CN105111174A - Derivative with 5,2'-dihydroxy-4'-methoxy-3-geranylflavonoids skeleton, and preparation method and applications thereof - Google Patents
Derivative with 5,2'-dihydroxy-4'-methoxy-3-geranylflavonoids skeleton, and preparation method and applications thereof 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 derivative with a 5,2'-dihydroxy-4'-methoxy-3-geranylflavonoids skeleton, and a preparation method and applications thereof. The derivative comprises a general chemical structure represented by formula (I), or is a pharmaceutically acceptable salt with the general chemical structure, wherein R1 and R2 are used for representing -OCH3 or OH. The derivative possesses excellent anti-stomach cancer activity, and can be used for multi-target therapy, multi-link therapy, and multiple response therapy; toxicity is low; and drug resistance is not easily caused.
Description
Technical field
The present invention relates to and have 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, be specifically related to A ring 6 isopentene groups and replaced 5,2 '-dihydroxyl-4 '-methoxyl group-3-geranyl flavones and its production and use.
Background technology
Cancer of the stomach is to one of dangerous maximum disease of human health and quality of life, therefore seeks efficient, high to select and anti-gastric cancer medicament that toxic side effect is little is the Main way of drug research.Flavonoid compound is that a class is present in natural, to have 2-phenyl chromone structure compound, and its biological activity is varied, and has very strong pharmacologically active.There are some researches show, flavonoid compound has anti-tumor activity, in the treatments such as lung cancer, colorectal carcinoma, mammary cancer and prevention, play significant role, and it stops the mechanism such as cancer cell multiplication, inducing apoptosis of tumour cell, anti-oxidant activity, the formation of suppression new vessel.But obtain flavonoid compound at present and mainly pass through traditional Chinese medicine extraction, volume production is carried out more difficult by separation and Extraction, and flavonoid compound complex structure, act as a little many, cause for poor selectivity, its mechanism of action, basic substance all do not have clear and definite theoretical explanation, thus structural formula, targeting all have can not be handling.
Therefore, modified its structure of modification by chemosynthesis, find the modification flavonoid compound of a kind of activity is better, side effect is less Mutiple Targets, too many levels, manifold effect, strengthening its specific pharmacologically active to treat cancer of the stomach is need the technical barrier of solution at present badly.
Summary of the invention
As the result of various extensive and careful research and experiment, the present inventor has been found that the volume ratio controlling column chromatography in building-up process technique, and described compound contributes to the performance improving treatment cancer of the stomach.Based on this discovery, complete the present invention.
An object of the present invention is to solve at least the problems referred to above and/or defect, and the advantage will illustrated at least is below provided.
A further object of the invention is to provide one and has 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, it is active that it has good anti-cancer of the stomach, Mutiple Targets, too many levels, heterogeneous should, toxicity is low, not easily produces resistance.
A further object of the invention is to provide described in one has 5,2 '-dihydroxyl-4 ' method of organic synthesis of derivative of-methoxyl group-3-geranyl lavonoid backbone, by isopentene group, methylate, become ester, rearrangement, geranylgeranylation, Guan Huan and demethylation, preparation method simply, easily controls, improve the target spot of described compound, to obtain better selectivity and activity.
In order to realize according to these objects of the present invention and other advantage, provide one and have 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, this derivative has following chemical general formula (I) or its pharmacy acceptable salt;
Wherein, R
1, R
2expression-OCH
3or OH.
Preferably, described has 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone is one of following compound of structural formula:
One has 5,2 '-dihydroxyl-4 ' preparation method of the derivative of-methoxyl group-3-geranyl lavonoid backbone, comprise the following steps:
Step one, be starting raw material with 2,4-dihydroxyacetophenone, carry out isopentene glycosylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of yellow liquid;
Step 2, described first intermediate product is dissolved in acetic acid, carries out methylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the second intermediate product of yellow oily;
Step 3, get 2,4-dimethoxybenzoic acid and thionyl chloride, backflow, adds after vacuum rotary steam in the anhydrous pyridine being dissolved with described second intermediate product, carries out into ester reaction, rearrangement reaction, adopts column chromatography, V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the 3rd intermediate product of yellow oily;
Step 4, get described 3rd intermediate product and carry out geranylgeranylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the 4th intermediate product of yellow oily;
Step 5, described 4th intermediate product is dissolved in methyl alcohol, carries out ring closure reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=5:1, obtains the 5th intermediate product of yellow liquid;
Step 6, described 5th intermediate product is dissolved in HMPA, carries out demethylating reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the target product of yellow liquid.
