CN107383147A - A kind of Sitosterolum and Epalrestat conjugate and its production and use - Google Patents
A kind of Sitosterolum and Epalrestat conjugate and its production and use Download PDFInfo
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- CN107383147A CN107383147A CN201710573393.9A CN201710573393A CN107383147A CN 107383147 A CN107383147 A CN 107383147A CN 201710573393 A CN201710573393 A CN 201710573393A CN 107383147 A CN107383147 A CN 107383147A
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- CN
- China
- Prior art keywords
- epalrestat
- cupreol
- conjugate
- sitosterolum
- pyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to natural medicine field, discloses a kind of Sitosterolum and Epalrestat conjugate and its production and use.The conjugate is formed by Sitosterolum and Epalrestat coupling, structure such as formula (I).Preparation includes step：Sitosterolum and Epalrestat are dissolved in anhydrous methylene chloride, under the catalysis of pyridine and 4 dimethylamino naphthyridines, room temperature reaction overnight, filtering, crosses silica gel chromatographic column, rotates, and dries, you can obtains target compound.By external MTT test experiences, it is found that it has good inhibition to tumor cell line, than the IC of Sitosterolum50It is worth strong 36 times but less toxic to normal liver cell L O2.Compound treating cancer in a manner of two drug molecule couplings are into prodrug, the problem of overcoming Sitosterolum cancer resistance deficiency and cooperate with targeted inhibition cancer cell aldose reductase target, reaches the effect that cancer cell is removed by the approach for strengthening Apoptosis.
Description
Technical field
The invention belongs to natural medicine field, more particularly to a kind of cupreol and Epalrestat conjugate and its preparation side
Method and purposes.
Background technology
Cancer is to seriously endanger a big chronic disease of human health, turns into the second largest killer for being only second to cardiovascular disease,
So find antineoplastic safely, effectively, less toxic and study its mechanism of action, it is significant.
Cupreol (β-sitosterol, BST) is the main constituents of animal and plant cells film, currently has more than 200 to plant
Phytosterol is identified out, wherein most abundant, commonly cupreol, brassicasterol, stigmasterol.About over one hundred plantation
Thing is it has been reported that contain cupreol.Cupreol shows extensive pharmacological activity, mainly has：Antibacterial, anti-inflammatory, anticancer
It is (breast cancer, the carcinoma of the rectum, prostate cancer, fibroma, cervical carcinoma), anti-oxidant, immunological regulation, lipidemia, anti arteriosclerosis, anti-
Ulcer, analgesia, suppress platelet aggregation etc..(60 days) subcutaneous administration rat cupreol for a long time, its hepatic and renal tissue function have no
Abnormal, in addition to blood fat has obvious reduce, other Serum Indexes are all in Normal reference range (Nutr Cancer.2015；67
(8):1214-20.；Steroids.2015；100:27-35.；Bioorg Med Chem Lett.2015；25(21):4976-
9.；Eur J Pharmacol.2015；760:154-62.).However, natural BST antitumor activities are relatively weak, in order to enter
One step improves BST antitumor activity, and people carry out structural modification and transformation to it, obtains the higher BST of some activity and spreads out
Biology has become hot subject.
Epalrestat is aldose reductase inhibitor, reversibly to suppress related to the pathogenesis of diabetic complication
Polyalcohol metabolism in glucose be converted into the aldose reductase of sorbierite and play a role.Recent research indicate that Epalrestat
Aldose reductase (the J Exp Med.2017Mar 7.pii of alternative targeted inhibition cancer cell:Jem.20160903.), this
To be coupled target tumor specific inhibitor prodrug with BST, the research strategy for the anticarcinogenic effect for improving BST implements treatment malignant tumour
Provide brand-new possibility.
The content of the invention
In order to overcome shortcoming and defect present in prior art, primary and foremost purpose of the invention is to provide a kind of β-paddy steroid
Alcohol and Epalrestat conjugate；The conjugate is formed by cupreol and Epalrestat coupling.
Another object of the present invention is to provide the preparation method of a kind of above-mentioned cupreol and Epalrestat conjugate.
It is still another object of the present invention to provide the purposes of above-mentioned cupreol and Epalrestat conjugate.
The purpose of the present invention is achieved through the following technical solutions：
A kind of cupreol and Epalrestat conjugate, the conjugate are formed by cupreol and Epalrestat coupling,
With the structural formula as shown in following formula (I)：
The cupreol passes through linkage with Epalrestat.
The preparation method of a kind of above-mentioned cupreol and Epalrestat conjugate, including following operating procedure：By β-paddy
Sterol is dissolved in anhydrous methylene chloride with Epalrestat, under the catalysis of pyridine and DMAP, is reacted at room temperature
At night, filtering, silica gel chromatographic column is crossed, rotated, dried, you can obtain target compound.
