CN104803962B - The preparation method of flavones glycine Schiff base - Google Patents
The preparation method of flavones glycine Schiff base Download PDFInfo
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- CN104803962B CN104803962B CN201410036052.4A CN201410036052A CN104803962B CN 104803962 B CN104803962 B CN 104803962B CN 201410036052 A CN201410036052 A CN 201410036052A CN 104803962 B CN104803962 B CN 104803962B
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Abstract
The present invention relates to a kind of preparation method of flavones glycine Schiff base, it is to be dissolved in Quercetin, cyanidenon, apiolin, myricetin, dihydroquercetin in absolute ethyl alcohol respectively, it is separately added into a certain amount of Na OH alcoholic solutions, radiated in microwave instrument, while magnetic agitation, then be separately added into the alcohol liquid of a certain amount of glycine and reacted, generate the precipitation insoluble in ethanol, reacted with TLC tracing detections, alcohol is washed, and obtains product.The compound synthesized with the preparation method remains the mother nucleus structure and antitumor activity of chromocor compound, flavones-glycine Schiff base is synthesized with glycine, its water-soluble, targeting and antitumor activity are better than former flavone compound, and preparation method is simple, yield is high, and cost is low.
Description
Technical field：
The present invention relates to a kind of preparation method of flavones-glycine Schiff base, the flavonoids medicine being related to is specially Mongolian oak
Pi Su, cyanidenon, apiolin, myricetin and dihydroquercetin are condensed the Schiff bases compound to be formed with glycine.
Background technology：
Flavone compound is the major class natural organic-compound for being widely present in nature, has C6-C3-C6Substantially
Configuration, is the metabolin of plant Polyphenols, and flavone compound has anticancer, antitumor, resisting cardiovascular disease, anti-inflammatory town
Bitterly, immunological regulation, hypoglycemic, treatment osteoporosis, antibacterial, antiviral, anti-oxidant, anti-aging, radioresistance and other effects, therefore,
Flavone compound is a kind of natural products that current people compare concern, it has also become domestic and international natural drug utilization research
Focus, flavone compound effect is extensive, but because flavone compound water solubility is poor, such compound is inhaled in enteron aisle
Receipts very do not absorb less or completely, limit their clinical practice.For this problem, domestic and international researcher actively innovation pair
It carries out structural modification, is concentrated mainly on 2,3, C rings, A rings 5,6,7,8, and the position of B rings 2 ', 3 ', 4 ', substituent mainly has halogen
Element, alkane (oxygen) base, aryl, pyridine radicals, amino, carboxyl, sulfonic group, phosphate etc., by enriching its species and changing its chemistry
Property improves the water solubility of flavone compound, strengthens its antitumor activity, improves its bioavilability.Although flavonoids
The structural modification of compound achieves achievement, but because the modification group species of introducing is different, configurations, analogy is poor, it is difficult to pair
The modification group of introducing carries out the screening of " purposeful ", therefore is difficult to orient on the basis of analytic induction " structure-activity relationship " and sets
Count the flavonoids anti-cancer agent of synthesizing efficient.
The content of the invention：
It is an object of the invention to overcome disadvantages mentioned above, there is provided a kind of preparation method of flavones-glycine Schiff base, selection
Minimum amino acids glycine, modified is strong and is played a key effect in terms of cancer cell multiplication, to flavone compound
Perform the derivatization, and good water solubility, stability is high, the strong flavones of targeting-glycine Schiff base compound.The present invention's
Purpose is achieved in that adds glycine into the ethanol equipped with flavones in the basic conditions, and microwave radiation technology makes glycine
The carbonyl condensation of amino and flavones forms schiff bases.
By 0.302g Quercetins, 0.2286g cyanidenons, 0.4035g apiolins, 0.318 myricetin, 0.304 dihydro Mongolian oak
Pi Su is dissolved in 50mL absolute ethyl alcohols respectively, is separately added into 0.08g, 0.04g, 0.08g, 0.08g, 0.08g NaOH alcoholic solutions
1mL, radiated in microwave instrument, while magnetic agitation, temperature setting is 56 DEG C, power 400W, then is separately added into glycine
0.0375g, 0.075g, 0.075g, 0.075g, 0.075g alcoholic solution 10mL, 0.5h is reacted, generation is insoluble in the heavy of ethanol
Form sediment, reacted with TLC tracing detections, proved response is complete after raw material point is wholly absent, and alcohol is washed 2 times, obtains product.The sweet ammonia added
Acid can also be alanine, lysine, aspartic acid.The compound synthesized with the preparation method remains the mother of chromocor compound
Nuclear structure and antitumor activity, flavones-glycine Schiff base is synthesized with glycine, its water-soluble, targeting and antitumor work
Property be better than former flavone compound, preparation method is simple, and yield is high, and cost is low.
