CN106083879A - Norcantharidin mono-acid monoester derivates and antitumor application thereof - Google Patents
Norcantharidin mono-acid monoester derivates and antitumor application thereof Download PDFInfo
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Abstract
The invention provides a kind of norcantharidin mono-acid monoester derivates and application thereof, its structural formula as shown in Equation 3,
Description
Technical field
The invention belongs to new drug design and synthesis field, be specifically related to a class novel norcantharidin mono-acid monoester derivates
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, Mylabris internal containing a kind of sesquiterpenoids derivant, referred to as cantharidin
(cantharidin, C10H12O4), there is higher active anticancer, there is the highest medical value.Cantharidin is colourless knot
Crystalline substance, insoluble in cold water, is slightly soluble in hot water, is dissolved in acetone and chloroform.Cantharidin is primarily present in various insects, can make human body skin
Skin is blistered, and cantharidin and derivant antineoplastic mechanism thereof mainly suppression protein and sour synthesis, enhancing body is to tumor
The lethality of cell and reach therapeutic purposes.Cantharidin and the like has good treatment to hepatocarcinoma, ovarian cancer, esophageal carcinoma etc.
Effect, it is the activity by changing protein, and antineoplastic invasion shifts, and causes cell cycle arrest, suppresses tumor growth, thus
Make it dead.Its antineoplastic mechanism is by reducing cancerous cell to amino acid whose picked-up, the synthesis of suppression protein, stimulation
Lymphocyte, macrophage, polymorphonuclear cell produce interleukin, thus improve immunity of organisms, kill tumor thin simultaneously
Born of the same parents and reach therapeutic purposes, compared with other antitumor drug, cantharidin and derivant thereof have many advantages: it is swollen in suppression
While tumor, not only there is no 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 the norcantharidin mono-acid monoester derivates structure designing and synthesizing open loop
And synthetic method.
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 norcantharidin mono-acid monoesters and spread out
Biology, 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 norcantharidin mono-acid monoester derivates, its structural formula such as formula 3 institute
Show,
Wherein, R is selected from alkyl or the benzyl of C1-C3.Described R is more preferably methyl, ethyl, propyl group, isopropyl, benzyl.
On the other hand, the invention provides the synthetic method of norcantharidin mono-acid monoester derivates 3 as above, bag
Include following steps: 1), 5-alkene norcantharidin hydrogenating reduction the most in the presence of a catalyst obtain norcantharidin
2,2), norcantharidin 2 reacts with corresponding alcohol (ROH) and obtains norcantharidin mono-acid monoester derivates 3；Synthetic route is:
In said synthesis route, in alcohol roh, R group chooses with R group corresponding in compound structure shown in above-mentioned formula 3
Choose identical.
In above-mentioned synthetic method, described step 1) catalyst selected from Pd/C, Pd (OH)2/ C, Pt/C or Raney Ni etc.
Hydrogenation catalyst；Described step 1) preferred Pd/C or Pd of catalyst (OH)2/C。
In above-mentioned synthetic method, described step 2) alcohol roh selected from selected from the alkyl of C1-C3 or benzyl；More preferably first
Alcohol, ethanol, propanol, isopropanol, benzylalcohol.
In said synthesis route, organic solvent can be according to reaction to temperature, the demand of solvent polarity, from N, N-diformazan
Base Methanamide, dimethyl sulfoxide, dichloromethane, chloroform, acetonitrile, oxolane or ether select.
Such as, described step 1) the reaction dissolvent of employing be ether solvent, halogenated hydrocarbons or alcohols solvent, such as: ether,
Propyl ether, oxolane, dichloromethane, chloroform, methanol or ethanol etc..
Described step 2) in use reaction dissolvent can be corresponding alcoholic solvent or halogenated hydrocarbon solvent, such as: two
Chloromethanes, chloroform etc..
Active testing proves, the present invention designs and synthesizes the norcantharidin mono-acid monoester derivates 3 obtained to hepatocarcinoma, stomach
Cancer and three kinds of tumor cells of colon cancer have good inhibitory activity.Therefore, a third aspect of the present invention provides demethylcantharidin
The element mono-acid monoester derivates 3 purposes in the medicine preparing anti-liver cancer and anti-, gastric cancer and three kinds of tumors of colon cancer.
Term
Abbreviation herein has a following meanings: hour be abbreviated as h, minute is abbreviated as min；Oxolane is abbreviated as THF,
N,N-dimethylformamide is abbreviated as DMF, dimethyl sulfoxide is abbreviated as DMSO；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 furan used in the present invention, the reagent such as maleic anhydride is all from Shanghai traditional Chinese medicines group；Solvent for use
From Zun Yi Shuan Ju Chemical Co., Ltd..Unless otherwise indicated, agents useful for same is chemical pure.
