CN105130938A - Derivative having apigenin framework, preparation method and application thereof - Google Patents
Derivative having apigenin framework, preparation method and application thereof Download PDFInfo
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—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 having an apigenin framework, a preparation method and an application thereof. The derivative is a compound represented as the general formula (I) or pharmaceutically acceptable salt thereof, wherein R is represented as one in the following two structures. The derivative has excellent activity of resisting cervical cancer and liver cancer, is multiple in target point, has multiple links and multiple response, is low in toxicity and is not liable to cause drug resistance.
Description
Technical field
The present invention relates to the derivative with apigenin skeleton, be specifically related to B ring 4 ' position bromo 3-alkyl and replace 4',5,7-trihydroxyflavone derivative and its production and use.
Background technology
Cervical cancer is to one of dangerous maximum disease of women's health and quality of life, and liver cancer is the deputy malignant tumour of the mortality ratio each large tumor mortality rate of row, therefore seeks efficient, high to select and cancer therapy drug that toxic side effect is little is the Main way of drug research.4',5,7-trihydroxyflavone Apigenin is a kind of natural flavone compound, is mainly present in Selaginaceae, thymelaeceae, Verbenaceae, and this plant comes from samphire celery ApiumgraveolensL.var.dulceDC. leaf.Apigenin not only has the multiple pharmacological effect such as resistance state, anti-inflammatory, but also has restraining effect to multiple cancer cells.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 cancer cell multiplication, inducing apoptosis of tumour cell, anti-oxidant activity, the formation of suppression new vessel etc.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, action site is 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, by chemosynthesis, its structure of modification is modified, find the modification flavonoid compound of a kind of activity is better, side effect is less Mutiple Targets, too many levels, manifold effect, strengthen its specific pharmacologically active to treat cervical cancer and liver cancer needs 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 cervical cancer and liver cancer.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 a kind of derivative with apigenin skeleton, and it has good anti-cervical cancer and liver cancer activity, Mutiple Targets, too many levels, heterogeneous should, toxicity is low, not easily produces resistance.
A further object of the invention be to provide a kind of described in there is the preparation method of the derivative of apigenin skeleton; by methylating, acidylate, rearrangement, geranylgeranylation/isopentene group, Guan Huan; preparation method simply, easily controls; improve the target spot of compound, to obtain better selectivity and activity.
In order to realize according to these objects of the present invention and other advantage, provide a kind of derivative with the derivative skeleton of apigenin skeleton, this derivative has following chemical general formula (I) or its pharmacy acceptable salt;
Wherein, R represents
There is a preparation method for the derivative of apigenin skeleton, comprise the following steps:
Step one, with 2,4,6-trihydroxy-acetophenone for starting raw material, carry out methylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of white crystalline;
Step 2, get 4-bromo-benzoic acid and thionyl chloride, add after vacuum rotary steam in the anhydrous pyridine being dissolved with described first intermediate product, carry out acylation reaction, after rearrangement reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=16:1, obtains the second intermediate product of yellow oily;
Step 3, get described second intermediate product and carry out geranylgeranylation reaction, ring closure reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product of yellow oily.
There is a preparation method for the derivative of apigenin skeleton, comprise the following steps:
Step one, with 2,4,6-trihydroxy-acetophenone for starting raw material, carry out methylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of white crystalline;
Step 2, get 4-bromo-benzoic acid and thionyl chloride, add after vacuum rotary steam in the anhydrous pyridine being dissolved with described first intermediate product, carry out acylation reaction, after rearrangement reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=16:1, obtains the second intermediate product of yellow oily;
Step 3, get described second intermediate product and carry out isopentene glycosylation reaction, ring closure reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product of yellow oily.
