CN107235916A - A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity - Google Patents
A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity Download PDFInfo
- Publication number
- CN107235916A CN107235916A CN201710650036.8A CN201710650036A CN107235916A CN 107235916 A CN107235916 A CN 107235916A CN 201710650036 A CN201710650036 A CN 201710650036A CN 107235916 A CN107235916 A CN 107235916A
- Authority
- CN
- China
- Prior art keywords
- licochalcone
- synthetic method
- reaction
- dmso
- toluene
- 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
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses the licochalcone A deracil analog derivative and its synthetic method that a class has antitumor activity.Such compound is obtained using licochalcone A, thiourea as raw material in toluene as reaction synthesis under solvent.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, the research available for antitumor lead compound.
Description
Technical field
The present invention relates to the licochalcone A deracil analog derivative of class tool antitumor activity and its synthetic method,
Belong to medicinal chemistry arts.
Background technology：
Tumour has seriously threatened the health of the mankind, finds the small antineoplastic of effective and safe, toxic side effect and is always
The target that tumour medicine R＆D worker seek assiduously.With pharmaceutical chemical development, using pyrimidine ring as the chemical combination of 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, have very big Development volue in field of medicaments.But licochalcone A is that flatness is strong
Molecule, poorly water-soluble.
The content of the invention：
It is an object of the invention to provide a class have antitumor activity licochalcone A deracil analog derivative and
Its synthetic method, to improve the water solubility and antitumor activity of licochalcone A.
The implementation process of the present invention is as follows：
Compound shown in general structure (I),
Wherein：R be C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,
Nitro；
Described being substituted by is monosubstituted or polysubstituted, and substituent is：Halogen, C1-C4 alkoxy, cyano group, trifluoromethyl, benzene oxygen
Base.
The synthetic method of compound shown in general structure (I), using licochalcone A, thiourea as raw material, with
Organic base is catalyst, is synthesized under conditions of toluene or DMF are as reaction dissolvent.
Specifically, comprise the following steps,
(1) it is 1 in molar ratio into reactor:1~1:1.5 add licochalcone A and thiourea, add organic molten
Agent 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 is dried to obtain target production
Thing.
The mol ratio of licochalcone A and thiourea described in step (1) is preferably 1:1~1:1.3, it is organic
Solvent is toluene or DMF, and reaction temperature is preferably 105 DEG C~115 DEG C, and organic base is preferably triethylamine.
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, it is adaptable to industrialized production, the problem of solving prior art low yield, while pyrimidine ring is drawn
Enter into the chemical constitution of licochalcone A, have to the bioactivity for probing into such compound with summary structure-activity relationship 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.
The synthetic method of one class licochalcone A deracil analog derivative comprises the following steps：
(1) it is 1 in molar ratio into reactor:1~1:1.5, add licochalcone A, thiourea, plus 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 in course of reaction using thin-layer chromatography, the carry out degree of monitoring reaction in time stops after after raw material reaction completely
Heating, removes condensing unit；
(3) after the solidliquid mixture of step (2) reaction system is concentrated under reduced pressure, column chromatography for separation purification is dried to obtain target production
Thing.
Structural formula of compound in certain preferred embodiments of the present invention is as follows：
Embodiment 1
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- methyl -5,6-
The preparation of dihydro-pyrimidin -2 (1H)-thioketones (1).
200mg licochalcone As and 68.44mg 1- methylthioureas are added in the reactor, plus 50ml toluene and 5mLDMF make anti-
Solvent is answered, 0.5mL triethylamines are added as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 3 hours.Thin layer
Chromatogram following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder 113mg, total recovery 46.57%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 6.95
(1H, s), 6.75 (2H, d, J=7.52Hz), 6.41 (1H, s), 6.30 (1H, m), 5.33 (2H, s), 5.00-4.98 (2H, m),
4.0(1H,t),3.83(3H,s),3.10(3H,s),1.76-1.51(2H,m),1.69(6H,s)；13C NMR(100MHz,
DMSO-d6)δ(ppm):181.5,164.6,160.2,156.1,155.0,148.5,133.2,129.2,125.2,116.2,
111.1,103.8,62.0,56.1,40.2,28.6.MS(ESI)for(M+H)+:411.2.
