CN106083877A - Unsaturated norcantharidin methyl ester barium salt and antitumor application thereof - Google Patents
Unsaturated norcantharidin methyl ester barium salt and antitumor application thereof Download PDFInfo
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- CN106083877A CN106083877A CN201610450166.2A CN201610450166A CN106083877A CN 106083877 A CN106083877 A CN 106083877A CN 201610450166 A CN201610450166 A CN 201610450166A CN 106083877 A CN106083877 A CN 106083877A
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- norcantharidin
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- methyl ester
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The invention provides a kind of unsaturated norcantharidin methyl ester barium salt derivative I and application thereof, its structural formula shown in formula I,
Description
Technical field
The invention belongs to new drug design and synthesis field, be specifically related to the novel unsaturated norcantharidin methyl ester barium salt of a class
And antitumor application.
Background technology
Mylabris, also the writing speckle insect destructive of the roots of seedlings, the class's of being commonly called as Seedling, SPANISH FLY etc., at the Chinese materia medica monograph " book on Chinese herbal medicine of China's earliest extant
Detailed outline ", the most on the books in Shennong's Herbal etc..Mylabris is being dried of the big speckle insect destructive of the roots of seedlings in Meloidae insecticide south or the yellow black stigma insect destructive of the roots of seedlings
Body, belongs to coleoptera Meloidae insecticide, is one of medical material with antitumaous effect of finding the earliest of China.Mylabris property is pungent, heat, has
The strongest nephrotoxicity, has removing blood stasis simultaneously, removes alluvial, detumescence and effect of counteracting toxic substances phagedenoma, and clinic is usually used in malignant boil,
The treatment that stubborn dermatitis, rabies and cancer swell and ache etc..Research then shows, the internal of Mylabris derives containing a kind of sesquiterpenoids
Thing, referred to as cantharidin (cantharidin, C10H12O4), there is higher active anticancer, there is the highest medical value.
Cantharidin is colourless crystallization, insoluble in cold water, is slightly soluble in hot water, is dissolved in acetone and chloroform.Cantharidin is primarily present in multiple elder brother
In worm, human body skin can be made to blister, cantharidin and derivant antineoplastic mechanism thereof mainly suppression protein and sour synthesis,
Enhancing body reaches therapeutic purposes to the lethality of tumor cell.Cantharidin and the like is to hepatocarcinoma, ovarian cancer, esophageal carcinoma
Etc. there being good curative effect, it is the activity by changing protein, and antineoplastic invasion shifts, causes cell cycle arrest, suppression
Tumor growth, so that it is dead.Its antineoplastic mechanism is by reducing cancerous cell to amino acid whose picked-up, suppression albumen
The synthesis of matter, stimulates lymphocyte, macrophage, polymorphonuclear cell to produce interleukin, thus improves immunity of organisms, with
Time killing tumor cell and reach therapeutic purposes, compared with other antitumor drug, cantharidin and derivant thereof have many excellent
Point: it, while suppression tumor, does not only have immunosuppressant side effect, moreover it is possible to promote body leukocyte etc..
But cantharidin has bigger toxic and side effects to urinary system and gastrointestinal system, cantharidin is that antineoplastic activity becomes
Point, also it is the main component of toxicity simultaneously.It is carried out appropriate structural modification, can be on the basis retaining its anti-tumor activity
On, significantly lower the toxic and side effects to body, as a example by the synthesis of norcantharidin derivative.Norcantharidin not only remains
Its stronger anti-tumor activity and the effect of leukocyte increasing, also eliminate its side effect to urinary system, later, with nor-
Cantharidin is that lead compound carries out structure of modification and becomes the focus of research.This advantage is the most rare in antitumor drug
, paying close attention to widely so causing, having synthesized its toxic and side effects of many minimizings successively but having retained again the similar of its activity simultaneously
Medicine, it is a good research direction that exploitation updates the derivant of high-efficiency low-toxicity.
For treating the appearance the most successively of the derivant of cancer after cantharidin is carried out structural modification, and start to use
In clinical treatment.Such as norcantharidin, it is few two methyl than cantharidin, and its toxicity substantially lowers, and therapeutical effect is excellent
In Cantharidin.
