines, IC50It is 26.42 μ respectively
M、23.74μM.Compound C1 is less than compound C2 to MCF-7 and A549 inhibitory action, and the suppression to HepG2 and Hela is made
With being but higher than compound C2.
Claims (5)
1. a kind of anticancer contains cholesteric coumarin derivatives, it is characterised in that the compound has formula C chemical constitution
Formula:
R=H-CH3-OCH3
In formula C:
R is selected from H atom, N, TMSDEA N diethylamine base, methyl, methoxyl group.
2. the preparation method as claimed in claim 1 containing cholesteric coumarin derivatives, using the salicylide of 5 substitutions as
Initiation material, react through Knoevenagel to obtain 7-R- Coumarin-3-carboxylic Acid Ethyl Esters, basic hydrolysis, acid with diethyl malonate
Change obtains 7-R- coumarin-3-carboxy acids, and ultimately producing target product has two kinds of approach, approach one：7-R- coumarin-3-carboxy acids after
It is continuous to generate 7-R- cumarin -3- formyl chlorides with thionyl chloride reaction, then obtained with cholesterine by acylation reaction containing cholesteric
The target compound of coumarin derivatives；Approach two：7-R- coumarin-3-carboxy acids directly pass through dicyclohexyl carbon with cholesterine
Target compound of the esterification generation containing cholesteric coumarin derivatives occurs for diimine dehydration esterification method DCC methods；
The R is selected from H atom, N, TMSDEA N diethylamine base, methyl, methoxyl group.
3. the application containing cholesteric coumarin derivatives in cancer cell medicine is suppressed as claimed in claim 1.
4. application according to claim 3, it is characterised in that described JEG-3 behaviour hepatocellular carcinoma H22, Ren Gong
Neck cancer cell Hela, human breast cancer cell line Bcap-37, human lung cancer cell A549.
5. there is liquid crystalline phase containing cholesteric coumarin derivatives as claimed in claim 1, available for LCDs.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108570055A (en) * | 2018-06-03 | 2018-09-25 | 曾庆强 | A kind of amide derivatives and its application in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108570056A (en) * | 2018-06-03 | 2018-09-25 | 曾庆强 | A kind of amide derivatives and its application in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108586445A (en) * | 2018-06-03 | 2018-09-28 | 曾庆强 | Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108586472A (en) * | 2018-06-03 | 2018-09-28 | 曾庆强 | Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108658958A (en) * | 2018-06-03 | 2018-10-16 | 曾庆强 | A kind of amide derivatives and its application as endothelin-receptor antagonists |
| CN109096357A (en) * | 2018-08-24 | 2018-12-28 | 大连理工大学 | The synthesis of the naphthalimide analog derivative of Sulfide-containing Hindered and cholesterol ester and application |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108570055A (en) * | 2018-06-03 | 2018-09-25 | 曾庆强 | A kind of amide derivatives and its application in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108570056A (en) * | 2018-06-03 | 2018-09-25 | 曾庆强 | A kind of amide derivatives and its application in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108586445A (en) * | 2018-06-03 | 2018-09-28 | 曾庆强 | Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108586472A (en) * | 2018-06-03 | 2018-09-28 | 曾庆强 | Amide derivatives and its application as endothelin-receptor antagonists in the diseases such as cardiovascular and cerebrovascular, pulmonary hypertension |
| CN108658958A (en) * | 2018-06-03 | 2018-10-16 | 曾庆强 | A kind of amide derivatives and its application as endothelin-receptor antagonists |
| CN109096357A (en) * | 2018-08-24 | 2018-12-28 | 大连理工大学 | The synthesis of the naphthalimide analog derivative of Sulfide-containing Hindered and cholesterol ester and application |
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