Embodiment 2
1- benzyls -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -5,6-
The preparation of dihydro-pyrimidin -2 (1H)-thioketones (2).
200mg licochalcone As and 107.73mg 1- benzylthioureas are added in the reactor, plus 50ml toluene and 5mL DMF make
Reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 5 hours.It is thin
Layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder 124.72mg, total recovery
43.36%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.33-
7.23 (5H, m), 6.90 (1H, s), 6.75 (2H, d, J=7.52Hz), 6.41 (1H, s), 6.30 (1H, m), 5.33 (2H, s),
5.00-4.98(2H,m),4.0(1H,t),3.83(3H,s),3.80(2H,s),1.76-1.51(2H,m),1.69(6H,s)；13C
NMR(100MHz,DMSO-d6)δ(ppm):181.2,164.8,161.0,156.2,155.1,147.8,136.5,133.2,
129.1,128.6,127.4,125.0,116.2,111.1,104.0,59.4,55.4,40.5,39.7,28.3.MS(ESI)for
(M+H)+:487.2.
Embodiment 3
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- phenyl -5,6-
The preparation of dihydro-pyrimidin -2 (1H)-thioketones (3).
200mg licochalcone As and 116.95mg 1- phenylthioureas are added in the reactor, plus 50ml toluene and 5mL DMF make
Reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.It is thin
Layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder 115.31mg, total recovery
41.28%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.87 (2H, d, J=7.52Hz), 7.25
(2H, t), 6.95 (1H, s), 6.83 (2H, d, J=7.52Hz), 6.75 (1H, m), 6.60 (2H, m), 6.41 (1H, s), 6.30
(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69(6H,s),1.63
(1H,d)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,155.1,154.7,148.9,
140.3,134.3,129.1,128.4,126.2,121.6,117.0,111.1,103.8,69.9,56.1,41.1,39.8,
28.6.MS(ESI)for(M+H)+:473.2
Embodiment 4
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (adjacent toluene
Base) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (4) preparation.
Add 200mg licochalcone As and 97.73mg 1- (o-tolyl) thiocarbamide in the reactor, plus 50ml toluene and
5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction
6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder (121.79mg),
Total recovery 42.35%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.18
(1H, d), 7.04 (1H, t), 6.95 (1H, s), 6.83 (2H, d, J=7.52Hz), 6.65 (1H, t), 6.41 (1H, s), 6.30
(1H,q),6.19(1H,d),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),2.12(3H,s),1.88
(1H,d),1.69(6H,s),1.63(1H,d)；13CNMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,
155.1,154.7,147.8,139.2,137.2,133.2,131.8,129.4,128.3,126.0,123.2,121.7,
116.0,111.1,103.8,70.2,55.1,40.1,39.8,28.6,18.2.MS(ESI)for(M+H)+:487.2.
Embodiment 5
1- (2- chlorphenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes
Base) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (5) preparation.
Add 200mg licochalcone As and 113.41mg 1- (2- chlorphenyls) thiocarbamide in the reactor, plus 50ml toluene and
5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction
4 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder (148.23mg),
Total recovery 49.46%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.85 (2H, d, J=7.52Hz), 7.43
(1H, d), 7.11 (1H, t), 6.95 (1H, s), 6.85 (2H, d, J=7.52Hz), 6.71 (1H, t), 6.54 (1H, d), 6.41
(1H,s),6.30(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69
(6H,s),1.63(1H,d)；13CNMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,155.1,154.7,
147.8,146.0,138.8,133.2,131.7,130.2,129.1,128.3,127.5,125.2,122.6,116.0,
111.1,103.8,68.4,56.1,40.1,39.8,28.6.MS(ESI)for(M+H)+:507.2.
Embodiment 6
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (2- methoxyl groups
Phenyl) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (6) preparation.
