CN105111174B - Derivative with the geranyl lavonoid backbone of 5,2 ' dihydroxy, 4 ' methoxyl group 3 and its production and use - Google Patents
Derivative with the geranyl lavonoid backbone of 5,2 ' dihydroxy, 4 ' methoxyl group 3 and its production and use Download PDFInfo
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- C07D311/30—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 not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention discloses a kind of derivative with the geranyl lavonoid backbone of 5,2 ' dihydroxy, 4 ' methoxyl group 3 and its production and use, the derivative has following chemical general formula (I) or its pharmaceutically acceptable salt；(I), wherein, R1, R2Represent OCH3Or OH.The derivative that the present invention obtains has a good anti-gastric cancer activity, Mutiple Targets, too many levels, more corresponding, and toxicity is low, is not likely to produce drug resistance.
Description
Technical field
The present invention relates to the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, and in particular to
6 isopentene groups substitution 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl flavones of A rings and its production and use.
Background technology
Stomach cancer is one of disease maximum to human health and quality of life danger, therefore seeks efficient, high selection and poison
The anti-gastric cancer medicament of Small side effects is the Main way of drug research.Flavone compound is that one kind is present in nature, tool
There is the compound of 2- phenyl chromone structures, its bioactivity is varied, and has very strong pharmacological activity.There is research table
Bright, flavone compound has antitumor activity, and significant role is played in the treatment and prevention such as lung cancer, colon cancer, breast cancer,
It prevents the mechanism such as cancer cell multiplication, inducing apoptosis of tumour cell, antioxidation activity, suppression new vessels formation.But at present
Obtain flavone compound and mainly pass through traditional Chinese medicine extraction, it is relatively difficult by separation and Extraction progress volume production, and flavonoid
Thing is complicated, act as a little more, causes to be directed to poor selectivity, its mechanism of action, material base are without clear and definite Theory Solution
Release, therefore structural formula, targeting are respectively provided with not controllability.
Therefore, its structure of modification is modified by chemical synthesis, finds more targets that a kind of activity is more preferable, side effect is smaller
Point, too many levels, the modification flavone compound of manifold effect, it is current urgent need to resolve to strengthen its specific pharmacological activity to treat stomach cancer
Technical barrier.
The content of the invention
As the result of various extensive and careful research and experiment, it has been found by the inventor that synthesizing
The volume ratio of column chromatography is controlled in journey technique, the compound is favorably improved the performance for the treatment of stomach cancer.It is complete based on this discovery
Into the present invention.
It is an object of the invention to solve at least the above and/or defect, and provide at least will be described later it is excellent
Point.
It is a still further object of the present invention to provide one kind to have 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl flavones bones
The derivative of frame, it has a good anti-gastric cancer activity, Mutiple Targets, too many levels, more corresponding, and toxicity is low, is not likely to produce drug resistance.
It is a still further object of the present invention to provide have 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyls yellow described in one kind
The method of the organic synthesis of the derivative of ketone skeleton, by isopentene group, methylate, into ester, rearrangement, geranylgeranylation, cyclization
And demethylation, preparation method is simple, is easily controlled, and improves the target spot of the compound, to obtain preferably selectivity and to live
Property.
In order to realize according to object of the present invention and further advantage, there is provided one kind have 5,2 '-dihydroxy -4 ' -
The derivative of methoxyl group -3- geranyl lavonoid backbones, the derivative has following chemical general formula (I) or its is pharmaceutically acceptable
Salt；
Wherein, R1, R2Expression-OCH3Or OH.
Preferably, it is described to have 5, the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, be
One of following compound of structural formula：
One kind have 5, the preparation method of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, including
Following steps：
Step 1: using 2,4-dihydroxyacetophenone as initiation material, iso-amylene glycosylation reaction is carried out, using column chromatography,
V(petroleum ether)：V(ethyl acetate)=10:1, obtain the first intermediate product of yellow liquid；
Step 2: first intermediate product is dissolved in acetic acid, methylation reaction is carried out, using column chromatography,
V(petroleum ether)：V(ethyl acetate)=10:1, obtain the second intermediate product of yellow oily；
Step 3: take 2,4- dimethoxybenzoic acids and thionyl chloride, backflow, add after vacuum rotary steam dissolved with described the
In the anhydrous pyridine of two intermediate products, ester reaction, rearrangement reaction, using column chromatography, V are carried out into(petroleum ether)：V(ethyl acetate)=4:1, obtain
To the 3rd intermediate product of yellow oily；
Step 4: the 3rd intermediate product is taken to carry out geranylgeranylation reaction, using column chromatography, V(petroleum ether)：V(ethyl acetate)=
10:1, obtain the 4th intermediate product of yellow oily；
Step 5: the 4th intermediate product is dissolved in methanol, ring closure reaction is carried out, using column chromatography, V(petroleum ether)：
V(ethyl acetate)=5:1, obtain the 5th intermediate product of yellow liquid；
Step 6: the 5th intermediate product is dissolved in HMPA, demethylating reaction is carried out, is used
Column chromatography, V(petroleum ether)：V(ethyl acetate)=4:1, obtain the target product of yellow liquid.
Preferably, it is described to have 5, the system of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation Method, the iso-amylene glycosylation reaction in the step 1 specifically include：By 180~220 parts by weight 2,4- resacetophenones
It is dissolved in acetone soln, adds 15~21 pbw of potassium carbonate and stir 8~12min of backflow, 20~30 parts by weight isoamyls are added dropwise
Alkenyl bromine 8~12h of backflow, is cooled to room temperature, and decompression removes solvent, organic phase is extracted with ethyl acetate, and is eaten successively with water, saturation
Salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography is carried out afterwards and obtains first intermediate product, is produced among described first
Thing structure is analyzed through IR, NMR and MS and determined.
