CN107382864A - A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity - Google Patents

A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity Download PDF

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CN107382864A
CN107382864A CN201710650031.5A CN201710650031A CN107382864A CN 107382864 A CN107382864 A CN 107382864A CN 201710650031 A CN201710650031 A CN 201710650031A CN 107382864 A CN107382864 A CN 107382864A
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licochalcone
synthetic method
compound
amino
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梁承远
鞠伟会
田丹妮
贾敏
贾敏一
裴少萌
田蕾
丁顺军
刘柯
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Shaanxi University of Science and Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

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Abstract

The invention discloses a kind of licochalcone A pyrazoline Carbox amide and its synthetic method with antitumor activity.Such compound is reacted using licochalcone A, amino carbamide compounds as raw material in the case where toluene is as solvent, has synthesized a kind of licochalcone A pyrazoline Carbox amide for having no report.This method processing safety is high, and reaction condition is gentle, suitable for industrialized production.Show that the type compound has preferable antitumor activity through preliminary biological activity test, the research available for antitumor lead compound.

Description

A kind of licochalcone A pyrazoline Carbox amide for having antitumor activity And its synthetic method
Technical field：
The present invention relates to medicinal chemistry arts, and in particular to one kind has the licochalcone A dihydro pyrrole of antitumor activity Azoles Carbox amide and its synthetic method.
Background technology：
To the health of the mankind, find the small antineoplastic of effective and safe, toxic side effect is always serious threat tumour The target that tumour medicine R＆D worker seek assiduously.With pharmaceutical chemical development, the chemical combination using pyrazole ring as structure parent nucleus Effect of the thing in oncotherapy causes extensive concern.
Licochalcone A is considered as the species specificity composition of swollen fruit Radix, and its structure is as follows.
In recent years, research finds that licochalcone A has anti-inflammatory, antibacterial, anti-oxidant, antitumor, lipid-loweringing, spasmolysis and antimalarial The multiple biological activities such as anti parasitic, there is very big Development volue in field of medicaments.But licochalcone A is that flatness is strong Molecule, poorly water-soluble, so, strengthen the water solubility of licochalcone A by reasonable, safe structural modification, exploitation is naturally More bioactivity of product licochalcone A, turn into urgent problem to be solved.
The content of the invention：
It is an object of the present invention to provide a kind of licochalcone A pyrazoline benzamide type with antitumor activity Compound.
The implementation process of the present invention is as follows：
Compound shown in general structure (I)
Wherein：R is hydrogen-based, C1-C4 alkyl, the substituted or unsubstituted phenyl of halogen, amino.
The synthetic method of compound shown in general structure (I), it is characterised in that：By licochalcone A, amino ureas Compound is raw material, is synthesized by catalyst of organic base；
Specifically comprise the following steps：
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A and amino carbamide compounds, add organic Solvent is well mixed, and adds organic alkali catalyst, 80 DEG C~120 DEG C back flow reactions 3~8 hours；
(2) after the solidliquid mixture of step (1) reaction system is concentrated under reduced pressure, column chromatography for separation purification, it is dried to obtain target production Thing.
Licochalcone A described in step (1)：The molar ratio range of amino carbamide compounds is 1:1~1:1.3；Have Solvent is toluene or DMF；Reaction temperature is 105 DEG C~115 DEG C；Organic alkali catalyst is triethylamine.
Pyrazole ring is the core texture unit in many native compounds and synthetic drug, as one in heterocyclic compound Individual important branch, pyrazole compound because its have efficiently, low toxicity, and its ring substituents can with multi-faceted conversion and It is used widely in drug field.Pyrazole ring is introduced into the chemical constitution of licochalcone A, it is living that its biology can be strengthened Property, selectivity is improved, there is important theory value and actual application value.
The advantage of the invention is that：Raw material environmental protection, production cost is low, and processing safety is high, and reaction condition is gentle, can be achieved Reaction raw materials make full use of, and suitable for industrialized production, solve the problems, such as prior art low yield, while pyrazole ring is drawn Enter into the chemical constitution of licochalcone A, to probe into the bioactivity of such compound with summarize structure-activity relationship have it is important Theory value and application value.