Specific embodiment：
Embodiment 1：The synthesis of Quercetin-glycine Schiff base
Take Quercetin 1mmol (0.302g) to be dissolved in 50mL absolute ethyl alcohols, add 2mmol (0.08g) NaOH alcoholic solutions
1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine
0.5mmol (0.0375g) alcoholic solution 10mL, 0.5h is reacted, generates the precipitation insoluble in ethanol, reacted with TLC tracing detections,
Proved response is complete after the raw material point of Quercetin is wholly absent, and alcohol is washed 2 times, is filtrated to get the compound I of brown,13C-NMR
(D2O)δ:127.33 (C-2), 112.01 (C-3), 164.91 (C-4), 159.88 (C-5), 97.78 (C-6), 162.66 (C-
7), 97.78 (C-8), 162.66 (C-9), 97.78 (C-10), 128.33 (C-1 '), 120.39 (C-2 '), 145.99 (C-3 '),
143.77 (C-4 '), 116.80 (C-5 '), 114.42 (C-6 '), 173.48,57.52 (be respectively C=O, CH in glycine2),
Composite structure is as follows：
Embodiment 2：The synthesis of cyanidenon-glycine Schiff base
1mmol (0.2286g) cyanidenon is taken to be dissolved in 50mL absolute ethyl alcohols, the NaOH alcohol for adding 1mmol (0.04g) is molten
Liquid 1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine
1mmol (0.075g) alcoholic solution 10mL, 0.5h is reacted, generate the precipitation insoluble in ethanol, reacted with TLC tracing detections, when
The raw material point of cyanidenon is wholly absent that rear proved response is complete, and alcohol is washed 2 times, is filtrated to get the compound ii of brown,13C-NMR
(D2O)δ:161.93 (C-2), 85.97 (C-3), 164.09 (C-4), 159.62 (C-5), 98.55 (C-6), 161.93 (C-7),
98.55 (C-8), 161.93 (C-9), 102.65 (C-10), 128.83 (C-1 '), 119.99 (C-2 '), 144.99 (C-3 '),
142.43 (C-4 '), 116.52 (C-5 '), 112.74 (C-6 '), 171.00,56.25 (be respectively C=O, CH in glycine2),
Composite structure is as follows：
Embodiment 3：The synthesis of apiolin-glycine Schiff base
Apiolin 1.5mmol (0.4035g) is taken to be dissolved in 50mL absolute ethyl alcohols, the NaOH alcohol for adding 2mmol (0.08g) is molten
Liquid 1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine
1mmol (0.075g) alcoholic solution 10mL, 0.5h is reacted, generate the precipitation insoluble in ethanol, reacted with TLC tracing detections, when
The raw material point of Quercetin is wholly absent that rear proved response is complete, and alcohol is washed 2 times, is filtrated to get the compound III of brown,13C-NMR
(D2O)δ:162.82 (C-2), 87.50 (C-3), 164.40 (C-4), 159.62 (C-5), 99.90 (C-6), 162.80 (C-7),
98.03 (C-8), 159.62 (C-9), 108.04 (C-10), 128.66 (C-1 '), 128.66 (C-2 '), 116.77 (C-3 '),
154.23 (C-4 '), 119.18 (C-5 '), 128.66 (C-6 '), 177.55,56.71 (be respectively C=O, CH in glycine2),
Composite structure is as follows：
Embodiment 4：The synthesis of myricetin-glycine Schiff base
Take myricetin 1mmol (0.318g) to be dissolved in 50mL absolute ethyl alcohols, add 2mmol (0.08g) NaOH alcoholic solutions
1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine
1mmol (0.075g) alcoholic solution 10mL, 0.5h is reacted, generate the precipitation insoluble in ethanol, reacted with TLC tracing detections, when
The raw material point of Quercetin is wholly absent that rear proved response is complete, and alcohol is washed 2 times, is filtrated to get the compounds Ⅳ of brown,13C-NMR
(D2O)δ:135.24 (C-2), 112.15 (C-3), 164.76 (C-4), 160.14 (C-5), 98.03 (C-6), 161.68 (C-
7), 95.21 (C-8), 160.14 (C-9), 107.01 (C-10), 128.83 (C-1 '), 108.30 (C-2 '), 147.30 (C-
3 '), 130.88 (C-4 '), 144.22 (C-5 '), 109.58 (C-6 '), 172.97,55.94 (it is respectively C=O in glycine,
CH2), composite structure is as follows：
Embodiment 5：The synthesis of dihydroquercetin-glycine Schiff base
Take dihydroquercetin 1mmol (0.304g) to be dissolved in 50mL absolute ethyl alcohols, add 2mmol (0.08g) NaOH alcohol
Solution 1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add sweet ammonia
The alcoholic solution 10mL of sour 1mmol (0.075g), 0.5h is reacted, generates the precipitation insoluble in ethanol, reacted with TLC tracing detections,