At present, cantharidin and norcantharidin all have been applied in clinic, and the two medicine respectively has clinical characters,
But weak point is: the water solublity of the two medicine is the most poor, and bioavailability is the highest.Chemically structure is found out, cantharidin
With the structure of norcantharidin all contains intramolecular acid anhydride structure.And after the anhydride hydrolysis of the i.e. cantharidin compound of Cantharidic acid.
The dicarboxylic acid compound obtained；Cantharidic acid. is not also developed to into medicine, only report its structural formula.
Additionally, be investigated sodium cantharidinate clinically, sodium norcantharidate, N-methylcantharidimide etc., these structure of modification are equal
The inner-acid anhydride ring of cantharidin and norcantharidin is opened, exists in an open-loop manner, chemically see in structure；Corresponding open loop
Its corresponding dissolubility of compound is relatively big, and its vivo biodistribution availability is the highest.The structure of cantharidin is modified, finds the lowest
The cantharidin antitumor drug of poison, has important industrial application value and market prospect widely.Application No.
The Chinese patent of ZL201410163619.4, ZL201410163711.0, ZL201410163705.5 discloses prepares demethyl
The method of cantharidin hydrochlorate, so far, not yet has been reported that and designs and synthesizes unsaturated norcantharidin methyl ester barium salt structure.
Summary of the invention
For solving the deficiencies in the prior art, it is an object of the invention to provide a kind of novel unsaturated norcantharidin methyl ester
Barium salt, its synthetic method and antitumor application thereof.In order to realize above-mentioned target, the present invention adopts the following technical scheme that:
On the one hand, the invention provides a kind of novel unsaturated norcantharidin methyl ester barium salt, its structural formula such as Formulas I institute
Show,
On the other hand, the invention provides unsaturated norcantharidin methyl ester barium salt I (or making compound I) as above
Synthetic method, including step: 1), compound A and ethanol synthesis obtain compound B, 2), compound B reacts with barium hydroxide
Obtain unsaturated norcantharidin methyl ester barium salt I；Synthetic route is:
In the synthetic method of above-claimed cpd I, it is preferable that described step 1) add organic amine, more preferably triethylamine conduct
Organic base auxiliary agent.
The synthetic method of above-claimed cpd I, it is preferable that described step 1) reaction temperature be 10 DEG C-50 DEG C；It is preferably room
Temperature.
The synthetic method of above-claimed cpd I, it is preferable that described step 1) reaction temperature be 10 DEG C-50 DEG C；It is preferably room
Temperature.
Additionally, each step reaction of the present invention, spectrum can be used in conjunction by chromatography, liquid matter and monitor reaction process.In chromatography,
Applicable thin layer chromatography TLC, it is also possible to gas chromatography or liquid chromatography such as HPLC replacement etc..
Active testing proves, it is thin to hepatocarcinoma that the present invention designs and synthesizes the unsaturated norcantharidin methyl ester barium salt I obtained
Born of the same parents have good inhibitory activity.
Therefore, a third aspect of the present invention provides unsaturated norcantharidin methyl ester barium salt I for preparing anti-liver cancer drug
Purposes in thing.
Term
Abbreviation herein has following meanings: room temperature also refers to room temperature, and temperature range includes the room temperature in the four seasons, i.e. 10 DEG C-35
Between DEG C.Hour it is abbreviated as h, minute is abbreviated as min；Dimethyl sulfoxide is abbreviated as DMSO, and in synthetic example, M represents mol/
L。
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.
Without departing from the inventive concept of the premise, those skilled in the art can be within the scope of the claims to preparation method and use instrument
Device makes improvements, and these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended
Claim is as the criterion.The reagent used in the present invention is from Shanghai traditional Chinese medicines group；And reaction dissolvent is from Zun Yi, and double huge chemical industry have
Limit company.Unless otherwise indicated, agents useful for same and solvent are chemical pure.
The preparation of embodiment 1. compound A
From reagent bottle, take out a certain amount of maleic anhydride, be placed in dry grinding body finely ground, then use electronic balance
Weigh finely ground maleic anhydride 12.021g, be placed in dry there-necked flask, cap, then the stirring that adds diethyl ether, in second
When ether amount is 90mL, maleic anhydride is completely dissolved.After maleic anhydride is completely dissolved, it is slowly added to Dropping funnel
13mL furan, used time 13min.Control temperature and start reaction at 38 DEG C.After reaction 1h, there is white solid in solution, and the time is the longest
White solid is the most.React sucking filtration to 24h, obtain the compound A of white solid.It is dried and is weighed as 17.46g, yield 85.8%.
