CN106565657A - Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof - Google Patents
Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof Download PDFInfo
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- CN106565657A CN106565657A CN201611034012.1A CN201611034012A CN106565657A CN 106565657 A CN106565657 A CN 106565657A CN 201611034012 A CN201611034012 A CN 201611034012A CN 106565657 A CN106565657 A CN 106565657A
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- DVRXFRYDIUTJRU-DGOUCMFKSA-N COc1ccc([C@H](CC2=O)Oc3c2c(O)cc(OC(/C=C/c(cc2)ccc2[N+]([O-])=O)=O)c3)cc1O Chemical compound COc1ccc([C@H](CC2=O)Oc3c2c(O)cc(OC(/C=C/c(cc2)ccc2[N+]([O-])=O)=O)c3)cc1O DVRXFRYDIUTJRU-DGOUCMFKSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a hesperetin cinnamate compound with anti-tumor activity and a synthetic method thereof. The hesperetin cinnamate compound with a novel structure is synthesized by using hesperidin and a derivative thereof, and cinnamate and a derivative thereof as raw materials through simple reactions like hydrolytic desugarization and esterification with DMF as a solvent. The method provided by the invention has the advantages of easily available raw materials, mild reaction conditions, and applicability to industrial production.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of hesperetin cinnamate derivative with anti-tumor activity
Compound and its synthetic method.
Background technology
Tumor is a kind of serious disease for threatening human health, and tumor is inherently genopathy.Various environment and lose
The carcinogenic factor of biography causes DNA damage in the way of cooperateing with or be sequential, so as to activate proto-oncogene and (or) inactivation tumor suppression
Gene, adds the change of apoptosis gene and (or) DNA-repair gene, causes then the exception of expression, makes target cell
Generation is converted.The cell being converted is first more in Clonal hypertrophy, through a very long multistage evolution process, wherein one
It is individual to clone relatively unconfined amplification, by addition mutation, the sub-clone (heterogeneousization) with different characteristics is formed selectively,
So as to the ability (vicious transformation) for being infiltrated and being shifted, malignant tumor is formed.The mechanism of action and medicine of antitumor drug
Action target spot be it is diversified, and due to tumor cell be also easy to produce multidrug resistance often lead to treat failure.Searching has
The little antitumor drug of effect safety, toxic and side effects is always the target that tumour medicine R＆D worker seek assiduously.
The public praise that hesperetin is had no side effect with its extensive source and safety, unique characteristic electron and superior biology it is living
Property, requisite mother nucleus structure in many medicines is had evolved into, its multifunctionality causes the concern of people, to hesperetin
The synthesis and structure modification of its derivant has become the focus of current new drug development, the hesperetin derivant of various structure diversities
Arise at the historic moment.In fact, hesperetin inherently has more pharmaceutical properties, such as it has hyperglycemia, and anticancer, antibacterial resist true
Bacterium, antiviral etc. are acted on.Hesperetin source is relatively broad, mainly hydrolyzes from Hesperidin, and Hesperidin can be from Citrus etc.
Extract in Fruit Peel sarcocarp and obtain, therefore hesperetin.By consulting relevant information, inventor learns that hesperetin also has recently
Antineoplastic action.
Cinnamic acid, also known as β-cinnamic acid, are the organic acid isolated from Cortex Cinnamomi or Benzoinum.It is mainly used in essence fragrant
The aspects such as material, food additive, medical industry, beauty, pesticide, organic synthesiss.In medical industry, can be used for synthesis treatment coronary disease
The satisfying fixed and mepramidil of important drugs lactic acid of disease, and synthesis baclofen and cinnarizine, for manufacturing " heart can be pacified ",
Local anesthetic, antibacterial, hemorrhage etc..Baclofen and cinnarizine can also be synthesized, as vertebra bone relaxant
And spasmolytic.It is mainly used in the diseases such as cerebral thrombosiss, cerebral arteriosclerosis, coronary atherosclerosis.Which is for lung adenocarcinoma cell increasing in addition
Growing has obvious inhibiting effect.Cinnamic acid is the effective inhibitor of A-5491 human lung adenocarcinoma cells, is had in anticancer aspect great
Using value.In addition ferulic acid also plays the role of its uniqueness in anti-tumor aspect as one of the derivant of cinnamic acid.Therefore invention
People determines to combine the medicine that two kinds have anti-tumor active ingredient by the method for organic synthesiss.
