CN106699717A - A cyclotrimethoxone-substituted salicylate compound and anti-tumor effect thereof - Google Patents

A cyclotrimethoxone-substituted salicylate compound and anti-tumor effect thereof Download PDF

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CN106699717A
CN106699717A CN201611076987.0A CN201611076987A CN106699717A CN 106699717 A CN106699717 A CN 106699717A CN 201611076987 A CN201611076987 A CN 201611076987A CN 106699717 A CN106699717 A CN 106699717A
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compound
trimethoxy
solution
cyclotrimethoxone
reaction
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CN106699717B (en
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邓湘萍
王哲
唐国涛
熊润德
熊淑娟
刘娟
俞晨泽
袁昊
邹柳
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University of South China
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—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

Abstract

The invention relates to the technical field of medicines, and designs and synthesizes a novel A cyclotrimethoxy 4'-hydroxyflavone compound and an A cyclotrimethoxone-substituted salicylate compound. The figure 1 is a general formula of the A cyclotrimethoxone-substituted salicylate compound, wherein in the formula, R1, R2 and R3 are equal to OCH3 or R2, R3 and R4 are equal to OCH3; R5- is equal to OCH3, CH3, F, Cl, Br, I or the like. The novel A cyclotrimethoxy 4'-hydroxyflavone compound and the A cyclotrimethoxone-substituted salicylate compound can have an obvious inhibiting effect on MGC-803 (human gastric carcinoma cells), HepG2 (human hepatoma carcinoma cells), MCF-7 (human breast cancer cells) and hopefully become anti-tumor drugs. The invention discloses a preparation method of the novel A cyclotrimethoxy 4'-hydroxyflavone compound and the A cyclotrimethoxone-substituted salicylate compound.

Description

A ring trimethoxy flavone substituted salicylic acid esters compounds and its antitumor action
Technical field
The present invention relates to pharmaceutical technology field, and in particular to the new class A rings trimethoxy flavone substituted salicylic acid of a class Ester type compound and its antitumor action.
Background technology
Flavone compound is widely present in nature, with various pharmacological activity, with anticancer, antitumor, the anti-heart It is cranial vascular disease, anti-inflammatory and antalgic, immunological regulation, hypoglycemic, treatment osteoporosis, inhibitory anti-virus, anti-oxidant, anti-aging, anti- The effects such as radiation, research shows that flavone compound can suppress hypoxia inducible factor, so as to reduce tumour cell glycolysis side Face, especially, can suppress the flavone compound structure of hypoxia inducible factor is with CR or 4 ' flavonols It is main, also, acetic acid flavones is the earliest vascular disrupting agents for finding.
Most of tumor vessel blocking agents be the colchicin binding site with tubulin as target spot, we are to this kind ofization The chemical constitution of compound is analyzed conclusion, and from CA4P, OXi4503, AVE8062, ZD2126, BNC-105, CKD-516 etc. change Find that it is benzene trimethoxy to have common building stone in the structure of compound.
Aspirin, also known as acetylsalicylic acid, are conventional time-honored non-steroid anti-inflammatory drugs, are used to solve earliest Heat, analgesia, anti-inflammatory;Find to suppress platelet aggregation and be used for prevention and treatment of coronary heart disease afterwards.With basis and the development of clinical research, It was found that can reduce alimentary tract cancer using aspirin occurring.Research shows that the energy of tumour cell is essentially from glycolysis Journey.Acetylsalicylic acid and salicylic acid can suppress one of 3 rate-limiting enzymes of glycolytic pathway phosphofructokinase and breast cancer cell The glycolysis level of MCF-7, so as to play antineoplastic action.
In view of studying above, we design the double target spot inhibitor of new tumour tubulin/HIF-1 α, and plan is with flavones Mother nucleus structure, trimethoxy is introduced in the A rings of flavones, first synthesizes A ring 4 '-flavonols of trimethoxy, then by esterification Substituted salicylic acid is introduced in 4 '-hydroxy position of A ring 4 '-flavonols of trimethoxy, synthesizes a series of A rings trimethoxies 4 '-flavonol substituted salicylic acid esters compound.This Novel series compound may have simultaneously suppression tubulin and The double action of HIF-l α, many targets of a medicine, with hypotoxicity and good anti-inflammatory, active anticancer, to find the anti-of high-efficiency low-toxicity Scorching cancer therapy drug provides Research foundation.