Preferably, the described preparation method with the derivative of apigenin skeleton, methylation reaction in described step one specifically comprises: by 90 ~ 110 weight parts 2, 4, 6-trihydroxy-acetophenone is dissolved in 700 ~ 850 weight part anhydrous propanones, 120 ~ 160 weight part Anhydrous potassium carbonates are slowly added under stirring, then 140 ~ 160 parts sulfuric acid dimethyl esters are dripped with in constant pressure funnel 8 ~ 12min, back flow reaction 18 ~ 22h, be cooled to room temperature, add ethyl acetate, pour dilute hydrochloric acid into, water extracts, use anhydrous sodium sulfate drying again, 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, the described preparation method with the derivative of apigenin skeleton, acylation reaction in described step 2, rearrangement reaction specifically refers to: in 12 ~ 16 weight part 4-bromo-benzoic acids, add 40 ~ 44 weight part thionyl chlorides, 0.8 ~ 1.2h is reacted at 60 ~ 80 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in 96 ~ 101 weight part anhydrous pyridines of the first intermediate product described in dissolving 6 ~ 10 weight part, 90 ~ 110 DEG C of reaction 1.5 ~ 2.5h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 96 ~ 101 weight part anhydrous pyridines, be heated to 75 ~ 85 DEG C, add the potassium hydroxide powder that 3 ~ 5 weight parts are preheated, stirring reaction 20 ~ 40min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, 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, the described preparation method with the derivative of apigenin skeleton, geranylgeranylation described in described step 3 reacts, ring closure reaction specifically refers to: be dissolved in by the second intermediate product described in 3 ~ 4.5 weight parts in 100 ~ 135 weight part anhydrous propanones, be placed in 50 ~ 62 DEG C of oil baths, 2 ~ 2.5 weight part Anhydrous potassium carbonates are added under stirring, stir 8 ~ 12min, drip 3 ~ 3.5 weight part geranyl bromides, backflow 1 ~ 3h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use dilute hydrochloric acid successively, water, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product, then the 3rd intermediate product described in 2 ~ 2.5 weight parts is dissolved in 70 ~ 88 parts by weight Methanol, lower dropping 1 ~ 2 vitriol oil is stirred in 60 ~ 70 DEG C, back flow reaction 1 ~ 3h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, described target product structure is through IR, NMR and MS analyzes and determines.
Preferably, the described preparation method with the derivative of apigenin skeleton, isopentene glycosylation reaction described in described step 3, ring closure reaction specifically refers to: be dissolved in by the second intermediate product described in 3 ~ 4.5 weight parts in 100 ~ 135 weight part anhydrous propanones, be placed in 50 ~ 62 DEG C of oil baths, 2 ~ 2.5 weight part Anhydrous potassium carbonates are added under stirring, stir 8 ~ 12min, drip 2 ~ 2.5 weight part isoprenyl bromides, backflow 1 ~ 3h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use dilute hydrochloric acid successively, water, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product, then the 3rd intermediate product described in 2 ~ 2.3 weight parts is dissolved in 70 ~ 88 parts by weight Methanol, lower dropping 1 ~ 2 vitriol oil is stirred in 60 ~ 70 DEG C, back flow reaction 1 ~ 3h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, described target product structure is through IR, NMR and MS analyzes and determines.
There is a purposes for the derivative of apigenin skeleton, for the preparation of the medicine for the treatment of cervical cancer.
There is a purposes for the derivative of apigenin skeleton, for the preparation of the medicine of Hepatoma therapy.