Preferably, it is described to have 5, the system of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation Method, the methylation reaction in the step 2 refer specifically to：First intermediate product described in 5~8 parts by weight is dissolved in anhydrous
In acetone, the Anhydrous potassium carbonate for adding 10~15 parts by weight stirs 8~12min, with being added dropwise in 8~12min of constant pressure funnel
3.5~5 parts sulfuric acid dimethyl esters, 5~7h of back flow reaction, are cooled to room temperature, adjust pH value to 2 with hydrochloric acid, use ethyl acetate
Extract organic phase, successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out afterwards column chromatography obtain it is described
Second intermediate product, the second intermediate product structure are analyzed through IR, NMR and MS and determined.
Preferably, it is described to have 5, the system of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation Method, described to be reacted into ester in the step 3, rearrangement reaction refers specifically to：Weigh 10~15 parts by weight 2,4- dimethoxys
Benzoic acid adds 26~32 parts by weight thionyl chlorides, 0.8~1.2h of backflow in round-bottomed flask, and vacuum rotary steam removes excessive dichloro
Sulfoxide, it is then added into the anhydrous pyridine of the second intermediate product described in 8~12 parts by weight of dissolving, 70~90 DEG C of reactions
1.5~2.5h, it is cooled to room temperature and adds ethyl acetate extraction organic phase, it is organic with watery hydrochloric acid, water, saturated common salt water washing successively
Phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, intermediate compound is obtained, the intermediate compound is not purified, is dissolved in
In pyridine, the preheated potassium hydroxide powder of 4~6 parts by weight is added, 95~105 DEG C of 20~40min of reaction, is cooled to room temperature,
Ethyl acetate extraction organic phase is added, successively with watery hydrochloric acid, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, it
Column chromatography is carried out afterwards and obtains the 3rd intermediate product, and the 3rd intermediate product structure is analyzed through IR, NMR and MS and determined.
Preferably, it is described to have 5, the system of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation Method, in the step 4, the geranylgeranylation reaction refers specifically to：3rd intermediate product described in 7~10 parts by weight is dissolved
In anhydrous propanone, 8~10.5 parts by weight Anhydrous potassium carbonates, 8~12min of backflow is added, 6~8.5 parts by weight geranyls are added dropwise
Bromine, flow back 2~4h, and cooling is spin-dried for solvent, adds ethyl acetate extraction organic phase, respectively water, saturated common salt water washing organic phase,
Anhydrous sodium sulfate drying, afterwards column chromatography obtain the 4th intermediate product, the 4th intermediate product structure is through IR, NMR and MS
Analysis determines.
Preferably, it is described to have 5, the system of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation Method, in the step 5, the ring closure reaction refers specifically to：4th intermediate product described in 8~11 parts by weight is dissolved in 10
In~14 parts by weight Methanol, 2~4 drop concentrated sulfuric acids are added dropwise, flow back 2~4h, evaporated under reduced pressure solvent, and it is organic to add ethyl acetate extraction
Phase, respectively with saturated common salt water washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography obtain the 5th intermediate product, institute
State the 5th intermediate product structure and analyze determination through IR, NMR and MS.
Preferably, it is described to have 5, the system of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation Method, in the step 6, the demethylating reaction refers specifically to：2~2.5 parts by weight ethyl mercaptans are dissolved under argon gas protection
40~60 parts by weight HMPAs in 0~2 DEG C stir 8~12min, add 6~8 parts by weight concentration be 2~3M just
Butyl lithium reacts 25~35min, and the HMPA solution dissolved with the 5th intermediate product described in 5~6 parts by weight is added
Enter into freshly prepd ethylmercapto group lithium, 60~80 DEG C of 5~7h of reaction, add 50~70 parts by weight saturated ammonium chlorides and reaction is quenched,
Be extracted with ethyl acetate organic phase, saturation lithium chloride washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography obtain target production
Thing, target product structure are analyzed through IR, NMR and MS and determined.
One kind has 5, the purposes of the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, for preparing
Treat the medicine of stomach cancer.
The present invention comprises at least following beneficial effect：
Firstth, flavone compound intervenes the enzymatic activity during cell goes to procedure, so as to suppress proliferation of human gastric cancer cell, and it is right
Normal cell nonhazardous acts on, and antioxidation and positive immunoregulation effect can be shown, due to can be taken with multiple
The position in generation, can be modified can strengthen the anti-gastric cancer medicament of its specific pharmacological activity with acquisition；
Secondth, cancel the oxo of 7, A rings, introduce C 3 geranyls of ring, selective carbon improves flavones for geranylgeranylation
The bioactivity of class compound, the effect of the anti-gastric cancer having had and faint cytotoxicity；
3rd, A 6 isopentene groups of ring are introduced, avoids forming larger repulsion with geranyl, ensures the stabilization of compound
Property, and acted synergistically with skeleton, the presence of isopentenyl side chain adds the lipophilicity of flavone compound, makes it in biology
It is easier to, through cell membrane arrival effect target, strengthen the bioactivity of flavone compound in body；
4th, the preparation method that uses of the present invention is simple to operate, the reaction time is short, and the compound purity of preparation is high, form
It is good.
