CN103214445B - The Preparation method and use of Quercetin amide derivatives - Google Patents

The Preparation method and use of Quercetin amide derivatives Download PDF

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CN103214445B
CN103214445B CN201310165359.XA CN201310165359A CN103214445B CN 103214445 B CN103214445 B CN 103214445B CN 201310165359 A CN201310165359 A CN 201310165359A CN 103214445 B CN103214445 B CN 103214445B
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quercetin
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CN103214445A (en
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翟广玉
渠文涛
颜子童
马海英
王俊巍
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Zhengzhou University
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Abstract

The invention discloses the preparation method of Quercetin amide derivatives and preparing the application in antitumor drug.With the rutin of cheapness for raw material, the steps such as ether reaction, DCC condensation reaction, shortening are become to prepare a series of Quercetin amide derivatives through benzyl selective protection, Williamson.The method achieve the orientation to Quercetin 3, efficiently modify, reaction conditions is gentle, easy and simple to handle, and aftertreatment is simple, is convenient to suitability for industrialized production.The inhibited proliferation of gained Quercetin amide derivatives to Human esophageal squamous cell cancer cell EC109, Human esophageal squamous cell cancer cell EC9706, gastric carcinoma cells SGC7901 and B16 mouse melanoma cell line-F10 is obviously better than Quercetin, is the very potential antitumor candidate compound of a class.

Description

The Preparation method and use of Quercetin amide derivatives
Technical field
The invention belongs to medicinal chemistry art, specifically, relate to synthetic method and the antitumor activity thereof of quercetin derivative.
Background technology
Flavonoid compound is that a class is extensively present in botanic natural polyphenol compounds, Quercetin (quercetin, 3,3 ', 4 ', 5,7-pentahydroxyflavone) be one of them Typical Representative, extensively be present in daily edible veterinary antibiotics, herbal medicine and beverage, as onion, apple, grape, strawberry, ginkgo, green tea and red wine etc., average content is about 10mg/Kg, level (the Pietta P G. J Nat Prod that what content was high even can reach 300mg/Kg, 2000,63 (7): 1035 ~ 1042; Manach C, Wiliamsoni G, Morand C, et al.Am J Clin Nutrit, 2005,81:230 ~ 242.).Research shows; Quercetin has many-sided pharmacologically active and biological activity; as (Hirpara KV such as anti-oxidant, antitumor, antibacterial, anti-infective, anti-mutation and protection cardiovascular systemss; Aggarwal P; Mukherjee AJ; et al. Anticancer Agents Med Chem, 2009,9:138 ~ 161.).Quercetin is natural antioxidant and free-radical scavengers, has good cancer prevention and therapeutic action, simultaneously or important metal ion chelation agent (Bischoff SC. Curr Opin Clin Nutr Metab Care. 2008 Nov; 11 (6): 733-40; Choi JA, Kimj Y, Lee J Y. et al.Int J Oncol, 2001,19 (4): 837 ~ 844; Zhai Guangyu, canal literary composition great waves, Duan Yandan, etc. chemical reagent 2013,35 (2): 133 ~ 139.).Noori-Daloii MR etc. study display, Quercetin has many-sided restraining effect to Human Prostate Cancer Cells PC-3 cell, can inhibition of cell proliferation, regulate its genetic expression, and make it degrade, apoptosis (Noori-Daloii M R, Momeny M, Yousefi M, et .al. Med Oncol. 2011,28 (4): 1395 ~ 1404.).Kim WK etc. study display, and 50 μMs of ol/L Quercetin process HT-29 cells present obvious DNA ladder shape apoptosis feature, and Bcl-2 expresses (the Kim WK that declines, Bang MH, Kim ES, et a1. Nutr Biochem, 2005,16 (3): 155 ~ 162).After Choi EJ etc. use Quercetin handler mammary cancer MDA-MB-453 cell, Bax albumen, Caspase-3 and PARP express increase, and Bcl-2 protein expression declines, and illustrate that Quercetin plays antitumor action by approach such as regulatory gene expression.Therefore Quercetin is as a very potential natural product with antitumour activity, always by extensive concern (Choi E J, Bae S M, Ahn W S. Arch Pharm Res., 2008,31 (10): 1281 ~ 1285; Chen Chen, Jane Zhou, Chunyan Ji. Life Sciences, 2010,87 (11-12): 333 ~ 338.).
In existing antitumor drug, compared with chemical synthetic drug, natural antitumor curative effect of medication is good, side effect is little, therefore plays an important role, as taxanes, and Cephalotaxus fortunei class, camptothecine etc.Along with people's going deep into researches on natural drugs, extracting effective components from natural drug also carries out composition optimizes and modification, can find more antitumor activity component, and provides new approach for the research and development of new type antineoplastic medicine.But because Quercetin is flush type molecule, molecular stuffing is tightr, intermolecular attraction is larger, not easily by solvent dispersion, so the solvability of Quercetin is poor, bioavailability lower (peak plasma concentration is only 0.13 ~ 7.6 μM/L), and make the activity research of Quercetin and clinical application be subject to great restriction (Sun Tiemin, Sun Changshan, Dai Guangyuan, etc. Chinese pharmaceutical chemistry magazine, 2003,13 (6): 345 ~ 348; Bakhtiyor F. Rasulev, Nasrulla D. Abdullaev, Vladimir N. Syrov, et al. QSAR Comb. Sci.24,2005,9:1056 ~ 1065.).For this reason, special proposition the present invention.The present invention utilizes chemical process to carry out structural modification to Quercetin, designing, having synthesized a series of solvability enhancing, the quercetin derivative that bioavailability is improved, to developing the medicine that activity is higher, have more clinical value.