Preferably, described has 5, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, isopentene glycosylation reaction in described step one specifically comprises: by 180 ~ 220 weight parts 2, 4-resacetophenone is dissolved in acetone soln, add 15 ~ 21 pbw of potassium carbonate and stir backflow 8 ~ 12min, drip 20 ~ 30 parts by weight isoprenyl bromide backflow 8 ~ 12h, be cooled to room temperature, solvent is removed in decompression, be extracted with ethyl acetate organic phase, use water successively, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography afterwards and obtain described first intermediate product, described first intermediate product structure is through IR, NMR and MS analyzes and determines.
Preferably, described has 5, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, methylation reaction in described step 2 specifically refers to: be dissolved in anhydrous propanone by the first intermediate product described in 5 ~ 8 weight parts, the Anhydrous potassium carbonate adding 10 ~ 15 weight parts stirs 8 ~ 12min, 3.5 ~ 5 parts sulfuric acid dimethyl esters are dripped with in constant pressure funnel 8 ~ 12min, back flow reaction 5 ~ 7h, be cooled to room temperature, regulate pH value to 2 with hydrochloric acid, be extracted with ethyl acetate organic phase, use water successively, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography afterwards and obtain described second intermediate product, described second intermediate product structure is through IR, NMR and MS analyzes and determines.
Preferably, described has 5, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, in described step 3, described one-tenth ester reaction, rearrangement reaction specifically refers to: take 10 ~ 15 weight parts 2, 4-dimethoxybenzoic acid is in round-bottomed flask, add 26 ~ 32 weight part thionyl chloride backflow 0.8 ~ 1.2h, vacuum rotary steam removes excessive thionyl chloride, then joined in the anhydrous pyridine of the second intermediate product described in dissolving 8 ~ 12 weight part, 70 ~ 90 DEG C of reaction 1.5 ~ 2.5h, cool to room temperature adds extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in pyridine, add the potassium hydroxide powder that 4 ~ 6 weight parts are preheated, 95 ~ 105 DEG C of reaction 20 ~ 40min, cool to room temperature, add extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography afterwards and obtain described 3rd intermediate product, described 3rd intermediate product structure is through IR, NMR and MS analyzes and determines.
Preferably, described has 5, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, in described step 4, described geranylgeranylation reaction specifically refers to: be dissolved in anhydrous propanone by the 3rd intermediate product described in 7 ~ 10 weight parts, add 8 ~ 10.5 weight part Anhydrous potassium carbonate backflow 8 ~ 12min, drip 6 ~ 8.5 weight part geranyl bromides, backflow 2 ~ 4h, cooling is spin-dried for solvent, add extraction into ethyl acetate organic phase, water respectively, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography obtains described 4th intermediate product afterwards, described 4th intermediate product structure is through IR, NMR and MS analyzes and determines.
Preferably, described has 5, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, in described step 5, described ring closure reaction specifically refers to: be dissolved in 10 ~ 14 parts by weight Methanol by the 4th intermediate product described in 8 ~ 11 weight parts, drip 2 ~ 4 vitriol oils, backflow 2 ~ 4h, evaporated under reduced pressure solvent, add extraction into ethyl acetate organic phase, use saturated common salt water washing organic phase respectively, anhydrous sodium sulfate drying, column chromatography obtains described 5th intermediate product afterwards, described 5th intermediate product structure is through IR, NMR and MS analyzes and determines.
Preferably, described has 5, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, in described step 6, described demethylating reaction specifically refers to: under argon shield, 2 ~ 2.5 weight part sulfur alcohols are dissolved in 40 ~ 60 weight part HMPA and stir 8 ~ 12min in 0 ~ 2 DEG C, add n-Butyl Lithium reaction 25 ~ 35min that 6 ~ 8 weight part concentration are 2 ~ 3M, the HMPA solution being dissolved with the 5th intermediate product described in 5 ~ 6 weight parts is joined in freshly prepd ethylmercapto group lithium, 60 ~ 80 DEG C of reaction 5 ~ 7h, add 50 ~ 70 weight part saturated ammonium chloride cancellation reactions, be extracted with ethyl acetate organic phase, saturated lithium chloride washing organic phase, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, target product structure is through IR, NMR and MS analyzes and determines.