Further advantage, target and the feature of the present invention embodies part by following explanation, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Embodiment
With reference to embodiment, the present invention is described in further detail, to make those skilled in the art with reference to specification
Word can be implemented according to this.
Embodiment 1：
Derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, target product II, target production
Thing III, structural formula are as follows：
Preparation method is as follows：
Step 1: 2.205g 2,4-dihydroxyacetophenones are dissolved in acetone soln, add 2.057g potassium carbonate and stir back
8min is flowed, 2.012g isoprenyl bromides backflow 8h is added dropwise, is cooled to room temperature, decompression removes solvent, is extracted with ethyl acetate organic
Phase, successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)=
10:1, the first intermediate product (1.113g yields 34.23%) of yellow liquid is obtained, structure is analyzed through IR, NMR and MS and determined,
Structural formula is as follows：
Step 2: 0.789g the first intermediate product is dissolved in anhydrous propanone, adds 1.502g Anhydrous potassium carbonates and stir
12min is mixed, with 0.505g dimethyl suflfates are added dropwise in constant pressure funnel 12min, back flow reaction 7h, room temperature are cooled to, use salt
Acid regulation pH value is extracted with ethyl acetate organic phase, done successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate to 2
It is dry, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)=10:1, obtain the second intermediate product (0.443g yields of yellow oily
64.62%), structure is analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 3: weighing 1.052g 2,4- dimethoxybenzoic acids add 3.188g dichloros in 100mL round-bottomed flasks
Sulfoxide backflow 1.2h, vacuum rotary steam remove excessive thionyl chloride, are then added into the dissolving intermediate products of 1.222g second
In anhydrous pyridine, 90 DEG C of reaction 2.5h, it is cooled to room temperature and adds ethyl acetate extraction organic phase, successively with watery hydrochloric acid, water, saturation
Brine It organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtain intermediate compound, the intermediate compound without
Purifying, is dissolved in pyridine, adds the preheated potassium hydroxide powders of 0.601g, 105 DEG C of reaction 40min, is cooled to room
Temperature, ethyl acetate extraction organic phase is added, is done successively with watery hydrochloric acid, water, saturated common salt water washing organic phase, anhydrous sodium sulfate
It is dry, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)=4:1, obtain the 3rd intermediate product (0.897g yields of yellow oily
53.20%), structure is analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 4: the intermediate products of 0.712g the 3rd are dissolved in anhydrous propanone, the backflow of 0.823g Anhydrous potassium carbonates is added
8min, dropwise addition 0.628g geranyl bromides, backflow 2h, cooling are spin-dried for solvent, add ethyl acetate extraction organic phase, difference water, satisfy
With brine It organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V(petroleum ether)：V(ethyl acetate)=10:1, obtain yellow oily
4th intermediate product (1.121g yields 85.45%), structure are analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 5: the intermediate products of 0.812g the 4th are dissolved in 12mL methanol, the 2 drop concentrated sulfuric acids are added dropwise, flow back 2h, decompression
Solvent evaporated, ethyl acetate extraction organic phase is added, respectively with saturated common salt water washing organic phase, anhydrous sodium sulfate drying, it
Column chromatography V afterwards(petroleum ether)：V(ethyl acetate)=5:1, obtain the 5th intermediate product (0.717g yields 73.69%) of yellow liquid, structure
Analyze and determine through IR, NMR and MS, structural formula is as follows：
5th intermediate product：IR(KBr):3104,2972,2838,1641,1616,1504,1394,1210,1155,
1093,833,816cm-1。1HNMR (300MHz, Chloroform-d) δ 7.33 (d, J=8.4Hz, 1H), 7.28 (d, J=
9.0Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 6.55 (m, 2H), 5.45-5.12 (m, 2H), 5.06 (t, J=6.5Hz, 1H),
3.95 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H), 3.36 (d, J=7.4Hz, 2H), 3.08 (d, J=6.8Hz, 2H),
2.10–1.84(m,4H),1.70(s,3H),1.64(s,3H),1.57(s,6H),1.39(s,3H).13CNMR(75MHz,
CDCl3)δ178.321,162.321,158.468,158.052,157.995,156.029,134.634,132.881,
132.553,131.542,131.061,124.497,123.791,122.285,122.247,121.742,115.418,