Fusing point: 122～123 DEG C, Rf value Rf:0.52 (developing solvent is petroleum ether: ethyl acetate=3: 1)；1HNMR (CDCl3): δ:
3.18 (s, 2H), 5.47 (s, 2H), 6.58 (s, 2H).
The preparation of embodiment 2. compound B
Weigh Compound A4.15g (25mmol), is dissolved in 25ml methanol, forms suspension, is added dropwise in suspension
0.73ml triethylamine (5mmol), under room temperature, (25 DEG C) are stirred overnight；After reaction terminates, rotation is evaporated off methanol, the residue that will obtain
Material is dissolved in 25ml dichloromethane, washed once with the 1M hydrochloric acid of 7ml, leaves organic facies, washes with 10ml saturated common salt
Wash once, leave organic facies；Adding appropriate anhydrous magnesium sulfate and be dried 15-30min, sucking filtration, filter cake dichloromethane rinses 2-3
Secondary, leave filtrate, filtrate decompression is removed solvent and obtains the compound B 2.70g of solid product, yield 54.5%.1HNMR
(DMSO-d6): δ: 6.44 (q, J=8Hz, 2H), 5.06 (s, 2H), 3.67 (d, J=24Hz, 2H), 3.46 (d, J=48Hz,
2H), 2.71 (s, 2H).13CNMR (DMSO-d6): δ: 173.03,172.48,137.10,136.98,80.39,80.06,
51.87,46.33,39.48.
The preparation of embodiment 3. compound I
Compound C 500mg (2.5mmol) is dissolved in 10ml methanol, adds barium hydroxide eight hydrate 418.13mg
(1.33mmol), stirring reaction under room temperature, after reaction terminates, removal of solvent under reduced pressure, cross silicagel column with methanol for eluent, point
Plate, collects colour developing sample, and rotation is evaporated dry, obtains the compound I (i.e. unsaturated norcantharidin ethyl ester barium salt I) of solid product
667.9mg, yield 83.9%.1HNMR (CDCl3): δ: 6.34 (d, J=48Hz, 2H), 5.29 (s, 2H), 3.67 (s, 3H),
2.66 (dd, J=8Hz, 8Hz, 2H).13CNMR (CDCl3): δ: 179.02,177.24,137.40,134.59,82.78,
81.63,52.91,49.93,46.21.
The anti-tumor activity test of the unsaturated norcantharidin methyl ester barium salt I of experimental example 4.
Cell strain and solvent
Human liver cancer cell HEPG2,
Gastric carcinoma cells BGC803,
Human colon cancer cell SW480,
Cell is incubated at culture medium in the RPMI1640 containing 10% hyclone,
Solvent: dimethyl sulfoxide (referred to as DMSO).
CCK-8 staining detection cell anti-tumor activity embodiment
This test is according to SRB method, and with Cantharidin as positive control, DMSO solvent is blank, has carried out concentration and has been
The unsaturated norcantharidin methyl ester barium salt I of 50nnmol/mL is to hepatocarcinoma cell line HEPG2, gastric carcinoma cells BGC803 and colon cancer
The inhibitory activity test of three kinds of tumor cells of cell SW480.
Concrete testing scheme is: the cell selecting tumor living cell ratio to be measured to reach more than 90% is tested.Cell increases
Grow inhibition test and use EnoGeneCellTMCounting Kit-8 (referred to as CCK-8) cell viability detection kit.Cell
Digesting, count, make the cell suspension that concentration is 1 × 105/mL, in 96 orifice plates, every hole adds 100 μ L cell suspension (every holes 1
× 104 cells)；96 orifice plates are placed in 37 DEG C, cultivate 24 hours in 5%CO2 incubator；Every hole adds the 100 corresponding pastilles of μ L
The culture medium of thing, activity is 50 μMs of ol/L (that is: micromoles per liter), sets up negative control group, Vehicle controls group, sun simultaneously
Property matched group (positive control selects cantharidin and camptothecine respectively), the often multiple holes of group 5；96 orifice plates are placed in 37 DEG C, and 5%CO2 cultivates
After case is cultivated 72 hours；Every hole adds 10 μ L CCK-8 solution, is hatched by culture plate 4 hours, use microplate reader in incubator
Measure the light absorption value at 450nm (being called for short OD value), calculate each compound to human liver cancer cell HEPG2, gastric carcinoma cells
BGC803 and the suppression ratio of Colon Carcinoma.