One has 5,2 '-dihydroxyl-4 ' purposes of the derivative of-methoxyl group-3-geranyl lavonoid backbone, for the preparation of the medicine for the treatment of cancer of the stomach.
The present invention at least comprises following beneficial effect:
The first, flavonoid compound intervene cell go to procedure in enzymic activity, thus suppression proliferation of human gastric cancer cell, and to the effect of not normal cells evil, antioxygenation and forward immunoregulation effect can be shown, owing to having multiple position be substituted, can be modified to obtain the anti-gastric cancer medicament that can strengthen its specific pharmacologically active;
The second, cancel the oxo of 7, A ring, introduce C ring 3 geranyls, selectivity carbon, for geranylgeranylation, improves the biological activity of flavonoid compound, the effect of the anti-cancer of the stomach had and faint cytotoxicity;
Three, A ring 6 isopentene groups are introduced, avoid forming larger repulsion with geranyl, ensure the stability of compound, and act synergistically with skeleton, the existence of isopentenyl side chain adds the lipotropy of flavonoid compound, make it in organism, be easier to permeate through cell membranes arrival effect target, strengthen the biological activity of flavonoid compound;
Four, the preparation method of the present invention's use is simple to operate, the reaction times is short, and the compound purity of preparation is high, form good.
Part is embodied by explanation below by other advantage of the present invention, target and feature, part also will by research and practice of the present invention by those skilled in the art is understood.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, can implement according to this with reference to specification sheets word to make those skilled in the art.
Embodiment 1:
Have 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, target product II, target product III, structural formula is as follows:
Preparation method is as follows:
Step one, by 2.205g2,4-resacetophenone is dissolved in acetone soln, add 2.057g salt of wormwood and stir backflow 8min, drip 2.012g isoprenyl bromide backflow 8h, be cooled to room temperature, solvent is removed in decompression, be extracted with ethyl acetate organic phase, use water, saturated common salt water washing organic phase successively, anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (1.113g productive rate 34.23%) of yellow liquid, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, first intermediate product of 0.789g is dissolved in anhydrous propanone, add 1.502g Anhydrous potassium carbonate and stir 12min, 0.505g methyl-sulfate is dripped with in constant pressure funnel 12min, back flow reaction 7h, is cooled to room temperature, regulates pH value to 2 with hydrochloric acid, be extracted with ethyl acetate organic phase, use water, saturated common salt water washing organic phase successively, anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(oil ether): V
(ethyl acetate)=10:1, obtains second intermediate product (0.443g productive rate 64.62%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, take 1.052g2, 4-dimethoxybenzoic acid is in 100mL round-bottomed flask, add 3.188g thionyl chloride backflow 1.2h, vacuum rotary steam removes excessive thionyl chloride, then joined in the anhydrous pyridine dissolving 1.222g second intermediate product, 90 DEG C of reaction 2.5h, cool to room temperature adds extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in pyridine, add the potassium hydroxide powder that 0.601g is preheated, 105 DEG C of reaction 40min, cool to room temperature, add extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=4:1, obtains the 3rd intermediate product (0.897g productive rate 53.20%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 4,0.712g the 3rd intermediate product is dissolved in anhydrous propanone, add 0.823g Anhydrous potassium carbonate backflow 8min, drip 0.628g geranyl bromide, backflow 2h, cooling is spin-dried for solvent, adds extraction into ethyl acetate organic phase, respectively water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the 4th intermediate product (1.121g productive rate 85.45%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 5, be dissolved in 12mL methyl alcohol by 0.812g the 4th intermediate product, drip 2 vitriol oils, backflow 2h, evaporated under reduced pressure solvent, adds extraction into ethyl acetate organic phase, uses saturated common salt water washing organic phase respectively, anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=5:1, obtains the 5th intermediate product (0.717g productive rate 73.69%) of yellow liquid, and 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, CDCl
3) δ 178.321,162.321,158.468,158.052,157.995,156.029,134.634,132.881,132.553,131.542,131.061,124.497,123.791,122.285,122.247,121.742,115.418,113.929,105.123,104.364,98.597,56.225,55.460,55.429,39.689,27.908,26.718,25.726,25.627,24.757,17.637,17.566,15.874; (ESI)-MS, m/z:517.2949 [M+H]
+(theoretical value 517.2954).