The present invention at least comprises following beneficial effect:
The first, apigenin can suppress cervical cancer cell and hepatoma cell proliferation, and to normal liver cell toxicological harmless effect, antioxygenation and forward immunoregulation effect can be shown, owing to having multiple position be substituted, can be modified to obtain the anti-cervical cancer and medicines resistant to liver cancer that can strengthen its specific pharmacologically active;
The second, introduce C ring 3 geranyls or isopentene group, selectivity carbon, for geranylgeranylation, improves the biological activity of flavonoid compound, the anti-cervical cancer had and effect of liver cancer and faint cytotoxicity; The existence of isopentenyl side chain adds the lipotropy of flavonoid compound, makes it in organism, be easier to permeate through cell membranes arrival effect target, strengthens the biological activity of flavonoid compound;
Three, halogen medicine is particularly responsive to malignant cell, introduce B ring 4 ' position bromo, avoid forming larger repulsion with geranyl or isopentene group, ensure the stability of compound, and the activity of act synergistically with skeleton, can suppress well, eliminate cervical cancer cell and liver cancer cell;
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 the derivative of the derivative skeleton of apigenin skeleton, target product II structural formula is as follows:
Preparation method is as follows:
Step one, by 9.121g2,4,6-trihydroxy-acetophenone is dissolved in 89mL anhydrous propanone, slowly adds 12g Anhydrous potassium carbonate under stirring, then 14g methyl-sulfate is dripped with in constant pressure funnel 8min, back flow reaction 18h, is cooled to room temperature, adds ethyl acetate, pour dilute hydrochloric acid into, water extracts, then uses anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (7.202g productive rate 70.12%) of white crystalline, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, 4.011g thionyl chloride is added in 1.226g4-bromo-benzoic acid, 0.8h is reacted at 60 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in the 9mL anhydrous pyridine dissolving the first intermediate product described in 0.667g, 90 DEG C of reaction 1.5h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 9mL anhydrous pyridine, be heated to 75 DEG C, add the potassium hydroxide powder that 0.345g is preheated, stirring reaction 20min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, carry out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=16:1, obtains second intermediate product (0.945g, productive rate 50.34%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, 0.312g second intermediate product is dissolved in 10mL anhydrous propanone, be placed in 50 DEG C of oil baths, 0.201g Anhydrous potassium carbonate is added under stirring, stir 8min, drip 0.312g geranyl bromide, backflow 1h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use dilute hydrochloric acid successively, water, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product (0.319g productive rate 70%), then the 3rd intermediate product described in 0.205g is dissolved in 8.5mL methyl alcohol, lower dropping 1 vitriol oil is stirred in 60 DEG C, back flow reaction 1h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product II (0.156g productive rate 71%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Target product II:IR (KBr): 3460; 2966; 2933; 1723; 1687; 1609; 1568; 1450; 1413; 1331; 1262; 1225; 1155; 1106; 1045; 931; 808; 730; 587.1HNMR(400MHz,CDCl3)δppm：7.60(d，J＝8Hz，2H)；7.51(d，J＝8Hz，2H)；6.425(d，J＝4Hz，1H)；6.355(d，J＝8Hz，1H)；5.28(t，J＝16Hz，1H)；5.07(t，J＝16Hz，1H)；3.95(s，3H)；3.87(s，3H)；3.175(d，J＝4Hz，2H)；2.09-1.96(m，4H)；1.65(s，3H)；1.59(s，3H)；1.55(s，3H)；13CNMR(100MHz，CDCl3)δppm：176；163；161；159；157；136；132；131.5；131.3；130；128.6；124.4；124.2；122.6；122.3；108；95；92；55.3；55；39；26；25；24；17；16。(ESI)-MS,m/z:497.1315[M+NH4]+。
Embodiment 2:
Have the derivative of the derivative skeleton of apigenin skeleton, target product II structural formula is as follows:
Preparation method is as follows:
Step one, by 11.232g2,4,6-trihydroxy-acetophenone is dissolved in 108mL anhydrous propanone, slowly adds 16g Anhydrous potassium carbonate under stirring, then 16g methyl-sulfate is dripped with in constant pressure funnel 12min, back flow reaction 22h, is cooled to room temperature, adds ethyl acetate, pour dilute hydrochloric acid into, water extracts, then uses anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (7.205g productive rate 72.65%) of white crystalline, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, 4.455g thionyl chloride is added in 1.612g4-bromo-benzoic acid, 1.2h is reacted at 80 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in the 11mL anhydrous pyridine dissolving the first intermediate product described in 1.017g, 110 DEG C of reaction 2.5h, add ethyl acetate and be cooled to room temperature, dilute hydrochloric acid successively, water, saturated common salt water washing, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 11mL anhydrous pyridine, be heated to 85 DEG C, add the potassium hydroxide powder that 0.511g is preheated, stirring reaction 40min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, column chromatography V
(sherwood oil): V
(ethyl acetate)=16:1, obtains second intermediate product (0.976g productive rate 49.98%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, 0.451g second intermediate product is dissolved in 20mL anhydrous propanone, be placed in 62 DEG C of oil baths, 0.251g Anhydrous potassium carbonate is added under stirring, stir 12min, drip 0.350g geranyl bromide, backflow 3h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use water successively, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product (0.333g productive rate 72%), then the 3rd intermediate product described in 0.250g is dissolved in 11.5mL methyl alcohol, lower dropping 2 vitriol oils are stirred in 80 DEG C, back flow reaction 3h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product II (0.165g productive rate 76%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Target product II:IR (KBr): 3460; 2966; 2933; 1723; 1687; 1609; 1568; 1450; 1413; 1331; 1262; 1225; 1155; 1106; 1045; 931; 808; 730; 587.1HNMR(400MHz,CDCl3)δppm：7.60(d，J＝8Hz，2H)；7.51(d，J＝8Hz，2H)；6.425(d，J＝4Hz，1H)；6.355(d，J＝8Hz，1H)；5.28(t，J＝16Hz，1H)；5.07(t，J＝16Hz，1H)；3.95(s，3H)；3.87(s，3H)；3.175(d，J＝4Hz，2H)；2.09-1.96(m，4H)；1.65(s，3H)；1.59(s，3H)；1.55(s，3H)；13CNMR(100MHz，CDCl3)δppm：176；163；161；159；157；136；132；131.5；131.3；130；128.6；124.4；124.2；122.6；122.3；108；95；92；55.3；55；39；26；25；24；17；16。(ESI)-MS,m/z:497.1315[M+NH4]+。
Embodiment 3:
Have the derivative of the derivative skeleton of apigenin skeleton, target product II structural formula is as follows:
Preparation method is as follows:
Step one, by 9.300g2,4,6-trihydroxy-acetophenone is dissolved in 100mL anhydrous propanone, slowly adds 14g Anhydrous potassium carbonate under stirring, then 15g methyl-sulfate is dripped with in constant pressure funnel 10min, back flow reaction 20h, is cooled to room temperature, adds ethyl acetate, pour dilute hydrochloric acid into, water extracts, then uses anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (7.401g productive rate 76%) of white crystalline, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, 4.200g thionyl chloride is added in 1.400g4-bromo-benzoic acid, 1h is reacted at 70 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in the 10mL anhydrous pyridine dissolving the first intermediate product described in 0.800g, 100 DEG C of reaction 2h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid successively, water, saturated common salt water washing, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, intermediate compound is not purified, be dissolved in 10mL anhydrous pyridine, be heated to 80 DEG C, add the potassium hydroxide powder that 0.450g is preheated, stirring reaction 30min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, column chromatography V
(stone oil ether): V
(ethyl acetate)=16:1, obtains second intermediate product (0.981g productive rate 51.60%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, 0.380g second intermediate product is dissolved in 15mL anhydrous propanone, be placed in 56 DEG C of oil baths, 0.220g Anhydrous potassium carbonate is added under stirring, stir 10min, drip 0.320g geranyl bromide, backflow 2h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use water successively, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product (0.357g productive rate 77%), then the 3rd intermediate product described in 0.227g is dissolved in 10mL methyl alcohol, lower dropping 1 vitriol oil is stirred in 65 DEG C, back flow reaction 2h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, adopt column chromatography, V
(sherwood oil): V