113.929,105.123,104.364,98.597,56.225,55.460,55.429,39.689,27.908,26.718,
25.726,25.627,24.757,17.637,17.566,15.874；(ESI)-MS,m/z:517.2949[M+H]+(theoretical value
517.2954)。
Step 6: 0.232mL ethyl mercaptans are dissolved in into 4mL HMPAs under argon gas protection stirs 8min in 0 DEG C,
Add the n-BuLi that 0.690mL concentration is 2M and react 25min, by the hexamethyl phosphinylidyne dissolved with the intermediate products of 0.526g the 5th
Triamine solution is added in freshly prepd ethylmercapto group lithium, 60 DEG C of reaction 5h, adds 3mL saturated ammonium chlorides and reaction is quenched, use acetic acid
Ethyl ester extracts organic phase, saturation lithium chloride washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V(petroleum ether)：V(ethyl acetate)=
4:1, obtain target product II (0.132g yields 32.71%), the III (0.214g yields 52.42%) of yellow liquid, target production
Thing II, III structure are analyzed through IR, NMR and MS and determined, structural formula is as follows：
Target product II：IR(KBr):3433,3112,2962,2912,1645,1576,1394,1382,1063,1030,
961,826cm-1.1HNMR (300MHz, Chloroform-d) δ 12.70 (s, 1H), 7.27 (m, 2H), 6.64 (d, J=
8.3Hz, 1H), 6.61 (s, 1H), 6.57 (d, J=2.5Hz, 1H), 5.23 (t, J=7.2Hz, 1H), 5.17 (t, J=6.8Hz,
1H), 5.06 (t, J=6.3Hz, 1H), 3.87 (s, 3H), 3.37 (d, J=7.3Hz, 2H), 3.20 (d, J=6.8Hz, 2H),
2.06–1.89(m,4H),1.73(s,3H),1.65(s,3H),1.63(s,3H),1.58(s,3H),1.47(s,3H).13CNMR
(75MHz,CDCl3)δ183.499,162.827,160.915,158.264,155.474,153.875,136.619,
135.063,133.588,131.331,131.326,124.232,121.693,121.493,120.857,119.594,
112.581,110.086,110.051,107.085,102.212,55.451,39.596,27.619,26.545,25.720,
25.637,24.209,17.723,17.671,15.986；(ESI)-MS,m/z:[489.2658 M+H]+(theoretical value
489.2641)。
Target product III：IR(KBr):3423,2967,2917,2885,1644,1551,1489,1402,1310,
1220,1060,1035,941,826cm-1.1HNMR (300MHz, Chloroform-d) δ 12.87 (s, 1H), 7.36 (d, J=
8.3Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 6.74 (d, J=8.3Hz, 1H), 6.64-6.46 (m, 2H), 6.38 (s, 1H),
5.26 (t, J=7.3Hz, 1H), 5.15 (t, J=6.5Hz, 1H), 5.06 (t, J=6.5Hz, 1H), 3.80 (s, 3H), 3.37
(d, J=7.3Hz, 2H), 3.13 (d, J=6.6Hz, 2H), 1.97 (m, 4H), 1.71 (s, 3H), 1.65 (s, 3H), 1.59 (s,
3H),1.58(s,3H),1.44(s,3H).13CNMR(75MHz,CDCl3)δ183.823,161.892,159.321,
158.666,158.537,154.235,135.756,134.801,132.927,131.529,131.289,124.279,
121.727,121.620,121.217,119.590,114.525,110.394,109.818,107.232,99.274,
55.508,39.624,27.544,26.608,25.716,25.625,24.161,17.652,17.600,15.921；(ESI)-
MS,m/z:511.2460 [M+Na]+(theoretical value 511.2461).
Embodiment 2：
Derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, target product II, target production
Thing III, structural formula are as follows：
Preparation method is as follows：
Step 1: 1.812g 2,4-dihydroxyacetophenones are dissolved in acetone soln, add 1.523g potassium carbonate and stir back
12min is flowed, 3.012g isoprenyl bromides backflow 12h is added dropwise, is cooled to room temperature, decompression removes solvent, has been extracted with ethyl acetate
Machine phase, successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)
=10:1, the first intermediate product (1.121g yields 35.52%) of yellow liquid is obtained, structure is analyzed true through IR, NMR and MS
Fixed, structural formula is as follows：
Step 2: 0.521g the first intermediate product is dissolved in anhydrous propanone, adds 1.012g Anhydrous potassium carbonates and stir
8min is mixed, with 0.355g dimethyl suflfates are added dropwise in constant pressure funnel 8min, back flow reaction 5h, room temperature are cooled to, use hydrochloric acid
PH value is adjusted to 2, organic phase is extracted with ethyl acetate, is done successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate
It is dry, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)=10:1, obtain the second intermediate product (0.421g yields of yellow oily
62.61%), structure is analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 3: weighing 1.495g 2,4- dimethoxybenzoic acids add 2.642g dichloros in 100mL round-bottomed flasks
Sulfoxide backflow 0.8h, vacuum rotary steam remove excessive thionyl chloride, are then added into the dissolving intermediate products of 0.832g second
In anhydrous pyridine, 70 DEG C of reaction 1.5h, it is cooled to room temperature and adds ethyl acetate extraction organic phase, successively with watery hydrochloric acid, water, saturation
Brine It organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtain intermediate compound, the intermediate compound without
Purifying, is dissolved in pyridine, adds the preheated potassium hydroxide powders of 0.465g, 95 DEG C of reaction 20min, is cooled to room
