CN107445903A - A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method - Google Patents
A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method Download PDFInfo
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- CN107445903A CN107445903A CN201710598887.2A CN201710598887A CN107445903A CN 107445903 A CN107445903 A CN 107445903A CN 201710598887 A CN201710598887 A CN 201710598887A CN 107445903 A CN107445903 A CN 107445903A
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- licochalcone
- melbine
- synthetic method
- cyclized derivative
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- 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
Abstract
A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method.Such compound is reacted using licochalcone A and melbine as raw material in the case where absolute ethyl alcohol is as solvent, has synthesized a kind of licochalcone A for having no report and melbine cyclized derivative.This method processing safety is high, and reaction condition is gentle, suitable for industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of licochalcone A and diformazan with antitumor activity
Biguanide derivative and its synthetic method.
Background technology
To the health of the mankind, find the small antineoplastic of effective, safety, toxic side effect is always serious threat tumour
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, there is very big Development volue in field of medicaments.But licochalcone A is
The strong molecule of flatness, its water solubility are very poor.So strengthen the water of licochalcone A by reasonable, safe structural modification
Dissolubility, more bioactivity of natural products licochalcone A are developed, turn into urgent problem to be solved in its practical application.
Pyrimidine ring is the core texture unit in many native compounds and synthetic drug, as one in heterocyclic compound
Individual important branch, pyrimidines because its have efficiently, low toxicity and ring substituents can multi-party bit map the characteristics of,
And it is 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.
Melbine is the medicine for being most commonly used for treating type ii diabetes, and it also has in addition to it can reduce blood glucose
Anticancer property.However, conventional therapeutic dose is not enough to effectively tackle cancer.Therefore, the present invention is with licochalcone A and two
First biguanides is raw material, and design synthesizes a kind of novel licochalcone A pyrimidine compound of structure, by the structure fragment of melbine
It is introduced into pyrimidine ring in the chemical constitution of licochalcone A, the anti-tumor biological of licochalcone A can be strengthened, is improved
To tumor cells selectivity, there is important application value.
The content of the invention
In order to overcome the deficiency above of prior art, it is an object of the invention to provide a kind of radix glycyrrhizae with antitumor activity
Chalcone A and melbine cyclized derivative and its synthetic method.The present invention has raw material environmental protection, and production cost is low, operation peace
Quan Xinggao, reaction condition is gentle, and reaction raw materials, suitable for industrialized production, solve prior art low yield using fully
Problem.
To achieve these goals, the technical scheme is that：
A kind of licochalcone A with antitumor activity and melbine cyclized derivative, it is characterised in that compound
Structure (I) it is as follows：
The synthetic method of a kind of licochalcone A with antitumor activity and melbine cyclized derivative, its feature
It is, uses licochalcone A and melbine, with ethanol as solvent, to be synthesized for raw material under conditions of being heated to reflux,
Its synthetic route is as follows：
It is detailed preparation process below：
1) licochalcone A and melbine are put into reactor in proportion, mol ratio 1:1~1:1.5, add appropriate
Organic solvent mixes, and adds proper catalyst after well mixed, is stirred and heated to 70 DEG C~85 DEG C, back flow reaction 3~6 hours；
2) thin-layered chromatography following response progress is used, question response stops heating, removes condensing unit afterwards completely；
3) solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, through column chromatographic isolation and purification, is dried to obtain structural formula
(I) compound.
Raw material molar ratio in the step 1) is 1:1~1:1.5, preferred molar ratio 1:1~1:1.3.
Catalyst in the step 1) is triethylamine.
Organic solvent in the step 1) is absolute ethyl alcohol.
Temperature in the step 1) is 70 DEG C~85 DEG C, preferably 70 DEG C~75 DEG C.
Reaction time in the step 1) is 3~6 hours, preferably 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 99.24mg melbine are added in the reactor, add 50ml absolute ethyl alcohols to react
Solvent, 0.5mL triethylamines are added to be placed on magnetic stirring apparatus and stir, be heated to 75 DEG C with electric jacket, back flow reaction as catalyst
5 hours.Thin-layered chromatography following response, after reaction terminates, after the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, cross post
Chromatography purifies, and is dried to obtain yellow crystalline powder (124.46mg), total recovery 46.84%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):9.72(2H,s),7.89(1H,s),7.80
(2H, d, J=7.52Hz), 7.22 (1H, s), 6.82 (2H, d, J=7.52Hz), 6.46 (1H, s), 6.30 (1H, m), 5.00-
4.96(2H,m),3.79(3H,s),2.85(6H,s),2.80(1H,m),2.67-2.33(2H,m),2.05(1H,s),1.44
(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):164.6,160.8,158.5,155.9,153.9,147.9,
133.8,129.0,128.5,125.0,118.0,116.4,110.1,101.9,56.6,47.5,40.1,39.9,39.3,
28.2.MS(ESI)for(M+H)+:450.3.
Embodiment 2
The antitumor activity test of the compounds of this invention.
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, 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 melbine 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 are placed in, 5%CO2, cultivate in the CO2gas incubator of saturated humidity.
Cell attachment is grown, and passes on 1 time within every 2~3 days, pours out nutrient solution first during passage, and PBS is washed 2 times, after pancreatin digestion, is added 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 bluish violet product not soluble in water 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, 96 well culture plates are inoculated in 2 × 104/mL density
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 acts 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), continue culture 4 hours, abandon supernatant, 100 μ l DMSO are added per hole, 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 melbine is shown in the 5 kinds of cell lines tested
Good antitumor activity, above test result indicates that, compound of the invention (I) has good antitumor activity, special
Be not it is preferable to human liver cancer cell (HepG2), and human cervical carcinoma cell (Hela) inhibition, its antitumor activity be equal to Ah
Sugared cytidine.
Claims (7)
1. a kind of licochalcone A with antitumor activity and melbine cyclized derivative, it is characterised in that the compound
Structure is following (I)：
2. the synthetic method of a kind of licochalcone A with antitumor activity and melbine cyclized derivative, its feature exist
In：Using licochalcone A and melbine as raw material, reacted under conditions of absolute ethyl alcohol is as reaction dissolvent, it is closed
It is as follows into route：
Specific synthesis step is as follows：
1) licochalcone A and melbine are put into reactor in proportion, mol ratio 1:1~1:1.5, add appropriate organic
Solvent mixes, and adds proper catalyst after well mixed, is stirred and heated to 70 DEG C~85 DEG C, back flow reaction 3~6 hours；
2) thin-layered chromatography following response progress is used, question response stops heating, removes condensing unit afterwards completely；
3) solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, through column chromatographic isolation and purification, is dried to obtain structural formula (I) change
Compound.
3. the synthetic method of licochalcone A according to claim 2 and melbine cyclized derivative, its feature exist
In the raw material molar ratio in the step 1) is 1:1~1:1.5.
4. the synthetic method of licochalcone A according to claim 2 and melbine cyclized derivative, its feature exist
In the catalyst in the step 1) is triethylamine.
5. the synthetic method of licochalcone A according to claim 2 and melbine cyclized derivative, its feature exist
In the organic solvent in the step 1) is absolute ethyl alcohol.
6. the synthetic method of licochalcone A according to claim 2 and melbine cyclized derivative, its feature exist
In the temperature in the step 1) is 70 DEG C~85 DEG C.
7. the synthetic method of licochalcone A according to claim 2 and melbine cyclized derivative, its feature exist
In the reaction time in the step 1) is 3~6 hours.
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| CN2017101033896 | 2017-02-24 |
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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 CN201710598887.2A patent/CN107445903A/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.》 * |
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