Under step 6, argon shield, 0.232mL sulfur alcohol is dissolved in 4mL HMPA and stirs 8min in 0 DEG C; add the n-Butyl Lithium reaction 25min that 0.690mL concentration is 2M; the HMPA solution being dissolved with 0.526g the 5th intermediate product is joined in freshly prepd ethylmercapto group lithium; 60 DEG C of reaction 5h; add 3mL saturated ammonium chloride cancellation reaction, be extracted with ethyl acetate organic phase, saturated lithium chloride washing organic phase; anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the target product II (0.132g productive rate 32.71%) of yellow liquid, III (0.214g productive rate 52.42%), and target product II, III structure is 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) δ 183.499, 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) δ 183.823, 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:
Have 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, target product II, target product III, structural formula is as follows:
Preparation method is as follows:
Step one, by 1.812g2,4-resacetophenone is dissolved in acetone soln, add 1.523g salt of wormwood and stir backflow 12min, drip 3.012g isoprenyl bromide backflow 12h, be cooled to room temperature, solvent is removed in decompression, be extracted with ethyl acetate organic phase, use water, saturated common salt water washing organic phase successively, anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (1.121g productive rate 35.52%) of yellow liquid, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, first intermediate product of 0.521g is dissolved in anhydrous propanone, add 1.012g Anhydrous potassium carbonate and stir 8min, 0.355g methyl-sulfate is dripped with in constant pressure funnel 8min, back flow reaction 5h, is cooled to room temperature, regulates pH value to 2 with hydrochloric acid, be extracted with ethyl acetate organic phase, use water, saturated common salt water washing organic phase successively, anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(oil ether): V
(ethyl acetate)=10:1, obtains second intermediate product (0.421g productive rate 62.61%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, take 1.495g2, 4-dimethoxybenzoic acid is in 100mL round-bottomed flask, add 2.642g thionyl chloride backflow 0.8h, vacuum rotary steam removes excessive thionyl chloride, then joined in the anhydrous pyridine dissolving 0.832g second intermediate product, 70 DEG C of reaction 1.5h, cool to room temperature adds extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in pyridine, add the potassium hydroxide powder that 0.465g is preheated, 95 DEG C of reaction 20min, cool to room temperature, add extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=4:1, obtains the 3rd intermediate product (0.877g productive rate 52.10%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 4,1.002g the 3rd intermediate product is dissolved in anhydrous propanone, add 1.051g Anhydrous potassium carbonate backflow 12min, drip 0.851g geranyl bromide, backflow 4h, cooling is spin-dried for solvent, adds extraction into ethyl acetate organic phase, respectively water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the 4th intermediate product (1.112g productive rate 84.93%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 5, be dissolved in 18mL methyl alcohol by 1.112g the 4th intermediate product, drip 4 vitriol oils, backflow 4h, evaporated under reduced pressure solvent, adds extraction into ethyl acetate organic phase, uses saturated common salt water washing organic phase respectively, anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=5:1, obtains the 5th intermediate product (0.701g productive rate 72.23%) of yellow liquid, and 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, CDCl
3) δ 178.321,162.321,158.468,158.052,157.995,156.029,134.634,132.881,132.553,131.542,131.061,124.497,123.791,122.285,122.247,121.742,115.418,113.929,105.123,104.364,98.597,56.225,55.460,55.429,39.689,27.908,26.718,25.726,25.627,24.757,17.637,17.566,15.874; (ESI)-MS, m/z:517.2949 [M+H]
+(theoretical value 517.2954).