Summary of the invention
The invention provides a kind of preparation method of quercetin derivative, it is characterized in that, Quercetin amide derivatives has having structure general formula:
Wherein R 1r 2the preferred following aminated compounds of N: Tri N-Propyl Amine, Isopropylamine, n-Butyl Amine 99, TERTIARY BUTYL AMINE, cyclopentamine, hexahydroaniline; Aniline, open-chain crown ether, o-toluidine, m-toluidine, P-nethoxyaniline, ORTHO ANISIDINE, m-anisidine, p-Nitroaniline, o-Nitraniline, m-nitraniline, p-ethoxyaniline, O-ethoxyl amine, m-oxethyl aniline, para-fluoroaniline; Benzylamine, to methylbenzylamine, adjacent methylbenzylamine, a methylbenzylamine, 4-Methoxybenzylamine, O-methoxy benzylamine, meta-methoxy benzylamine; P-aminophenol, DMA, phenylhydrazine, methyl naphthylamine, ethylnaphthalene amine.
Wherein R 1r 2the preferred following amino acids of N: glycine, leucine, Isoleucine, L-Ala, phenylalanine, L-glutamic acid, aspartic acid.
Quercetin amide derivatives provided by the invention can be prepared according to the following steps:
The first step: take rutin as raw material, obtain tribenzyl Quercetin through selective protection, acid hydrolysis.
Second step: tribenzyl Quercetin becomes ether reaction through Williamson, basic hydrolysis obtains tribenzyl Quercetin-3-O-acetic acid.
3rd step: DCC condensation reaction occurs for tribenzyl Quercetin-3-O-acetic acid and corresponding aminated compounds, then obtains target compound through shortening debenzylation.
Alkali involved in the present invention is NaOH, KOH, Na 2cO 3, NaHCO 3, K 2cO 3, KHCO 3, NaH, CH 3oNa, C 2h 5oNa, pyridine, triethylamine, Ca (OH) 2in one.
Acid involved in the present invention is the one in sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, glacial acetic acid.
Polypeptide condensing agent involved in the present invention is the one in DCC/HOBt, DCC/DMAP, EDCI/HOBt, EDCI/ HOAt.
Quercetin amide derivatives of the present invention, show through initial in vitro activity experiment, all obviously being better than Quercetin to the inhibited proliferation of Human esophageal squamous cell cancer cell EC109, Human esophageal squamous cell cancer cell EC9706, gastric carcinoma cells SGC7901 and B16 mouse melanoma cell line-F10 four strain tumour cell, is the very potential antitumor candidate compound of a class.
Embodiment
instrument and reagent
1.1 key instrument
Ultraviolet-visible pectrophotometer: UV2550, Japanese Shimadzu
Nuclear magnetic resonance analyser: Brucker 400MHz
Constant temperature blender with magnetic force: 85-2 type, Shanghai Si Le Instrument Ltd.
Vacuum pump using circulatory water: SHZ-D (III) type, Tianjin Hua Xin instrument plant
Micro melting point apparatus: XT-5 type, tech instrument plant of Beijing, thermometer does not correct
Rotary Evaporators: RE-52AA, Shanghai Yarong Biochemical Instrument Plant
1.2 main agents
Rutin (purity > 95%): the biochemical company limited of the fragrant star in Pingyu, Henan.
Cylite: the brilliant pure reagent company limited in Shanghai
Ethyl bromoacetate: the brilliant pure reagent company limited in Shanghai
N, N'-dicyclohexylcarbodiimide (DCC): the brilliant pure reagent company limited in Shanghai
1-hydroxyl-benzotriazole (anhydrous) (HOBt): the brilliant pure reagent company limited in Shanghai
Pd/C: Chemical Reagent Co., Ltd., Sinopharm Group
Thin layer silica gel/post silica gel: Haiyang Chemical Plant, Qingdao
All solvents and reagent are analytical pure or chemical pure
The Non-aqueous processing of methylene dichloride: plus hydrogenated calcium backflow 2-3h, air distillation
the preparation of 2 compounds
', the synthesis of 4 ', 7-O-tribenzyl Quercetin (1)
Rutin is placed in the dry 10h of vacuum drying oven of 80 DEG C, sloughs crystal water, get 4.88g(8 mmol) rutin is dissolved in 40mL DMF (DMF), then adds 3.86g(28 mmol) anhydrous K 2cO 3, stirring at room temperature 15min, slowly drips cylite 3.4mL(28 mmol under ice bath), turn room temperature reaction 16 h.Regulate pH to 6 ~ 7 with glacial acetic acid, adding distil water 200mL, stirs 3 h, separates out and water change clarification to solid.Abandon water layer, add ethanol 80 mL and dissolve, then add concentrated hydrochloric acid 18 mL, water-bath refluxes 2 h, separates out a large amount of yellow mercury oxide, filters, and washing obtains crude product, obtains 3.72 g sterlings 1, yield 81.2% through chloroform/methanol recrystallization.