The room temperature is 25-30 DEG C.
The mol ratio of the pyridine and DMAP is (1~4):2.
Eluting solvent used in the silica gel chromatographic column is ethyl acetate and petroleum ether, and solvent volume ratio is (3~15):8.
A kind of above-mentioned cupreol is preparing antineoplastic with Epalrestat conjugate and its pharmaceutically acceptable salt
Purposes in thing.
A kind of above-mentioned cupreol is preparing anti-inflammatory drug with Epalrestat conjugate and its pharmaceutically acceptable salt
Or the purposes in cosmetics.
A kind of pharmaceutical composition, wherein the above-mentioned cupreol containing therapeutically effective amount and Epalrestat conjugate or its
Pharmaceutically acceptable salt and carrier.
A kind of purposes of the above-mentioned pharmaceutical composition in antineoplastic, anti-inflammatory drug or cosmetics are prepared.
The present invention has the advantages of following prominent and beneficial effect compared with prior art：
The present invention has synthesized a kind of antineoplastic cupreol and the compound of anti-oxidation medicine Epalrestat coupling, leads to
External MTT test experiences are crossed, it is found that it has to tumor cell line (MCF-7, BC-3 and HepG2 cell) and suppresses to imitate well
Fruit, than the IC of cupreol50It is worth strong 3-6 times but less toxic to normal liver cell L-O2.The compound is coupled with two drug molecules
Into the mode treating cancer of prodrug, overcome cupreol activity weak, the anti-oxidant and glycometabolism of Epalrestat suppresses collaboration enhancing
The problem of its cancer therapy drug activity, reach the effect that cancer cell is removed by the approach for strengthening Apoptosis.
Embodiment
With reference to embodiment, the present invention is described in further detail, but the implementation of the present invention is not limited to this.
Embodiment 1：
Cupreol (1.2mmole) and Epalrestat (1.2eq) are dissolved in anhydrous methylene chloride (30ml), in pyrrole
Reacted under pyridine (0.5g) and the catalysis of DMAP (0.5g), at 25-30 DEG C of room temperature overnight, filtering, cross silica gel chromatograph
(eluting solvent used is volume ratio (3~15) to post:8 ethyl acetate and petroleum ether), rotate, dry, you can obtain white
Solid target compound.Analyzed through liquid chromatography mass and nuclear magnetic resonance technique, the freshly prepd white solid target compound of institute
For the conjugate with structure shown in formula (I)：
Embodiment 2
The extracorporeal anti-tumor Effect Evaluation of target compound.The present embodiment uses breast cancer MCF-7, lymthoma BC-3 and liver
Cancer HepG2 cells carry out evaluating drug effect to it, while LO2 liver cells carry out toxicity detection to it.
Take the logarithm the cell in growth period, 4~40 × 10 are inoculated with according to the size of cell3It is individual on 96 orifice plates, to be grown 24
After hour, supernatant is abandoned, is then administered by following packet：Tumour cell sets not dosing group and dosing group, and (1~150 μM of concentration is to swollen
Oncocyte, 5~250 μM of concentration is to LO2 cells), cupreol coupling Epalrestat BST-EPA (the i.e. gained targeteds of embodiment 1
Compound), cupreol BST, Epalrestat EPA and both equimolar mixture BST+EPA.Every group sets 4~6 multiple holes, culture
24 hours, supernatant is abandoned, adds MTT (tetrazolium) the serum-free medium culture 4h of 100 μ l containing 0.5mg/ml, adds 100 μ l
DMSO (dimethyl sulfoxide), is positioned on micro-oscillating instrument and vibrates 10min, then is placed on ELIASA detection OD values at 570nm.Normally
Human cell line LO2 is compareed.Experiment is repeated 3 times every time.
As a result show, as drug concentration increases, compared with accordingly not dosing control group, cell-proliferation activity respectively under
Drop, illustrate that compound suppresses tumor cell propagation in concentration dependent.And the propagation of normal hepatic cell line LO2 cells is lived
Property does not change, shows that the compound has low toxicity characteristic (table 1) to normal cell.
The IC of 1 different cells of table50It is worth (24h) and different compound IC50Ratio
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. a kind of cupreol and Epalrestat conjugate, it is characterised in that：The conjugate is by cupreol and Epalrestat
Coupling forms, and has the structural formula as shown in following formula (I)：
2. a kind of cupreol according to claim 1 and Epalrestat conjugate, it is characterised in that：The cupreol
Pass through linkage with Epalrestat.