The content of the invention
It is an object of the invention to synthesize A rings trimethoxy flavone and A ring trimethoxy flavone substituted salicylic acid esters Compound, obtains the compound compared with powerful antitumor, anti-inflammatory activity.
Technical scheme is as follows.
Fig. 1 is A ring trimethoxy flavone compound structure formula figures, in formula：R1,R2,R3=OCH3Or R2,R3,R4= OCH3 。
Fig. 2 is A ring trimethoxy flavone substituted salicylic acid esters compound structure formula figures, in formula：R1,R2,R3=OCH3 Or R2,R3,R4=OCH3 ; R5=OCH3、CH3, F, Cl, Br or I etc..
One kind prepares above-mentioned A rings trimethoxy flavone compound and A ring trimethoxy flavone substituted salicylic acid esters chemical combination The method of thing is as follows.
Step 1:Under anhydrous, anaerobic conditions, by 3,4,5- trimethoxy phenol, chloroacetonitrile and anhydrous zinc chloride (0.3g) mixes, and adds chloroform-absolute ether, is cooled down with ice salt bath, dry hydrogen chloride is passed through, by reaction bulb in ice after 2 hours Placed 1 day in case, then lead to hydrogen chloride 2 hours, placed 3 days in refrigerator, pour out ether, crude extract is gone to circle with hot water In the flask of bottom, flow back 1 hour, stand overnight, faint yellow fluffy solid is recrystallized to give with water, vacuum drying obtains chlorobenzene second Ketone.
Fig. 3 is to prepare above-mentioned A rings trimethoxy flavone compound and A ring trimethoxy flavone substituted salicylic acid esters chemical combination The reaction equation figure of the method and step 1 of thing.
Step 2:Compound chloro-acetophenone is mixed with parahydroxyben-zaldehyde, 95% ethanol is added, shaken up, be slowly added into 10%NaOH, is then aggressively shaken a moment, at room temperature stirring reaction 2 days, pH7 is adjusted with 10%HCl, then at stirring reaction at room temperature 2 days, suction filtration was to obtain glassy yellow fluffy solid with 95% ethyl alcohol recrystallization, and vacuum drying obtains bright yellow solid, that is, obtain The A ring trimethoxy flavone compounds of the invention described above.
Fig. 4 is to prepare above-mentioned A rings trimethoxy flavone compound and A ring trimethoxy flavone substituted salicylic acid esters chemical combination The reaction equation figure of the method and step 2 of thing.
Step 3:Substituted salicylic acid is dissolved in distilled water, 37 DEG C of heating water baths, adjusting solution PH with 30%NaOH is 10,30min is stirred, dimethyl suflfate is slowly added dropwise, reaction plate etching solution PH is changed into 7, then is with 30%NaOH regulation solution PHs 10, after reaction 1h, dimethyl suflfate is slowly added dropwise, reaction plate etching solution PH is changed into 7, then it is 10 to adjust solution PH with 30%NaOH, Reaction 1h, 15min is hydrolyzed under 80 DEG C of water bath conditions, is cooled to room temperature, and it is 5 to adjust pH with 10%HCl, has precipitation to generate, distillation Water washing is precipitated, and precipitation is vacuum dried；Dried precipitation is dissolved in dichloromethane, DMF and thionyl chloride, 40 DEG C of oil is added Bath is heated to reflux 0.5h, removes dichloromethane and thionyl chloride under reduced pressure, uses 10mL acetone solutions, adds A ring 4 '-hydroxyls of trimethoxy Base chromocor compound, is added dropwise triethylamine, reacts 3h, and suction filtration reclaims acetone, purified with silicagel column column chromatography, and eluant, eluent is：Acetic acid Ethyl ester：Petroleum ether=1:1~1:4, vacuum drying obtains faint yellow or yellow solid, obtains the A ring trimethoxies of the invention described above Flavones substituted salicylic acid esters compound.