Synthetic route is:
Each step reaction of said synthesis route, can be used in conjunction spectrum by chromatography, liquid matter and monitor reaction process.Chromatography
In, applicable thin layer chromatography TLC can also be used with gas chromatography or liquid chromatography such as HPLC replacement etc..
The preparation of embodiment 1. 5-alkene norcantharidin 1
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 1 of white solid, i.e. 5-alkene norcantharidin.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. norcantharidin 2
Take 5-alkene norcantharidin 1 (1.091g) in Shi Lanke bottle, add 20ml oxolane and make it dissolve, add
109mg palladium carbon, vacuum removes in flask and is passed through hydrogen after air, and at 25 DEG C, stirring makes it react, and reaction terminates rear sucking filtration and removes
Palladium carbon, steams the rotation of gained filtrate, is dried, obtains norcantharidin (72.2%), white solid 794.3mg.1HNMR(DMSO-
d6): δ: 4.85 (s, 2H), 3.34 (d, J=20Hz, 2H), 1.65 (d, J=8Hz, 4H).13CNMR(DMSO-d6): δ:
173.35,80.08,51.14,40.35,40.14,39.93,39.72,27.90.
The synthesis of embodiment 3. norcantharidin mono-acid ethyl ester (3, R=Et):
Step: remove norcantharidin 672mg in flask, adds 30ml dehydrated alcohol and makes it dissolve, and 80 DEG C are heated to reflux,
After 4.5 hours, reaction is completely, and rotation is steamed, and crosses silicagel column with ethyl acetate for eluent, puts plate, and the sample rotation collecting colour developing is steamed, dry
Dry, obtain norcantharidin mono-acid ethyl ester (87%), white solid 747.2mg.1HNMR (CDCl3): δ: 4.91 (d, J=
24Hz, 2H), 4.11 (d, J=8Hz, 2H), 2.99 (q, J=12Hz, 3H), 1.81 (t, J=4Hz, 2H), 1.52 (d, J=
8Hz, 2H), 1.21 (t, J=8Hz, 3H).13CNMR (CDCl3): δ: 176.45,170.87,78.59,78.29,77.03,
76.71,61.16,52.27,28.97,13.94.
The synthesis of embodiment 4. norcantharidin mono-acid methyl ester (3, R=Me):
Weigh norcantharidin 503.6mg (3mmol), be dissolved in 5ml methanol, be heated to 80 DEG C～85 DEG C, cooling for reflux,
Place after reaction 3.5h in refrigerator and cool down 12h, separate out colorless solid, sucking filtration, obtain norcantharidin mono-acid methyl ester product
145.2mg (0.725mmol), productivity 24.2%,1HNMR(DMSO-d6):δ:12.22(s,1H),4.66(s,2H),3.49(s,
3H),2.98(s,2H),1.48-1.54(m,4H).13CNMR(DMSO-d6): δ: 172.72,172.04,78.26,77.93,
76.71,61.16,52.27,28.97,13.94.
The synthesis of embodiment 5. norcantharidin mono-acid benzyl ester (3, R=Bn):
Remove norcantharidin 200mg (1.19mmol), be placed in round-bottomed flask, add 4ml dichloromethane and dissolve, add afterwards
0.17ml triethylamine and 0.13ml benzylalcohol (1.2mmol), after reaction 1h, be heated to reflux 5h at 160 DEG C, and after cooling, decompression removes
Solvent, obtains solid product 162.4mg by residue through column chromatography, productivity 49.4%,1HNMR(DMSO-d6):δ:12.29(s,
1H), 7.29-7.34 (m, 5H), 5.01 (d, J=16Hz, 1H), 4.99 (d, J=12Hz, 1H), 4.69 (t, J=4Hz, 2H),
3.03 (d, J=4Hz, 2H), 1.49-1.53 (m, 4H).13CNMR(DMSO-d6): δ: 172.76,171.49,136.17,
128.79,128.37,128.35,127.46,127.31,78.35,78.01,66.06,52.41,51.34,28.95,28.93.
The anti-tumor activity test of experimental example 6. norcantharidin mono-acid monoesters 3
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 RPMI 1640 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 norcantharidin mono-acid monoester derivates 3 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, norcantharidin mono-acid monoester derivates 3 are for the inhibitory activity of three kinds of tumor cells
| Test sample | HEPG2 | BGC803 | SW480 |
| Cantharidin (positive control) | 70.39% | 71.69% | 72.42 |
| DMSO solvent (blank) | 99.91% | 100.21% | 99.61% |
| Compound 3 (R=Et) | 32.71% | ||
| Compound 3 (R=Me) | 64.83% | 52.96% | 59.78% |
| Compound 3 (R=Bn) | 61.04% | 56.26% | 54.51% |
As shown in Table 1, under the at a fairly low activity of 50nmol/L, the present invention synthesizes the norcantharidin list obtained
Acid monoester derivant 3 is to human liver cancer cell HEPG2, gastric carcinoma cells BGC803 and three kinds of tumor cells of Colon Carcinoma
There is preferable inhibition, can use it for preparing above-mentioned three kinds of antineoplastic drug candidates.