Proved response is complete after the raw material point of Quercetin is wholly absent, and alcohol is washed 2 times, is filtrated to get the compound V of brown.13C-NMR
(D2O)δ:82.38 (C-2), 71.21 (C-3), 164.24 (C-4), 159.88 (C-5), 94.70 (C-6), 161.16 (C-7),
99.06 (C-8), 162.96 (C-9), 103.68 (C-10), 134.47 (C-1 '), 126.77 (C-2 '), 145.76 (C-3 '),
144.48 (C-4 '), 119.72 (C-5 '), 115.67 (C-6 '), 171.04,56.46 (be respectively C=O, CH in glycine2),
Composite structure is as follows：
The glycine added above can also be alanine, lysine, aspartic acid.Flavone compound and flavones-sweet
The comparison of propylhomoserin Schiff alkali solubility
| Compound name | Solubility (g/100mL) |
| Quercetin- | |
| Cyanidenon | - |
| Apiolin | - |
| Myricetin | - |
| Dihydroquercetin | - |
| Compound name | Solubility (g/100mL) |
| Quercetin-glycine Schiff base | 5.4 |
| Cyanidenon-glycine Schiff base | 1.83 |
| Apiolin-glycine Schiff base | 3.26 |
| Myricetin-glycine Schiff base | 2.33 |
| Dihydroquercetin-glycine Schiff base | 3.17 |
Flavones-glycine Schiff base is to growth of tumour cell Inhibition test
The MCF-7 cell routines in exponential phase are taken to digest, with 1640 complete mediums containing 10% hyclone
It is made 5 × 104Individual mL-1Cell suspension.Per hole be inoculated with 100 μ L cell suspensions, 37 DEG C, saturated humidity, 5%CO2Under the conditions of train
Support overnight.After cell attachment, respectively by 5 kinds of flavones ammonia-glycine Schiff base solution according to following concentration 10,20,40,80,
160、320mg·mL-1, 96 orifice plates are sequentially added per the μ L of hole 100, each concentration sets 5 multiple holes, is repeated 3 times, and continues to be incubated 24h.
After predetermined incubation time is reached, 20 μ L MTT (5mgmL are added per hole into 96 orifice plates-1) solution, lucifuge continue cultivate 4h
Afterwards, the supernatant abandoned in culture hole is carefully inhaled, the μ L of DMSO 150 are added per hole, gently vibrates, is completely dissolved purple crystal,
At 10min inherent 492nm wavelength its absorption value (OD) is surveyed with ELIASA.And inhibiting rate is calculated as follows：Cell growth inhibition
Rate=(1- experimental groups OD values/control group OD values) × 100%.As a result it is as follows：
Inhibitory action result of one Quercetin of the table-glycine Schiff base to breast cancer cell MCF-7
Inhibitory action result of two cyanidenons of the table-glycine Schiff base to breast cancer cell MCF-7
| Group | Drug concentration (mgmL-1) | Inhibiting rate (%) |
| Blank control | 0 | 0% |
| Cyanidenon-glycine | 10 | 10% |
| Cyanidenon-glycine | 20 | 19% |
| Cyanidenon-glycine | 40 | 32% |
| Cyanidenon-glycine | 80 | 34% |
| Cyanidenon-glycine | 160 | 37% |
| Cyanidenon-glycine | 320 | 57% |
Inhibitory action result of three apiolins of the table-glycine Schiff base to breast cancer cell MCF-7
| Group | Drug concentration (mgmL-1) | Inhibiting rate (%) |
| Blank control | 0 | 0% |
| Apiolin-glycine | 10 | 28% |
| Apiolin-glycine | 20 | 43% |
| Apiolin-glycine | 40 | 47% |
| Apiolin-glycine | 80 | 54% |
| Apiolin-glycine | 160 | 63% |
| Apiolin-glycine | 320 | 71% |
Inhibitory action result of four myricetins of the table-glycine Schiff base to breast cancer cell MCF-7
| Group | Drug concentration (mgmL-1) | Inhibiting rate (%) |
| Blank control | 0 | 0% |
| Myricetin-glycine | 10 | 21% |
| Myricetin-glycine | 20 | 24% |
| Myricetin-glycine | 40 | 25% |
| Myricetin-glycine | 80 | 26% |
| Myricetin-glycine | 160 | 29.5% |
| Myricetin-glycine | 320 | 32% |
Inhibitory action result of five dihydroquercetins of the table-glycine Schiff base to breast cancer cell MCF-7
| Group | Drug concentration (mgmL-1) | Inhibiting rate (%) |
| Blank control | 0 | 0% |
| Dihydroquercetin-glycine | 10 | 20% |
| Dihydroquercetin-glycine | 20 | 24% |