1H NMR (400 MHz, DMSO) δ 12.42 (s, 1H,5-OH), 9.72 (s, 1H,3-OH), 7.90 (d, J = 2.0 Hz, 1H,2′-H), 7.85 (dd, J = 8.7, 2.0 Hz, 1H, 6′-H), 7.52 – 7.33 (m, 15H, 3×OBn), 7.27 (d, J = 8.8 Hz, 1H, 5′-H), 6.87 (d, J = 2.1 Hz, 1H,8-H), 6.46 (d, J = 2.1 Hz, 1H,6-H), 5.25 (s, 4H, 2×Ar-CH 2), 5.21 (s, 2H, Ar-CH 2)。
2.2 the synthesis of 3 ', 4 ', 7-O-tribenzyl Quercetin-3-O-acetic acid (2)
The compound 1 that 2.3g (4 mmol) is dry is dissolved in 60 mL DMF, adds anhydrous K 2cO 3690 mg (5 mmol), stirring at room temperature 30 min, then slowly drip the DMF(15mL being dissolved with 735 mg (4.4 mmol) ethyl bromoacetate) solution, reacts 2 h under room temperature.Regulate pH to 6 ~ 7 with glacial acetic acid, then use ethyl acetate/water (100/80 mL) to extract 3 times, and wash with saturated common salt, ester layer anhydrous sodium sulfate drying spends the night, filtration, concentrating under reduced pressure.Add the distilled water 100mL being dissolved with 5g NaOH, backflow 1h.Be chilled to room temperature after reaction terminates, with in dilute hydrochloric acid and NaOH, then with ethyl acetate/water extraction, ester layer anhydrous sodium sulfate drying spends the night, and filters, concentrating under reduced pressure ester layer concentrates, obtain 2.27g compound 2.Yield 70.7%.
1H NMR (400 MHz, DMSO) δ 13.05 (s, 1H,COOH), 12.47 (s, 1H,5-OH), 8.00 (d, J = 2.0 Hz, 1H, 2′-H), 7.83 – 7.76 (m, 1H, 6′-H), 7.52 – 7.30 (m, 15H，3×OBn), 7.24 (d, J = 8.8 Hz, 1H, 5′-H), 6.86 (s, 1H,8-H), 6.47 (s, 1H,6-H), 5.24 (d, J = 9.3 Hz, 6H,3×Ar-CH 2), 4.75 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.16, 170.41, 164.68, 161.32, 156.55, 154.98, 151.25, 148.09, 137.49, 137.21, 137.01, 136.51, 129.01, 128.94, 128.89, 128.63, 128.41, 128.35, 128.09, 128.05, 127.89, 122.87, 122.82, 114.80, 113.92, 105.63, 98.92, 93.77, 70.62, 70.51, 70.30, 68.33.
the preparation of 2.3 Quercetin-3-O-amide derivatives (3)
embodiment 1: the preparation of Quercetin-3-O-acetyl-Isopropylamine (3-1)
In round-bottomed flask, add 1.26g (2mmol) compound 2, add anhydrous methylene chloride 40mL and be stirred to dissolve, add 454mg(2.2mmol) DCC and 297mg(2.2mmol) HOBt, stirs 1h under cryosel bath.By 130mg(2.2mmol) the anhydrous DCM dilution of Isopropylamine 20mL, and be slowly added drop-wise in reaction flask with constant pressure funnel, 20min drips off, and turns stirring at room temperature 8-24 hour gradually.After reaction terminates, be placed in refrigerator cold-storage half an hour.Cross and filter most of by product DCU, filtrate extracts, and HOBt is soluble in water and be removed, and organic over anhydrous dried over sodium sulfate is spent the night.Filter, concentrated by rotary evaporation, adds a small amount of acetone, has a small amount of white granular solid to separate out, and filter, filtrate is spin-dried for.With chloroform/methanol recrystallization, obtain faint yellow solid.Faint yellow solid is dissolved in the mixing solutions of 60mL methylene chloride/methanol (V/V 2:1), adds the Pd/C 67.2mg of 10%.Catalytic hydrogenation reaction 5h under room temperature 0.4MPa pressure.Reaction terminates, and crosses filter Pd/C with double-layer filter paper, and filtrate concentrates, and methyl alcohol/chloroform (3%-6%) column chromatography, obtains faint yellow solid 3-1, yield 40.8%.
M.p: 262.9~263.7 ℃； 1H NMR (400 MHz, DMSO) δ 12.52 (s, 1H,5-OH), 10.91 (s, 1H,7-OH), 9.84 (s, 1H, 4′-OH), 9.40 (s, 1H, 3′-OH), 7.92 (d, J = 7.9 Hz, 1H, NH), 7.51 – 7.47 (m, 2H, 2′-H, 6′-H ), 6.90 (d, J = 8.8 Hz, 1H, 2′-H), 6.43 (d, J = 2.0 Hz, 1H,8-H), 6.22 (d, J = 2.0 Hz, 1H,6-H), 4.33 (s, 2H,COCH 2), 3.92 (dq, J = 13.3, 6.6 Hz, 1H，NHCH), 1.09 (d, J = 6.6 Hz, 6H,2×CH 3).