3. the preparation method of a kind of cupreol according to claim 1 and Epalrestat conjugate, it is characterised in that：Bag
Include following operating procedure：Cupreol and Epalrestat are dissolved in anhydrous methylene chloride, in pyridine and 4- dimethylamino pyrroles
Under the catalysis of pyridine, room temperature reaction overnight, filtering, crosses silica gel chromatographic column, rotates, and dries, you can obtains target compound.
4. preparation method according to claim 3, it is characterised in that：The room temperature is 25-30 DEG C.
5. preparation method according to claim 3, it is characterised in that：The mol ratio of the pyridine and DMAP
For (1~4):2.
6. preparation method according to claim 3, it is characterised in that：Eluting solvent used in the silica gel chromatographic column is second
Acetoacetic ester and petroleum ether, solvent volume ratio are (3~15):8.
7. a kind of cupreol according to claim 1 is being made with Epalrestat conjugate and its pharmaceutically acceptable salt
Purposes in standby antineoplastic.
8. a kind of cupreol according to claim 1 is being made with Epalrestat conjugate and its pharmaceutically acceptable salt
Purposes in standby anti-inflammatory drug or cosmetics.
A kind of 9. pharmaceutical composition, wherein the cupreol and Epalrestat described in the claim 1 containing therapeutically effective amount are even
Join thing or its pharmaceutically acceptable salt and carrier.
10. a kind of pharmaceutical composition according to claim 9 is in antineoplastic, anti-inflammatory drug or cosmetics are prepared
Purposes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710573393.9A CN107383147A (en) | 2017-07-14 | 2017-07-14 | A kind of Sitosterolum and Epalrestat conjugate and its production and use |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710573393.9A CN107383147A (en) | 2017-07-14 | 2017-07-14 | A kind of Sitosterolum and Epalrestat conjugate and its production and use |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721302A (en) * | 2018-06-29 | 2018-11-02 | 佛山科学技术学院 | A kind of compound medicament composition and application thereof |
| CN110051668A (en) * | 2019-04-17 | 2019-07-26 | 南通大学附属医院 | A kind of verification method of application of the Epalrestat in preparation pancreatic cancer drug and the inhibiting effect to pancreatic cancer cell secretion excretion body |
| CN114478561A (en) * | 2022-02-23 | 2022-05-13 | 山东达因海洋生物制药股份有限公司 | Epalrestat lycorine conjugate and preparation method and application thereof |
Citations (3)
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|---|---|---|---|---|
| CN1134696A (en) * | 1993-11-15 | 1996-10-30 | 赫彻斯特股份公司 | Substituted 5-ring heterocycles, their preparation and their use |
| WO2005007123A2 (en) * | 2003-07-18 | 2005-01-27 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
| WO2011135303A2 (en) * | 2010-04-29 | 2011-11-03 | Iti Scotland Limited | Ubiquitination modulators |
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2017
- 2017-07-14 CN CN201710573393.9A patent/CN107383147A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1134696A (en) * | 1993-11-15 | 1996-10-30 | 赫彻斯特股份公司 | Substituted 5-ring heterocycles, their preparation and their use |
| WO2005007123A2 (en) * | 2003-07-18 | 2005-01-27 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
| WO2011135303A2 (en) * | 2010-04-29 | 2011-11-03 | Iti Scotland Limited | Ubiquitination modulators |
Non-Patent Citations (3)
| Title |
|---|
| NOELLE POTIER, ET AL.: "Study of non-covalent enzyme-inhibitor complexes of aldose reductase by electrospray mass spectrometry", 《EUR. J. BIOCHEM.》 * |
| POPOV-PERGAL ETAL.: "Synthesis and biological activity evaluation of new functionally substituted 5-arylidene-2,4-dioxotetrahydro-1,3-thiazoles", 《JOURNAL OF THE SERBIAN CHEMICAL SOCIETY》 * |
| ROSANNA MACCARI, ET AL.: "In vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721302A (en) * | 2018-06-29 | 2018-11-02 | 佛山科学技术学院 | A kind of compound medicament composition and application thereof |
| CN110051668A (en) * | 2019-04-17 | 2019-07-26 | 南通大学附属医院 | A kind of verification method of application of the Epalrestat in preparation pancreatic cancer drug and the inhibiting effect to pancreatic cancer cell secretion excretion body |
| CN114478561A (en) * | 2022-02-23 | 2022-05-13 | 山东达因海洋生物制药股份有限公司 | Epalrestat lycorine conjugate and preparation method and application thereof |
| CN114478561B (en) * | 2022-02-23 | 2022-12-20 | 山东达因海洋生物制药股份有限公司 | Epalrestat lycorine conjugate and preparation method and application thereof |
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Application publication date: 20171124 |