Embodiment：
With reference to specific embodiment, the present invention is further elaborated.These embodiments are only in order at the mesh of explanation , and do not limit the scope of the invention and essence.
A kind of synthetic method for the licochalcone A pyrazoline Carbox amide for having antitumor activity specifically includes Following steps：
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone As, amino carbamide compounds, add toluene or DMF is well mixed, and wherein solvent volume is less than the 2/3 of reactor volume, is added organic alkali catalyst triethylamine, is placed in magnetic force and stirs Mix and stirred on device, be heated to 80 DEG C~120 DEG C, back flow reaction 3~8 hours；
(2) followed the trail of, the carry out degree of monitoring reaction in time, stopped after raw material reaction completely using thin-layer chromatography in course of reaction Heating, removes condensing unit；
(3) solidliquid mixture of step (2) reaction system being concentrated under reduced pressure, concentrate crosses column chromatography, obtains target product crude product, Recrystallized added with solvent, filtering, be dried to obtain target product.
Structural formula of compound in certain preferred embodiments of the present invention is as follows：
Embodiment 1
5- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -3- (4- hydroxy phenyls) -4,5- dihydros - The preparation of 1H- pyrazoles -1- formamides (1).
200mg (0.6mmol) licochalcone As and 57.68mg (1.3mmol) semicarbazides are added in the reactor, add 50ml first Benzene and 5mLDMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 100 DEG C, magnetic agitation backflow Reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, it is concentrated under reduced pressure, column chromatography is de- dry to obtain brown ceramic powder (113.41mg), total recovery 48.65%.
Brown crystalline powder solid.1H-NMR(300MHz,DMSO-d6)δ(ppm):8.32(2H,s),7.93(2H,d,J =7.5Hz), 7.04 (1H, s), 6.93 (2H, d, J=7.5Hz), 6.52 (1H, s), 6.41 (1H, m), 5.82 (2H, s), 5.21-5.23 (2H, m, J=2.1Hz), 5.02 (1H, m), 3.93 (3H, d), 3.82 (3H, s), 1.74 (6H, s)；13C-NMR (75MHz,DMSO-d6)δ(ppm):161.8,156.3,155.1,153.7,152.9,147.8,128.1,127.3,124.2, 120.6,115.0,110.1,102.8,64.4,57.1,38.8,26.8；MS(ESI)for(M+H)+:396.2.
Embodiment 2
5- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -3- (4- hydroxy phenyls)-N- phenyl -4,5- The preparation of the formamide of dihydro-1 h-pyrazole -1 (2).
200mg (0.6mmol) licochalcone As and 116.15mg (1.3mmol) N- phenyl Hydrazinecarboxamidederivatives are added in the reactor, Add 50ml toluene and 5mLDMF to make reaction dissolvent, add 0.5mL triethylamines as catalyst, electric jacket is heated to 80 DEG C, magnetic force It is stirred at reflux reaction 3 hours.Thin-layer chromatography following response, after reaction terminates, it is concentrated under reduced pressure, column chromatography is de- dry to obtain brown powder Last (143.58mg), total recovery 51.52%.
Brownish-yellow powder solid.1H-NMR(300MHz,DMSO-d6)δ(ppm):8.05 (1H, s), 7.83 (2H, d, J= 1.5Hz), 7.31-7.34 (4H, m, J=7.5Hz), 6.86 (1H, s), 6.77 (2H, d, J=7.5Hz), 6.45 (1H, s), 6.23 (1H, m), 5.36 (2H, s), 5.11-5.13 (2H, m, J=2.1Hz), 4.76 (1H, m), 3.81 (3H, d), 3.62 (3H, s),1.92(6H,s)；13C-NMR(75MHz,DMSO-d6)δ(ppm):162.8,155.3,154.1,152.7,151.9, 146.8,127.1,126.3,123.2,121.6,114.0,109.1,101.8,66.4,52.1,35.8,20.8；MS(ESI) for(M+H)+:472.2.
Embodiment 3
N- (3- chlorphenyls) -5- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -3- (4- hydroxy benzenes Base) -4,5- dihydro-1 h-pyrazole -1- formamides (3) preparation.
200mg (0.6mmol) licochalcone As and 142.61mg (1.3mmol) N- (3- chlorphenyls) hydrazine are added in the reactor Formamide, add 50ml toluene and 5mLDMF to make reaction dissolvent, add 0.5mL triethylamines and be heated to 100 as catalyst, electric jacket DEG C, magnetic agitation back flow reaction 5 hours.Thin-layer chromatography following response, after reaction terminates, it is concentrated under reduced pressure, column chromatography, takes off dry obtain Brown ceramic powder (125.89mg), total recovery 42.01%.
Brown color crystalline powder solid.1H-NMR(300MHz,DMSO-d6)δ(ppm):8.23(1H,s),8.01(1H, M), 7.88 (2H, d, J=1.5Hz), 7.56-7.59 (3H, m, J=7.5Hz), 6.99 (1H, s), 6.81 (2H, d, J= 7.5Hz), 6.52 (1H, s), 5.44 (2H, s), 5.23-5.26 (2H, m, J=2.1Hz), 4.80 (1H, m), 3.87 (3H, d), 3.66(3H,s),1.73(6H,s)；13C-NMR(75MHz,DMSO-d6)δ(ppm):159.9,154.1,153.7,152.0, 150.9,147.8,136.4,133.5,131.3,128.1,124.2,120.6,117.7,115.0,110.1,102.8,61.4, 55.1,38.8,36.7,18.8；MS(ESI)for(M+H)+:506.2.
Embodiment 4