200mg licochalcone As and 110.02mg 1- (2- methoxyphenyls) thiocarbamide, plus 50ml toluene are added in the reactor
Make reaction dissolvent with 5mLDMF, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, and magnetic agitation backflow is anti-
Answer 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder
(135.94mg), total recovery 45.76%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 6.95
(1H, s), 6.88 (1H, m), 6.75 (2H, d, J=7.52Hz), 6.79 (1H, m), 6.66 (1H, m), 6.41 (1H, s), 6.39
(1H,d),6.30(1H,q),5.35(2H,s),5.00-4.99(2H,m),3.9(1H,t),3.83(6H,s),1.88-1.63
(2H,m),1.69(6H,s)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,166.9,164.6,160.8,155.1,
154.7,147.8,133.2,129.1,128.4,127.2,125.2,123.0,121.4,116.0,112.9,111.1,
103.8,75.2,56.1,56.8,40.1,39.8,28.6.MS(ESI)for(M+H)+:503.2.
Embodiment 7
1- (3- fluorophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes
Base) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (7) preparation.
Add 200mg licochalcone As and 130.77mg 1- (3- fluorophenyls) thiocarbamide in the reactor, plus 50ml toluene and
5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 90 DEG C, magnetic agitation back flow reaction 6
Hour.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 126.76mg, always
Yield 43.72%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.21
(1H, m), 6.95 (1H, s), 6.75 (2H, d, J=7.52Hz), 6.56 (1H, m), 6.54 (1H, m), 6.41 (1H, s), 6.37
(1H,m),6.30(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69
(6H,s),1.63(1H,d)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,163,2,160.8,155.1,
154.7,147.8,141.9,135.2,130.6,129.1,128.2,125.2,121.6,117.2,115.0,111.1,
103.8,67.9,56.1,40.1,39.8,28.6.MS(ESI)for(M+H)+:491.2.
Embodiment 8
3- (6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -2- is thio -
5,6- dihydro-pyrimidins 1 (2H)-yl) benzonitrile (8) preparation.
Add 200mg licochalcone As and 126.16mg 1- (3- cyano-phenyls) thiocarbamide in the reactor, plus 50ml toluene and
5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 105 DEG C, magnetic agitation back flow reaction
6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 117.83mg, always
Yield 40.06%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.30
(1H, m), 7.24 (1H, m), 6.95 (1H, s), 6.78 (1H, m), 6.85 (2H, d, J=7.52Hz), 6.69 (1H, m), 6.41
(1H,s),6.30(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69
(6H,s),1.63(1H,d)；13CNMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,155.1,154.7,
148.8,141.0,136.7,133.5,131.2,129.4,127.3,125.2,121.6,118.6,116.0,112.9,
111.1,106.8,69.9,56.1,40.1,39.8,28.6.MS(ESI)for(M+H)+:498.2.
Embodiment 9
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (3- (trifluoros
Methyl) phenyl) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (9) preparation.
200mg licochalcone As and 169.19mg 1- (3- (trifluoromethyl) phenyl) thiocarbamide, plus 50ml are added in the reactor
Toluene and 5mL DMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation
Back flow reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder
131.32mg, total recovery 41.10%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.85 (2H, d, J=7.52Hz), 7.16
(1H, t), 6.95 (1H, s), 6.94 (1H, m), 6.91 (1H, m), 6.75 (2H, d, J=7.52), 6.60 (1H, m), 6.41
(1H,s),6.30(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69
(6H,s),1.63(1H,d)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,155.1,153.7,
148.8,140.6,135.5,133.2,131.3,129.2,128.3,125.2.124.1,123.3,121.3,116.0,
111.1,103.8,69.9,56.1,40.1,39.8,28.6.MS(ESI)for(M+H)+:541.2.
Embodiment 10
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- is (to toluene
Base) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (10) preparation.