Twin medicine (TwinDrug) refers to will be two identical or different lead compound or medicine Jing covalently bonded, is conjugated
Into recruit, metabolism in vivo generates both the above medicine and produces synergism, strengthen activity or produce new pharmacology and live
Property, or the selectivity of raising effect.
Recently, cinnamic acid is combined with hesperetin according to the thought of twin medicine (twindrug) and is devised one group of Pericarpium Citri junoris by inventor
Plain cinnamate derivative compound, that is, lead to structure shown in formula (I), be expected that by synthesizing this class novel chemical entities affect its with
The combination of receptor binding site, improves bioavailability and biological activity, reduces the untoward reaction of medicine.And set based on this
Think, inventor has invented synthetic route of the class with hesperetin as critical materialses, and has easily synthesized designed hesperetin
Cinnamate compound and its derivant (structure shown in logical formula (I)), there is the reaction scheme raw material to be easy to get, and step is few, yield
High advantage.Jing preliminary anti tumor activity in vitro test, the compound of this class formation possess preferable tumors inhibition activity, its
The external activity of middle part of compounds is substantially better than known compound hesperetin, and this is found more with hesperetin as mother for us
The antitumoral compounds of core open new field.
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 Pericarpium Citri junoriss with anti-tumor activity
Plain cinnamate derivative compound and its synthetic method, raw material environmental protection are easy to get, low production cost, and processing safety is high, reactions steps
Few, reaction raw materials are using abundant, it is adaptable to industrialized production.
To achieve these goals, the technical solution used in the present invention is：
A kind of hesperetin cinnamate derivative compound with anti-tumor activity, its general structure is as shown in formula I：
Wherein, R1For any substituted or unsubstituted phenyl, heterocyclic radical, benzheterocycle base, low alkyl group or cycloalkyl, low
Level haloalkyl, rudimentary 4-nitro alkyl, lower cyanoalkyl, lower alkyl-cycloalkyl, Cycloalkyl-lower alkyl, lower alkyl
Base-Cycloalkyl-lower alkyl；
R2Be one or more (less than 3) hydrogen, halogen, nitro, alkoxyl, replacements or unsubstituted that can be independently
Phenyl, substituted or unsubstituted low alkyl group or cycloalkyl, lower alkyl-cycloalkyl, Cycloalkyl-lower alkyl, lower alkyl
Base-Cycloalkyl-lower alkyl
It is preferred that R1Represent following groups：Substituted or unsubstituted low alkyl group；
It is preferred that R2Represent following groups：It is halogen, nitro, alkoxyl, substituted or unsubstituted phenyl, substituted or unsubstituted
Low alkyl group or cycloalkyl.
A kind of synthetic method of the hesperetin cinnamate derivative compound with anti-tumor activity, with Hesperidin and its derivative
Thing, cinnamate and its derivant are raw material, are synthesized by a series of simple chemical reactions in the case where DMF is as solvent, its
Synthetic route is as follows：
Specific preparation process is as follows：
1) appropriate Hesperidin or derivatives thereof alkali organic solvent is dissolved, is placed in reactor, add reaction dissolvent
DMF, is heated to 100 DEG C under a certain amount of hydrochloric acid magnetic agitation of Deca, insulation reaction 2 hours；
2) hydrolyzed solution PH=5 or so is adjusted, stands and filter, precipitate dries to obtain intermediate hesperetin or derivatives thereof, its
Shown in structure such as formula (B)；
3) by (2) step intermediate (B) for obtaining of reaction withIn molar ratio 1:1～1:It 1.5 is placed in
In reactor, appropriate potassium carbonate is added, back flow reaction obtains target product in 4～6 hours at 60 DEG C～100 DEG C.