13C NMR (101 MHz, DMSO) δ 178.05, 167.10, 164.78, 161.64, 156.85, 156.47, 149.37, 145.84, 137.13, 121.52, 120.94, 116.21, 115.92, 104.47, 99.17, 94.17, 71.63, 40.65, 22.68.
embodiment 2: the synthesis of Quercetin-3-O-acetyl-TERTIARY BUTYL AMINE (3-2)
The same 3-1 of synthetic method.Compound 3-2 is faint yellow solid, yield 44.3%.
M.p: 274.8~276.6 ℃； 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H,5-OH), 10.93 (s, 1H,7-OH), 9.84 (s, 1H, 4′-OH), 9.41 (s, 1H, 3′-OH), 7.77 (s, 1H,NH), 7.46 (dt, J = 8.3, 2.2 Hz, 2H, 2′-H, 6′-H), 6.92 (d, J = 8.3 Hz, 1H, 5′-H), 6.44 (d, J = 2.0 Hz, 1H, 8-H), 6.23 (d, J = 2.0 Hz, 1H, 6-H), 4.25 (s, 2H,COCH2), 1.29 (s, 9H.3×CH 3).
13C NMR (101 MHz, DMSO) δ 178.16, 167.47, 164.84, 161.61, 156.88, 156.54, 149.41, 145.86, 137.49, 121.46, 120.91, 116.28, 115.95, 104.43, 99.20, 94.22, 72.38, 50.68, 28.86.
embodiment 3: the synthesis of Quercetin-3-O-acetyl-n-Butyl Amine 99 (3-3)
The same 3-1 of synthetic method.Compound 3-3 is faint yellow solid, yield 48.1%.
M.p: 219.1~221.3 ℃； 1H NMR (400 MHz, DMSO) δ 12.52 (s, 1H，5-OH), 10.91 (s, 1H,7-OH), 9.83 (s, 1H, 4′-OH), 9.39 (s, 1H, 3′-OH), 8.10 (t, J = 5.7 Hz, 1H,NH), 7.52 – 7.46 (m, 2H, 2′-H, 6′-H), 6.89 (d, J = 8.6 Hz, 1H, 5′-H), 6.43 (d, J = 2.0 Hz, 1H, 8-H), 6.22 (d, J = 2.0 Hz, 1H, 6-H), 4.36 (s, 2H,COCH 2), 3.14 (dd, J = 12.9, 6.7 Hz, 2H,NHCH 2), 1.42 (dd, J = 14.6, 7.2 Hz, 2H,CH 2), 1.29 (dd, J = 15.0, 7.3 Hz, 2H,CH 3CH 2), 0.89 (t, J = 7.3 Hz, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 178.01, 167.92, 164.78, 161.65, 156.85, 156.45, 149.37, 145.83, 136.95, 121.49, 120.94, 116.19, 115.89, 104.49, 99.17, 94.17, 71.41, 38.36, 31.57, 19.94, 14.12.
embodiment 4: the synthesis of Quercetin-3-O-acetyl-cyclopentamine (3-4)
The same 3-1 of synthetic method.Compound-4 is faint yellow solid, yield 46.7%.
M.p: 275.9~277.6 ℃； 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H,5-OH), 10.95 (s, 1H,7-OH), 9.88 (s, 1H, 4′-OH), 9.44 (s, 1H, 3′-OH), 8.07 (d, J = 7.5 Hz, 1H,NH), 7.49 (d, J = 7.9 Hz, 2H, 2′-H,6′-H), 6.89 (d, J = 8.1 Hz, 1H, 5′-H), 6.43 (d, J = 1.4 Hz, 1H,8-H), 6.21 (d, J = 1.4 Hz, 1H, 6-H), 4.33 (s, 2H,COCH 2), 4.06 (dd, J = 13.8, 6.9 Hz, 1H,NHCH), 1.80 (dd, J = 11.9, 5.5 Hz, 2H, CH 2), 1.64 (d, J = 6.3 Hz, 2H,CH 2), 1.55 – 1.47 (m, 2H,CH 2), 1.40 (dd, J = 12.1, 6.2 Hz, 2H,CH 2).
13C NMR (101 MHz, DMSO) δ 178.09, 167.53, 164.79, 161.61, 156.83, 156.45, 149.38, 145.83, 137.24, 121.53, 120.90, 116.19, 115.88, 104.43, 99.17, 94.17, 71.74, 50.38, 32.63, 23.88.
embodiment 5: the synthesis of Quercetin-3-O-acetyl-hexahydroaniline (3-5)
The same 3-1 of synthetic method.Compound 3-5 is faint yellow solid, yield 51.6%.