Fig. 5 is to prepare above-mentioned A rings trimethoxy flavone compound and A ring trimethoxy flavone substituted salicylic acid esters chemical combination The reaction equation figure of the method and step 3 of thing.
Test result indicate that, new A ring trimethoxy flavone compound of the invention and A rings trimethoxy flavone replace water Poplar acid esters compound, with good antitumor activity, the antitumor activity of majority of compounds is better than Chrysin, indivedual living Property outstanding antitumor activity of compound exceed 5 FU 5 fluorouracil, therefore the compounds of this invention can be used for preparing antineoplastic Thing.
The pharmacological activity of the compounds of this invention makes it can be used for preparing antineoplastic.The pharmaceutical composition can be solid Body form or liquid form.
Specific embodiment
The present invention is further described by following examples, but should be noted that the scope of the present invention is not implemented by these Any limitation of example.
Embodiment 1：5,6,7- -4 '-flavonols of trimethoxy.
Fig. 6 is the structural formula figure of 5,6,7- -4 '-flavonols of trimethoxy.
Under anhydrous, anaerobic conditions, by 3,4,5- trimethoxy phenol (2.208g, 0.012mol), chloroacetonitrile (1.5mL, 0.024mol) mixes with anhydrous zinc chloride (0.3g), adds chloroform-absolute ether（1:1）50m L, use ice salt bath Cooling, is passed through dry hydrogen chloride, places reaction bulb in refrigerator 1 day after 2 hours, then leads to hydrogen chloride 2 hours, in refrigerator Place 3 days, pour out ether, during crude extract is gone to round-bottomed flask with hot water, flow back 1 hour, stand overnight, tied again with water Crystalline substance, faint yellow fluffy solid is recrystallized to give with water, and vacuum drying obtains faint yellow solid, that is, obtain compound 2'- hydroxyls- 4', 5', 6'- trimethoxy -2- chloro-acetophenones 1.By 2'- hydroxyls -4', 5', 6'- trimethoxy -2- chloro-acetophenones ( 10mmol) mix with parahydroxyben-zaldehyde (11mmol), add 95% ethanol, shake up, be slowly added into 10%NaOH, it is then acute In strong shake a moment, stirring reaction 2 days, p H7 are adjusted with 10%HCl at room temperature, and then at stirring reaction 2 days at room temperature, suction filtration is used 95% ethyl alcohol recrystallization is to obtain glassy yellow fluffy solid, and this target compound is obtained after vacuum drying.Bright yellow solid 0.75g, Yield 34%.M.P.:172~175°C. 1H NMR (400 MHz, cdcl3) δ7.79-7.75(d,2H),6.91-6.86(d, 2H),6.73(s,1H), 6.53(s,1H), 4.24(s,3H), 3.96(s,3H),3.81(s,3H)。
Embodiment 2：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl O-Anisic Acid ester.
Fig. 7 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl O-Anisic Acid ester structure formula Figure.
By salicylic acid（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, adjusting pH value of solution with 30% NaOH is 10,30min is stirred, 2 mL dimethyl suflfates are slowly added dropwise, reaction to pH value of solution is changed into 7, then adjusts pH value of solution with 30% NaOH It is 10, after 1 h of reaction, the mL of dimethyl suflfate 1 is slowly added dropwise again, reaction to pH value of solution is changed into 7, then is adjusted with 30% NaOH PH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent is acetic acid second Ester：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white precipitate to generate, and distillation water washing is sunk Form sediment, precipitation is vacuum dried；Dried precipitation is dissolved in 10mL dichloromethane, adds two to drip DMF and 0.5mL thionyl chlorides, 40 DEG C of oil bath heatings 0.5 h of backflow, remove dichloromethane and thionyl chloride under reduced pressure, use 10mL acetone solutions, add embodiment 1 to obtain 5 for arriving, 6,7- trimethoxies -4 '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration reclaims acetone, silicon Glue post column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- trimethoxies- 4- oxo -4H- chromene -2- bases）Phenyl O-Anisic Acid ester.Pale yellow powder, yield is 56%.M.P.:172~175° C.1HNMR(400MHz,cdcl3)δ8.03-8.00(d,1H),7.93-7.89(d,1H),7.59-7.53(t,1H), 7.31- 7.27(d,2H), 7.07-7.02(t,2H),6.76(s,1H), 6.55(s,1H), 4.25(s,3H),3.98(s,3H), 3.94(s,3H),3.81(s,3H)。
Embodiment 3：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The chloro- 6- methoxyl groups of phenyl 2,3,5- tri- Benzoic ether.