Described step 1) in the preferred dimethyl sulfoxide of organic solvent, DMF and acetone, more preferably DMF.
In described step (2), hesperetin or derivatives thereof crystallize PH is 5.
Acid in described step (1) preferably hydrochloric acid, sulphuric acid, more preferably hydrochloric acid.
Intermediate B in described step (3) withIt is 1 in molar ratio:1～1:1.5.
The preferred potassium carbonate of alkali, potassium hydroxide, more preferably sodium carbonate, potassium carbonate in described step (3).
Response time in described step (3) is 4～6 hours.
Structural formula of compound in certain preferred embodiments of the present invention is as follows：
The invention has the beneficial effects as follows：
Raw material environmental protection is easy to get, low production cost, and processing safety is high, and reactions steps are few, and reaction raw materials are suitable for using abundant
In industrialized production.
Specific embodiment：
With reference to embodiments the present invention is further discussed below, but the present invention does not limit to and following examples.
Embodiment 1
Compound (S) -5- hydroxyl -2- (3- hydroxyl -4- methoxyphenyls) -4- oxo benzodihydropyran -7- base Cortex Cinnamomis
The preparation of sour (I -1)；
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring for obtaining is after 2 hours
The solid of precipitation is collected by filtration, and uses a small amount of washing with alcohol, obtain target compound (yellow solid, 40.1g, yield：
81.5%), shown in its structural formula such as following formula (I -1).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.60(2H,m),7.48(1H,s),7.40(2H,m),
7.33 (1H, m), 6.99 (1H, m), 6.81-6.75 (2H, J=7.5, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51
(1H,s),5.35(1H,s),3.83(3H,s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,DMSO)δ:196.8,
164.3,162.8,162.6,157.7,149.0,147.9,147.3,135.2,130.8,128.6,127.9,119.6,
115.5,113.8,113.0,107.0,103.3,102.7,82.8,56.1,43.0；HRMS(ESI)for(M+H)+:calcd
433.1282,found 433.1285.
Embodiment 2
Compound (S, E) -5- hydroxyl -2- (3- hydroxyl -4- methoxyphenyls) -4- oxo benzodihydropyran -7- base 3-
The preparation of (p-methylphenyl) acrylate (I -2).
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.Aluminum chloride is added, chlorine is passed through
Gas, the solution stirring for obtaining are collected by filtration the solid of precipitation after 2 hours, and use a small amount of washing with alcohol, obtain target compound (light
Yellow solid, 41.1g, yield：83.5%), shown in its structural formula such as following formula (I -2).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.68(2H,m),7.48(1H,s),7.44(2H,m),
6.99 (1H, m), 6.85-6.71 (2H, J=7.5, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51 (1H, s), 5.35
(1H,s),3.83(3H,s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,DMSO)δ:196.8,164.3,
162.8,162.6,157.7,149.0,147.9,147.3,133.5,133.3,130.8,129.0,128.7,119.6,
115.5,113.8,113.0,107.0,103.3,102.7,82.8,56.1,43.0；
HRMS(ESI)for(M+H)+:calcd 467.0892,found 467.0898。
Embodiment 3
Compound (S, E) -5- hydroxyl -2- (3- hydroxyl -4- methoxyphenyls) -4- oxo benzodihydropyran -7- base 3-
The preparation of (4- chlorphenyls) acrylate (I -3).
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor, adds nitric acid and sulphuric acid after stirring
Mixture, the solution stirring for obtaining are collected by filtration the solid of precipitation after 2 hours, and use a small amount of washing with alcohol, obtain target chemical combination
Thing (white solid, 39.8g, yield：79.6%), shown in its structural formula such as following formula (I -3).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),8.21(2H,m),8.03(2H,m),7.62(1H,s),
6.99 (1H, m), 6.81-6.75 (2H, J=7.5, m), 6.60 (1H, s), 6.52-6.48 (2H, m), 5.51 (1H, s), 5.35
(1H,s),3.83(3H,s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,DMSO)δ:196.8,164.3,
162.8,162.6,157.7,149.0,147.9,147.3,147.1,141.3,130.8,129.0,123.8,119.6,
115.5,113.8,113.0,107.0,103.3,102.7,82.8,56.1,43.0；
HRMS(ESI)for(M+H)+:calcd 478.1133,found 478.1136。
Embodiment 4
Compound (S, E) -5- hydroxyl -2- (3- hydroxyl -4- methoxyphenyls) -4- oxo benzodihydropyran -7- base 3-
The preparation of (4- fluorophenyls) acrylate (I -4).