Under step 6, argon shield, 0.291mL sulfur alcohol is dissolved in 6mL HMPA and stirs 12min in 2 DEG C; add the n-Butyl Lithium reaction 35min that 0.851mL concentration is 3M; the HMPA solution being dissolved with 0.606g the 5th intermediate product is joined in freshly prepd ethylmercapto group lithium; 80 DEG C of reaction 7h; add 5mL saturated ammonium chloride cancellation reaction, be extracted with ethyl acetate organic phase, saturated lithium chloride washing organic phase; anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the target product II (0.142g productive rate 34.74%) of yellow liquid, III (0.204g productive rate 51.43%), and target product II, III structure is 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) δ 183.499, 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) δ 183.823, 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:
Have 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, target product II, target product III, structural formula is as follows:
Preparation method is as follows:
Step one, by 2.000g2,4-resacetophenone is dissolved in acetone soln, add 1.816g salt of wormwood and stir backflow 10min, drip 2.549g isoprenyl bromide backflow 10h, be cooled to room temperature, solvent is removed in decompression, be extracted with ethyl acetate organic phase, use water, saturated common salt water washing organic phase successively, anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (1.146g productive rate 39.59%) of yellow liquid, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, first intermediate product of 0.681g is dissolved in anhydrous propanone, add 1.281g Anhydrous potassium carbonate and stir 10min, 0.427g methyl-sulfate is dripped with in constant pressure funnel 10min, back flow reaction 6h, is cooled to room temperature, regulates pH value to 2 with hydrochloric acid, be extracted with ethyl acetate organic phase, use water, saturated common salt water washing organic phase successively, anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(oil ether): V
(ethyl acetate)=10:1, obtains second intermediate product (0.483g productive rate 66.68%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, take 1.139g2, 4-dimethoxybenzoic acid is in 100mL round-bottomed flask, add 2.980g thionyl chloride backflow 1h, vacuum rotary steam removes excessive thionyl chloride, then joined in the anhydrous pyridine dissolving 0.977g second intermediate product, 80 DEG C of reaction 2h, cool to room temperature adds extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in pyridine, add the potassium hydroxide powder that 0.526g is preheated, 100 DEG C of reaction 30min, cool to room temperature, add extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=4:1, obtains the 3rd intermediate product (0.914g productive rate 55.00%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 4,0.894g the 3rd intermediate product is dissolved in anhydrous propanone, add 0.930g Anhydrous potassium carbonate backflow 10min, drip 0.731g geranyl bromide, backflow 3h, cooling is spin-dried for solvent, adds extraction into ethyl acetate organic phase, respectively water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the 4th intermediate product (1.129g productive rate 85.78%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 5, be dissolved in 15mL methyl alcohol by 0.970g the 4th intermediate product, drip 3 vitriol oils, backflow 3h, evaporated under reduced pressure solvent, adds extraction into ethyl acetate organic phase, uses saturated common salt water washing organic phase respectively, anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=5:1, obtains the 5th intermediate product (0.711g productive rate 73.58%) of yellow liquid), structure is analyzed through IR, NMR and MS and is 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, CDCl
3) δ 178.321,162.321,158.468,158.052,157.995,156.029,134.634,132.881,132.553,131.542,131.061,124.497,123.791,122.285,122.247,121.742,115.418,113.929,105.123,104.364,98.597,56.225,55.460,55.429,39.689,27.908,26.718,25.726,25.627,24.757,17.637,17.566,15.874; (ESI)-MS, m/z:517.2949 [M+H]
+(theoretical value 517.2954).
Under step 6, argon shield, 0.267mL sulfur alcohol is dissolved in 5mL HMPA and stirs 10min in 0 DEG C; add the n-Butyl Lithium reaction 30min that 0.761mL concentration is 2.5M; the HMPA solution being dissolved with 0.452g the 5th intermediate product is joined in freshly prepd ethylmercapto group lithium; 70 DEG C of reaction 6h; add 4mL saturated ammonium chloride cancellation reaction, be extracted with ethyl acetate organic phase, saturated lithium chloride washing organic phase; anhydrous sodium sulfate drying, afterwards column chromatography V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the target product II (0.157g productive rate 36.73%) of yellow liquid, III (0.230g productive rate 53.80%), and target product II, III structure is 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) δ 183.499, 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) δ 183.823, 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:
Select passing flavonoid compound A, B for the preparation for the treatment of cancer of the stomach of developing, structural formula is as follows respectively:
Its pharmaceutical activity and application thereof is further illustrated below by pharmacodynamic experiment.