Temperature, ethyl acetate extraction organic phase is added, is done successively with watery hydrochloric acid, water, saturated common salt water washing organic phase, anhydrous sodium sulfate
It is dry, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)=4:1, obtain the 3rd intermediate product (0.877g yields of yellow oily
52.10%), structure is analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 4: the intermediate products of 1.002g the 3rd are dissolved in anhydrous propanone, the backflow of 1.051g Anhydrous potassium carbonates is added
12min, dropwise addition 0.851g geranyl bromides, backflow 4h, cooling are spin-dried for solvent, add ethyl acetate extraction organic phase, difference water, satisfy
With brine It organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V(petroleum ether)：V(ethyl acetate)=10:1, obtain yellow oily
4th intermediate product (1.112g yields 84.93%), structure are analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 5: the intermediate products of 1.112g the 4th are dissolved in 18mL methanol, the 4 drop concentrated sulfuric acids are added dropwise, flow back 4h, decompression
Solvent evaporated, ethyl acetate extraction organic phase is added, respectively with saturated common salt water washing organic phase, anhydrous sodium sulfate drying, it
Column chromatography V afterwards(petroleum ether)：V(ethyl acetate)=5:1, obtain the 5th intermediate product (0.701g yields 72.23%) of yellow liquid, structure
Analyze and determine through IR, NMR and MS, structural formula is as follows：
5th intermediate product：IR(KBr):3104,2972,2838,1641,1616,1504,1394,1210,1155,
1093,833,816cm-1。1HNMR (300MHz, Chloroform-d) δ 7.33 (d, J=8.4Hz, 1H), 7.28 (d, J=
9.0Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 6.55 (m, 2H), 5.45-5.12 (m, 2H), 5.06 (t, J=6.5Hz, 1H),
3.95 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H), 3.36 (d, J=7.4Hz, 2H), 3.08 (d, J=6.8Hz, 2H),
2.10–1.84(m,4H),1.70(s,3H),1.64(s,3H),1.57(s,6H),1.39(s,3H).13CNMR(75MHz,
CDCl3)δ178.321,162.321,158.468,158.052,157.995,156.029,134.634,132.881,
132.553,131.542,131.061,124.497,123.791,122.285,122.247,121.742,115.418,
113.929,105.123,104.364,98.597,56.225,55.460,55.429,39.689,27.908,26.718,
25.726,25.627,24.757,17.637,17.566,15.874；(ESI)-MS,m/z:517.2949[M+H]+(theoretical value
517.2954)。
Step 6: 0.291mL ethyl mercaptans are dissolved in 6mL HMPAs in 2 DEG C of stirrings under argon gas protection
12min, add the n-BuLi that 0.851mL concentration is 3M and react 35min, by the pregnancy dissolved with the intermediate products of 0.606g the 5th
Base phosphoric triamide solution is added in freshly prepd ethylmercapto group lithium, 80 DEG C of reaction 7h, adds 5mL saturated ammonium chlorides and reaction is quenched,
It is extracted with ethyl acetate organic phase, saturation lithium chloride washing organic phase, anhydrous sodium sulfate drying, column chromatography V afterwards(petroleum ether)：
V(ethyl acetate)=4:1, obtain target product II (0.142g yields 34.74%), III (the 0.204g yields of yellow liquid
51.43%), target product II, III structures are analyzed through IR, NMR and MS and determined, structural formula is as follows：
Target product II：IR(KBr):3433,3112,2962,2912,1645,1576,1394,1382,1063,1030,
961,826cm-1.1HNMR (300MHz, Chloroform-d) δ 12.70 (s, 1H), 7.27 (m, 2H), 6.64 (d, J=
8.3Hz, 1H), 6.61 (s, 1H), 6.57 (d, J=2.5Hz, 1H), 5.23 (t, J=7.2Hz, 1H), 5.17 (t, J=6.8Hz,
1H), 5.06 (t, J=6.3Hz, 1H), 3.87 (s, 3H), 3.37 (d, J=7.3Hz, 2H), 3.20 (d, J=6.8Hz, 2H),
2.06–1.89(m,4H),1.73(s,3H),1.65(s,3H),1.63(s,3H),1.58(s,3H),1.47(s,3H).13CNMR
(75MHz,CDCl3)δ183.499,162.827,160.915,158.264,155.474,153.875,136.619,
135.063,133.588,131.331,131.326,124.232,121.693,121.493,120.857,119.594,
112.581,110.086,110.051,107.085,102.212,55.451,39.596,27.619,26.545,25.720,
25.637,24.209,17.723,17.671,15.986；(ESI)-MS,m/z:[489.2658 M+H]+(theoretical value
489.2641)。
Target product III：IR(KBr):3423,2967,2917,2885,1644,1551,1489,1402,1310,
1220,1060,1035,941,826cm-1.1HNMR (300MHz, Chloroform-d) δ 12.87 (s, 1H), 7.36 (d, J=
8.3Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 6.74 (d, J=8.3Hz, 1H), 6.64-6.46 (m, 2H), 6.38 (s, 1H),
5.26 (t, J=7.3Hz, 1H), 5.15 (t, J=6.5Hz, 1H), 5.06 (t, J=6.5Hz, 1H), 3.80 (s, 3H), 3.37
(d, J=7.3Hz, 2H), 3.13 (d, J=6.6Hz, 2H), 1.97 (m, 4H), 1.71 (s, 3H), 1.65 (s, 3H), 1.59 (s,
3H),1.58(s,3H),1.44(s,3H).13CNMR(75MHz,CDCl3)δ183.823,161.892,159.321,
158.666,158.537,154.235,135.756,134.801,132.927,131.529,131.289,124.279,
121.727,121.620,121.217,119.590,114.525,110.394,109.818,107.232,99.274,
55.508,39.624,27.544,26.608,25.716,25.625,24.161,17.652,17.600,15.921；(ESI)-
MS,m/z:511.2460 [M+Na]+(theoretical value 511.2461).