Fig. 8 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The chloro- 6- methoxybenzenes of phenyl 2,3,5- tri- Formic acid esters structural formula figure.
By the chloro-salicylic acids of 3,5,6- tri-（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, is adjusted with 30% NaOH Section pH value of solution is 10, stirs 30min, is slowly added dropwise 2 mL dimethyl suflfates, and reaction to pH value of solution is changed into 7, then uses 30% NaOH Regulation pH value of solution is 10, after 1 h of reaction, is slowly added dropwise the mL of dimethyl suflfate 1 again, and reaction to pH value of solution is changed into 7, then with 30% NaOH regulation pH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent It is ethyl acetate：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white precipitate to generate, and is distilled Water washing is precipitated, and precipitation is vacuum dried；Dried precipitation is dissolved in 10mL dichloromethane, adds two to drip DMF and 0.5mL chlorine Change sulfoxide, 40 DEG C of oil bath heatings 0.5 h of backflow remove dichloromethane and thionyl chloride under reduced pressure, use 10mL acetone solutions, add real Apply example 1 is obtained 5,6,7- trimethoxies -4 '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration is reclaimed Acetone, silicagel column column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- tri- Methoxyl group -4- oxo -4H- chromene -2- bases）The chloro- 6- methoxy benzoic acids esters of phenyl 2,3,5- tri-.Yellow greenish powder, yield is 39%。M.P.:172~175°C.1HNMR(400MHz,cdcl3)δ7.96-7.91(d,1H),7.61(s,1H),7.36-7.30(d, 2H),6.76(s,1H), 6.54(s,1H), 4.25(s,3H),4.00-3.95(d,6H),3.81(s,3H)。
Embodiment 4：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The chloro- O-Anisic Acids of phenyl 4- Ester.
Fig. 9 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The chloro- O-Anisic Acid esters of phenyl 4- Structural formula figure.
By 4- chloro-salicylic acids（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, solution is adjusted with 30% NaOH PH is 10, stirs 30min, is slowly added dropwise 2 mL dimethyl suflfates, and reaction to pH value of solution is changed into 7, then adjusts molten with 30% NaOH Liquid pH is 10, after 1 h of reaction, the mL of dimethyl suflfate 1 is slowly added dropwise again, and reaction to pH value of solution is changed into 7, then uses 30% NaOH Regulation pH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent is second Acetoacetic ester：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white precipitate to generate, distillation washing Precipitation is washed, precipitation is vacuum dried；Dried precipitation is dissolved in 10mL dichloromethane, adds two to drip DMF and 0.5mL protochlorides Sulfone, 40 DEG C of oil bath heatings 0.5 h of backflow, removes dichloromethane and thionyl chloride under reduced pressure, uses 10mL acetone solutions, adds embodiment 15,6, the 7- trimethoxies -4 for obtaining '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration reclaims third Ketone, silicagel column column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- front threes Epoxide -4- oxo -4H- chromene -2- bases）The chloro- O-Anisic Acid esters of phenyl 4-.Pale yellow powder, yield is 47%.M.P.: 172~175°C.1HNMR(400MHz,cdcl3)δ8.02-7.99 (d,1H), 7.92-7.87(d,1H),7.31-7.27(d, 2H), 7.06-7.02(t,2H), 6.75(s,1H),6.53(s,1H),4.24(s,3H),3.98(s,3H), 3.94 (s, 3H), 3.81(s,3H)。
Embodiment 5：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The chloro- O-Anisic Acids of phenyl 5- Ester.
Figure 10 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The chloro- O-Anisic Acid esters of phenyl 5- Structural formula figure.