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring for obtaining is after 2 hours
The solid of precipitation is collected by filtration, and uses a small amount of washing with alcohol, obtain target compound (yellow solid, 42.1g, yield：
84.2%), shown in its structural formula such as following formula (I -4).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.60(2H,m),7.48(1H,s),7.40(2H,m),
7.33 (1H, m), 7.03 (1H, m), 6.81 (2H, J=7.5, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51 (1H,
s),3.83(6H,s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,DMSO)δ:196.8,164.3,162.8,
162.6,157.7,150.0,148.7,147.9,135.2,130.4,128.5,127.9,119.3,115.5,112.6,
109.4,107.0,103.3,102.7,82.8,56.1,43.0；
HRMS(ESI)for(M+H)+:calcd 447.1438,found 447.1441。
Embodiment 5
Compound (S, E) -5- hydroxyl -2- (3- hydroxyl -4- methoxyphenyls) -4- oxo benzodihydropyran -7- base 3-
The preparation of (4- nitrobenzophenones) acrylate (I -5).
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.Then 8 hours are stirred at room temperature.After reaction is completed, 5L is added thereto to
Ethyl acetate and dichloromethane (3:2) mixed liquor, adds nitric acid and sulfuric acid mixture, and the solution stirring for obtaining is after 2 hours
The solid of precipitation is collected by filtration, and uses a small amount of washing with alcohol, obtain target compound (light yellow solid, 38.7g, yield：
76.4%), shown in its structural formula such as following formula (I -5).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.68(2H,m),7.48(1H,s),7.44(2H,m),
7.03 (1H, m), 6.81 (2H, J=7.5, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51 (1H, s), 3.83 (6H,
s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,DMSO)δ:196.8,164.3,162.8,162.6,157.7,
150.0,148.7,147.9,133.5,133.3,130.4,129.0,128.7,119.3,115.5,112.6,109.4,
107.0,103.3,102.7,82.8,56.1,43.0；
HRMS(ESI)for(M+H)+:calcd 481.1049,found 481.1051。
Embodiment 6
Compound (S, E) -5- hydroxyl -2- (3- hydroxyl -4- methoxyphenyls) -4- oxo benzodihydropyran -7- base 3-
The preparation of (4- hydroxy 3-methoxybenzene bases) acrylate (I -6).
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring for obtaining is after 2 hours
The solid of precipitation is collected by filtration, and uses a small amount of washing with alcohol, obtain target compound (yellow solid, 40.1g, yield：
81.5%), shown in its structural formula such as following formula (I -6).
1H-NMR(300MHz,DMSO)δ:7.48(1H,s),7.16(1H,m),6.99(1H,m),6.99(1H,m),
6.81-6.75 (2H, J=7.5, m), 6.79 (1H, m), 6.52-6.48 (2H, J=1.5, m), 6.31 (1H, s), 5.51 (1H,
s),5.35(1H,s),5.35(1H,s),5.35(1H,s),3.83(3H,s),3.83(3H,s),3.38(1H,s),3.13(1H,
s)；
13C-NMR(75MHz,DMSO)δ:196.8,164.3,162.8,162.6,157.7,149.1,147.9,147.3,
130.8,127.6,122.9,119.6,116.8,115.5,113.8,113.0,111.9,107.0,103.3,102.7,82.8,
56.1,43.0；HRMS(ESI)for(M+H)+:calcd 479.1337,found 479.1341。
Embodiment 7
Compound (S) -2- (3,4- Dimethoxyphenyls) -5- hydroxyl -4- oxo benzodihydropyran -7- base cinnamate
(I -7) prepare.