Embodiment 3：
Derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, target product II, target production
Thing III, structural formula are as follows：
Preparation method is as follows：
Step 1: 2.000g 2,4-dihydroxyacetophenones are dissolved in acetone soln, add 1.816g potassium carbonate and stir back
10min is flowed, 2.549g isoprenyl bromides backflow 10h is added dropwise, is cooled to room temperature, decompression removes solvent, has been extracted with ethyl acetate
Machine phase, successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)
=10:1, the first intermediate product (1.146g yields 39.59%) of yellow liquid is obtained, structure is analyzed true through IR, NMR and MS
Fixed, structural formula is as follows：
Step 2: 0.681g the first intermediate product is dissolved in anhydrous propanone, adds 1.281g Anhydrous potassium carbonates and stir
10min is mixed, with 0.427g dimethyl suflfates are added dropwise in constant pressure funnel 10min, back flow reaction 6h, room temperature are cooled to, use salt
Acid regulation pH value is extracted with ethyl acetate organic phase, done successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate to 2
It is dry, column chromatography V is carried out afterwards(petroleum ether)：V(ethyl acetate)=10:1, obtain the second intermediate product (0.483g yields of yellow oily
66.68%), structure is analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 3: weighing 1.139g 2,4- dimethoxybenzoic acids add 2.980g dichloros in 100mL round-bottomed flasks
Sulfoxide backflow 1h, vacuum rotary steam remove excessive thionyl chloride, are then added into the nothing of the dissolving intermediate products of 0.977g second
In water pyridine, 80 DEG C of reaction 2h, it is cooled to room temperature and adds ethyl acetate extraction organic phase, successively with watery hydrochloric acid, water, saturated common salt
Water washing organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, intermediate compound being obtained, the intermediate compound is not purified,
It is dissolved in pyridine, adds the preheated potassium hydroxide powders of 0.526g, 100 DEG C of reaction 30min, be cooled to room temperature, add
Enter ethyl acetate extraction organic phase, successively with watery hydrochloric acid, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, afterwards
Carry out column chromatography V(petroleum ether)：V(ethyl acetate)=4:1, obtain the 3rd intermediate product (0.914g yields 55.00%) of yellow oily, structure
Analyze and determine through IR, NMR and MS, structural formula is as follows：
Step 4: the intermediate products of 0.894g the 3rd are dissolved in anhydrous propanone, the backflow of 0.930g Anhydrous potassium carbonates is added
10min, dropwise addition 0.731g geranyl bromides, backflow 3h, cooling are spin-dried for solvent, add ethyl acetate extraction organic phase, difference water, satisfy
With brine It organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V(petroleum ether)：V(ethyl acetate)=10:1, obtain yellow oily
4th intermediate product (1.129g yields 85.78%), structure are analyzed through IR, NMR and MS and determined, structural formula is as follows：
Step 5: the intermediate products of 0.970g the 4th are dissolved in 15mL methanol, the 3 drop concentrated sulfuric acids are added dropwise, flow back 3h, decompression
Solvent evaporated, ethyl acetate extraction organic phase is added, respectively with saturated common salt water washing organic phase, anhydrous sodium sulfate drying, it
Column chromatography V afterwards(petroleum ether)：V(ethyl acetate)=5:1, obtain the 5th intermediate product (0.711g yields 73.58%) of yellow liquid), knot
Structure is analyzed through IR, NMR and MS and determined, structural formula is as follows：
5th intermediate product：IR(KBr):3104,2972,2838,1641,1616,1504,1394,1210,1155,
1093,833,816cm-1。1HNMR (300MHz, Chloroform-d) δ 7.33 (d, J=8.4Hz, 1H), 7.28 (d, J=
9.0Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 6.55 (m, 2H), 5.45-5.12 (m, 2H), 5.06 (t, J=6.5Hz, 1H),
3.95 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H), 3.36 (d, J=7.4Hz, 2H), 3.08 (d, J=6.8Hz, 2H),
2.10–1.84(m,4H),1.70(s,3H),1.64(s,3H),1.57(s,6H),1.39(s,3H).13CNMR(75MHz,
CDCl3)δ178.321,162.321,158.468,158.052,157.995,156.029,134.634,132.881,
132.553,131.542,131.061,124.497,123.791,122.285,122.247,121.742,115.418,
113.929,105.123,104.364,98.597,56.225,55.460,55.429,39.689,27.908,26.718,
25.726,25.627,24.757,17.637,17.566,15.874；(ESI)-MS,m/z:517.2949[M+H]+(theoretical value
517.2954)。
Step 6: 0.267mL ethyl mercaptans are dissolved in 5mL HMPAs in 0 DEG C of stirring under argon gas protection
10min, add the n-BuLi that 0.761mL concentration is 2.5M and react 30min, by six dissolved with the intermediate products of 0.452g the 5th
Methyl phosphoric triamide solution is added in freshly prepd ethylmercapto group lithium, 70 DEG C of reaction 6h, is added 4mL saturated ammonium chlorides and is quenched instead
Should, it is extracted with ethyl acetate organic phase, saturation lithium chloride washing organic phase, anhydrous sodium sulfate drying, column chromatography V afterwards(petroleum ether)：
V(ethyl acetate)=4:1, obtain target product II (0.157g yields 36.73%), III (the 0.230g yields of yellow liquid
53.80%), target product II, III structures are analyzed through IR, NMR and MS and determined, structural formula is as follows：
Target product II：IR(KBr):3433,3112,2962,2912,1645,1576,1394,1382,1063,1030,
961,826cm-1.1HNMR (300MHz, Chloroform-d) δ 12.70 (s, 1H), 7.27 (m, 2H), 6.64 (d, J=
8.3Hz, 1H), 6.61 (s, 1H), 6.57 (d, J=2.5Hz, 1H), 5.23 (t, J=7.2Hz, 1H), 5.17 (t, J=6.8Hz,
1H), 5.06 (t, J=6.3Hz, 1H), 3.87 (s, 3H), 3.37 (d, J=7.3Hz, 2H), 3.20 (d, J=6.8Hz, 2H),