By 5- chloro-salicylic acids（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, solution is adjusted with 30% NaOH PH is 10, stirs 30min, is slowly added dropwise 2 mL dimethyl suflfates, and reaction to pH value of solution is changed into 7, then adjusts molten with 30% NaOH Liquid pH is 10, after 1 h of reaction, the mL of dimethyl suflfate 1 is slowly added dropwise again, and reaction to pH value of solution is changed into 7, then uses 30% NaOH Regulation pH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent is second Acetoacetic ester：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white precipitate to generate, distillation washing Precipitation is washed, precipitation is vacuum dried；Dried precipitation is dissolved in 10mL dichloromethane, adds two to drip DMF and 0.5mL protochlorides Sulfone, 40 DEG C of oil bath heatings 0.5 h of backflow, removes dichloromethane and thionyl chloride under reduced pressure, uses 10mL acetone solutions, adds embodiment 15,6, the 7- trimethoxies -4 for obtaining '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration reclaims third Ketone, silicagel column column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- front threes Epoxide -4- oxo -4H- chromene -2- bases）The chloro- O-Anisic Acid esters of phenyl 5-.Pale yellow powder, yield is 41%.M.P.: 172~175°C.1HNMR(400MHz,cdcl3)δ8.12-8.09(d,1H), 7.93-7.89(d,2H),7.65-7.61(t, 2H), 7.29-7.25(t,2H), 6.95-6.91(d,1H),6.76(s,1H),6.55(s,1H),4.25(s,3H),3.98 (s,3H),3.94(s,3H), 3.81(s,3H)。
Embodiment 6：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl 2- methoxyl group -4- methylbenzene first Acid esters.
Figure 11 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl 2- methoxyl group -4- methyl benzoic acids Ester structure formula figure.
By 4- cresotinic acids（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, adjusts molten with 30% NaOH Liquid pH is 10, stirs 30min, is slowly added dropwise 2 mL dimethyl suflfates, and reaction to pH value of solution is changed into 7, then is adjusted with 30% NaOH PH value of solution is 10, after 1 h of reaction, is slowly added dropwise the mL of dimethyl suflfate 1 again, and reaction to pH value of solution is changed into 7, then with 30% NaOH regulation pH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent It is ethyl acetate：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white gray precipitate to generate, 50 DEG C distillation water washing precipitation, will precipitation vacuum drying；Dried precipitation is dissolved in 10mL dichloromethane, add two drip DMF and 0.5mL thionyl chlorides, 40 DEG C of oil bath heatings 0.5 h of backflow, remove dichloromethane and thionyl chloride under reduced pressure, molten with 10mL acetone Solution, 5,6, the 7- trimethoxies -4 for adding embodiment 1 to obtain '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, Suction filtration, reclaims acetone, the purifying of silicagel column column chromatography, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4- （5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl 2- methoxyl group -4- methyl benzoic acid esters.Pale yellow powder, produces Rate is 47%.M.P.:172~175°C.1HNMR(400MHz,cdcl3)δ8.00-7.96(d,1H), 7.91-7.87(d,1H), 7.31-7.27(d,2H), 7.07-7.02(t,2H), 6.76(s,1H),6.55(s,1H),4.25(s,3H),3.98(s, 3H),3.94(s,3H),3.81(s,3H),2.57(s,3H)。
Embodiment 7：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl 2- methoxyl group -5- bromobenzoic acids Ester.
Figure 12 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl 2- methoxyl group -5- bromo-benzoates Structural formula figure.
