CN105949214A - Sodium demethylcantharide derivatives and antitumor application thereof - Google Patents
Sodium demethylcantharide derivatives and antitumor application thereof Download PDFInfo
- Publication number
- CN105949214A CN105949214A CN201610451349.6A CN201610451349A CN105949214A CN 105949214 A CN105949214 A CN 105949214A CN 201610451349 A CN201610451349 A CN 201610451349A CN 105949214 A CN105949214 A CN 105949214A
- Authority
- CN
- China
- Prior art keywords
- norcantharidin
- sodium salt
- acid sodium
- mono
- alkene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D493/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides sodium demethylcantharide derivatives of which the structural formula is disclosed as Formula 7. The activity test proves that the designed and synthesized sodium demethylcantharide derivatives 7 have favorable inhibiting activities for liver cancer, stomach cancer and colon cancer, and thus, are hopeful to be used for preparing antitumor drugs for liver cancer, stomach cancer and colon cancer.
Description
Technical field
The invention belongs to new drug design and synthesis field, be specifically related to a class novel norcantharidin mono-acid sodium salt derivative
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 the norcantharidin mono-acid sodium salt derivative 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 sodium salt 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 sodium salt derivative, its structural formula such as formula 7 institute
Show,
On the other hand, the invention provides the synthetic method of norcantharidin mono-acid sodium salt derivative 7 as above, bag
Include following steps: 1), 5-alkene norcantharidin 1 reacts with benzylalcohol and obtains 5-alkene norcantharidin mono-acid benzyl ester 5,2), 5-alkene goes
Norcantharidin mono-acid benzyl ester 5 is reacted with sodium hydrate aqueous solution and is obtained 5-alkene norcantharidin mono-acid sodium salt 6,3), go to 5-alkene
Norcantharidin mono-acid sodium salt 6 hydrogenating reduction the most in the presence of a catalyst obtains norcantharidin mono-acid sodium salt 7；Close
One-tenth route is:
In above-mentioned synthetic method, described step 3) 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, 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 3)
Use reaction dissolvent be ether solvent, halogenated hydrocarbons or alcohols solvent, such as: methanol, ethanol, propanol, ethyl acetate, ether,
Propyl ether, oxolane, dichloromethane or chloroform etc.；It is furthermore preferred that described step 3) the reaction dissolvent of employing be methanol, second
Alcohol, propanol, ethyl acetate or oxolane.
Active testing proves, the present invention designs and synthesizes the norcantharidin mono-acid sodium salt derivative 7 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 sodium salt derivative 7 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,
Asking, DMF is abbreviated as DMF, dimethyl sulfoxide is abbreviated as DMSO；DMAP is abbreviated as DMAP and is existed
In synthetic example, M represents mol/L, and molecular weight is abbreviated as FW.
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, maleic anhydride, furan, oxolane, the reaction reagent such as dichloromethane
And organic solvent is all from Shanghai traditional Chinese medicines group.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 2.5-alkene nor-Cantharidin mono-acid benzyl ester 5
Step: weigh 5-alkene norcantharidin 3g (C8H6O4, 18.06mmol), it is dissolved in dichloromethane 30ml, adds
2.81ml benzylalcohol (27.09mmol, 1.5e.q.) and DMAP 220.63g (18.06mmol, 0.1equ.), stirring reaction under room temperature
3 days, reaction terminated to occur in rear solvent white solid product, sucking filtration, vacuum drying, obtains 5-alkene nor-Cantharidin mono-acid benzyl ester 5
Solid product 2.538g, productivity is 51.24%,1HNMR(DMSO-d6): δ: 12.43 (s, 1H), 7.31-7.35 (m, 5H),
6.43 (d, J=4Hz, 2H), 4.92-5.10 (m, 4H), 2.76 (t, J=8Hz, 2H).13CNMR(DMSO-d6), δ: 173.07,
171.93,137.15,136.97,128.79,128.40,80.49,80.15,66.30,47.14,46.41.