(second acetoacetic ester)=2:1, obtains the target product II (0.174g productive rate 81%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Target product II:IR (KBr): 3460; 2966; 2933; 1723; 1687; 1609; 1568; 1450; 1413; 1331; 1262; 1225; 1155; 1106; 1045; 931; 808; 730; 587.1HNMR(400MHz,CDCl3)δppm：7.60(d，J＝8Hz，2H)；7.51(d，J＝8Hz，2H)；6.425(d，J＝4Hz，1H)；6.355(d，J＝8Hz，1H)；5.28(t，J＝16Hz，1H)；5.07(t，J＝16Hz，1H)；3.95(s，3H)；3.87(s，3H)；3.175(d，J＝4Hz，2H)；2.09-1.96(m，4H)；1.65(s，3H)；1.59(s，3H)；1.55(s，3H)；13CNMR(100MHz，CDCl3)δppm：176；163；161；159；157；136；132；131.5；131.3；130；128.6；124.4；124.2；122.6；122.3；108；95；92；55.3；55；39；26；25；24；17；16。(ESI)-MS,m/z:497.1315[M+NH4]+。
Embodiment 4:
Have the derivative of the derivative skeleton of apigenin skeleton, target product III structural formula is as follows:
Preparation method is as follows:
Step one, by 9.121g2,4,6-trihydroxy-acetophenone is dissolved in 89mL anhydrous propanone, slowly adds 12g Anhydrous potassium carbonate under stirring, then 14g methyl-sulfate is dripped with in constant pressure funnel 8min, back flow reaction 18h, is cooled to room temperature, adds ethyl acetate, pour dilute hydrochloric acid into, water extracts, then uses anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (7.202g productive rate 70.12%) of white crystalline, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, 4.011g thionyl chloride is added in 1.226g4-bromo-benzoic acid, 0.8h is reacted at 60 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in the 9mL anhydrous pyridine dissolving the first intermediate product described in 0.667g, 90 DEG C of reaction 1.5h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid successively, water, saturated common salt water washing, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 11mL anhydrous pyridine, be heated to 85 DEG C, add the potassium hydroxide powder that 0.511g is preheated, stirring reaction 40min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, column chromatography V
(sherwood oil): V
(ethyl acetate)=16:1, obtains second intermediate product (0.976g productive rate 49.98%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, second intermediate product described in 0.312g is dissolved in 10mL anhydrous propanone, be placed in 50 DEG C of oil baths, 0.201g Anhydrous potassium carbonate is added under stirring, stir 8min, drip 0.202g isoprenyl bromide, backflow 1h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use water successively, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product (0.312g productive rate 71%), then the 3rd intermediate product described in 0.200g is dissolved in 8.5mL methyl alcohol, lower dropping 1 vitriol oil is stirred in 60 DEG C, back flow reaction 1h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product III (0.144g productive rate 76%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Target product III:IR (KBr): 3432; 2932; 2845; 2359; 1683; 1608; 1575; 1459; 1422; 1308; 1327; 1263; 1215; 1155; 1109; 1046; 1004; 932; 822; 666; 624.1HNMR(300MHz,CDCl3)δppm：7.54(d，J＝8Hz，2H)；7.46(d，J＝8Hz，2H)；6.25(s，1H)；6.14(s，1H)；4.78(t，J＝8Hz，1H)；3.86(s，3H)；3.84(s，3H)；2.01-1.96(m，1H)；1.84-1.79(m，1H)；1.46(s，3H)；1.18(s，3H)；13CNMR(75MHz，CDCl3)δppm：191；165；162；159；136；133；131；128；123；119；106；104；93.7；93.3；57；56；55；26；25；17。(ESI)-MS,m/z:429.0716[M+H]+。
Embodiment 5:
Have the derivative of the derivative skeleton of apigenin skeleton, target product III structural formula is as follows:
Preparation method is as follows:
Step one, by 11.232g2,4,6-trihydroxy-acetophenone is dissolved in 108mL anhydrous propanone, slowly adds 16g Anhydrous potassium carbonate under stirring, then 16g methyl-sulfate is dripped with in constant pressure funnel 12min, back flow reaction 22h, is cooled to room temperature, adds ethyl acetate, pour dilute hydrochloric acid into, water extracts, then uses anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains first intermediate product (7.205g productive rate 72.65%) of white crystalline, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, 4.455g thionyl chloride is added in 1.612g4-bromo-benzoic acid, 1.2h is reacted at 80 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in the 11mL anhydrous pyridine dissolving the first intermediate product described in 1.017g, 110 DEG C of reaction 2.5h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid successively, water, saturated common salt water washing, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 9mL anhydrous pyridine, be heated to 75 DEG C, add the potassium hydroxide powder that 0.345g is preheated, stirring reaction 20min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, carry out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=16:1, obtains