CN107235915A - A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method - Google Patents
A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method Download PDFInfo
- Publication number
- CN107235915A CN107235915A CN201710598886.8A CN201710598886A CN107235915A CN 107235915 A CN107235915 A CN 107235915A CN 201710598886 A CN201710598886 A CN 201710598886A CN 107235915 A CN107235915 A CN 107235915A
- Authority
- CN
- China
- Prior art keywords
- licochalcone
- buformin
- synthetic method
- cyclized derivative
- antitumor activity
- 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.)
- Pending
Links
- 0 CCCC*C(CNC(N)=N)=N Chemical compound CCCC*C(CNC(N)=N)=N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method.Such compound is reacted as under solvent in absolute ethyl alcohol using licochalcone A, buformin as raw material, has synthesized a kind of licochalcone A for having no report and buformin cyclized derivative.This method processing safety is high, and reaction condition is gentle, it is adaptable to industrialized production.Show that the type compound has preferable antitumor activity through preliminary biological activity test, be worth with important medical applications.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of licochalcone A with antitumor activity and fourth good fortune
Bright cyclized derivative and its synthetic method.
Background technology
Tumour has seriously threatened the health of the mankind, finds the small antineoplastic of effective, safety, toxic side effect and is always
The target that tumour medicine R＆D worker seek assiduously.Licochalcone A have anti-inflammatory, antibacterial, anti-oxidant, antitumor, lipid-loweringing,
The multiple biological activities such as spasmolysis and antimalarial anti parasitic, have very big Development volue in field of medicaments.But licochalcone A is
The strong molecule of flatness, its water solubility is very poor.So, strengthen the water of licochalcone A by reasonable, safe structural modification
Dissolubility, develops more bioactivity of natural products licochalcone A, as urgent problem to be solved in its practical application.
Pyrimidine ring is the core texture unit in many native compounds and synthetic drug, is used as one in heterocyclic compound
Individual important branch, pyrimidines because its have efficiently, low toxicity and ring substituents can in many ways bit map the characteristics of,
And be used widely in drug field.In recent years, a series of pyridine derivatives for synthesizing different base group modifications enter to sieve
Medicine of the choosing with efficient bio-active, is one of study hotspot of numerous scientific research personnel.
Buformin is common hypoglycemic drug, and it can not only reduce blood glucose, also with anticancer property.However, conventional
Therapeutic dose is not enough to effectively tackle cancer.Therefore, the present invention is using licochalcone A and buformin as raw material, design synthesis
A kind of novel licochalcone A pyrimidine compound of structure, licochalcone A is introduced by the structure fragment of buformin and pyrimidine ring
Chemical constitution in, can strengthen the anti-tumor biological of licochalcone A, improve to tumor cells selectivity, with weight
The application value wanted.
The content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, it is an object of the invention to provide a kind of radix glycyrrhizae with antitumor activity
Chalcone A and buformin cyclized derivative and its synthetic method.The present invention has raw material environmental protection, and production cost is low, safe operation
Property it is high, reaction condition is gentle, reaction raw materials using it is abundant the characteristics of, the problem of solving prior art low yield.
To achieve these goals, the technical solution adopted by the present invention is：
A kind of licochalcone A with antitumor activity and buformin cyclized derivative, it is characterised in that the compound
Structural formula (I) is as follows：
A kind of synthetic method of licochalcone A with antitumor activity and buformin cyclized derivative, its feature exists
In, it is raw material by licochalcone A and insoral, is synthesized under conditions of absolute ethyl alcohol is as reaction dissolvent, its conjunction
It is as follows into route：
It is detailed preparation process below：
1) licochalcone A and buformin are put into reactor in proportion, mol ratio is 1:1~1:1.5, plus have in right amount
Machine solvent, adds proper catalyst after being well mixed, is stirred and heated to 70 DEG C~85 DEG C, back flow reaction 3~6 hours；
2) follow the trail of complete to reaction using thin-layered chromatography, stop heating, remove condensing unit；
3) through column chromatography for separation, purifying after the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, it is dried to obtain structure
Formula (I) compound.