By 5 bromosalicylic acid（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, solution is adjusted with 30% NaOH PH is 10, stirs 30min, is slowly added dropwise 2 mL dimethyl suflfates, and reaction to pH value of solution is changed into 7, then adjusts molten with 30% NaOH Liquid pH is 10, after 1 h of reaction, the mL of dimethyl suflfate 1 is slowly added dropwise again, and reaction to pH value of solution is changed into 7, then uses 30% NaOH Regulation pH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent is second Acetoacetic ester：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white precipitate to generate, distillation washing Precipitation is washed, precipitation is vacuum dried；Dried precipitation is dissolved in 10mL dichloromethane, adds two to drip DMF and 0.5mL protochlorides Sulfone, 40 DEG C of oil bath heatings 0.5 h of backflow, removes dichloromethane and thionyl chloride under reduced pressure, uses 10mL acetone solutions, adds embodiment 15,6, the 7- trimethoxies -4 for obtaining '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration reclaims third Ketone, silicagel column column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- front threes Epoxide -4- oxo -4H- chromene -2- bases）Phenyl 2- methoxyl group -5- bromo-benzoates.Yellow powder, yield is 50%.M.P.: 172~175°C.1HNMR(400MHz,cdcl3)δ8.12-8.09(d,1H), 7.93-7.89(d,2H),7.65-7.61(t, 2H), 7.29-7.25(t,2H), 6.95-6.91(d,1H),6.76(s,1H),6.55(s,1H),4.25(s,3H),3.98 (s,3H),3.94(s,3H),3.81(s,3H)。
Embodiment 8：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The bromo- 2- methoxybenzenes of phenyl 3,5- bis- Formic acid esters.
Figure 13 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）The bromo- 2- methoxybenzenes first of phenyl 3,5- bis- Acrylate structure formula figure.
By 3,5- dibromosalicylic acids（5mmol）It is dissolved in 15mL distilled water, 37 DEG C of heating water baths, is adjusted with 30% NaOH PH value of solution is 10, stirs 30min, is slowly added dropwise 2 mL dimethyl suflfates, and reaction to pH value of solution is changed into 7, then is adjusted with 30% NaOH Section pH value of solution is 10, after 1 h of reaction, is slowly added dropwise the mL of dimethyl suflfate 1 again, and reaction to pH value of solution is changed into 7, then with 30% NaOH regulation pH value of solution is 10, reacts 1 h, and 15 min, TLC monitoring reaction process are hydrolyzed under 80 DEG C of water bath conditions（Solvent It is ethyl acetate：Petroleum ether=1:1~1:4）, room temperature is cooled to, it is 5 to adjust pH with 10% HCl, has white precipitate to generate, and is distilled Water washing is precipitated, and precipitation is vacuum dried；Dried precipitation is dissolved in 10mL dichloromethane, adds two to drip DMF and 0.5mL chlorine Change sulfoxide, 40 DEG C of oil bath heatings 0.5 h of backflow remove dichloromethane and thionyl chloride under reduced pressure, use 10mL acetone solutions, add real Apply example 1 is obtained 5,6,7- trimethoxies -4 '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration is reclaimed Acetone, silicagel column column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- tri- Methoxyl group -4- oxo -4H- chromene -2- bases）The bromo- O-Anisic Acid esters of phenyl 3,5- bis-.Pale yellow powder, yield is 43%。M.P.:172~175°C.1HNMR(400MHz,cdcl3)δ8.12-8.09(d,1H), 7.93-7.89(d,2H),7.65- 7.62(t,2H), 7.30-7.26(t,2H), 6.95-6.92(d,1H),6.54(s,1H),4.25(s,3H),3.98(s, 3H),3.94(s,3H),3.81(s,3H)。
Embodiment 9：4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl Aspirin ester.
Figure 14 is 4-（5,6,7- trimethoxy -4- oxo -4H- chromene -2- bases）Phenyl Aspirin ester knot Structure formula figure.
By acetylsalicylic acid（5mmol）10mL dichloromethane is dissolved in, adds two to drip DMF and 0.5mL thionyl chlorides, 40 DEG C Oil bath heating 0.5 h of backflow, removes dichloromethane and thionyl chloride under reduced pressure, uses 10mL acetone solutions, adds what embodiment 1 was obtained 5,6,7- trimethoxies -4 '-flavonol 80mg, 1mL triethylamines are added dropwise over, 3 h are reacted, suction filtration reclaims acetone, silicagel column Column chromatography is purified, and eluant, eluent is：Ethyl acetate：Petroleum ether=1:1~1:4, obtain compound 4-（5,6,7- trimethoxy -4- oxygen Generation -4H- chromene -2- bases）Phenyl Aspirin ester.Pale yellow powder, yield is 37%.M.P.:172~175° C.1HNMR(400MHz,cdcl3)δ8.05-8.01(d,1H), 7.92-7.87(d,2H),7.60-7.53(t,1H), 7.32- 7.27(t,2H),7.08-7.03(d,1H),6.76(s,1H),6.55(s,1H),4.25(s,3H), 3.98(s,3H), 3.94 (s,3H),3.81(s,3H)。
Embodiment 10：The anti-tumor activity test of the compounds of this invention.