second intermediate product (0.945g, productive rate 50.34%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, second intermediate product described in 0.451g is dissolved in 20mL anhydrous propanone, be placed in 62 DEG C of oil baths, 0.251g Anhydrous potassium carbonate is added under stirring, stir 12min, drip 0.257g isoprenyl bromide, backflow 3h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use water successively, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product (0.307g productive rate 69%), then then the 3rd intermediate product described in 0.231g is dissolved in 11.5mL methyl alcohol, lower dropping 2 vitriol oils are stirred in 80 DEG C, back flow reaction 3h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, adopt column chromatography, V
(stone oil ether): V
(ethyl acetate)=2:1, obtains the target product III (0.156g productive rate 80%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Target product III:IR (KBr): 3432; 2932; 2845; 2359; 1683; 1608; 1575; 1459; 1422; 1308; 1327; 1263; 1215; 1155; 1109; 1046; 1004; 932; 822; 666; 624.1HNMR(300MHz,CDCl3)δppm：7.54(d，J＝8Hz，2H)；7.46(d，J＝8Hz，2H)；6.25(s，1H)；6.14(s，1H)；4.78(t，J＝8Hz，1H)；3.86(s，3H)；3.84(s，3H)；2.01-1.96(m，1H)；1.84-1.79(m，1H)；1.46(s，3H)；1.18(s，3H)；13CNMR(75MHz，CDCl3)δppm：191；165；162；159；136；133；131；128；123；119；106；104；93.7；93.3；57；56；55；26；25；17。(ESI)-MS,m/z:429.0716[M+H]+。
Embodiment 6:
Have the derivative of the derivative skeleton of apigenin skeleton, target product III structural formula is as follows:
Preparation method is as follows:
Step one, by 9.300g2,4,6-trihydroxy-acetophenone is dissolved in 100mL anhydrous propanone, slowly adds 14g Anhydrous potassium carbonate under stirring, then 15g methyl-sulfate is dripped with in constant pressure funnel 10min, back flow reaction 20h, is cooled to room temperature, adds ethyl acetate, pour dilute hydrochloric acid into, water extracts, then uses anhydrous sodium sulfate drying, carries out column chromatography V afterwards
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of white crystalline, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 2, 4.200g thionyl chloride is added in 1.400g4-bromo-benzoic acid, 1h is reacted at 70 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in the 10mL anhydrous pyridine dissolving the first intermediate product described in 0.800g, 100 DEG C of reaction 2h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid successively, water, saturated common salt water washing, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 10mL anhydrous pyridine, be heated to 80 DEG C, add the potassium hydroxide powder that 0.450g is preheated, stirring reaction 30min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, column chromatography V
(sherwood oil): V
(ethyl acetate)=16:1, obtains second intermediate product (0.981g productive rate 51.60%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Step 3, by the second intermediate product described in 0.380g, be dissolved in 15mL anhydrous propanone, be placed in 56 DEG C of oil baths, 0.220g Anhydrous potassium carbonate is added under stirring, stir 10min, drip 0.223g isoprenyl bromide, backflow 2h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use water successively, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product (0.356g productive rate 81%), then the 3rd intermediate product described in 0.214g is dissolved in 10mL methyl alcohol, lower dropping 1 vitriol oil is stirred in 65 DEG C, back flow reaction 2h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product III (0.169g productive rate 85%) of yellow oily, and structure is analyzed through IR, NMR and MS and determined, structural formula is as follows:
Target product III:IR (KBr): 3432; 2932; 2845; 2359; 1683; 1608; 1575; 1459; 1422; 1308; 1327; 1263; 1215; 1155; 1109; 1046; 1004; 932; 822; 666; 624.1HNMR(300MHz,CDCl3)δppm：7.54(d，J＝8Hz，2H)；7.46(d，J＝8Hz，2H)；6.25(s，1H)；6.14(s，1H)；4.78(t，J＝8Hz，1H)；3.86(s，3H)；3.84(s，3H)；2.01-1.96(m，1H)；1.84-1.79(m，1H)；1.46(s，3H)；1.18(s，3H)；13CNMR(75MHz，CDCl3)δppm：191；165；162；159；136；133；131；128；123；119；106；104；93.7；93.3；57；56；55；26；25；17。(ESI)-MS,m/z:429.0716[M+H]+。
Comparative example:
Select passing develop for the preparation for the treatment of flavonoid compound A, B of cervical cancer and flavonoid compound C, the D for the preparation of Hepatoma therapy, structural formula is as follows respectively:
Its pharmaceutical activity and application thereof is further illustrated below by pharmacodynamic experiment.