The Hesperidin that 100g is bought and the potassium carbonate of 45.4g are dissolved in dimethylformamide at 10 DEG C, Celsius 90
The lower stirring of degree 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 is then stirred at room temperature little
When.After reaction is completed, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring 2 for obtaining is little
When after the solid of precipitation is collected by filtration, and use a small amount of washing with alcohol, obtain target compound (yellow solid, 41.3g, yield：
81.9%), shown in its structure such as following formula (I -7).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.59(2H,m),7.48(1H,s),7.18(2H,m),
6.99 (1H, m), 6.81-6.75 (2H, J=7.5, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51 (1H, s), 5.35
(1H,s),3.83(3H,s),3.38(1H,s),3.13(1H,s),2.34(3H,s)；13C-NMR(75MHz,DMSO)δ:196.8,
164.3,162.8,162.6,157.7,149.0,147.9,147.3,137.6,132.2,130.8,128.5,119.6,
115.5,113.8,113.0,107.0,103.3,102.7,82.8,56.1,43.0,21.3；
HRMS(ESI)for(M+H)+:calcd 447.1438,found 447.1440。
Embodiment 8
Compound (S, E) -2- (3,4- Dimethoxyphenyl) -5- hydroxyl -4- oxo benzodihydropyran -7- base 3- are (right
Tolyl) acrylate (I -8) preparation
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring for obtaining is after 2 hours
The solid of precipitation is collected by filtration, and uses a small amount of washing with alcohol, (faint yellow solid, 38.1g are received to obtain target compound (I -8)
Rate：77.5%), shown in its structure such as following formula (I -8).
1H-NMR(300MHz,DMSO)δ:11.35 (1H, m), 7.72 (2H, J=1.5, m), 7.48 (1H, s), 7.19
(2H, J=1.5, m), 6.99 (1H, m), 6.81-6.75 (2H, J=7.5, m), 6.52-6.48 (2H, J=1.5, m), 6.31
(1H,s),5.51(1H,s),5.35(1H,s),3.83(3H,s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,
DMSO)δ:196.8,164.3,162.8,162.6,162.1,157.7,149.0,147.9,147.3,130.8,130.4,
119.6,115.5,113.8,113.0,107.0,103.3,102.7,82.8,56.1,43.0；
HRMS(ESI)for(M+H)+:calcd 451.1188,found 451.1191。
Embodiment 9
Compound (S, E) -2- (3,4- Dimethoxyphenyl) -5- hydroxyl -4- oxo benzodihydropyran -7- base 3- (4-
Chlorphenyl) acrylate (I -9) preparation.
The Hesperidin that 100g is bought and the potassium carbonate of 45.4g are dissolved in dimethylformamide at 10 DEG C, Celsius 90
The lower stirring of degree 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 is then stirred at room temperature little
When.After reaction is completed, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring 2 for obtaining is little
When after the solid of precipitation is collected by filtration, and use a small amount of washing with alcohol, obtain target compound (yellow solid, 40.9g, yield：
82.2%), shown in its structure such as following formula (I -9)
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.48(1H,s),7.16(1H,m),6.99(1H,m),
6.99 (1H, m), 6.81-6.75 (2H, J=7.5, m), 6.79 (1H, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51
(1H,s),5.35(2H,s),3.83(3H,s),3.83(3H,s),3.38(1H,s),3.13(1H,s)；13C-NMR(75MHz,
DMSO)δ:196.8,164.3,162.8,162.6,157.7,149.
1,147.9,147.3,130.8,127.6,122.9,119.6,116.8,115.5,113.8,113.0,111.9,
107.0,103.3,102.7,82.8,56.1,43.0；HRMS(ESI)for(M+H)+:calcd 479.1337,found
479.1341。
Embodiment 10
Compound (S, E) -2- (3,4- Dimethoxyphenyl) -5- hydroxyl -4- oxo benzodihydropyran -7- base 3- (4-
Fluorophenyl) acrylic ester (I -10) preparation.