Described step 1) in licochalcone A and buformin mol ratio be 1:1~1:1.5, preferred molar ratio is 1:1
~1:1.3.
Described step 1) in catalyst be triethylamine.
Described step 1) in organic solvent be absolute ethyl alcohol.
Described step 1) in temperature 70 C~85 DEG C, preferable temperature be 70 DEG C~75 DEG C.
Described step 1) in reaction time be 3~6 hours, preferred reaction time be 4~5 hours.
Embodiment
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.
Embodiment 1
3- (4- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -6- (4- hydroxy phenyls) -4,5-
Dihydro-pyrimidin -2- bases) -1,1- dimethylguanidines preparation.
200mg licochalcone As and 120.80mg buformins are added in the reactor, plus 50ml absolute ethyl alcohols are made to react molten
Agent, plus 0.5mL triethylamines are as catalyst, are placed on magnetic stirring apparatus and stir, 75 DEG C, back flow reaction 5 are heated to electric jacket
Hour.Thin-layered chromatography following response, after reaction terminates, the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, and crosses post layer
Separating-purifying is analysed, yellow crystalline powder 125.00mg, total recovery 44.28% is dried to obtain.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):9.71(2H,s),7.90(1H,s),7.80
(2H, d, J=7.52Hz), 7.20 (1H, s), 6.85 (2H, d, J=7.46Hz), 6.46 (1H, s), 6.30 (1H, m, J=
8.02Hz), 5.00-4.98 (2H, m, J=8.02Hz), 3.77 (3H, s), 3.60 (2H, t, J=7.52Hz), 3.02 (1H, m, J
=7.94Hz), 2.65~2.33 (3H, m, J=7.46Hz), 2.04 (1H, s), 1.49 (2H, m, J=7.94Hz), 1.44 (6H,
S), 1.31 (2H, m, J=8.02Hz), 0.99 (3H, m)；13C NMR(100MHz,DMSO-d6)δ(ppm):165.3,161.4,
160.1,155.0,153.0,147.8,133.0,129.0,125.9,118.0,116.9,110.1,101.9,56.6,47.2,
42.3,40.2,40.9,32.7,28.0,20.0,13.5.MS(ESI)for(M+H)+:478.3.
Embodiment 2
The antitumor activity test of the compounds of this invention.
Compound to the present invention has carried out Cytostatic to tumor cell experiment, and test method is using conventional mtt assay.
Cell line is selected：Human liver cancer cell (HepG2), human lung carcinoma cell (A-549), human cervical carcinoma cell (Hela), people
Stomach cancer cell (SGC-7901), human colon cancer cell (HCT-8).Nutrient solution is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：After being dissolved with DMSO (Merck), add 100 μm of ol/L solution that PBS (-) is made into or
Uniform suspension, then with DMSO PBS (-) dilution, ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ
mol/L。
Sample refers to the derivative (I) of the licochalcone A and buformin prepared in corresponding embodiment.
The antineoplastic cytarabine (Ara-C) of listing is made into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell is incubated at containing 10% inactivation NBCS and penicillin, strepto-
In the 1640 culture medium of plain (each 1,000,000 U/L), 37 DEG C, 5%CO are placed in2, cultivate in the CO2gas incubator of saturated humidity.
Cell attachment grows, and passes on 1 time within every 2~3 days, pours out nutrient solution during passage first, PBS is washed 2 times, after pancreatin digestion, adds new
Fresh nutrient solution piping and druming is uniform, and adjustment cell to debita spissitudo is moved into new blake bottle, and addition nutrient solution is to appropriate.Take the logarithm
Growth period cell is used to test.
Mtt assay detects cytoactive and IC50Measure：
Experimental principle：The MTT of yellow can be reduced into water insoluble bluish violet product by dehydrogenase in living cells mitochondria
Formazan (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell is not this
Function.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the light absorbs determined with ELIASA
Value can reflect cell survival rate.