Experiment one: cell in vitro determination of activity:
The target product II of employing the embodiment 3 and target product III of embodiment 3 is as experimental group, adopt the passing flavonoid compound (A, B, C, D) developed as a control group, cytoactive detection is carried out to human body cervical carcinoma cell and human hepatoma cell and human normal hepatic cell.Select cervical cancer cell lines (Hela), human hepatoma cell strain (SMMC-7721) and human normal hepatic cell (HL-7702) adopt mtt assay, carry out cell in vitro determination of activity.
The Hela cell of taking the logarithm vegetative period and SMMC-7721 cell and HL-7702 cell 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 in the logarithmic phase cell cultivated in 96 orifice plates, add testing sample (II, III, A, B, C, D), 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, drug level is obtained to the IC of each sample
50value, result as shown in Table 1 and Table 2.
Table 1
| Compound | Hela(μmol/L) |
| III | 10.9 |
| A | 38.8 |
| B | 42.9 |
Can show from table 1, target product III of the present invention is less than A, B to the 503nhibiting concentration of s lower than 15, has an obvious growth-inhibiting effect.Illustrate that B ring 4 ' position of the present invention bromo 3-alkyl replaces 4',5,7-trihydroxyflavone derivative can treat cervical cancer medicine with screening.
Table 2
| Compound | 7721(μmol/L) | 7702(μmol/L) |
| II | 28.4 | >150.0 |
| III | 8.8 | >150.0 |
| C | 49.9 | >150.0 |
| D | 44.7 | >150.0 |
Can show from table 2, target product II, III of the present invention are all less than C, D to the 503nhibiting concentration of hepatoma cell strain 7721 cell lower than 30, wherein target product III is lower than 10, obvious growth-inhibiting effect is had to hepatoma cell strain 7721 cell, active to human normal hepatic cell HL-7702 unrestraint.Illustrate that B ring 4 ' position of the present invention bromo 3-alkyl replaces the medicine that 4',5,7-trihydroxyflavone derivative can use screening Hepatoma therapy.
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 (9)
1. have a derivative for the derivative skeleton of apigenin skeleton, it is characterized in that, this derivative has following chemical general formula (I) or its pharmacy acceptable salt;
Wherein, R represents
or
2. there is a preparation method for the derivative of apigenin skeleton as claimed in claim 1, it is characterized in that, comprise the following steps:
Step one, with 2,4,6-trihydroxy-acetophenone for starting raw material, carry out methylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of white crystalline;
Step 2, get 4-bromo-benzoic acid and thionyl chloride, add after vacuum rotary steam in the anhydrous pyridine being dissolved with described first intermediate product, carry out acylation reaction, after rearrangement reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=16:1, obtains the second intermediate product of yellow oily;
Step 3, get described second intermediate product and carry out geranylgeranylation reaction, ring closure reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product of yellow oily.
3. there is a preparation method for the derivative of apigenin skeleton as claimed in claim 1, it is characterized in that, comprise the following steps:
Step one, with 2,4,6-trihydroxy-acetophenone for starting raw material, carry out methylation reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=10:1, obtains the first intermediate product of white crystalline;
Step 2, get 4-bromo-benzoic acid and thionyl chloride, add after vacuum rotary steam in the anhydrous pyridine being dissolved with described first intermediate product, carry out acylation reaction, after rearrangement reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=16:1, obtains the second intermediate product of yellow oily;
Step 3, get described second intermediate product and carry out isopentene glycosylation reaction, ring closure reaction, adopt column chromatography, V
(sherwood oil): V
(ethyl acetate)=2:1, obtains the target product of yellow oily.