M.p: 273.6~2775.4 ℃； 1H NMR (400 MHz, DMSO) δ 12.52 (s, 1H,5-OH), 10.92 (s, 1H,7-OH), 9.84 (s, 1H, 4′-OH), 9.40 (s, 1H,3′-OH), 7.95 (d, J = 8.1 Hz, 1H,NH), 7.52 – 7.45 (m, 2H, 2′-H, 6′-H), 6.91 (d, J = 8.8 Hz, 1H, 5′-H), 6.43 (d, J = 2.0 Hz, 1H,8-H), 6.22 (d, J = 2.0 Hz, 1H,6-H), 4.34 (s, 2H,COCH 2), 2.28 (s, 1H,NHCH), 1.71 (t, J = 14.1 Hz, 4H,2CH 2), 1.56 (d, J = 12.2 Hz, 1H,CH), 1.32 – 1.14 (m, 5H, 2×CH 2,CH).
13C NMR (101 MHz, DMSO) δ 178.08, 167.09, 164.80, 161.64, 156.86, 156.50, 149.40, 145.85, 137.24, 121.54, 120.94, 116.23, 115.93, 104.47, 99.19, 94.19, 79.64, 71.74, 47.68, 32.64, 25.59, 24.96, 18.04.
embodiment 6: the synthesis of Quercetin-3-O-acetyl-benzylamine (3-6)
The same 3-1 of synthetic method.Compound 3-6 is faint yellow solid, yield 60.4%.
M.p: 240.1~242.5 ℃； 1H NMR (400 MHz, DMSO) δ 12.52 (s, 1H, 5-OH), 10.89 (s, 1H, 7-OH), 9.84 (s, 1H, 4′-OH), 9.43 (s, 1H, 3′-OH), 8.72 (t, J = 6.1 Hz, 1H, NH), 7.53 (dd, J = 6.7, 2.1 Hz, 2H, 2′-H, 6′-H), 7.36 – 7.23 (m, 5H, 5×ph-H), 6.90 (d, J = 9.0 Hz, 1H, 2′-H, 5′-H), 6.44 (d, J = 2.0 Hz, 1H,8-H), 6.23 (d, J = 2.0 Hz, 1H,6-H), 4.47 (s, 2H, COCH 2), 4.38 (d, J = 6.1 Hz, 2H, NHCH 2).
13C NMR (101 MHz, DMSO) δ 177.96, 168.28, 164.78, 161.66, 156.84, 156.41, 149.36, 145.83, 139.65, 136.81, 128.70, 127.63, 127.22, 121.52, 121.00, 116.21, 115.91, 104.50, 99.19, 94.17, 71.21, 42.27,
embodiment 7: the synthesis of Quercetin-3-O-acetyl-to methylbenzylamine (3-7)
The same 3-1 of synthetic method.Compound 3-7 is faint yellow solid, yield 64.2%.
M.p: 260.1~262.2 ℃； 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H,7-OH), 10.86 (s, 1H,7-OH), 9.62 (s, 1H, 4′-OH), 9.45 (s, 1H, 3′-OH), 8.65 (s, 1H,NH), 7.52 (dd, J = 6.9, 2.1 Hz, 2H, 2′-H, 6′-H), 7.19 (d, J = 8.0 Hz, 2H,2×ph-H), 7.13 (d, J = 8.0 Hz, 2H, 2×ph-H), 6.89 (d, J = 9.0 Hz, 1H, 5′-H), 6.44 (d, J = 2.0 Hz, 1H,8-H), 6.22 (d, J = 1.9 Hz, 1H,6-H), 4.45 (s, 2H,COCH 2), 4.32 (d, J = 6.1 Hz, 2H,NHCH 2), 2.29 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 177.96, 168.16, 164.80, 161.66, 156.84, 156.40, 149.36, 145.82, 136.81, 136.60, 136.26, 129.25, 127.65, 121.51, 120.98, 116.21, 115.89, 104.49, 99.18, 94.17, 71.22, 42.02, 21.16.
embodiment 8: the synthesis of Quercetin-3-O-acetyl-4-Methoxybenzylamine (3-8)
The same 3-1 of synthetic method.Compound 3-8 is faint yellow solid, yield 59.7%.
M.p: 163.4~165.3 ℃； 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H,5-OH), 10.87 (s, 1H,7-OH), 9.82 (s, 1H, 4′-OH), 9.43 (s, 1H, 3′-OH), 8.62 (t, J = 6.0 Hz, 1H,NH), 7.55 – 7.47 (m, 2H, 2′-H, 6′-H), 7.22 (d, J = 8.6 Hz, 2H, 2×ph-H), 6.89 (d, J = 8.6 Hz, 3H, 2×ph-H , 5′-H,), 6.43 (d, J = 1.9 Hz, 1H,8-H), 6.22 (d, J = 1.9 Hz, 1H,6-H), 4.44 (s, 2H,COCH 2), 4.29 (d, J = 6.0 Hz, 2H,NHCH 2), 3.74 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 177.96, 168.07, 164.79, 161.65, 158.68, 156.84, 156.41, 149.35, 145.82, 136.81, 131.58, 129.02, 121.51, 120.98, 116.21, 115.90, 114.12, 104.49, 99.18, 94.16, 71.22, 55.53, 41.73.
embodiment 9: the synthesis of Quercetin-3-O-acetyl-aniline (3-9)
The same 3-1 of synthetic method.Compound 3-9 is faint yellow solid, yield 63.5%.