Experimental method：Take the logarithm growth period cell, digestion, count, with 2 × 104/ mL density is inoculated in 96 well culture plates
In, per the μ l of hole 100.Culture 24 hours after, by testing compound with 0.1,1,10,20,40,60,80,100 μm of ol/L concentration at
Manage cell.The each concentration of experimental group sets 5 multiple holes, is compared with the nutrient solution containing 0.4%DMSO.After medicine is acted on 48 hours,
Supernatant is removed, 100 μ l MTT (2- (4,5- dimethyl -2- thiazolyls) -3,5- diphenyl -2H- tetrazoliums hydrobromate) are added per hole
(1mg/mL), continues to cultivate 4 hours, abandons supernatant, and 100 μ l DMSO are added per hole, and vibration is mixed, surveyed with ELIASA at 570nm
Absorbance is determined, using IC50Software for calculation obtains half-inhibition concentration (IC50), result of the test refers to table 1, and table 1 is compound
To the half-inhibition concentration IC of different tumour cells50(unit：μmol/L).
Table 1
According to table 1, the derivative (I) of licochalcone A and buformin is shown in the 5 kinds of cell lines tested
Good antitumor activity, above test result indicates that, compound (I) of the invention has good antitumor activity, especially
It is that to human liver cancer cell (HepG2), and human cervical carcinoma cell (Hela) inhibition is preferably, its antitumor activity is close to arabinose born of the same parents
Glycosides.
Claims (7)
1. a kind of licochalcone A with antitumor activity and buformin cyclized derivative, it is characterised in that the compound knot
Structure formula is following (I)：
2. the synthetic method of a kind of licochalcone A with antitumor activity and buformin cyclized derivative, it is characterised in that：
It is raw material by licochalcone A and buformin, is reacted under conditions of organic solvent is as reaction dissolvent, its synthetic route
It is as follows：
In order to realize said synthesis route, synthesis step of the invention is as follows：
1) licochalcone A and buformin are put into reactor in proportion, mol ratio is 1:1~1:1.5, plus it is appropriate organic molten
Agent is mixed, and is added proper catalyst after being well mixed, is stirred and heated to 70 DEG C~85 DEG C, back flow reaction 3~6 hours；
2) follow the trail of complete to reaction using thin-layered chromatography, stop heating, remove condensing unit；
3) through column chromatography for separation, purifying after the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, it is dried to obtain structural formula (I)
Compound.
3. the synthetic method of licochalcone A according to claim 2 and buformin cyclized derivative, it is characterised in that：
The step 1) in raw material molar ratio be 1:1~1:1.5.
4. the synthetic method of licochalcone A according to claim 2 and buformin cyclized derivative, it is characterised in that：
The step 1) in catalyst be triethylamine.
5. the synthetic method of licochalcone A according to claim 2 and buformin cyclized derivative, it is characterised in that：
The step 1) in organic solvent be absolute ethyl alcohol.
6. the synthetic method of licochalcone A according to claim 2 and buformin cyclized derivative, it is characterised in that：
The step 1) in reaction temperature be 70 DEG C~85 DEG C.