| Dihydroquercetin-glycine | 40 | 29% |
| Dihydroquercetin-glycine | 80 | 34% |
| Dihydroquercetin-glycine | 160 | 49% |
| Dihydroquercetin-glycine | 320 | 62% |
Claims (1)
- A kind of 1. preparation method of flavones-glycine Schiff base, it is characterised in that：In the basic conditions to the ethanol equipped with flavones Middle addition glycine, microwave radiation technology make the amino of glycine and the carbonyl condensation of flavones form schiff bases,A, take Quercetin 1mmol (0.302g) to be dissolved in 50mL absolute ethyl alcohols, add 2mmol (0.08g) NaOH alcoholic solutions 1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine 0.5mmol (0.0375g) alcoholic solution 10mL, 0.5h is reacted, generates the precipitation insoluble in ethanol, reacted with TLC tracing detections, Proved response is complete after the raw material point of Quercetin is wholly absent, and alcohol is washed 2 times, is filtrated to get the compound I of brown, composite structure It is as follows：B, take myricetin 1mmol (0.318g) to be dissolved in 50mL absolute ethyl alcohols, add 2mmol (0.08g) NaOH alcoholic solutions 1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine 1mmol (0.075g) alcoholic solution 10mL, 0.5h is reacted, generate the precipitation insoluble in ethanol, reacted with TLC tracing detections, when The raw material point of Quercetin is wholly absent that rear proved response is complete, and alcohol is washed 2 times, is filtrated to get the compounds Ⅳ of brown, composite structure It is as follows：C, dihydroquercetin 1mmol (0.304g) is taken to be dissolved in 50mL absolute ethyl alcohols, the NaOH alcohol for adding 2mmol (0.08g) is molten Liquid 1mL, radiated in microwave instrument, while magnetic agitation, temperature setting are 56 DEG C, power 400W, then add glycine 1mmol (0.075g) alcoholic solution 10mL, 0.5h is reacted, generate the precipitation insoluble in ethanol, reacted with TLC tracing detections, when The raw material point of Quercetin is wholly absent that rear proved response is complete, and alcohol is washed 2 times, is filtrated to get the compound V of brown, composite structure It is as follows：
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| CN113304113A (en) * | 2021-05-31 | 2021-08-27 | 桂林医学院 | Co-amorphous solid dispersion for improving dissolution of quercetin and preparation method thereof |
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| WO2008047249A2 (en) * | 2006-10-18 | 2008-04-24 | Centre National De La Recherche Scientifique | Alpha-galactoceramide analogs, their methods of manufacture, intermediate compounds useful in these methods, and pharmaceutical compositions containing them |
| WO2009074518A1 (en) * | 2007-12-12 | 2009-06-18 | Glaxo Group Limited | Combinations of prolinamide p2x7 modulators with further therapeutic agents |
| CN102516104A (en) * | 2011-10-25 | 2012-06-27 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing chiral alpha-alkyl substituted glycine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008047249A2 (en) * | 2006-10-18 | 2008-04-24 | Centre National De La Recherche Scientifique | Alpha-galactoceramide analogs, their methods of manufacture, intermediate compounds useful in these methods, and pharmaceutical compositions containing them |
| WO2009074518A1 (en) * | 2007-12-12 | 2009-06-18 | Glaxo Group Limited | Combinations of prolinamide p2x7 modulators with further therapeutic agents |
| CN102516104A (en) * | 2011-10-25 | 2012-06-27 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing chiral alpha-alkyl substituted glycine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| Unexpected influence of tetra- and pentafluoroethyl groups on the direction of reactions of 2-polyfluoroalkylchromones with 2-aminoethanol;Vyacheslav Ya. Sosnovskikh，等;《Mendeleev Commun》;20010424;第10卷(第6期);第240页左栏图1、右栏第3段、第241页右栏最后两段 * |
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