The potassium carbonate of 100g Hesperidins and 45.4g is dissolved in dimethylformamide at 10 DEG C, is stirred under 90 degrees Celsius
Mix 6 hours.The liquid of reaction is cooled to into room temperature.100g iodomethane is added in solution, 8 hours are then stirred at room temperature.Instead
After should completing, 5L ethyl acetate and dichloromethane (3 are added thereto to:2) mixed liquor.The solution stirring for obtaining is after 2 hours
The solid of precipitation is collected by filtration, and uses a small amount of washing with alcohol, obtain target compound (yellow solid, 42.1g, yield：
83.5%), shown in its structural formula such as following formula (I -10).
1H-NMR(300MHz,DMSO)δ:11.35(1H,m),7.59(2H,m)7.48(1H,s),7.18(2H,m),7.03
(1H, m), 6.81 (2H, J=7.5, m), 6.52-6.48 (2H, m), 6.31 (1H, s), 5.51 (1H, s), 3.83 (6H, s),
3.38(1H,s),3.13(1H,s),2.34(3H,s)；13C-NMR(75MHz,DMSO)δ:196.8,164.3,162.8,162.6,
157.7,150.0,148.7,147.9,137.6,132.2,130.4,128.9.128.5,119.3,115.5,112.6,
109.4,107.0,103.3,102.7,82.8,56.1,43.0,21.3；
HRMS(ESI)for(M+H)+:calcd 461.1595,found 461.1598。
EXPERIMENTAL EXAMPLE
The anti-tumor activity test of the compounds of this invention
Cytostatic to tumor cell test is carried out to the compound of the present invention, test method adopts conventional mtt assay (such as
Lv Qiujun is edited《Developmental pharmacology research method》, 2007：242-243)
Cell strain is selected：Non-small cell lung cancer cell (A549), human liver cancer cell (SMMC-7721), human glioma cells
(U251), human gastric adenocarcinoma (SGC-7901), human breast cancer cell (MCF-7).Culture fluid is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：After with DMSO (Merck) dissolvings, add the solution of 100 μm of ol/L that PBS (-) is made into or
Uniform suspension, then with PBS (-) dilution of DMSO, ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ
mol/L。
The antitumor drug cytosine arabinoside (Ara-C) of listing is made into into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell is incubated at containing 10% inactivation new-born calf serum and penicillin, strepto-
In the RPMI-1640 of plain (each 1,000,000 U/L), 37 DEG C are placed in, 5%CO2, cultivate in the CO2 gas incubator of saturated humidity.
Cell attachment grows, and passed on per 2～3 days 1 time, pours out culture fluid when passing on first, and PBS is washed 2 times, after pancreatin digestion, adds new
Fresh culture fluid piping and druming is uniform, adjusts cell to debita spissitudo and moves in new culture bottle, and addition culture fluid is to appropriate.Take the logarithm
Trophophase cell is used to test.
Mtt assay detects cytoactive and IC50Measure；
Experimental principle：In living cells mitochondria, the MTT of yellow can be reduced into water-fast bluish violet product by dehydrogenase
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 microplate reader
Value can reflect cell survival rate.
Experimental technique：Take the logarithm trophophase cell, digestion, count, 96 well culture plates are inoculated in the density of 2 × 104/mL
In, per 100 μ l of hole.After culture 24 hours, by testing compound with 0.1, at 1,10,20,40,60,80,100 μm of ol/L concentration
Reason cell.Experimental group each concentration sets 5 multiple holes, is compared with the culture fluid 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- tetrazolium hydrobromates) are added per hole
(1mg/mL), continue culture 4 hours, abandon supernatant, add per hole 100 μ l DMSO, vibration to mix, surveyed at 570nm with microplate reader
Determine absorbance, using IC50Software for calculation obtains half-inhibition concentration (IC50)。
Result of the test refers to table, wherein, the hesperetin cinnamate derivative compound that sample is prepared in referring to corresponding embodiment,
The concrete numbering of the compound obtained by sample number into spectrum correspondence preparation embodiment.