Cytostatic to tumor cell experiment is carried out to compound of the invention, test method is using conventional mtt assay.
Cell line selects MGC-803 (gastric carcinoma cells), HepG2 (human liver cancer cell) and MCF-7（Human breast cancer cell）. Nutrient solution is that DMEM+15% NBS+ are dual anti-.
Sample liquid is prepared：After being dissolved with DMSO (Merck), PBS (-) is added to be made into the solution of 1mmol/mL or uniform Suspension, then with the PBS of DMSO (-) dilution, ultimate density be respectively 384 μm of ol/L, 192 μm of ol/L, 96 μm of ol/L, 48μmol/L、24μmol/L、12μmol/L、6μmol/L、3μmol/L。
The antineoplastic 5 FU 5 fluorouracil of listing is made into reference substance solution with same condition.
It is 3 × 10 that 96 orifice plates add concentration per hole4The μ L of cell suspension 100 of individual/mL, i.e., 8000 cells/wells are put 37 DEG C, 5% CO2In incubator.After 48 hours, sample liquid and reference substance liquid are separately added into, 10 μ L/ holes, 37 DEG C of effects 48 are small When.Add the MTT (3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyltetrazoliumbromide father-in-law bromide) of 5mg/mL molten per hole The μ L of liquid 20, effect adds lysate DMSO after 4 hours, and 100 μ L/ holes are put in incubator, secondary daily MK-2 full-automatic enzymes mark Instrument surveys 570nm OD values.Calculation of half inhibitory concentration IC50。
Result of the test refers to Figure 14, wherein, compound refers to the A ring trimethoxy flavone chemical combination of preparation in corresponding embodiment Thing and A ring trimethoxy flavone substituted salicylic acid esters compounds, such as compound a represented resulting 5,6 in embodiment 1, 7- trimethoxy -4 '-flavonol compounds, similarly analogize.
Figure 15 is A 4 '-flavonols of ring trimethoxy and A ring trimethoxy 4 '-flavonol substituted salicylic acid esters Half-inhibition concentration IC of the compound to tumour cell MGC-803, HepG2 and MCF-750(unit：μm ol/L) form.
Above test result indicate that, compound of the invention has good antitumor activity, A ring trimethoxy flavones Compound and A ring trimethoxy flavone substituted salicylic acid esters compounds are in vitro to MGC-803 (gastric carcinoma cells), HepG2 (people HCC) and MCF-7（Human breast cancer cell）Cell shows a certain degree of inhibitory activity.Wherein compound c, d, f, Growths of the g to MGC-803 cells has good inhibiting effect, and activity is better than positive control medicine 5 FU 5 fluorouracil.Compound The growth of c, f to HepG2 cells has good inhibiting effect, and activity is better than positive control medicine 5 FU 5 fluorouracil.Compound c There is good inhibiting effect to the growth of MCF-7 cells, activity is better than positive control medicine 5 FU 5 fluorouracil.

Claims (3)

1. a kind of A rings trimethoxy flavone compound, its structure such as formula（）It is as follows：
In formula：R1,R2,R3=OCH3Or R2,R3,R4=OCH3 。
2. a series of A rings trimethoxy flavone substituted salicylic acid esters compounds, it is characterised in that the A rings trimethoxy is yellow The structure such as formula of ketone substituted salicylic acid esters compound（）It is shown：
In formula：R1,R2,R3=OCH3Or R2,R3,R4=OCH3 ; R5=OCH3、CH3, F, Cl, Br or I etc..
3. A ring trimethoxy flavone compounds described in claim 1 and 2 and A ring trimethoxy flavone substituted salicylic acid esters Application of the compound in cancer therapy drug is prepared.
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