M.p: 267.6~279.4 ℃； 1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H,5-OH), 10.94 (s, 1H,7-OH), 10.27 (s, 1H,NH), 9.81 (s, 1H, 4′-OH), 9.44 (s, 1H, 3′-OH), 7.68 (d, J = 7.6 Hz, 2H, 2′-H, 6′-H), 7.56 (dd, J = 6.3, 2.2 Hz, 2H, 2×ph-H), 7.35 (t, J = 7.9 Hz, 2H, 2×ph-H), 7.10 (t, J = 7.4 Hz, 1H, 5′-H), 6.92 (d, J = 9.0 Hz, 1H, ph-H), 6.46 (d, J = 2.0 Hz, 1H,8-H), 6.24 (d, J = 2.0 Hz, 1H,6-H), 4.59 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.10, 167.16, 164.88, 161.59, 156.89, 156.38, 149.44, 145.84, 138.74, 137.28, 129.27, 124.19, 121.57, 120.94, 120.00, 116.28, 116.00, 104.45, 99.27, 94.25, 71.77.
embodiment 10: the synthesis of Quercetin-3-O-acetyl-open-chain crown ether (3-10)
The same 3-1 of synthetic method.Compound 3-10 is faint yellow solid, yield 66.7%.
M.p: 219.4~221.3 ℃； 1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H,5-OH), 10.92 (s, 1H,7-OH), 10.17 (s, 1H,NH), 9.83 (s, 1H, 4′-OH), 9.42 (s, 1H, 3′-OH), 7.57 – 7.54 (m, 4H, 2′-H, 6′-H, 2×ph-H), 7.14 (d, J = 8.3 Hz, 2H, 2×ph-H), 6.92 (d, J = 9.0 Hz, 1H, 5′-H), 6.46 (d, J = 2.0 Hz, 1H,8-H), 6.24 (d, J = 2.0 Hz, 1H,6-H), 4.56 (s, 2H,COCH 2), 2.27 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 178.10, 166.90, 164.87, 161.59, 156.88, 156.39, 149.44, 145.83, 137.29, 136.23, 133.14, 129.64, 121.56, 120.93, 119.98, 116.28, 115.99, 104.45, 99.26, 94.24, 71.78, 20.93.
embodiment 11: the synthesis of Quercetin-3-O-acetyl-m-toluidine (3-11)
The same 3-1 of synthetic method.Compound 3-11 is faint yellow solid, yield 63.9%.
M.p: 270.7~272.6 ℃； 1H NMR (400 MHz, DMSO) δ 12.47 (s, 1H,5-OH), 10.95 (s, 1H,7-OH), 10.15 (s, 1H,NH), 9.86 (s, 1H, 4′-OH), 9.44 (s, 1H, 3′-OH), 7.55 (dd, J = 5.9, 2.2 Hz, 2H, 2′-H,6 ′-H), 7.46 (d, J = 8.7 Hz, 2H, 2×ph-H), 7.22 (t, J = 7.7 Hz, 1H, 5′-H), 6.94 – 6.89 (m, 2H, 2×ph-H), 6.46 (d, J = 2.0 Hz, 1H,8-H), 6.24 (d, J = 2.0 Hz, 1H,6-H), 4.58 (s, 2H,COCH 2), 2.30 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 178.08, 167.07, 164.86, 161.58, 156.87, 156.33, 149.44, 145.84, 138.63, 138.49, 137.26, 129.10, 124.89, 121.57, 120.93, 120.47, 117.14, 116.28, 115.99, 104.44, 99.25, 94.24, 71.75, 21.65.
embodiment 12: the synthesis of Quercetin-3-O-acetyl-o-toluidine (3-12)
The same 3-1 of synthetic method.Compound 3-12 is faint yellow solid, yield 68.1%.
M.p: 249.7~251.6 ℃； 1H NMR (400 MHz, DMSO) δ 12.47 (s, 1H,5-OH), 10.93 (s, 1H,7-OH), 9.85 (s, 1H, 4′-OH), 9.75 (s, 1H,NH), 9.43 (s, 1H, 3′-OH), 7.57 (s, 2H, 2′-H, 6′-H), 7.48 (s, 1H, ph-H), 7.23 (dd, J = 24.3, 7.6 Hz, 2H, 2×ph-H), 7.13 (dd, J = 7.4, 1.1 Hz, 1H, 5′-H), 6.93 (d, J = 8.5 Hz, 1H, ph-H), 6.47 (d, J = 2.0 Hz, 1H,8-H), 6.24 (d, J = 2.0 Hz, 1H,6-H), 4.60 (s, 2H,COCH 2), 2.28 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 178.08, 167.12, 164.87, 161.60, 156.90, 156.47, 149.46, 145.86, 137.23, 136.12, 131.51, 130.84, 126.56, 125.70, 124.59, 121.52, 120.91, 116.29, 115.96, 104.45, 99.25, 94.26, 71.90, 18.04.
embodiment 13: the synthesis of Quercetin-3-O-acetyl-P-nethoxyaniline (3-13)
The same 3-1 of synthetic method.Compound 3-13 is faint yellow solid, yield 70.1%.