4. there is the preparation method of the derivative of apigenin skeleton as claimed in claim 2 or claim 3, it is characterized in that, methylation reaction in described step one specifically comprises: by 90 ~ 110 weight parts 2, 4, 6-trihydroxy-acetophenone is dissolved in 700 ~ 850 weight part anhydrous propanones, 120 ~ 160 weight part Anhydrous potassium carbonates are slowly added under stirring, then 140 ~ 160 parts sulfuric acid dimethyl esters are dripped with in constant pressure funnel 8 ~ 12min, back flow reaction 18 ~ 22h, be cooled to room temperature, add ethyl acetate, pour dilute hydrochloric acid into, water extracts, use anhydrous sodium sulfate drying again, 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. there is the preparation method of the derivative of apigenin skeleton as claimed in claim 2 or claim 3, it is characterized in that, acylation reaction in described step 2, rearrangement reaction specifically refers to: in 12 ~ 16 weight part 4-bromo-benzoic acids, add 40 ~ 44 weight part thionyl chlorides, 0.8 ~ 1.2h is reacted at 60 ~ 80 DEG C, vacuum rotary steam removes excessive thionyl chloride, then joined in 96 ~ 101 weight part anhydrous pyridines of the first intermediate product described in dissolving 6 ~ 10 weight part, 90 ~ 110 DEG C of reaction 1.5 ~ 2.5h, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid successively, water, saturated common salt water washing, use anhydrous sodium sulfate drying again, concentrating under reduced pressure, obtain intermediate compound, described intermediate compound is not purified, be dissolved in 96 ~ 101 weight part anhydrous pyridines, be heated to 75 ~ 85 DEG C, add the potassium hydroxide powder that 3 ~ 5 weight parts are preheated, stirring reaction 20 ~ 40min, add ethyl acetate and be cooled to room temperature, use dilute hydrochloric acid and water washing successively, use anhydrous sodium sulfate drying again, pressurization is concentrated, 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. there is the preparation method of the derivative of apigenin skeleton as claimed in claim 2, it is characterized in that, geranylgeranylation described in described step 3 reacts, ring closure reaction specifically refers to: be dissolved in by the second intermediate product described in 3 ~ 4.5 weight parts in 100 ~ 135 weight part anhydrous propanones, be placed in 50 ~ 62 DEG C of oil baths, 2 ~ 2.5 weight part Anhydrous potassium carbonates are added under stirring, stir 8 ~ 12min, drip 3 ~ 3.5 weight part geranyl bromides, backflow 1 ~ 3h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, dilute hydrochloric acid, water, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product, then the 3rd intermediate product described in 2 ~ 2.5 weight parts is dissolved in 70 ~ 88 parts by weight Methanol, lower dropping 1 ~ 2 vitriol oil is stirred in 60 ~ 70 DEG C, back flow reaction 1 ~ 3h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, described target product structure is through IR, NMR and MS analyzes and determines.
7. there is the preparation method of the derivative of apigenin skeleton as claimed in claim 3, it is characterized in that, isopentene glycosylation reaction described in described step 3, ring closure reaction specifically refers to: be dissolved in by the second intermediate product described in 3 ~ 4.5 weight parts in 100 ~ 135 weight part anhydrous propanones, be placed in 50 ~ 62 DEG C of oil baths, 2 ~ 2.5 weight part Anhydrous potassium carbonates are added under stirring, stir 8 ~ 12min, drip 2 ~ 2.5 weight part isoprenyl bromides, backflow 1 ~ 3h, cooling, solvent evaporated, pour ethyl acetate into, add dilute hydrochloric acid removing salt of wormwood, use water successively, saturated common salt water washing, anhydrous sodium sulfate drying, obtain the 3rd intermediate product, then the 3rd intermediate product described in 2 ~ 2.3 weight parts is dissolved in 70 ~ 88 parts by weight Methanol, lower dropping 1 ~ 2 vitriol oil is stirred in 60 ~ 70 DEG C, back flow reaction 1 ~ 3h, water is poured in cooling into, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography obtains target product afterwards, described target product structure is through IR, NMR and MS analyzes and determines.
8. there is a purposes for the derivative of apigenin skeleton as claimed in claim 1, it is characterized in that, for the preparation of the medicine for the treatment of cervical cancer.
9. there is a purposes for the derivative of apigenin skeleton as claimed in claim 1, it is characterized in that, for the preparation of the medicine of Hepatoma therapy.
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