N- (4- chlorphenyls) -5- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -3- (4- hydroxy benzenes Base) -4,5- dihydro-1 h-pyrazole -1- formamides (4) preparation.
200mg (0.6mmol) licochalcone As and 142.61mg (1.3mmol) N- (4- chlorphenyls) hydrazine are added in the reactor Formamide, add 50ml toluene and 5mLDMF to make reaction dissolvent, add 0.5mL triethylamines and be heated to 120 as catalyst, electric jacket DEG C, magnetic agitation back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, it is concentrated under reduced pressure, column chromatography, takes off dry obtain Brown ceramic powder (146.01mg), total recovery 48.82%.
Yellow powder solid.1H-NMR(300MHz,DMSO-d6)δ(ppm):7.78 (2H, d, J=1.5Hz), 7.59 (2H, M, J=7.5Hz), 6.99 (1H, s), 6.81 (2H, d, J=7.5Hz), 6.63 (2H, d, J=7.5Hz), 6.42 (1H, s), 5.40 (2H, s), 5.33-5.35 (2H, m, J=2.1Hz), 5.13 (1H, s), 4.65 (1H, m), 3.70 (3H, d), 3.51 (3H, s),1.65(6H,s)；13C-NMR(75MHz,DMSO-d6)δ(ppm):161.7,156.2,155.8,154.2,152.8, 149.7,138.6,134.5,130.1,129.2,127.3,126.4,122.0,121.9,117.8,112.5,104.6,63.6, 57.3,38.4,37.2,17.1；MS(ESI)for(M+H)+:522.2.
Embodiment 5
5- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -3- (4- hydroxy phenyls) -4,5- dihydros - The preparation of 1H- pyrazoles -1- thio-hydrazides (5).
200mg (0.6mmol) licochalcone As and 81.55mg (1.3mmol) hydrazine thio-hydrazide are added in the reactor, are added 50ml toluene and 5mLDMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, electric jacket is heated to 115 DEG C, and magnetic force stirs Mix back flow reaction 8 hours.Thin-layer chromatography following response, after reaction terminates, it is concentrated under reduced pressure, column chromatography is de- dry to obtain brown ceramic powder (128.37mg), total recovery 50.92%.
Tan crystalline solid.1H-NMR(300MHz,DMSO-d6)δ(ppm):7.92 (2H, d, J=1.5Hz), 7.21 (1H, s),6.94(2H,d),6.62(1H,s),6.40(1H,m),5.46(2H,s),5.12(2H,d),4.31(1H,s),4.22(2H, s),4.02(3H,m),3.92(3H,s),1.72(6H,s)；13C-NMR(75MHz,DMSO-d6)δ(ppm):182.5,161.8, 154.1,153.7,152.0,150.9,147.8,128.1,127.0,126.2,125.6,115.0,114.1,102.8,66.5, 55.1,42.4,35.8,27.6；MS(ESI)for(M+H)+:427.2.
Embodiment 6
5- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -3- (4- hydroxy phenyls) -4,5- dihydros - The preparation of 1H- pyrazoles -1- carbohydrazides (6).
200mg (0.6mmol) licochalcone As and 69.21mg (1.3mmol) diazanyl hydrazides are added in the reactor, add 50ml Toluene and 5mLDMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 105 DEG C, and magnetic agitation is returned Stream reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, it is concentrated under reduced pressure, column chromatography is de- dry to obtain brown ceramic powder (117.08mg), total recovery 48.26%.
Tan crystalline solid.1H-NMR(300MHz,DMSO-d6)δ(ppm):8.11 (2H, s), 7.87 (2H, d, J= 7.5Hz), 7.09 (1H, s), 6.89 (2H, d, J=7.5Hz), 6.61 (1H, s), 6.31 (1H, m), 5.80 (2H, s), 5.11- 5.14 (2H, m, J=2.1Hz), 4.97 (1H, m), 4.51 (1H, s), 3.85 (3H, d), 3.73 (3H, s), 1.66 (6H, s)；13C-NMR(75MHz,DMSO-d6)δ(ppm):162.6,155.0,153.9,152.1,151.5,147.5,128.3,127.7, 125.8,121.2,115.5,110.4,102.5,69.2,53.8,41.4,37.2,23.2；MS(ESI)for(M+H)+: 411.2.
The antitumor activity test of the compounds of this invention of embodiment 7
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 prostata cancer (PC-3), human gastric adenocarcinoma (SGC-7901), human lung carcinoma cell (A-549).Culture Liquid 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。
Antineoplastic 5 FU 5 fluorouracil (5-FU) 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 Chan Wu formazans not soluble in water by dehydrogenase in living cells mitochondria (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell does not have this work( Energy.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the absorbance value determined with ELIASA Cell survival rate can be reflected.
Experimental method：Take the logarithm growth period cell, digestion, count, with 3 × 105/ 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 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, wherein, sample refers to the licochalcone A pyrazoline first prepared in corresponding embodiment Amide derivatives, sample number into spectrum correspondingly prepare the specific numbering of compound resulting in embodiment.
Half-inhibition concentration IC of the compound of table 1 to different tumour cells50(unit：μmol/L)
The result of table 1 shows that compound 1-6 shows different degrees of antitumor activity in the 3 kinds of cell lines tested, Wherein the activity of compound 1 and 5 preferably, stronger inhibition is presented to cell, antitumor activity is excellent in specific cells strain In or be equal to 5 FU 5 fluorouracil, there is obvious selectivity to different tumor cell lines.To sum up, licochalcone A of the invention Pyrazoline carboxamides derivatives can further carry out preclinical study as antitumor drug candidate, can also be as anti-swollen Knurl lead compound is further studied.