2.06–1.89(m,4H),1.73(s,3H),1.65(s,3H),1.63(s,3H),1.58(s,3H),1.47(s,3H).13CNMR
(75MHz,CDCl3)δ183.499,162.827,160.915,158.264,155.474,153.875,136.619,
135.063,133.588,131.331,131.326,124.232,121.693,121.493,120.857,119.594,
112.581,110.086,110.051,107.085,102.212,55.451,39.596,27.619,26.545,25.720,
25.637,24.209,17.723,17.671,15.986；(ESI)-MS,m/z:[489.2658 M+H]+(theoretical value
489.2641)。
Target product III：IR(KBr):3423,2967,2917,2885,1644,1551,1489,1402,1310,
1220,1060,1035,941,826cm-1.1HNMR (300MHz, Chloroform-d) δ 12.87 (s, 1H), 7.36 (d, J=
8.3Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 6.74 (d, J=8.3Hz, 1H), 6.64-6.46 (m, 2H), 6.38 (s, 1H),
5.26 (t, J=7.3Hz, 1H), 5.15 (t, J=6.5Hz, 1H), 5.06 (t, J=6.5Hz, 1H), 3.80 (s, 3H), 3.37
(d, J=7.3Hz, 2H), 3.13 (d, J=6.6Hz, 2H), 1.97 (m, 4H), 1.71 (s, 3H), 1.65 (s, 3H), 1.59 (s,
3H),1.58(s,3H),1.44(s,3H).13CNMR(75MHz,CDCl3)δ183.823,161.892,159.321,
158.666,158.537,154.235,135.756,134.801,132.927,131.529,131.289,124.279,
121.727,121.620,121.217,119.590,114.525,110.394,109.818,107.232,99.274,
55.508,39.624,27.544,26.608,25.716,25.625,24.161,17.652,17.600,15.921；(ESI)-
MS,m/z:511.2460 [M+Na]+(theoretical value 511.2461).
Comparative example：
Passing flavone compound A, B for being used to prepare treatment stomach cancer developed is selected, structural formula is distinguished as follows：
Its pharmaceutical activity and its application are further illustrated below by pharmacodynamic experiment.
Experiment one：Vitro cytotoxicity is tested：
Experimental group is used as using the target product (II, III) of example 3, using flavone compound A, B as a control group,
Cytotoxicity test is carried out to stomach cancer cell.From stomach cancer cell line (7901), using mtt assay, vitro cytotoxicity survey is carried out
Examination.
Take the logarithm growth period 7901 cells with 104Individual/mL density is inoculated in 96 orifice plates, and 200 μ L are inoculated with per hole, are placed in
CO2Cultivated in incubator 24 hours, then add testing sample (II, III, A, B) by default concentration gradient, each gradient is set
Three parallel holes, while set up blank (first three hole adds the μ L of RPM I1640 liquid-baseds 200 of not drug containing, and rear three hole adds without cell not
The μ L of RPM I1640 liquid-baseds 200 of drug containing), after cultivating 72 hours, 20 μ L MTT (5mg/mL) is added per hole, is subsequently placed in 37 DEG C
Incubated 4 hours in incubator, 200 μ L DMSO is added after extraction supernatant, concussion 10min dissolving precipitations, then uses ELIASA
Check OD values, wavelength 570nm.Sample is obtained under sample finite concentration to the inhibiting rate of cell with following formula：
Inhibiting rate=[(control OD- blank OD)-(administration OD- blank OD)]/(control OD- blank OD) * 100%
Fig. 1 is made to drug concentration with inhibiting rate, obtains the IC of each sample50Value, as a result as shown in table 1.
Table 1
| Compound | 7901(μmol/L) |
| II | 7.2 |
| III | 9.4 |
| A | 25.3 |
| B | 23.4 |
It can be shown by table 1, the 503nhibiting concentration of target product of the invention (II, III) is far below A, B less than 10, substitution
Activity is suitable with cis-platinum.Illustrate that 6 isopentene group substitution 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyls of A rings of the present invention are yellow
Ketone has obvious growth inhibition effect to the cell of stomach cancer 7901, the medicine available for screening treatment stomach cancer.
Although embodiment of the present invention is disclosed as above, it is not restricted in specification and embodiment listed
With it can be applied to various suitable the field of the invention completely, can be easily for those skilled in the art
Other modification is realized, therefore under the universal limited without departing substantially from claim and equivalency range, it is of the invention and unlimited
In specific details and shown here as the embodiment with description.
Claims (9)
1. one kind has 5, the derivative of 2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones, it is characterised in that this spreads out
Biology has following structural formula；
A kind of 2. derivative as claimed in claim 1 with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Preparation method, it is characterised in that comprise the following steps：
Step 1: with 2,6- resacetophenones for initiation material, iso-amylene glycosylation reaction is carried out, using column chromatography, VPetroleum ether：
VEthyl acetate=10:1, obtain the first intermediate product of yellow liquid；
Step 2: first intermediate product is dissolved in anhydrous propanone, methylation reaction is carried out, using column chromatography, VPetroleum ether：
VEthyl acetate=10:1, obtain the second intermediate product of yellow oily；
Step 3: taking 2,4- dimethoxybenzoic acids and thionyl chloride, flow back, add and be dissolved with described second after vacuum rotary steam
Between product anhydrous pyridine in, carry out into ester reaction, rearrangement reaction, using column chromatography, VPetroleum ether：VEthyl acetate=4:1, obtain yellow
3rd intermediate product of oily；
Step 4: the 3rd intermediate product is taken to carry out geranylgeranylation reaction, using column chromatography, VPetroleum ether：VEthyl acetate=10:1, obtain
4th intermediate product of yellow oily；
Step 5: the 4th intermediate product is dissolved in methanol, ring closure reaction is carried out, using column chromatography, VPetroleum ether：VEthyl acetate
=5:1, obtain the 5th intermediate product of yellow liquid；
Step 6: the 5th intermediate product is dissolved in HMPA, demethylating reaction is carried out, using post layer
Analysis, VPetroleum ether：VEthyl acetate=4:1, obtain the target product of yellow liquid.