7. the synthetic method of licochalcone A according to claim 2 and buformin cyclized derivative, it is characterised in that：
The step 1) in reaction time be 3~6 hours.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710104410 | 2017-02-24 | ||
| CN2017101044104 | 2017-02-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107235915A true CN107235915A (en) | 2017-10-10 |
Family
ID=59988062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710598886.8A Pending CN107235915A (en) | 2017-02-24 | 2017-07-21 | A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107235915A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632074A (en) * | 2016-12-31 | 2017-05-10 | 陕西科技大学 | Licochalcone A dihydropyrimidine compound with antitumor activity and synthesizing method thereof |
| CN106632043A (en) * | 2016-12-31 | 2017-05-10 | 陕西科技大学 | Licochalcone A pyrazoline derivatives with antitumor activity and synthesis method thereof |
| CN106674128A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
| CN106674115A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A dihydropyrazolamide compounds with antineoplastic activity and synthetic method thereof |
| CN106674129A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A dihydro-amino miazines compound with antitumor activity and synthetic method of licochalcone A dihydro-amino miazines compound |
-
2017
- 2017-07-21 CN CN201710598886.8A patent/CN107235915A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632074A (en) * | 2016-12-31 | 2017-05-10 | 陕西科技大学 | Licochalcone A dihydropyrimidine compound with antitumor activity and synthesizing method thereof |
| CN106632043A (en) * | 2016-12-31 | 2017-05-10 | 陕西科技大学 | Licochalcone A pyrazoline derivatives with antitumor activity and synthesis method thereof |
| CN106674128A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
| CN106674115A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A dihydropyrazolamide compounds with antineoplastic activity and synthetic method thereof |
| CN106674129A (en) * | 2016-12-31 | 2017-05-17 | 陕西科技大学 | Licochalcone A dihydro-amino miazines compound with antitumor activity and synthetic method of licochalcone A dihydro-amino miazines compound |
Non-Patent Citations (2)
| Title |
|---|
| M. SRINIVAS，等: "Microwave Mediated Synthesis And Evaluation Of Some Novel Pyrimidines For Antimicrobial Activity", 《INTERNATIONAL JOURNAL OF PHARMTECH RESEARCH》 * |
| S.A. F. ROSTOM,等: "Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents", 《ARCH. PHARM. CHEM. LIFE SCI.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107235902A (en) | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity | |
| CN108610348A (en) | A kind of simultaneously [2,3-b] pyridine -3- carbonitrile derivatives and its preparation and application of the 5H- chromenes containing imidazole substituent | |
| CN107235916A (en) | A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity | |
| CN107311937A (en) | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity | |
| CN106432259A (en) | Bergenin derivative and synthetic method and application thereof | |
| CN107540658A (en) | A kind of lappaconitine azepine cinnamic acid heterozygote and its synthetic method for having antitumor activity | |
| CN107235917A (en) | The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity | |
| CN107417580A (en) | One kind has the gossypol L arginine Schiff bases compounds and its synthetic method of antitumor activity | |
| CN107382864A (en) | A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity | |
| CN108727329A (en) | N- hydroxyethyl formamide base substituted diphenylamines and xanthene and its application | |
| CN107573318A (en) | A kind of new gossypol Schiff bases derivative and its synthetic method for having antitumor activity | |
| CN103435560B (en) | Synthesis and application of aceanthrylene [1,2-b] quinoxaline derivative with flexible side chain | |
| CN107235915A (en) | A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method | |
| CN107253949A (en) | One class thia Rutaecarpine compound and its application in antineoplastic | |
| CN106565657A (en) | Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof | |
| CN113444095A (en) | Triazine substituted imidazole compound and preparation method and application thereof | |
| CN107445903A (en) | A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method | |
| CN113603694A (en) | 1, 2-diketone compound and preparation method and application thereof | |
| CN107311936A (en) | A kind of licochalcone A with antitumor activity and insoral cyclized derivative and its synthetic method | |
| CN108484623B (en) | Camptothecin derivative and preparation method and application thereof | |
| CN104230786B (en) | Indole-structure-containing compound with anti-tumor activity and synthesis method thereof | |
| CN103435574B (en) | Mercapto benzothiazole substituent acenaphtho-heterocycle compound and application thereof | |
| CN107857766A (en) | A kind of synthetic method of spiral Benzazole compounds based on phenylalanine and more carbonyl class cyclic ketone compounds and its application | |
| CN108358898B (en) | Para-naphthoquinone derivative with anticancer activity and synthesis method thereof | |
| CN106632322A (en) | Pyrazol purrocoline compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171010 |
|
| WD01 | Invention patent application deemed withdrawn after publication |