Experiment one: vitro cytotoxicity is tested:
Adopt the target product (II, III) of example 3 as experimental group, adopt flavonoid compound A, B as a control group, cytotoxicity test is carried out to stomach cancer cell.Select stomach cancer cell line (7901), adopt mtt assay, carry out vitro cytotoxicity test.
7901 cells of taking the logarithm vegetative period are with 10
4the density of individual/mL is inoculated in 96 orifice plates, and 200 μ L are inoculated in every hole, are placed in CO
2cultivate 24 hours in incubator, then testing sample (II is added by the concentration gradient preset, III, A, B), each gradient establishes three parallel holes, set up blank (first three hole adds the RPMI1640 liquid base 200 μ L of not pastille simultaneously, rear three holes add not containing the RPMI1640 liquid base 200 μ L of cell not pastille), cultivate after 72 hours, every hole adds the MTT (5mg/mL) of 20 μ L, then 37 DEG C of incubator incubations are placed in 4 hours, the DMSO of 200 μ L is added after extracting supernatant liquor, concussion 10min dissolution precipitation, OD value is checked subsequently by microplate reader, wavelength 570nm.Under obtaining sample finite concentration with following formula, sample is to the inhibiting rate of cell:
Inhibiting rate=[(the blank OD of contrast OD-)-(the blank OD of administration OD-)]/(blank OD of contrast OD-) * 100%
With inhibiting rate, Fig. 1 is done to drug level, obtain the IC of each sample
50value, result is as shown in table 1.
Table 1
| Compound | 7901(μmol/L) |
| II | 7.2 |
| III | 9.4 |
| A | 25.3 |
| B | 23.4 |
Can be shown by table 1, the 503nhibiting concentration of target product of the present invention (II, III) all far below A, B, replaces active suitable with cis-platinum lower than 10.Illustrating that A ring of the present invention 6 isopentene groups replace 5,2 '-dihydroxyl-4 '-methoxyl group-3-geranyl flavones has obvious growth-inhibiting effect to cancer of the stomach 7901 cell, can be used for the medicine screening treatment cancer of the stomach.
Although embodiment of the present invention are open as above, but it is not restricted to listed in specification sheets and embodiment utilization, it can be applied to various applicable the field of the invention completely, for those skilled in the art, can easily realize other amendment, therefore do not deviating under the universal that claim and equivalency range limit, the present invention is not limited to specific details and illustrates here and the embodiment described.
Claims (10)
1. one kind has 5,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, this derivative has following chemical general formula (I) or its pharmacy acceptable salt;
Wherein, R
1, R
2expression-OCH
3or OH.
2. have 5 as claimed in claim 1,2 '-dihydroxyl-4 ' derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, be one of following compound of structural formula:
3. one kind has 5,2 '-dihydroxyl-4 as described in any one of claim 1 or 2 ' preparation method of the derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, comprise the following steps:
Step one, be starting raw material with 2,4-dihydroxyacetophenone, carry out isopentene glycosylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of yellow liquid;
Step 2, described first intermediate product is dissolved in acetic acid, carries out methylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the second intermediate product of yellow oily;
Step 3, get 2,4-dimethoxybenzoic acid and thionyl chloride, backflow, adds after vacuum rotary steam in the anhydrous pyridine being dissolved with described second intermediate product, carries out into ester reaction, rearrangement reaction, adopts column chromatography, V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the 3rd intermediate product of yellow oily;
Step 4, get described 3rd intermediate product and carry out geranylgeranylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the 4th intermediate product of yellow oily;
Step 5, described 4th intermediate product is dissolved in methyl alcohol, carries out ring closure reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=5:1, obtains the 5th intermediate product of yellow liquid;
Step 6, described 5th intermediate product is dissolved in HMPA, carries out demethylating reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=4:1, obtains the target product of yellow liquid.
4. have 5 as claimed in claim 3, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, isopentene glycosylation reaction in described step one specifically comprises: by 180 ~ 220 weight parts 2, 4-resacetophenone is dissolved in acetone soln, add 15 ~ 21 pbw of potassium carbonate and stir backflow 8 ~ 12min, drip 20 ~ 30 parts by weight isoprenyl bromide backflow 8 ~ 12h, be cooled to room temperature, solvent is removed in decompression, be extracted with ethyl acetate organic phase, use water successively, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography afterwards and obtain described first intermediate product, described first intermediate product structure is through IR, NMR and MS analyzes and determines.