M.p: 237.3~239.2 ℃； 1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H,5-OH), 10.93 (s, 1H,7-OH), 10.11 (s, 1H,NH), 9.84 (s, 1H, 4′-OH), 9.41 (s, 1H, 3′-OH), 7.59 – 7.52 (m, 4H, 2′-H, 6′-H, 2×ph-H), 6.90 (d, J = 9.0 Hz, 3H, 2×ph-H ,5′-H), 6.44 (d, J = 1.9 Hz, 1H,8-H), 6.22 (d, J = 1.9 Hz, 1H,6-H), 4.53 (s, 2H,COCH 2), 3.72 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 178.09, 166.64, 164.84, 161.59, 156.87, 156.39, 156.00, 149.43, 145.82, 137.25, 131.85, 121.57, 120.93, 116.26, 115.98, 114.36, 104.45, 99.24, 94.24, 71.73, 55.63.
embodiment 14: the synthesis of Quercetin-3-O-acetyl-ORTHO ANISIDINE (3-14)
The same 3-1 of synthetic method.Compound 3-14 is faint yellow solid, yield 67.2%.
M.p: 257.8~259.7 ℃； 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H,5-OH), 10.95 (s, 1H,7-OH), 9.85 (s, 1H, 4′-OH), 9.68 (s, 1H,NH), 9.48 (s, 1H,3′-OH), 8.18 (d, J = 7.9 Hz, 1H, 2′-H), 7.51 (dd, J = 19.5, 4.9 Hz, 2H, 6′-H, 5′-H), 7.11 (d, J = 6.4 Hz, 2H,2×ph-H), 6.94 (dd, J = 18.7, 8.2 Hz, 2H,2×ph-H), 6.46 (s, 1H,8-H), 6.24 (s, 1H,6-H), 4.59 (s, 2H,COCH 2), 3.84 (s, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 177.95, 166.86, 164.87, 161.62, 156.91, 156.52, 149.45, 149.21, 145.90, 136.97, 127.22, 124.85, 121.32, 120.93, 120.79, 120.50, 116.33, 115.86, 111.62, 104.46, 99.23, 94.27, 71.94, 56.32.
embodiment 15: the synthesis of Quercetin-3-O-acetyl-p-ethoxyaniline (3-15)
The same 3-1 of synthetic method.Compound 3-15 is faint yellow solid, yield 64.5%.
M.p: 205.4~207.3 ℃； 1H NMR (400 MHz, DMSO) δ 12.47 (s, 1H,5-OH), 10.94 (s, 1H,7-OH), 10.12 (s, 1H,NH), 9.84 (s, 1H, 4′-OH), 9.44 (s, 1H, 3′-OH), 7.59 – 7.54 (m, 4H, 2′-H, 6′-H,2×ph-H), 6.93 – 6.87 (m, 3H, 5′-H,2×ph-H), 6.46 (d, J = 1.9 Hz, 1H,8-H), 6.24 (d, J = 1.9 Hz, 1H,6-H), 4.54 (s, 2H,COCH 2), 3.99 (q, J = 7.0 Hz, ,CH 3CH 2), 1.32 (t, J = 7.0 Hz, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 178.09, 166.62, 164.86, 161.59, 156.87, 156.39, 155.27, 149.43, 145.83, 137.25, 131.75, 121.55, 120.93, 116.26, 115.98, 114.87, 104.45, 99.24, 94.23, 71.74, 63.55, 15.16.
embodiment 16: the synthesis of Quercetin-3-O-acetyl-O-ethoxyl amine (3-16)
The same 3-1 of synthetic method.Compound 3-16 is faint yellow solid, yield 59.7%.
M.p: 226.3~228.1 ℃； 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H,5-OH), 10.96 (s, 1H,7-OH), 9.77 (d, J = 49.4 Hz, 2H,NH, 4′-OH), 9.48 (s, 1H,3′-OH), 8.24 (d, J = 7.9 Hz, 1H, 2′-H), 7.55 (d, J = 2.1 Hz, 1H, 6′-H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H, 5′-H), 7.08 (d, J = 4.0 Hz, 2H,2×ph-H), 6.98 – 6.90 (m, 2H,2×ph-H), 6.47 (d, J = 1.8 Hz, 1H,8-H), 6.24 (d, J = 1.8 Hz, 1H,6-H), 4.57 (s, 2H,COCH 2), 4.11 (q, J = 6.9 Hz, 2H,CH 3CH 2), 1.31 (t, J = 6.9 Hz, 3H,CH 3).
13C NMR (101 MHz, DMSO) δ 177.91, 166.87, 164.91, 161.60, 156.92, 156.49, 149.49, 148.21, 145.93, 136.99, 127.54, 124.67, 121.24, 120.92, 120.73, 120.03, 116.35, 115.80, 112.56, 104.39,99.23, 94.30, 72.15, 64.54, 14.93.
embodiment 17: the synthesis of Quercetin-3-O-acetyl-to N, accelerine (3-17)
The same 3-1 of synthetic method.Compound 3-17 is faint yellow solid, yield 45.2%.