Claims (7)
1. a novel norcantharidin mono-acid monoester derivates, its structural formula as shown in Equation 3,
Wherein, R is selected from alkyl or the benzyl of C1-C3.
2. the synthetic method of the norcantharidin mono-acid monoester derivates 3 described in claim 1, including step: 1), 5-alkene nor-
Cantharidin hydrogenating reduction the most in the presence of a catalyst obtains norcantharidin 2,2), norcantharidin 2 is with corresponding
Alcohol (ROH) reaction obtain norcantharidin mono-acid monoester derivates 3；Synthetic route is:
In said synthesis route, in alcohol roh, R group chooses with the choosing of corresponding R group in compound structure shown in above-mentioned formula 3
Identical.
Synthetic method the most according to claim 2, wherein, described step 1) catalyst selected from Pd/C, Pd (OH)2/ C,
The hydrogenation catalysts such as Pt/C or Raney Ni；Described step 1) preferred Pd/C or Pd of catalyst (OH)2/C。
Synthetic method the most according to claim 2, wherein, described step 2) alcohol roh selected from selected from C1-C3 alkyl or
Benzyl；More preferably methanol, ethanol, propanol, isopropanol or benzylalcohol.
Synthetic method the most according to claim 2, wherein, described step 1) the reaction dissolvent of employing be ether solvent,
Halogenated hydrocarbons or alcohols solvent, such as: ether, propyl ether, oxolane, dichloromethane, chloroform, methanol or ethanol.
Synthetic method the most according to claim 2, wherein, described step 2) in the reaction dissolvent that uses can be corresponding
Alcoholic solvent or halogenated hydrocarbon solvent, such as: dichloromethane or chloroform.
7. to be used for preparing hepatocarcinoma, gastric cancer and colon cancer three kinds anti-for the norcantharidin mono-acid monoester derivates 3 described in claim 1
The purposes of tumour medicine.
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| CN111233883A (en) * | 2020-03-17 | 2020-06-05 | 遵义医科大学 | Norcantharidin fluorine-containing benzyl ester salt derivative, synthesis method and anti-tumor application |
| CN111253415A (en) * | 2020-03-17 | 2020-06-09 | 遵义医科大学 | Norcantharidin carboxylic acid trifluorobenzyl ester and synthetic method and application thereof |
| CN111253414A (en) * | 2020-03-17 | 2020-06-09 | 遵义医科大学 | Synthesis of perfluorobenzyl norcantharidinate carboxylate and anti-tumor application thereof |
| CN111269242A (en) * | 2020-03-17 | 2020-06-12 | 遵义医科大学 | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof |
| CN111303179A (en) * | 2020-03-17 | 2020-06-19 | 遵义医科大学 | Synthesis of norcantharidin carboxylic acid difluoro benzyl ester and anti-tumor application thereof |
| CN111362962A (en) * | 2020-03-17 | 2020-07-03 | 遵义医科大学 | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof |
| CN112300187A (en) * | 2019-07-25 | 2021-02-02 | 贵州柏强制药有限公司 | Cantharidin derivative, pharmaceutical composition and application thereof |
| CN113620969A (en) * | 2020-05-07 | 2021-11-09 | 贵州医科大学 | Cyclohexane dicarboxylic acid derivative with bridged ring, and pharmaceutical composition and application thereof |
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| CN111233883A (en) * | 2020-03-17 | 2020-06-05 | 遵义医科大学 | Norcantharidin fluorine-containing benzyl ester salt derivative, synthesis method and anti-tumor application |
| CN111253415A (en) * | 2020-03-17 | 2020-06-09 | 遵义医科大学 | Norcantharidin carboxylic acid trifluorobenzyl ester and synthetic method and application thereof |
| CN111253414A (en) * | 2020-03-17 | 2020-06-09 | 遵义医科大学 | Synthesis of perfluorobenzyl norcantharidinate carboxylate and anti-tumor application thereof |
| CN111269242A (en) * | 2020-03-17 | 2020-06-12 | 遵义医科大学 | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof |
| CN111303179A (en) * | 2020-03-17 | 2020-06-19 | 遵义医科大学 | Synthesis of norcantharidin carboxylic acid difluoro benzyl ester and anti-tumor application thereof |
| CN111362962A (en) * | 2020-03-17 | 2020-07-03 | 遵义医科大学 | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof |
| CN111253415B (en) * | 2020-03-17 | 2022-08-09 | 遵义医科大学 | Norcantharidin carboxylic acid trifluoro benzyl ester and synthetic method and application thereof |
| CN111303179B (en) * | 2020-03-17 | 2022-12-02 | 遵义医科大学 | Synthesis of norcantharidin carboxylic acid difluoro benzyl ester and anti-tumor application thereof |
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Application publication date: 20161109 |
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