Add 200mg licochalcone As and 127.73mg 1- (p- tolyl) thiocarbamide in the reactor, plus 50ml toluene and
5mL DMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 115 DEG C, and magnetic agitation backflow is anti-
Answer 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 139.51mg,
Total recovery 48.51%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.01
(2H, d, J=7.34Hz), 6.95 (1H, s), 6.75 (2H, d, J=7.52Hz), 6.41 (1H, s), 6.30 (1H, q), 6.13
(2H, d, J=7.34Hz), 5.35 (2H, s), 4.99 (2H, m), 3.9 (1H, t), 3.83 (3H, s), 2.34 (3H, s), 1.88
(1H,d),1.69(6H,s),1.63(1H,d)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,
155.1,153.7,148.8,138.3,137.3,134.2,129.2,128.3,125.2,122.6,116.0,111.1,
103.8,69.9,56.1,41.1,39.8,28.6,21.3.MS(ESI)for(M+H)+:487.2.
Embodiment 11
1- (4- fluorophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy benzenes
Base) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (11) preparation.
Add 200mg licochalcone As and 120.77mg 1- (4- fluorophenyls) thiocarbamide in the reactor, plus 50ml toluene and
5mLDMF makees reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 120 DEG C, magnetic agitation back flow reaction
6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, it is de- it is dry obtain brown ceramic powder 136.21mg, always
Yield 46.98%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.02
(2H, t), 6.95 (1H, s), 6.75 (2H, d, J=7.52Hz), 6.58 (2H, m), 6.41 (1H, s), 6.30 (1H, q), 5.35
(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69(6H,s),1.63(1H,d)；13C
NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,163.3,160.8,155.1,154.7,147.8,135.9,
133.2,129.1,128.2,123.2,121.6,116.0,115.8,111.1,103.8,68.9,56.1,40.1,39.8,
28.6.MS(ESI)for(M+H)+：491.2.
Embodiment 12
6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxy phenyls) -1- (4- phenoxy groups
Phenyl) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (12) preparation.
200mg licochalcone As and 157.71mg 1- (4- Phenoxyphenyls) thiocarbamide, plus 50ml toluene are added in the reactor
Make reaction dissolvent with 5mL DMF, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation backflow
Reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder
147.08mg, total recovery 44.07%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.41
(2H, t), 7.17 (1H, m), 7.14 (2H, m), 6.95 (1H, s), 6.75 (2H, d, J=7.52Hz), 6.79 (2H, m), 6.78
(2H,m),6.41(1H,s),6.30(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88
(1H,d),1.69(6H,s),1.63(1H,d)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,
157.0,155.1,154.7,151.2,148.8,133.3,129.1,128.3,126.2,125.2,122.7,118.9,
116.0,115.7,111.1,103.8,68.9,56.1,40.1,39.8,28.6.MS(ESI)for(M+H)+:565.2.
Embodiment 13
1- (3,5- dichlorophenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4- hydroxyls
Phenyl) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (13) preparation.
200mg licochalcone As and 169.87mg 1- (3,5- dichlorophenyl) thiocarbamide, plus 50ml toluene are added in the reactor
Make reaction dissolvent with 5mL DMF, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation backflow
Reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder
134.25mg, total recovery 41.95%.
Brown color crystalline powder solid.1HNMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.01
(1H, m), 6.95 (1H, s), 6.75 (2H, d, J=7.52Hz), 6.66 (2H, s), 6.41 (1H, s), 6.30 (1H, q), 5.35
(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69(6H,s),1.63(1H,d)；13C
NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,155.1,154.7,147.8,143.1,138.8,
133.2,129.2,128.3,123.2,121.6,116.0,111.1,103.8,68.9,56.1,40.1,39.8,28.6.MS
(ESI)for(M+H)+:541.1.
Embodiment 14
1- (double (trifluoromethyl) phenyl of 3,5-) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -
The preparation of 4- (4- hydroxy phenyls) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (14).