3. the system of the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones as claimed in claim 2
Preparation Method, it is characterised in that the iso-amylene glycosylation reaction in the step 1 specifically includes：By 180~220 parts by weight 2,6- bis-
Hydroxy acetophenone is dissolved in acetone soln, is added 15~21 pbw of potassium carbonate and is stirred 8~12min of backflow, 20~30 weights are added dropwise
Number isoprenyl bromide 8~12h of backflow is measured, is cooled to room temperature, decompression removes solvent, organic phase is extracted with ethyl acetate, successively
With water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography is carried out afterwards and obtains first intermediate product, institute
State the first intermediate product structure and analyze determination through IR, NMR and MS.
4. the system of the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones as claimed in claim 2
Preparation Method, it is characterised in that the methylation reaction in the step 2 refers specifically to：By the first intermediate product described in 5~8 parts by weight
Be dissolved in anhydrous propanone, add 10~15 parts by weight Anhydrous potassium carbonate stir 8~12min, with constant pressure funnel 8~
3.5~5 parts sulfuric acid dimethyl esters are added dropwise in 12min, 5~7h of back flow reaction, are cooled to room temperature, with salt acid for adjusting pH value to 2,
Organic phase is extracted with ethyl acetate, successively with water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carries out post afterwards
Second intermediate product is chromatographed to obtain, the second intermediate product structure is analyzed through IR, NMR and MS and determined.
5. the system of the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones as claimed in claim 2
Preparation Method, it is characterised in that described to be reacted into ester in the step 3, rearrangement reaction refers specifically to：10~15 parts by weight 2 are weighed,
4- dimethoxybenzoic acids add 26~32 parts by weight thionyl chlorides, 0.8~1.2h of backflow in round-bottomed flask, and vacuum rotary steam removes
Excessive thionyl chloride is removed, is then added into the anhydrous pyridine of the second intermediate product described in 8~12 parts by weight of dissolving, 70~
90 DEG C of 1.5~2.5h of reaction, it is cooled to room temperature and adds ethyl acetate extraction organic phase, successively with watery hydrochloric acid, water, saturated aqueous common salt
Organic phase is washed, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtains intermediate compound, the intermediate compound is not purified, will
It is dissolved in pyridine, adds the preheated potassium hydroxide powder of 4~6 parts by weight, 95~105 DEG C of 20~40min of reaction, cooling
To room temperature, ethyl acetate extraction organic phase is added, successively with watery hydrochloric acid, water, saturated common salt water washing organic phase, anhydrous sodium sulfate
Dry, carry out column chromatography afterwards and obtain the 3rd intermediate product, the 3rd intermediate product structure is analyzed true through IR, NMR and MS
It is fixed.
6. the system of the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones as claimed in claim 2
Preparation Method, it is characterised in that in the step 4, the geranylgeranylation reaction refers specifically to：In the 3rd described in 7~10 parts by weight
Between product be dissolved in anhydrous propanone, add 8~10.5 parts by weight Anhydrous potassium carbonates flow back 8~12min, be added dropwise 6~8.5 weight
Part geranyl bromide, flow back 2~4h, and cooling is spin-dried for solvent, adds ethyl acetate extraction organic phase, difference water, saturated common salt washing
Wash organic phase, anhydrous sodium sulfate drying, afterwards column chromatography obtain the 4th intermediate product, the 4th intermediate product structure warp
IR, NMR and MS analysis determine.
7. the system of the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones as claimed in claim 2
Preparation Method, it is characterised in that in the step 5, the ring closure reaction refers specifically to：Is produced from 4th centre described in 8~11 parts by weight
Thing is dissolved in 10~14 parts by weight Methanol, 2~4 drop concentrated sulfuric acids is added dropwise, flow back 2~4h, evaporated under reduced pressure solvent, adds acetic acid second
Ester extracts organic phase, respectively with saturated common salt water washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography obtain in the described 5th
Between product, the 5th intermediate product structure through IR, NMR and MS analyze determine.
8. the system of the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones as claimed in claim 2
Preparation Method, it is characterised in that in the step 6, the demethylating reaction refers specifically to：By 2~2.5 parts by weight under argon gas protection
Ethyl mercaptan is dissolved in 40~60 parts by weight HMPAs and stirs 8~12min in 0~2 DEG C, adds 6~8 parts by weight concentration
25~35min is reacted for 2~3M n-BuLi, by the hexamethyl phosphinylidyne dissolved with the 5th intermediate product described in 5~6 parts by weight
Triamine solution is added in freshly prepd ethylmercapto group lithium, 60~80 DEG C of 5~7h of reaction, adds 50~70 parts by weight saturated ammonium chlorides
Reaction is quenched, is extracted with ethyl acetate organic phase, saturation lithium chloride washing organic phase, anhydrous sodium sulfate drying, column chromatography afterwards
Target product is obtained, target product structure is analyzed through IR, NMR and MS and determined.
9. as claimed in claim 1 prepared by the derivative with 5,2 '-dihydroxy -4 '-methoxyl group -3- geranyl lavonoid backbones
Treat the purposes of the medicine of stomach cancer.
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