5. have 5 as claimed in claim 3, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, methylation reaction in described step 2 specifically refers to: be dissolved in anhydrous propanone by the first intermediate product described in 5 ~ 8 weight parts, the Anhydrous potassium carbonate adding 10 ~ 15 weight parts stirs 8 ~ 12min, 3.5 ~ 5 parts sulfuric acid dimethyl esters are dripped with in constant pressure funnel 8 ~ 12min, back flow reaction 5 ~ 7h, be cooled to room temperature, regulate pH value to 2 with hydrochloric acid, be extracted with ethyl acetate organic phase, use water successively, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography afterwards and obtain described second intermediate product, described second intermediate product structure is through IR, NMR and MS analyzes and determines.
6. have 5 as claimed in claim 3, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, in described step 3, described one-tenth ester reaction, rearrangement reaction specifically refers to: take 10 ~ 15 weight parts 2, 4-dimethoxybenzoic acid is in round-bottomed flask, add 26 ~ 32 weight part thionyl chloride backflow 0.8 ~ 1.2h, vacuum rotary steam removes excessive thionyl chloride, then joined in the anhydrous pyridine of the second intermediate product described in dissolving 8 ~ 12 weight part, 70 ~ 90 DEG C of reaction 1.5 ~ 2.5h, cool to room temperature adds extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in pyridine, add the potassium hydroxide powder that 4 ~ 6 weight parts are preheated, 95 ~ 105 DEG C of reaction 20 ~ 40min, cool to room temperature, add extraction into ethyl acetate organic phase, use dilute hydrochloric acid successively, water, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, carry out column chromatography afterwards and obtain described 3rd intermediate product, described 3rd intermediate product structure is through IR, NMR and MS analyzes and determines.
7. have 5 as claimed in claim 3, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, in described step 4, described geranylgeranylation reaction specifically refers to: be dissolved in anhydrous propanone by the 3rd intermediate product described in 7 ~ 10 weight parts, add 8 ~ 10.5 weight part Anhydrous potassium carbonate backflow 8 ~ 12min, drip 6 ~ 8.5 weight part geranyl bromides, backflow 2 ~ 4h, cooling is spin-dried for solvent, add extraction into ethyl acetate organic phase, water respectively, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, column chromatography obtains described 4th intermediate product afterwards, described 4th intermediate product structure is through IR, NMR and MS analyzes and determines.
8. have 5 as claimed in claim 3, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, in described step 5, described ring closure reaction specifically refers to: be dissolved in 10 ~ 14 parts by weight Methanol by the 4th intermediate product described in 8 ~ 11 weight parts, drip 2 ~ 4 vitriol oils, backflow 2 ~ 4h, evaporated under reduced pressure solvent, add extraction into ethyl acetate organic phase, use saturated common salt water washing organic phase respectively, anhydrous sodium sulfate drying, column chromatography obtains described 5th intermediate product afterwards, described 5th intermediate product structure is through IR, NMR and MS analyzes and determines.
9. have 5 as claimed in claim 3, 2 '-dihydroxyl-4 ' preparation method of derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, in described step 6, described demethylating reaction specifically refers to: under argon shield, 2 ~ 2.5 weight part sulfur alcohols are dissolved in 40 ~ 60 weight part HMPA and stir 8 ~ 12min in 0 ~ 2 DEG C, add n-Butyl Lithium reaction 25 ~ 35min that 6 ~ 8 weight part concentration are 2 ~ 3M, the HMPA solution being dissolved with the 5th intermediate product described in 5 ~ 6 weight parts is joined in freshly prepd ethylmercapto group lithium, 60 ~ 80 DEG C of reaction 5 ~ 7h, add 50 ~ 70 weight part saturated ammonium chloride cancellation reactions, be extracted with ethyl acetate organic phase, saturated lithium chloride washing organic phase, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, target product structure is through IR, NMR and MS analyzes and determines.
10. one kind has 5,2 '-dihydroxyl-4 as claimed in claim 1 or 2 ' purposes of the derivative of-methoxyl group-3-geranyl lavonoid backbone, it is characterized in that, for the preparation of the medicine for the treatment of cancer of the stomach.
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