200mg licochalcone As and 221.44mg 1- (3,5- double (trifluoromethyl) phenyl) thiocarbamide are added in the reactor, plus
50ml toluene and 5mL DMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic force
It is stirred at reflux reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown powder
Last 153.09mg, total recovery 42.56%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 7.33
(1H, m), 6.95 (1H, s), 6.91 (2H, s), 6.75 (2H, d, J=7.52Hz), 6.41 (1H, s), 6.30 (1H, q), 5.35
(2H,s),4.99(2H,m),3.9(1H,t),3.83(3H,s),1.88(1H,d),1.69(6H,s),1.63(1H,d)；13C
NMR(100MHz,DMSO-d6)δ(ppm):178.7,164.6,160.8,156.1,154.7,147.8,140.9,133.2,
131.6,129.1,128.3,125.4,122.6,119.1,116.0,111.1,103.8,68.9,56.1,40.1,39.8,
28.6.MS(ESI)for(M+H)+:609.2.
Embodiment 15
1- (2,4- Dimethoxyphenyls) -6- (4- hydroxyl -2- methoxyl groups -5- (2- methyl butyl- 3- alkene -2- bases) phenyl) -4- (4-
Hydroxy phenyl) -5,6- dihydro-pyrimidins -2 (1H)-thioketones (15) preparation.
200mg licochalcone As and 163.09mg 1- (2,4- 3,5-dimethylphenyl) thiocarbamide, plus 50ml first are added in the reactor
Benzene and 5mL DMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 100 DEG C, and magnetic agitation is returned
Stream reaction 6 hours.Thin-layer chromatography following response, after reaction terminates, is concentrated under reduced pressure, column chromatography, de- dry to obtain brown ceramic powder
135.70mg, total recovery 43.11%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6):7.75 (2H, d, J=7.52Hz), 6.95
(1H, s), 6.75 (2H, d, J=7.52Hz), 6.41 (1H, s), 6.38 (1H, m), 6.36 (1H, m), 6.33 (1H, m), 6.30
(1H,q),5.35(2H,s),4.99(2H,m),3.9(1H,t),3.83(9H,s),1.88(1H,d),1.69(6H,s),1.63
(1H,d)；13C NMR(100MHz,DMSO-d6)δ(ppm):178.7,170.0,164.6,160.8,157.6,155.1,
154.7,148.8,133.2,129.1,127.4,125.2,121.6,119.5,116.0,111.1,105.9,103.8,
100.7,70.2,56.1,56.8,40.1,39.8,28.6.MS(ESI)for(M+H)+:533.2.
Embodiment 16
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), gastric carcinoma cells (SGC-7901).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。
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 Chan Wu formazans by dehydrogenase in living cells mitochondria
(MTTformazan), and it is deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell does not have this function.
DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the absorbance value determined with ELIASA 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, wherein, sample refers to the licochalcone A deracil class prepared in corresponding embodiment
Derivative, sample number into spectrum correspondence prepares 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)
Compound 7 and compound 2 show good antitumor activity, chemical combination in the 3 kinds of cell lines tested
Thing 1 and 11 takes second place, and good antitumor activity is also shown in different cell lines.Above test result indicates that, this hair
The activity that bright compound has good antitumor activity, particularly part licochalcone A deracil analog derivative exists
Antitumor activity is better than or is equal to cytarabine in specific cells strain, the research available for antineoplastic.
Claims (7)
1. general structure（Ⅰ）Shown compound：
Wherein：R be C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,
Nitro；The substituent is selected from halogen, C1-C4 alkoxy, cyano group, trifluoromethyl, phenoxy group.
2. general structure（I）The synthetic method of shown compound, it is characterised in that：Using licochalcone A, thiourea as
Raw material, using organic base as catalyst, is synthesized under conditions of toluene or DMF are as reaction dissolvent
。
3. the 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 As and thiourea, add toluene or
DMF is well mixed, and adds organic alkali catalyst triethylamine, 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 is dried to obtain target production
Thing.
4. synthetic method according to claim 3, it is characterised in that：Step（1）Described in licochalcone A and sulphur
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）The reaction temperature is 105 DEG C ~ 115
℃。
6. application of the compound described in claim 1 in treatment antineoplastic is prepared.