Claims (9)

1. general structure（Ⅰ）Shown compound：
Wherein：R is hydrogen, C1-C4 alkyl, the substituted or unsubstituted phenyl of halogen or amino.
2. general structure（I）The synthetic method of shown compound, it is characterised in that：By licochalcone A, amino carbamide compounds For raw material, synthesized by catalyst of organic base：
。
3. synthetic method according to claim 2, it is characterised in that comprise the following steps：
（1）It is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A and amino carbamide compounds, add organic Solvent is well mixed, and adds organic alkali catalyst, 80 DEG C ~ 120 DEG C back flow reactions 3 ~ 8 hours；
（2）By step（1）After the solidliquid mixture of reaction system is concentrated under reduced pressure, column chromatography for separation purification, target production is dried to obtain Thing.
4. synthetic method according to claim 3, it is characterised in that：Step（1）Described in licochalcone A：Amino The mol ratio of carbamide compounds is 1:1~1:1.3.
5. synthetic method according to claim 3, it is characterised in that：Step（1）Described in organic solvent for toluene or DMF。
6. synthetic method according to claim 3, it is characterised in that：Step（1）Described in reaction temperature for 105 DEG C ~ 115℃。
7. synthetic method according to claim 3, it is characterised in that：Step（1）Described in organic alkali catalyst be three Ethamine.
8. compound described in claim 1 is preparing the application in treating antineoplastic.
9. apply according to claim 8, it is characterised in that the tumour is human prostata cancer, people's sdenocarcinoma of stomach or human lung cancer.
CN201710650031.5A 2016-12-31 2017-08-02 A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity Pending CN107382864A (en)

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CN107311953A (en) * 2016-12-31 2017-11-03 陕西科技大学 A kind of dihydro-isoxazole licochalcone A and its synthetic method for having antitumor activity
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CN107311936A (en) * 2017-02-24 2017-11-03 陕西科技大学 A kind of licochalcone A with antitumor activity and insoral cyclized derivative and its synthetic method
CN107445903A (en) * 2017-02-24 2017-12-08 陕西科技大学 A kind of licochalcone A with antitumor activity and melbine cyclized derivative and its synthetic method

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Application publication date: 20171124