The preparation of embodiment 3.5-alkene norcantharidin benzyl ester sodium salt 6
Step: take 5-alkene nor-Cantharidin mono-acid benzyl ester 1g (C15H14O5, 3.65mmol), it is dissolved in 35ml methanol, adds hydrogen
Sodium oxide 153mg (3.83mmol), stirring reaction under room temperature, after reaction terminates, removal of solvent under reduced pressure, with methanol for eluent mistake
Silicagel column, puts plate, collects colour developing sample, and rotation is evaporated dry, obtains solid product 1.075g (296.4), and productivity is 99%, Rf=
0.71 (developing solvent is petroleum ether: ethyl acetate=3: 1),1HNMR(D2O): δ: 7.25-7.28 (m, 5H), 6.30 (d, J=
36Hz, 2H), 4.90 (dd, J=12Hz, 12Hz, 4H), 2.64 (dd, J=8Hz, 4Hz, 2H).13CNMR(D2O): δ: 178.71,
175.11,137.03,135.38,128.62,128.37,128.27,81.02,79.74,67.12,49.64,46.10.
The preparation of embodiment 4. norcantharidin mono-acid sodium salt 7
Take 5-alkene norcantharidin benzyl ester sodium salt 615.8mg (C15H13NaO5, FW296.25,2.08mmol), add 5ml first
Alcohol 40ml water makes it dissolve, and adds 61.58mg palladium carbon, and vacuum removes air in flask, is passed through hydrogen, stirring reaction under room temperature,
Reaction terminates rear sucking filtration and removes palladium carbon, removal of solvent under reduced pressure, is dried, obtains product 242.5mg, and productivity is 56.05%,1HNMR
(CD3OD)+D2O: δ: 4.65 (s, 2H), 2.81 (s, 2H), 1.50 (dd, J=8Hz, 4Hz, 2H).
The anti-tumor activity test of experimental example 5. norcantharidin mono-acid sodium salt 7
Cell strain and solvent
Human liver cancer cell HEPG2,
Gastric carcinoma cells BGC803,
Human colon cancer cell SW480,
Human pancreatic cancer cell PANK-1,
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 sodium salt derivative 7 of 50nnmol/mL is to hepatocarcinoma cell line HEPG2, gastric carcinoma cells BGC803, colon cancer
The inhibitory activity test of three kinds of tumor cells of cell SW480 and human pancreatic cancer cell PANK-1.
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 human colon cancer cell SW480 tumor cell.
Experimental result refers to table 1.
Table 1, norcantharidin mono-acid sodium salt derivative 7 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) | 99.78% | 99.21% | 100.61% |
| Compound 7 (R=Me, M=Na) | 38.98% | 47.31% | 62.86% |
As shown in Table 1, under the at a fairly low activity of 50nmol/L, the present invention synthesizes the norcantharidin list obtained
Acid sodium-salt derivant 7 is thin to human liver cancer cell HEPG2, gastric carcinoma cells BGC803 and tri-kinds of tumors of human colon cancer cell SW480
Born of the same parents have certain inhibition, can use it for preparing the drug candidate of anti-liver cancer and anti-.
Claims (7)
1. a norcantharidin mono-acid sodium salt derivative, its structural formula as shown in Equation 7,
2. the synthetic method of norcantharidin mono-acid sodium salt derivative 7 as claimed in claim 1, comprises the following steps: 1), 5-
Alkene norcantharidin 1 and benzylalcohol react and obtain 5-alkene norcantharidin mono-acid benzyl ester 5,2), 5-alkene norcantharidin mono-acid benzyl ester 5
React with sodium hydrate aqueous solution and obtain 5-alkene norcantharidin mono-acid sodium salt 6,3), to 5-alkene norcantharidin mono-acid sodium salt 6
Hydrogenating reduction obtains norcantharidin mono-acid sodium salt 7 the most in the presence of a catalyst；Synthetic route is:
。
3. synthetic method as claimed in claim 2, it is characterised in that described step 3) catalyst selected from including Pd/C, Pd
(OH)2/ C, Pt/C or Raney Ni etc. are at interior hydrogenation catalyst；Described step 1) preferred Pd/C or Pd of catalyst (OH)2/
C。
4. synthetic method as claimed in claim 5, it is characterised in that described step 3) catalyst select Pd/C or Pd (OH)2/
C。
5. the synthetic method as described in claim 2-4 any one, it is characterised in that described step 3) the reaction of employing molten
Agent is alcohols solvent, esters solvent, ether solvent or halogenated hydrocarbons.