Half-inhibition concentration IC of 1 compound of table to different tumor cells50(unit：μmol/L)
Above test result indicate that, the present invention compound there is good anti-tumor activity, compound 1-1,1-2,1-
3rd, the anti tumor activity in vitro of 1-4,1-6,1-7,1-8,1-9,1-10 in the cell strain of part is preferable, therefore hesperetin of the present invention
Cinnamate derivative compound and its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or its mixture conduct
The pharmaceutical composition of active ingredient can be used for preparing antitumor drug.
Claims (8)
1. a kind of hesperetin cinnamate derivative compound with anti-tumor activity, it is characterised in that its general structure such as formula I
It is shown：
Wherein, R1For any substituted or unsubstituted phenyl, heterocyclic radical, benzheterocycle base, low alkyl group or cycloalkyl, rudimentary halogen
Substituted alkyl, rudimentary 4-nitro alkyl, lower cyanoalkyl, lower alkyl-cycloalkyl, Cycloalkyl-lower alkyl, low alkyl group-ring
Alkyl-lower alkyl；
R2Be one or more (less than 3) hydrogen, halogen, nitro, alkoxyl, substituted or unsubstituted benzene that can be independently
Base, substituted or unsubstituted low alkyl group or cycloalkyl, lower alkyl-cycloalkyl, Cycloalkyl-lower alkyl, low alkyl group-ring
Alkyl-lower alkyl.
2. a kind of synthetic method of the hesperetin cinnamate derivative compound with anti-tumor activity, it is characterised in that with Pericarpium Citri junoriss
Glycosides and its derivant, cinnamate and its derivant are raw material, are entered by a series of simple chemical reactions in the case where DMF is as solvent
Row synthesis, its synthetic route are as follows：
Specific preparation process is as follows：
1) appropriate Hesperidin or derivatives thereof alkali organic solvent is dissolved, is placed in reactor, add reaction dissolvent DMF,
100 DEG C are heated under a certain amount of hydrochloric acid magnetic agitation of Deca, insulation reaction 2 hours；
2) hydrolyzed solution PH=5 or so is adjusted, stands and filter, precipitate dries to obtain intermediate hesperetin or derivatives thereof, its structure
As shown in formula (B)；
3) by (2) step intermediate (B) for obtaining of reaction withIn molar ratio 1:1～1:1.5 are placed in reaction
In device, appropriate potassium carbonate is added, back flow reaction obtains target product in 4～6 hours at 60 DEG C～100 DEG C.
3. the synthesis side of a kind of hesperetin cinnamate derivative compound with anti-tumor activity according to claim 2
Method, it is characterised in that described step 1) in the preferred dimethyl sulfoxide of organic solvent, DMF and acetone.
4. the synthesis side of a kind of hesperetin cinnamate derivative compound with anti-tumor activity according to claim 2
Method, it is characterised in that hesperetin or derivatives thereof crystallize PH is 5 in described step (2).
5. the synthesis side of a kind of hesperetin cinnamate derivative compound with anti-tumor activity according to claim 2
Method, it is characterised in that the acid in described step (1) preferably hydrochloric acid, sulphuric acid.
6. the synthesis side of a kind of hesperetin cinnamate derivative compound with anti-tumor activity according to claim 2
Method, it is characterised in that intermediate B in described step (3) withIt is 1 in molar ratio:1～1:
1.5。
7. the synthesis side of a kind of hesperetin cinnamate derivative compound with anti-tumor activity according to claim 2
Method, it is characterised in that the preferred potassium carbonate of alkali, potassium hydroxide, sodium carbonate in described step (3).
8. the synthesis side of a kind of hesperetin cinnamate derivative compound with anti-tumor activity according to claim 2
Method, it is characterised in that the response time in described step (3) is 4～6 hours.
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| CN108840871A (en) * | 2018-07-18 | 2018-11-20 | 陕西科技大学 | 13- hydroxyl sparteine cinnamate derivative compound with anti-tumor activity and preparation method thereof |
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