CN101265249B - 4-position carbonyl nitrogen-containing derivative of 6-methoxy-4',7-dihydroxyisoflavone and medical use thereof - Google Patents
4-position carbonyl nitrogen-containing derivative of 6-methoxy-4',7-dihydroxyisoflavone and medical use thereof Download PDFInfo
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- CN101265249B CN101265249B CN 200810034474 CN200810034474A CN101265249B CN 101265249 B CN101265249 B CN 101265249B CN 200810034474 CN200810034474 CN 200810034474 CN 200810034474 A CN200810034474 A CN 200810034474A CN 101265249 B CN101265249 B CN 101265249B
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- 0 COC(C[C@](C(OC=C1c(cc2)ccc2O)=C2)C1=N*)=C2O Chemical compound COC(C[C@](C(OC=C1c(cc2)ccc2O)=C2)C1=N*)=C2O 0.000 description 6
- SXRZZVXFDXPIDI-FBMGVBCBSA-N COc(cc(c(OC=C1c(cc2)ccc2O)c2)/C1=N\N)c2O Chemical compound COc(cc(c(OC=C1c(cc2)ccc2O)c2)/C1=N\N)c2O SXRZZVXFDXPIDI-FBMGVBCBSA-N 0.000 description 4
- GBUOAWLMHAMBFD-UHFFFAOYSA-N COc(cc(c(NC=C1c(cc2)ccc2O)c2)/C1=N\OC)c2O Chemical compound COc(cc(c(NC=C1c(cc2)ccc2O)c2)/C1=N\OC)c2O GBUOAWLMHAMBFD-UHFFFAOYSA-N 0.000 description 1
- DXYUAIFZCFRPTH-UHFFFAOYSA-N COc(cc(c(OC=C1c(cc2)ccc2O)c2)C1=O)c2O Chemical compound COc(cc(c(OC=C1c(cc2)ccc2O)c2)C1=O)c2O DXYUAIFZCFRPTH-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N Cc(cc1)ccc1S(Cl)(=O)=O Chemical compound Cc(cc1)ccc1S(Cl)(=O)=O YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N NNc1ccccc1 Chemical compound NNc1ccccc1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a 6-methoxy-4',7-bihydroxylisoflavone (glycitein)-4-carbonyl nitrogen-containing derivative (formula 1), which belongs to the field of medicine synthesis. The bioactivity measured result of the compound indicates that the derivative has remarkable inhibiting effect on A-549 human lung cancer cell and anti-tumor activity, and can be further made into anti-tumor drugs, wherein X is -OH, -NH2, -R, -Ar, -OR, -NHR, -OCOR, -NHCOR or -NHSO2R,and R is hydrocarbon group containing 1-8 carbon atoms.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to the nitrogen containing derivative of compound 6-methoxyl group-4',7-Dihydroxy-isoflavone (glycitein) 4-position carbonyl, preparation method and application pharmaceutically.
Background technology
Soybean isoflavones (Soybean isoflavones) is the class secondary metabolite that soybean etc. forms in process of growth, is a kind of Vitamin P complex, mainly refers to the compound take 3-phenyl benzopyrane ketone as parent nucleus, can not synthesize in the human body.It distributes limited at occurring in nature, mainly be present in the leguminous plants, with the content in the soybean for the highest, so be called soybean isoflavones.Soybean isoflavones is a kind of of phytoestrogen, has the molecular structure similar to oestrogenic hormon and molecular weight, and women's body inner estrogen level is had dual regulation.Studies show that cross when low when human body inner estrogen level, soybean isoflavones can play the effect of complementing estrogen to human body; And when estrogen level is too high in vivo (such as cyclomastopathy, hysteromyoma etc.), soybean isoflavones can stop again the excessive women's of the acting on target organ of oestrogenic hormon, thereby maid's gonosome inner estrogen activity keeping balance.Therefore the soybean isoflavones setter of women estrogen level that is otherwise known as.
There is epidemiological study to show, China, Japan and other high crowds of Asian countries's soybean intake, the sickness rate of its mammary cancer, prostate cancer, colorectal carcinoma and uterus carcinoma etc. is usually lower.The case control study of Ingrain report provides the result who relatively determines, shows to metabolite to be that the high women breast cancer onset risk of phytoestrogen intake of Equol (equol) and wooden fat enterolactone reduces really.The intestines lactones (enterolac-tone) of the case control study prompting serum lower concentration of Pietinen etc. is negative correlation with causing danger property of women breast cancer, and odds ratio (OR) is 0.3, P＜0.03.The epidemiological studies such as Hulten have also shown similar results.Between American scholar Wu report 1995～1998 years to crowd's case control study of American asian ancestry women, find that it is 12mg that asian ancestry women's isoflavones every day is taken the photograph people's amount, although only have 1/3 of nearest Chinese Shanghai report, but soybean isoflavones is taken the photograph people and its breast cancer incidence low relevant (risk factor is 0.77) Childhood of having been found that, and adulthood continues to take and can further reduce mammary cancer generation (risk factor is 0.53).Nowadays the bioactive ingredients of soybean isoflavones has become the research focus that common people gaze at.
At present, clear and definite soybean isoflavones antitumor mechanism has following 6 aspects: (1) similar female estrogen and estrogenic antagonist; (2) suppress and the effect of Tumor-assaciated enzymic activity, particularly to Tyrosylprotein kinase; (3) in the tumor cell proliferation stage, has antiangiogenic activities; (4) Scavenging active oxygen, thus antioxygenation had; (5) regulate the cell cycle; (6) genistein (Genistein) has the effect that suppresses partly to cut off with DNA Activities of Related Enzymes.In a word, soybean isoflavones can play certain prophylaxis of tumours effect by different mechanisms, particularly weak estrogen effect.
Summary of the invention
The purpose of this invention is to provide a kind of glycitein, be specifically related to the nitrogen containing derivative of 6-methoxyl group-4',7-Dihydroxy-isoflavone 4-position carbonyl.
6-methoxyl group-4 ', the 7-dihydroxy isoflavone is one of main component of soybean isoflavones, be commonly called as glycitein or Daidezin (Glycitin), compound 6-methoxyl group-4 ' provided by the invention, the nitrogen containing derivative of 7-dihydroxy isoflavone 4-position carbonyl, prove that through experiment in vitro this analog derivative shows the significant restraining effect of A-549 human lung carcinoma cell line, has anti-tumor activity.
Further purpose of the present invention provides the pharmaceutical usage of above-claimed cpd, and specifically described compound is in the purposes of anti-tumor aspect.
The nitrogen containing derivative of 6-methoxyl group provided by the present invention-4',7-Dihydroxy-isoflavone 4-position carbonyl has the structure of formula 1,
X=-OH wherein ,-NH
2,-R ,-Ar ,-OR ,-NHR ,-OCOR ,-NHCOR or-NHSO
2R, wherein said R be, contains the alkyl of 1-8 carbon atom, comprises alkyl, alkylene and aryl.
Compound of the present invention prepares by following method:
6-methoxyl group-the 4',7-Dihydroxy-isoflavone of employing formula 2 and all kinds of nitrogenous carbonyl reagent direct polycondensation make,
Described nitrogenous carbonyl reagent is selected from oxammonium hydrochloride, hydrazine hydrate, substituted phenylhydrazines or contain the primary amine of 1-8 carbon atom; Or,
6-methoxyl group-4',7-Dihydroxy-isoflavone of the X=-OH of employing formula 3-4-ketoxime and all kinds of hydrocarbonylation reagent or acylating reagent reaction make,
Described hydrocarbonylation reagent or acylating reagent are selected from the halohydrocarbon that contains 1-8 carbon atom, contain the acetyl halide compound of 1-8 carbon atom or contain the sulfonyl halogen compound of 1-8 carbon atom;
Or,
The X=-NH of employing formula 4
26-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketone hydrazone and all kinds of hydrocarbonylation reagent or acylating reagent reaction make,
Described hydrocarbonylation reagent or acylating reagent are selected from the halohydrocarbon that contains 1-8 carbon atom, contain the acetyl halide compound of 1-8 carbon atom or contain the sulfonyl halogen compound of 1-8 carbon atom.
The 6-methoxyl group-4 ' of formula 1 provided by the present invention, 7-dihydroxy isoflavone 4-position carbonyl derivative has carried out biological activity determination, and the result shows has significant restraining effect to the A-549 human lung carcinoma cell, have anti-tumor activity, can further prepare antitumor drug.
Embodiment
Embodiment 1 synthetic 6-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketoxime
2.09g (7.34mmol) add 25mL methyl alcohol in the raw material, 50mL pyridine, not fully dissolving, reaction solution is the incarnadine dirty solution, adds 2.00g oxammonium hydrochloride (28.78mmol) again, and reaction solution becomes faint yellow immediately, add 25mL Py, the reaction solution clarification is for orange-yellow.Reflux after 48 hours, raw material disappears fully substantially, and reaction solution is poured in the 200mL water, uses the ethyl acetate extraction water, merges organic phase, and evaporating solvent obtains oily matter.The crude product column chromatography is got product with the mixing solutions recrystallization of ethanol/methylene, obtains white needles solid 1.62g (5.43mmol, 74%).
Embodiment 2 synthetic 6-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketone hydrazones
1.91g (6.72mmol) raw material places the 50mL round-bottomed flask, adds 20mL Py, 10mL methyl alcohol, and heated and stirred, raw material is not molten clear.Add 0.5mL hydrazine hydrate (672mg, 13.44mmol), reaction solution is become yellow muddy immediately by pink colour again.Reflux, reaction solution is clarified gradually.React after 8 hours, raw material disappears substantially fully.Remove solvent under reduced pressure, get dark-brown oily matter.The crude product column chromatography gets yellow solid 1.84g (6.17mmol, 92%).
Embodiment 3 synthetic 6-methoxyl group-4',7-Dihydroxy-isoflavone-O-methyl-4-ketoximes
1.05g (3.67mmol) add 15mL methyl alcohol and 25mL pyridine in the raw material, fully not molten clear, add 1.50g oxammonium hydrochloride methyl ether (17.96mmol), reaction solution becomes faint yellow, and reflux stirs, and the reaction solution clarification is for orange-yellow.Raw material disappears fully substantially after 48 hours, and reaction solution is poured in the 100mL water, and the ethyl acetate extraction water merges organic phase, the dry oily matter that concentrates to get.Column chromatography is got white solid 0.77g (2.45mmol, 66.7%).
Embodiment 4 synthetic 6-methoxyl group-4',7-Dihydroxy-isoflavone-N-phenyl-4-ketone hydrazones
Add 10mL pyridine and 3mL methyl alcohol in 625mg (2.20mmol) raw material, stir adding 0.65mL phenylhydrazine (713mg, 6.60mmol), 3 hours afterreactions of reflux become clarification.Continue reaction after 40 hours, molecular balance.The reaction solution cooling is poured in the 200mL water, has solid to separate out.Filter, reclaim raw material 102mg.The filtrate ethyl acetate extraction merges organic phase, and anhydrous sodium sulfate drying concentrates to get oily matter.The crude product column chromatography is got white solid 461mg (1.23mmol, 56.0%)
Embodiment 56-methoxyl group-4',7-Dihydroxy-isoflavone-N-tolysulfonyl-4-ketone hydrazone
500mg (1.68mmol) raw material 6-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketone hydrazone places the 25mL round-bottomed flask, and adding 5mL pyridine is molten clear, adds 328mg Tosyl chloride (1.72mmol) under the room temperature condition.Stirring at room to raw material disappears, and reaction solution is poured in the 50mL water, and ethyl acetate extraction merges organic layer, anhydrous sodium sulfate drying.Filtration removes solvent under reduced pressure, and the residue column chromatography is got white powder solid 472mg (1.04mmol, 62.1%).
Embodiment 66-methoxyl group-4',7-Dihydroxy-isoflavone-N-acetyl-4-ketone hydrazone
450mg (1.51mmol) raw material 6-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketone hydrazone places the 25mL round-bottomed flask, and adding 5mL pyridine is molten clear, adds at twice 0.3mL Acetyl Chloride 98Min. (333mg, 4.24mmo1) under the condition of ice bath.Keep ice bath to stir, until raw material disappears.Reaction solution is poured in the 50mL water, and ethyl acetate extraction merges organic layer, anhydrous sodium sulfate drying.Filter steaming and desolventize, post residue column chromatography is got white powder solid 412mg (1.21mmol, 80.2%).
Embodiment 76-methoxyl group-4',7-Dihydroxy-isoflavone-N-methylsulfonyl-4-ketone hydrazone
400mg (1.34mmol) raw material 6-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketone hydrazone places the 25mL round-bottomed flask, and adding 4mL pyridine is molten clear, and room temperature condition adds 0.3mL methylsulfonyl chloride (450mg, 3.93mmol) lower minute three times.Stirring at room disappears to raw material.Reaction solution is poured in the 50mL water, and ethyl acetate extraction merges organic phase, and anhydrous sodium sulfate drying filters, and steaming desolventizes, and the residue column chromatography is got white powder solid 392mg (1.04mmol, 77.8%).
Embodiment 8 anti-tumor biological body outer screening tests
Adopt sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method, (available from The National Center for Drug Screening) screens to the A-549 human lung carcinoma cell, be 72 hours action time, the biological activity determination result shows, compound of the present invention is inhibited to the A-549 human lung carcinoma cell, has anti-tumor activity, and wherein embodiment 1 and embodiment 2 described compounds reach 10 to the half-inhibition concentration of A-549 human lung carcinoma cell
-5Mmol/L.
Table 1 is that compound of the present invention is to the inhibiting rate % of growth of tumour cell.
Table 1
| Concentration (mol/L) sample | 10 -4 | 10 -5 | 10 -6 |
| 2ME2 | 73.9 | 62.7 | 60.1 |
| EXAMPLE l | 81.3 | 66.1 | 8.3 |
| Embodiment 2 | 96.4 | 53.0 | 15.7 |
| Embodiment 3 | 91.1 | 40.2 | 7.2 |
| Embodiment 4 | 25.3 | 8.6 | 0 |
| Embodiment 5 | 81.9 | 11.0 | 0 |
| Embodiment 6 | 88.2 | 8.6 | 0 |
| Embodiment 7 | 35.9 | 18.2 | 0 |
Claims (5)
1. the compound of formula 1,
Wherein, X=-OH ,-NH
2,-R ,-OR ,-NHR ,-OCOR ,-NHCOR ,-OSO
2R or-NHSO
2R, wherein said R are the alkyl that contains 1-8 carbon atom.
2. by the described compound of claim 1, it is characterized in that wherein said alkyl is alkyl, alkylene or aryl.
3. a method for preparing claim 1 or 2 described compounds is characterized in that the 6-methoxyl group-4',7-Dihydroxy-isoflavone of employing formula 2 and nitrogenous carbonyl reagent direct polycondensation make,
Described nitrogenous carbonyl reagent is selected from oxammonium hydrochloride H
2N-OH,-oxyl amine H
2N-OR, hydrazine hydrate H
2N-NH
2Or contain the primary amine H of 1-8 carbon atom
2N-R, wherein said alkyl R is with the definition of claim 1 or 2;
Or
6-methoxyl group-4',7-Dihydroxy-isoflavone of the X=-OH of employing formula 3-4-ketoxime and hydrocarbonylation reagent or acylating reagent reaction make,
Described hydrocarbonylation reagent or acylating reagent are selected from the halohydrocarbon RX that contains 1-8 carbon atom, contain the acetyl halide compound RCOX of 1-8 carbon atom or contain the sulfonyl halogen compound RSO of 1-8 carbon atom
2X, wherein said R is with the definition of claim 1 or 2;
Or
The X=-NH of employing formula 4
26-methoxyl group-4',7-Dihydroxy-isoflavone-4-ketone hydrazone and hydrocarbonylation reagent or acylating reagent reaction make,
Described hydrocarbonylation reagent or acylating reagent are selected from the halohydrocarbon RX that contains 1-8 carbon atom, contain the acetyl halide compound RCOX of 1-8 carbon atom or contain the sulfonyl halogen compound RSO of 1-8 carbon atom
2X, wherein said R are with claim 1 or 2.
4. the described compound of claim 1 is in the purposes of preparation in the antitumor drug.
5. by purposes claimed in claim 4, wherein said tumour is lung cancer.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1093086A (en) * | 1993-04-03 | 1994-10-05 | 华西医科大学药物研究所 | Isoflavone alicyclic hydrocarbon-ether and 9 oxime derivate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1093086A (en) * | 1993-04-03 | 1994-10-05 | 华西医科大学药物研究所 | Isoflavone alicyclic hydrocarbon-ether and 9 oxime derivate thereof |
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