Experimental result refers to table 1.
Table 1, unsaturated norcantharidin methyl ester barium salt I are for the inhibitory activity of three kinds of tumor cells
| Test sample | HEPG2 |
| Cantharidin (positive control) | 70.4% |
| DMSO solvent (blank) | 99.9% |
| Compound I | 41.3% |
As shown in Table 1, under the low concentration of 50nmol/L (being converted into 0.05 μm ol/L), unsaturated norcantharidin methyl ester
Barium salt I has certain inhibition to human liver cancer cell HEPG2, can use it for preparing anti-liver cancer and anti-drug candidate.
Claims (9)
1. a novel unsaturated norcantharidin methyl ester barium salt derivant, its structural formula shown in formula I,
2. the synthetic method of the unsaturated norcantharidin methyl ester barium salt I described in claim 1, including step: 1), compound A
Obtain compound B with ethanol synthesis, 2), compound B reacts with barium hydroxide and obtains unsaturated norcantharidin methyl ester barium salt I；
Synthetic route is:
Synthetic method the most according to claim 2, wherein, described step 1) add organic amine as organic base auxiliary agent.
Synthetic method the most according to claim 3, wherein, described organic amine is triethylamine.
Synthetic method the most according to claim 2, wherein, described step 1) reaction temperature be 10 DEG C-50 DEG C.
Synthetic method the most according to claim 5, wherein, described step 1) reaction temperature be room temperature.
Synthetic method the most according to claim 2, wherein, described step 2) reaction temperature be 10 DEG C-50 DEG C.
Synthetic method the most according to claim 7, wherein, described step 2) reaction temperature be room temperature.
9. the unsaturated norcantharidin methyl ester barium salt I described in claim 1 is for preparing the purposes in medicines resistant to liver cancer.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101662939A (en) * | 2007-02-06 | 2010-03-03 | 利克斯特生物技术控股公司 | Oxa-bicyclo heptane and oxabicyclo heptene, their preparation and purposes |
| CN103588780A (en) * | 2013-11-15 | 2014-02-19 | 遵义医学院 | Barium cantharidate and preparation method thereof |
| WO2015073802A1 (en) * | 2013-11-15 | 2015-05-21 | Lixte Biotechnology, Inc. | Protein phosphatase inhibitors that cross the blood brain barrier |
| CN104817574A (en) * | 2015-05-26 | 2015-08-05 | 遵义医学院 | Novel camptothecin derivative and antitumor application thereof |
-
2016
- 2016-06-21 CN CN201610450166.2A patent/CN106083877A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101662939A (en) * | 2007-02-06 | 2010-03-03 | 利克斯特生物技术控股公司 | Oxa-bicyclo heptane and oxabicyclo heptene, their preparation and purposes |
| CN103588780A (en) * | 2013-11-15 | 2014-02-19 | 遵义医学院 | Barium cantharidate and preparation method thereof |
| WO2015073802A1 (en) * | 2013-11-15 | 2015-05-21 | Lixte Biotechnology, Inc. | Protein phosphatase inhibitors that cross the blood brain barrier |
| CN104817574A (en) * | 2015-05-26 | 2015-08-05 | 遵义医学院 | Novel camptothecin derivative and antitumor application thereof |
Non-Patent Citations (2)
| Title |
|---|
| ADAM MCCLUSKEY 等: "Anhydride Modified Cantharidin Analogues: Synthesis, Inhibition of Protein Phosphatases 1 and 2A and Anticancer Activity", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JENNETTE A. SAKOFF 等: "Anticancer activity and protein phosphatase 1 and 2A inhibition of a new generation of cantharidin analogues", 《INVESTIGATIONAL NEW DRUGS》 * |
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Application publication date: 20161109 |