6. synthetic method as claimed in claim 5, it is characterised in that described step 3) the reaction dissolvent of employing be methanol,
Ethanol, propanol, ethyl acetate or oxolane.
7. to be used for preparing hepatocarcinoma, gastric cancer and colon cancer three kinds anti-for the norcantharidin mono-acid sodium salt derivative 7 described in claim 1
The purposes of tumour medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610451349.6A CN105949214B (en) | 2016-06-21 | 2016-06-21 | Norcantharidin mono-acid sodium salt derivative and its antitumor application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610451349.6A CN105949214B (en) | 2016-06-21 | 2016-06-21 | Norcantharidin mono-acid sodium salt derivative and its antitumor application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105949214A true CN105949214A (en) | 2016-09-21 |
| CN105949214B CN105949214B (en) | 2018-10-16 |
Family
ID=56906946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610451349.6A Active CN105949214B (en) | 2016-06-21 | 2016-06-21 | Norcantharidin mono-acid sodium salt derivative and its antitumor application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105949214B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 2016-06-21 CN CN201610451349.6A patent/CN105949214B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105949214B (en) | 2018-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106083879A (en) | Norcantharidin mono-acid monoester derivates and antitumor application thereof | |
| CN100540548C (en) | Synthesizing of dehydrophenylahistin and analogue thereof and dehydrophenylahistin and analogue thereof | |
| CN106749494B (en) | With the active α of tumor drug resistance reversal-hederagenin derivative and its preparation method and application | |
| CN105399757A (en) | Acid-sensitive camptothecin-site 20 norcantharidate derivative and antineoplastic application thereof | |
| CN108727329B (en) | N-hydroxyethyl formamido substituted dibenzoxanthene and application thereof | |
| CN105949214A (en) | Sodium demethylcantharide derivatives and antitumor application thereof | |
| CN106008546A (en) | Norcantharidin monoester salt derivative and anti-tumor application thereof | |
| CN107226826A (en) | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition | |
| CN105968064B (en) | Two tolyl tetrazine diformamide compounds of one kind and preparation and application | |
| CN106117236A (en) | Unsaturated norcantharidin benzyl ester barium salt and antitumor application thereof | |
| CN108690033B (en) | Fluorescent probe containing flavonoid drug active molecules and preparation method and application thereof | |
| CN109336940A (en) | Acridone derivatives and its preparation method and application of the one kind containing galactolipin | |
| CN106243114B (en) | Molecular targeted azepine aromatic rings axial substituted phthalocyanine complex and preparation method | |
| CN115260053A (en) | Compound with antitumor activity and preparation method and application thereof | |
| CN111362962B (en) | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof | |
| CN111362873B (en) | Synthetic method of gatifloxacin metabolite | |
| CN106083877A (en) | Unsaturated norcantharidin methyl ester barium salt and antitumor application thereof | |
| CN103435560A (en) | Synthesis and application of aceanthrylene [1,2-b] quinoxaline derivative with flexible side chain | |
| CN108014113A (en) | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
| CN106008545A (en) | Composite norcantharidin salt derivative and anti-tumor application thereof | |
| CN106083878A (en) | 5,6 pairs of dehydrogenation norcantharidin ethyl ester barium salt derivants and antitumor application thereof | |
| CN110003291B (en) | Fluoro glycosyl modified taxol compound and synthesis method and application thereof | |
| CN101633655A (en) | Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof | |
| CN111269242A (en) | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof | |
| CN115304605B (en) | Oxetane derivatives with antitumor activity, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |