CN1300129C - Compound of 3,15-dicarbonyl erythro mildew acid kind and its ester and salt - Google Patents
Compound of 3,15-dicarbonyl erythro mildew acid kind and its ester and salt Download PDFInfo
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- CN1300129C CN1300129C CNB2004100219392A CN200410021939A CN1300129C CN 1300129 C CN1300129 C CN 1300129C CN B2004100219392 A CNB2004100219392 A CN B2004100219392A CN 200410021939 A CN200410021939 A CN 200410021939A CN 1300129 C CN1300129 C CN 1300129C
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Abstract
The present invention relates to a novel gibberellic acid-3, 15-carbonyl gibberellic acid class compound and ester and salt thereof, a preparation method thereof and the application of a medical composition using the compound as active components on the aspect of cancer resistance. The compound is represented by the structure general formula (I): the gibberellic acid (GA3) of the present invention obtained easily with low cost is used as raw materials for synthesizing gibberellic acid ester (R<1>=CH3, CH2 C6 H5, etc.), the raw materials are converted into hydroxy or carbonyl through 3-site acidylation and 15-site oxidization, and tens of gibberellic acid derivants are synthesized. Compounds oxidized into carbonyl by 3-site and 15-site simultaneously have strong anticancer activity discovered through in vitro anticancer activity screening and has low toxicity to normal cells simultaneously.
Description
Technical field: the present invention relates to novel gibberic acid-3,15-carbonyl gibberic acid compounds and ester and salt, its preparation method is the application of the pharmaceutical composition of active ingredient at anticancer aspect with this compound.
Background technology: cancer is a class disease of serious threat human health.The main means that are used for the treatment of cancer at present are chemotherapy.The chemotherapeutics overwhelming majority of clinical application makes toxic side effect such as the patient feels sick, vomiting, leukopenia, bone marrow depression, has influenced patient's body health, has also limited the clinical application of chemotherapeutics greatly.Therefore, seek high reactivity, nontoxic or hypotoxic anticancer compound becomes an important topic of new drug research.
Summary of the invention: Plant hormones regulators,gibberellins is that a class extensively is present in plant and the microbe, has multiple bioactive tetracyclic diterpene compounds, and the present inventor utilizes the Plant hormones regulators,gibberellins of commercialization fermentative production (as GA
3, GA
4, GA
4+7) carry out structural modification and transformation for raw material, discovery has plant-growth promotion preferably or plant growth inhibiting activity and other and such as new active Plant hormones regulators,gibberellins such as antibiotic, anticancer and derivative thereof important academic significance and practical value is arranged, with gibberic acid (GA cheap and easy to get
3) be that raw material synthesizes gibberellic acid ester (R
1=CH
3, CH
2C
6H
5Deng); through 3-position acidylate or oxidation, the 15-position is oxidized to hydroxyl or carbonyl, has synthesized tens of kinds of Plant hormones regulators,gibberellins derivatives; the compound that external antitumour activity screening discovery 3-position and 15-position are oxidized to carbonyl simultaneously has very strong antitumour activity, and is very low to normal cytotoxicity simultaneously.
Gibberic acid provided by the invention-3,15-carbonyl gibberic acid compounds and ester thereof and salt are represented with following general structural formula (I):
R＝H，CH
3，CH
2Ph，Li，Na，K，Mg，Ca，Cu，Zn，Fe，Mn，La，CeR
1＝H，OH，OAc
(I)
Wherein: R
1Be CH
3, CH
2C
6H
5,, H or basic metal, transition metal; Basic metal is sodium, potassium, lithium etc.
Above-claimed cpd 7-position is carboxylic acid, carboxylicesters and carboxylate salt, and metal ion adopts sodium, potassium, lithium and transition metal ion when it is salt.
A kind of preparation method with compound of general structure (I), this method may further comprise the steps:
A), gibberic acid (GA
3) be starting raw material, in acetone, be oxidized to 3-carbonyl gibberic acid through activated manganese dioxide earlier, consumption (gram g) is: gibberic acid/activated manganese dioxide=1/8～20, the temperature of reaction during oxidation are 10～69 ℃, and the acetone consumption is 30～100mL/g gibberic acid;
B), hydroxyl is introduced in the oxidation of 15-position, each compound amount (mol ratio mol) is: treat oxidation substrates/tin anhydride/tertbutanol peroxide=1/0.01～0.5/1～3, solvent adopts benzene, toluene, methylene dichloride, trichloromethane, ethyl acetate, butylacetate, acetone, butanone, normal hexane, hexanaphthene, sherwood oil, and consumption is that 10～100mL/g treats oxidation substrates;
C), after the Swern oxidation, obtain double carbonyl compound (I) again, adopting methylene dichloride, trichloromethane, benzene, toluene, tetrahydrofuran (THF), dioxane is solvent, methyl-sulphoxide and oxalyl chloride or sulfur oxychloride form oxygenant in temperature under-70 ℃ to-20 ℃ the low temperature, each compound amount (mol ratio mol) is: treat oxidation substrates/methyl-sulphoxide/oxalyl chloride/triethylamine=1/2～5/2～5/4～20, add the substrate reactions for the treatment of oxidation and add the triethylamine reaction after 15～50 minutes again, the methylene dichloride consumption is that 10～100mL/g treats oxidation substrates.
Above-mentioned when being oxidized to 3-carbonyl gibberic acid, oxidizing reaction temperature preferentially adopts 25 ℃, and the acetone consumption preferentially adopts the 50mL/g gibberic acid; When introducing 15-position hydroxyl, the preferential employing of each compound amount (mol ratio mol) treated oxidation substrates/tin anhydride/tertbutanol peroxide=1/0.1/2, and solvent preferentially adopts methylene dichloride, and consumption preferentially adopts 25mL/g to treat oxidation substrates; When the Swern oxidation, solvent preferentially adopts methylene dichloride, each compound amount (mol ratio mol) is preferential to be adopted: treat oxidation substrates/methyl-sulphoxide/oxalyl chloride/triethylamine=1/3/3/12, the methylene dichloride consumption preferentially adopts 50mL/g to treat oxidation substrates, and the compound that preferentially adopts methyl-sulphoxide and oxalyl chloride to form is an oxygenant.
The preparation method of above-claimed cpd can gibberic acid (GA
3, GA
4, GA
4+7) and ester be starting raw material, earlier introduce hydroxyls through 15 oxidations, obtain double carbonyl compound (I) through the Swern oxidation again, gibberellic acid ester is methyl esters or benzyl ester.
Above-mentioned preparation method, with 3, the 15-dicarbonyl gibberellic acid is a raw material, in dehydrated alcohol, acetic acid solvent with the metal acetate of equivalent, ethylate or oxyhydroxide reaction, prepare corresponding 3,15-dicarbonyl gibberellic acid salt.
Above-mentioned have the compound of general structure (I) and medicine that at least a pharmaceutically acceptable vehicle, diluent or carrier make can be used for treating cancer.
GA
3Methyl esters and benzyl ester are that gibberic acid is with halohydrocarbon or methyl-sulfate make with acid binding agent stirring reactions such as salt of wormwood, yellow soda ash, pyridine, triethylamines in appropriate solvents such as tetrahydrofuran (THF), methylene dichloride, acetone, butanone, ether, pyridine accordingly.
R=CH
3, CH
2C
6H
5, a) RX (R=CH
3, CH
2C
6H
5, X=Br, I), K
2CO
3/ solvent or Me
2SO
4, K
2CO
3/ solvent
GA
3And the 3-position carbonyl of ester is that its corresponding 3-position hydroxyl makes through activated manganese dioxide oxidation in methylene dichloride, trichloromethane, tetrahydrofuran (THF), acetone, butanone, ether equal solvent.
R=CH in the formula
3, CH
2C
6H
5, b) MnO
2/ solvent
15-position oxy-compound be corresponding Plant hormones regulators,gibberellins compounds and tin anhydride and hydrogen peroxide tertiary butyl in benzene, toluene, methylene dichloride, trichloromethane, ethyl acetate, butylacetate, acetone, butanone, normal hexane, hexanaphthene, sherwood oil equal solvent, stirring reaction makes under the room temperature.
R＝H、CH
3、CH
2C
6H
5，c)SeO
2，t-BuOOH/CH
2Cl
2
3,15-dicarbapentaborane Plant hormones regulators,gibberellins compounds and ester thereof are corresponding 3,15-dihydroxy compound or 3-carbonyl-15-oxy-compound, the oxygenant oxidation through methyl-sulphoxide and oxalyl chloride or sulfur oxychloride formation in methylene dichloride, benzene, toluene, tetrahydrofuran (THF), dioxane equal solvent makes.
R＝H、CH
3、CH
2C
6H
5，d)DMSO，ClOCCOCl，NEt
3/CH
2Cl
2
R＝H、CH
3、CH
2C
6H
5，e)DMSO，ClOCCOCl，NEt
3/CH
2Cl
2
3,15-dicarbonyl gibberellic acid salt is 3, and the 15-dicarbonyl gibberellic acid makes with the metal acetate of equivalent, ethylate or oxyhydroxide reaction in dehydrated alcohol, acetate equal solvent.
M=Na, K etc., f) MOH, EtOH
Embodiment: enumerate typical compound of the present invention below in conjunction with embodiment.
Compound 13, and the 15-dicarbonyl gibberellic acid (3,15-dicarbapentaborane-10,13-dihydroxyl-red is mould-1,16-diene-7,19-diacid-19,10-lactone)
Preparation process is as follows:
1.3-carbonyl gibberic acid: gibberic acid (GA
3, 3.46g 10mmol) is dissolved in acetone (150mL), adds activated manganese dioxide (30.0g) again.Stir under the room temperature and spend the night.After the silica gel thin-layer chromatography detection reaction is complete, remove by filter Manganse Dioxide, with small amount of acetone filter wash cake.Reclaim under reduced pressure acetone gets 3.338 light yellow xln, yield 96.9% to doing.
2.15 Alpha-hydroxy-3-carbonyl gibberic acid: 3-carbonyl gibberic acid (1.72g 5mmol) is dissolved in methylene dichloride (100mL), add again tin anhydride (0.555g, 0.5mmol) and the hydrogen peroxide tertiary butyl (0.9g, 10mmol), stirred overnight at room temperature.After the silica gel thin-layer chromatography detection reaction is complete, reaction solution changes separating funnel over to, after sodium hydroxide solution (10%, 10mL * 4) washing, water (10mL * 4) washing again, tell organic layer, add anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, get white crystals 1.18g through silica gel column chromatography, yield 62.8%.
3.3 the 15-dicarbonyl gibberellic acid: (0.78g 10mmol) and methylene dichloride (40mL), is cooled to-70 ℃, and (1.27g 10mmol), adds about 5 minutes, and control reaction temperature is between-70 ℃ to-40 ℃ to stir down the dropping oxalyl chloride to mix methyl-sulphoxide.Oxalyl chloride finishes after 10 minutes and to drip 15 Alpha-hydroxies-3-carbonyl gibberic acid (1.80g, 5mmol) and the solution that is made into of methylene dichloride (10mL), after adding about 5 minutes, stirring reaction is 20 minutes between-70 ℃ to-40 ℃.(3.03g 30mmol), continued between-70 ℃ to-40 ℃ stirring reaction 50 minutes, removed cryostat, was warming up to room temperature naturally to add triethylamine again.Reaction solution changes separating funnel over to, and organic layer is used hydrochloric acid (2N, 10mL * 1) and water (10mL * 2) washing successively, tell organic layer, add anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, and resistates gets white crystals 1.53g through purification by silica gel column chromatography, yield 83.6%.
Ultimate analysis C
19H
18O
7
Calculated value (%): C, 63.68; H, 5.06;
Measured value (%): C, 63.63; H, 5.10.
1H NMR(CDCl
3，500MHz)：δ7.18(d，J＝9.4Hz，1H)，6.25(S，1H)，6.07(d，J＝9.4Hz，1H)，5.88(s，1H)，3.60(d，J＝10.2Hz，1H)，2.80(d，J＝10.2Hz，1H)，2.77(d，J＝11.5Hz，1H)，2.65-2.58(m，1H)，2.48(d，J＝11.5Hz，1H)，2.38-2.07(m，4H)，1.86(m，1H)，1.33(s，3H).
13C NMR(CDCl
3，500MHz)：δ200.30，191.12，172.70，171.15，150.68，145.91，129.73，121.57，89.17，66.15，65.45，61.30，60.53，48.77，47.20，41.60，39.90，18.03，11.95.
Compound 23, and 15-dicarbonyl gibberellic acid methyl esters (3,15-dicarbapentaborane-10,13-dihydroxyl-red is mould-1,16-diene-7,19-diacid-19,10-lactone-7-methyl esters)
1.15 Alpha-hydroxy-Methyl gibberellate: Methyl gibberellate (1.80g 5mmol) is dissolved in methylene dichloride (50mL), add again tin anhydride (0.555g, 0.5mmol) and the hydrogen peroxide tertiary butyl (0.9g, 10mmol), stirred overnight at room temperature.After the silica gel thin-layer chromatography detection reaction is complete, reaction solution changes separating funnel over to, after sodium hydroxide solution (10%, 10mL * 4) washing, water (10mL * 4) washing again, tell organic layer, add anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, get white crystals 1.81g, yield 100%.
2.3,15-dicarbonyl gibberellic acid methyl esters: mix methyl-sulphoxide (1.17,15mmol) and methylene dichloride (40mL), be cooled to-70 ℃, (1.91g 15mmol), adds about 5 minutes, and control reaction temperature is between-70 ℃ to-40 ℃ to stir down the dropping oxalyl chloride.Oxalyl chloride finishes after 10 minutes and to drip 15 Alpha-hydroxies-Methyl gibberellate (1.81g, 5mmol) and the solution that is made into of methylene dichloride (10mL), after adding about 5 minutes, stirring reaction is 20 minutes between-70 ℃ to-40 ℃.(6.06g 60mmol), continued between-70 ℃ to-40 ℃ stirring reaction 50 minutes, removed cryostat, was warming up to room temperature naturally to add triethylamine again.Reaction solution changes separating funnel over to, and organic layer is used hydrochloric acid (2N, 20mL * 1) and water (10mL * 2) washing successively, tell organic layer, add anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, and resistates gets white crystals 1.21g through purification by silica gel column chromatography, yield 65.1%.
Ultimate analysis C
20H
20O
7
Calculated value (%): C, 64.51; H, 5.41;
Measured value (%): C, 64.50; H, 5.45.
1H NMR(CDCl
3，500MHz)：δ7.19(d，J＝9.4Hz，1H)，6.23(S，1H)，6.07(d，J＝9.4Hz，1H)，5.87(s，1H)，3.63(s，3H)，3.62(d，J＝10.2Hz，1H)，2.82(d，J＝10.2Hz，1H)，2.79(d，J＝11.5Hz，1H)，2.69-2.62(m，1H)，2.50(d，J＝11.5Hz，1H)，2.40-2.10(m，4H)，1.88(m，1H)，1.33(s，3H).
13C NMR(CDCl
3，500MHz)：δ200.35，191.08，172.71，170.23，150.73，145.81，129.75，121.41，89.17，65.95，65.45，61.28，60.54，52.49，48.87，47.25，41.60，39.86，18.02，11.93.
Compound 33, and 15-dicarbonyl gibberellic acid benzyl ester (3,15-dicarbapentaborane-10,13-dihydroxyl-red is mould-1,16-diene-7,19-diacid-19,10-lactone-7-benzyl ester)
With gibberic acid benzyl ester (2.18g, 5mmol) be starting raw material, the preparation of preparation method's (poly-, molar ratio of reaction step, order of addition(of ingredients), temperature of reaction etc.) and compound 2 (3,15-dicarbonyl gibberellic acid methyl esters) roughly the same, finally obtain white crystals 1.61g, two-step reaction total recovery 71.9%.
Ultimate analysis C
26H
24O
7
Calculated value (%): C, 69.63; H, 5.39;
Measured value (%): C, 69.58; H, 5.42.
1H NMR(CDCl
3，500MHz)：δ7.35-7.20(m，5H)，7.18(d，J＝9.4Hz，1H)，6.16(s，1H)，6.07(d，J＝9.4Hz，1H)，5.84(s，1H)，5.05(s，2H)，3.65(d，J＝10.4Hz，1H)，2.86(d，J＝10.4Hz，1H)，2.77(d，J＝11.5Hz，1H)，2.70-2.62(m，1H)，2.46(d，J＝11.5Hz，1H)，2.38-2.09(m，4H)，1.93-1.79(m，1H)，1.33(s，3H).
13C NMR(CDCl
3，500MHz)：δ200.42，191.06，172.69，169.61，150.82，145.79，134.92，129.77，128.67，128.63，121.26，89.17，67.58，65.90，65.45，61.24，60.60，49.04，47.32，41.60，39.73，18.04，12.01.
Compound 43, and 15-dicarbonyl gibberellic acid sodium salt (3,15-dicarbapentaborane-10,13-dihydroxyl-red is mould-1,16-diene-7,19-diacid-19,10-lactone-7-sodium salt)
3, (0.855g 2.5mmol) is dissolved in ethanol (10mL) to the 15-dicarbonyl gibberellic acid under the room temperature, (0.5mol/L 5mL), adds in 5 minutes, continues stirring at room reaction 5 minutes to stir the ethanolic soln that drips sodium ethylate down.Decompression steams solvent to doing, and gets white powder solid 0.913g, yield 100%, and molten point is higher than 300 ℃.It is yellow that flame reaction is.
Compound 53, and 15-dicarbonyl gibberellic acid sylvite (3,15-dicarbapentaborane-10,13-dihydroxyl-red is mould-1,16-diene-7,19-diacid-19,10-lactone-7-sylvite)
3, (0.855g 2.5mmol) is dissolved in ethanol (10mL) to the 15-dicarbonyl gibberellic acid under the room temperature, (0.5mol/L 5mL), adds in 5 minutes, continues stirring at room reaction 5 minutes to stir the ethanolic soln that drips potassium hydroxide down.Decompression steams solvent to doing, and gets white powder solid 0.913g, yield 100%, and molten point is higher than 300 ℃.Flame reaction is bluish voilet.
The antitumour activity experiment of compound 1～5
Compound 1～5 is during flow measurement is listed in the table below till death to the half of the cancerous cell line of EAC, SGC-7901, A231, Bcap-37 according to the MTT method
| Compound | EC 50(μg/mL) | |||
| EAC | SGC-7901 | A-231 | Bcap-37 | |
| 1 2 3 4 5 | 0.015 0.050 0.018 0.010 0.012 | 0.832 0.910 4.57 0.756 0.675 | 2.55 3.10 0.125 0.100 0.117 | 0.388 0.410 0.520 0.321 0.255 |
Compound 2 and 3 is measured the half of Vero cell (normal cell) according to the MTT method till death and is respectively: 17.54 and 21.53 μ g/mL.
Above data show that compound 1～5 certificate has good antitumour activity, and very little to Normocellular toxicity.
Claims (9)
1, have following general structural formula for (I) 3,15-dicarbonyl gibberellic acid compounds and ester thereof and salt:
R＝H，CH
3，CH
2Ph，Li，Na，K， Mg，Ca，Cu，Zn，Fe，Mn，La，CeR
1＝H，OH，OAc
2, compound according to claim 1 is characterized in that: the 7-position is carboxylic acid, carboxylicesters and carboxylate salt.
3, the preparation method of a kind of compound as claimed in claim 1 and ester and salt, this method may further comprise the steps:
A), gibberic acid GA
3Be starting raw material, be oxidized to 3-carbonyl gibberic acid through activated manganese dioxide in acetone earlier, consumption by gram is: gibberic acid/activated manganese dioxide=1/8～20, the temperature of reaction during oxidation are 10～69 ℃, and the acetone consumption is 30～100mL/g gibberic acid;
B), hydroxyl is introduced in the oxidation of 15-position, each compound amount is in molar ratio: treat oxidation substrates/tin anhydride/tertbutanol peroxide=1/0.01～0.5/1～3, solvent adopts benzene, toluene, methylene dichloride, trichloromethane, ethyl acetate, butylacetate, acetone, butanone, normal hexane, hexanaphthene, sherwood oil, and consumption is that 10～100mL/g treats oxidation substrates;
C, after the Swern oxidation, obtain double carbonyl compound (I) again, adopting methylene dichloride, trichloromethane, benzene, toluene, tetrahydrofuran (THF), dioxane is solvent, methyl-sulphoxide and oxalyl chloride or sulfur oxychloride form oxygenant in temperature under-70 ℃ to-20 ℃ the low temperature, each compound amount is in molar ratio: treat oxidation substrates/methyl-sulphoxide/oxalyl chloride/triethylamine=1/2～5/2～5/4～20, add the substrate reactions for the treatment of oxidation and add the triethylamine reaction after 15～50 minutes again, the methylene dichloride consumption is that 10～100mL/g treats oxidation substrates.
4, according to the preparation method of the described compound of claim 3, when it is characterized in that being oxidized to 3-carbonyl gibberic acid, oxidizing reaction temperature adopts 25 ℃, and the acetone consumption adopts the 50mL/g gibberic acid.
5, according to the preparation method of the described compound of claim 3, when it is characterized in that introducing 15-position hydroxyl, each compound amount adopts in molar ratio treats oxidation substrates/tin anhydride/tertbutanol peroxide=1/0.1/2, and solvent adopts methylene dichloride, and consumption adopts 25mL/g to treat oxidation substrates.
6, according to the preparation method of the described compound of claim 3, it is characterized in that solvent adopts methylene dichloride when the Swern oxidation, each compound amount adopts in molar ratio: treat oxidation substrates/methyl-sulphoxide/oxalyl chloride/triethylamine=1/3/3/12, the methylene dichloride consumption adopts 50mL/g to treat oxidation substrates, and the compound that adopts methyl-sulphoxide and oxalyl chloride to form is an oxygenant.
7,, it is characterized in that with gibberic acid GA according to the preparation method of the described compound of claim 3
3And ester is starting raw material, introduces hydroxyls through 15 oxidations earlier, obtains double carbonyl compound (I) through the Swern oxidation again, and gibberellic acid ester is methyl esters or benzyl ester.
8, preparation method according to claim 3, it is characterized in that with 3 the 15-dicarbonyl gibberellic acid is a raw material, metal acetate, ethylate or oxyhydroxide with equivalent in dehydrated alcohol, acetic acid solvent react, prepare corresponding 3,15-dicarbonyl gibberellic acid salt.
9, have the compound of general structure (I) and at least a pharmaceutically acceptable vehicle, diluent or carrier are treated cancer drug as preparation application.
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|---|---|---|---|
| CNB2004100219392A CN1300129C (en) | 2004-02-27 | 2004-02-27 | Compound of 3,15-dicarbonyl erythro mildew acid kind and its ester and salt |
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| CNB2004100219392A CN1300129C (en) | 2004-02-27 | 2004-02-27 | Compound of 3,15-dicarbonyl erythro mildew acid kind and its ester and salt |
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| CN1300129C true CN1300129C (en) | 2007-02-14 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101260095B (en) * | 2008-04-18 | 2012-05-23 | 云南大学 | 13-halo-3,15-dioxygibberellic acid ester and preparation method thereof |
| CN101933920A (en) * | 2010-07-30 | 2011-01-05 | 昆明医学院 | Application of 3,15-dicarbonyl gibberellic acid methyl ester in reversing tumor multidrug resistance |
| WO2013142873A2 (en) * | 2012-03-23 | 2013-09-26 | The Board Of Trustees Of The University Of Illinois | Complex and structurally diverse compounds |
| CN108276369B (en) * | 2018-02-09 | 2022-04-01 | 云南大学 | Polythiagibberellic acid ester compound, preparation method and anti-tumor application thereof |
| CN110317179B (en) * | 2018-03-29 | 2023-01-24 | 云南大学 | Gibberellin-like compound, preparation method thereof, pharmaceutical composition, application thereof and intermediate thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038816A (en) * | 1988-06-18 | 1990-01-17 | 高光周 | Reinforced gibberellin |
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2004
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038816A (en) * | 1988-06-18 | 1990-01-17 | 高光周 | Reinforced gibberellin |
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