7. apply according to claim 6, it is characterised in that：The tumour is liver cancer, lung cancer or stomach cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611265731.4A CN106674128A (en) | 2016-12-31 | 2016-12-31 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
| CN2016112657314 | 2016-12-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107235916A true CN107235916A (en) | 2017-10-10 |
Family
ID=58850627
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611265731.4A Withdrawn CN106674128A (en) | 2016-12-31 | 2016-12-31 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
| CN201710650036.8A Pending CN107235916A (en) | 2016-12-31 | 2017-08-02 | A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611265731.4A Withdrawn CN106674128A (en) | 2016-12-31 | 2016-12-31 | Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN106674128A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN107235915A (en) * | 2017-02-24 | 2017-10-10 | 陕西科技大学 | A kind of licochalcone A with antitumor activity and buformin cyclized derivative and its synthetic method |
| 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 |
| CN110437156B (en) * | 2019-08-26 | 2022-07-19 | 桂林医学院 | Paeonol dihydropyrimidinone derivative, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961735A (en) * | 2015-07-20 | 2015-10-07 | 武汉理工大学 | Pyrazoline derivative and application of pyrazoline derivative as tyrosinase inhibitor |
-
2016
- 2016-12-31 CN CN201611265731.4A patent/CN106674128A/en not_active Withdrawn
-
2017
- 2017-08-02 CN CN201710650036.8A patent/CN107235916A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961735A (en) * | 2015-07-20 | 2015-10-07 | 武汉理工大学 | Pyrazoline derivative and application of pyrazoline derivative as tyrosinase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| 杜立林: "含氮查尔酮衍生物CDK1抑制剂的设计、合成及构效关系研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106674128A (en) | 2017-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107235916A (en) | A kind of licochalcone A deracil analog derivative and its synthetic method for having antitumor activity | |
| CN107235917A (en) | The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity | |
| CN107311937A (en) | The licochalcone A dihydro amino-metadiazine compound and its synthetic method of one class tool antitumor activity | |
| CN107382864A (en) | A kind of licochalcone A pyrazoline Carbox amide and its synthetic method for having antitumor activity | |
| CN107235902A (en) | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity | |
| CN106632379A (en) | Bergenin azacinnamate compound with anti-tumor activity and synthetic method thereof | |
| CN103333119A (en) | 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound and its preparation method and use | |
| WO2018106907A1 (en) | Fused bicyclic alkylene linked imidodicarbonimidic diamides, methods for synthesis, and uses in therary | |
| CN107200731B (en) | Thiazole ring-containing pyridone derivative and preparation method and application thereof | |
| CN106966986B (en) | N- benzyl heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof | |
| CN109369623A (en) | 1,2,3 triazole diaryl pyrimidine derivatives of a kind of substitution and the preparation method and application thereof | |
| CN112679409B (en) | 4-indole-substituted thiosemicarbazide derivative and preparation method and application thereof | |
| CN108033913A (en) | A kind of pyrazoline quinoline derivant and its preparation method and application | |
| CN106565657A (en) | Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof | |
| EP3241823B1 (en) | Pyrrole amide compound, preparation method therefor, and use thereof | |
| CN106008506A (en) | Substituted purine derivative and preparation method and application thereof | |
| CN113493443A (en) | Erlotinib derivative with killing performance on wild lung cancer tumor cells and preparation method thereof | |
| CN106588749A (en) | Multi-substituted carbazole-type compound, synthesis method, and application thereof | |
| CN104829534A (en) | Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs | |
| CN104230786B (en) | Indole-structure-containing compound with anti-tumor activity and synthesis method thereof | |
| CN110437173A (en) | A kind of diphenylethylene compounds and its synthetic method and application containing thiazole ring | |
| CN110372630A (en) | The diphenyl ethylene analogue and its synthetic method of a kind of structure containing phenyl thiazole and application | |
| JP2000212087A (en) | Radiosensitizing agent containing nitro-5deazaflavin derivative as effective ingredient | |
| CN112920133B (en) | (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and preparation method and application thereof | |
| CN112225733B (en) | Preparation method of 1,3, 4-thiadiazole pyridine-2-ketone derivative and application of derivative as anti-cancer drug |
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 |