M.p: 241.2~243.3 ℃； 1H NMR (400 MHz, DMSO) δ 12.48 (s, 1H,5-OH), 10.94 (s, 1H, 7-OH), 9.97 (s, 1H,NH), 9.86 (s, 1H, 4′-OH), 9.43 (s, 1H, 3′-OH), 7.56 (d, J = 5.6 Hz, 2H, 2′-H, 6′-H), 7.48 (d, J = 8.9 Hz, 2H, 2×ph-H), 6.92 (d, J = 9.0 Hz, 1H, 5′-H), 6.71 (d, J = 9.0 Hz, 2H, 2×ph-H), 6.46 (d, J = 1.7 Hz, 1H,8-H), 6.24 (d, J = 1.7 Hz, 1H,6-H), 4.52 (s, 2H,CH 2), 2.86 (s, 6H,2×CH 3).
13C NMR (101 MHz, DMSO) δ 178.12（C=O）, 166.21（CH 2C=O）, 164.84, 161.60, 156.88, 156.42, 149.43, 147.80, 145.84, 137.31, 128.45, 121.55, 121.39, 120.94,116.28,115.97, 113.07, 104.46, 99.24, 94.23, 71.848(CH 2), 40.91(2CH 3).
embodiment 18: the synthesis of Quercetin-3-O-acetyl-p-aminophenyl amine (3-18)
The same 3-1 of synthetic method.Compound 3-18 is faint yellow solid, yield 29.3%.
M.p: 219.9~221.9 ℃； 1H NMR (400 MHz, DMSO) δ 12.48 (s, 1H,5-OH), 10.94 (s, 1H,7-OH), 9.83 (s, 1H, 4′-OH), 9.44 (s, 1H, 3′-OH), 8.32 (s, 1H,NH), 7.60 – 7.51 (m, 2H, 2′-H, 6′-H), 7.29 (d, J = 8.6 Hz, 2H, 2×ph-H), 6.92 (d, J = 9.0 Hz, 1H, 5′-H), 6.50 (dd, J = 32.8, 5.2 Hz, 3H, 2×ph-H ,8-H), 6.24 (d, J = 1.8 Hz, 1H,6-H), 4.99 (s, 2H,NH 2), 4.50 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.11, 166.02, 164.84, 161.59, 156.87, 156.40, 149.42, 145.83, 145.67, 137.31, 127.77, 121.66, 121.55, 120.94, 116.27, 115.97, 114.28, 104.45, 99.23, 94.23, 71.83.
embodiment 19: the synthesis of Quercetin-3-O-acetyl-m-aminophenyl amine (3-19)
The same 3-1 of synthetic method.Compound 3-19 is faint yellow solid, yield 22.6%.
M.p: 195.4~197.6 ℃； 1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H,5-OH), 10.96 (s, 1H,7-OH), 10.01 (s, 1H,NH), 9.86 (s, 1H, 4′-OH), 9.44 (s, 1H,3′-OH), 7.55 (dd, J = 5.5, 2.1 Hz, 2H, 2′-H, 6′-H), 7.01 (s, 1H, 5′-H), 6.98 – 6.90 (m, 2H, 2×ph-H), 6.75 (d, J = 7.9 Hz, 1H, ph-H), 6.46 (d, J = 2.0 Hz, 1H, ph-H), 6.30 (dd, J = 8.0, 1.2 Hz, 1H,8-H), 6.24 (d, J = 2.0 Hz, 1H,6-H), 5.15 (s, 2H,NH 2), 4.53 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.16, 166.71, 164.87, 161.57, 156.88, 156.37, 149.57, 149.44, 145.84, 139.32, 137.44, 129.52, 121.56, 120.91, 116.30, 115.96, 110.22, 107.65, 105.40, 104.41, 99.25, 94.24, 71.95.
embodiment 20: the synthesis of Quercetin-3-O-acetyl-para hydroxybenzene amine (3-20)
The same 3-1 of synthetic method.Compound 3-20 is faint yellow solid, yield 58.1%.
M.p: 289.1~291.3 ℃； 1H NMR (400 MHz, DMSO) δ 12.48 (s, 1H,5-OH), 10.96 (s, 1H,7-OH), 10.02 (s, 1H,NH), 9.88 (s, 1H, 4′-OH), 9.45 (s, 1H,3′-OH), 9.28 (s, 1H,ph-OH), 7.61 – 7.52 (m, 2H, 2′-H, 6′-H), 7.44 (d, J = 8.9 Hz, 2H, 2×ph-H), 6.96 – 6.88 (m, 1H, 5′-H), 6.73 (d, J = 8.8 Hz, 2H, 2×ph-H), 6.45 (d, J = 2.0 Hz, 1H,8-H), 6.23 (d, J = 2.0 Hz, 1H,6-H), 4.53 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.09, 166.41, 164.82, 161.58, 156.86, 156.37, 154.15, 149.41, 145.81, 137.25, 130.33, 121.77, 121.55, 120.92, 116.25, 115.95, 115.58, 104.44, 99.23, 94.22, 71.73.
embodiment 21: the synthesis of Quercetin-3-O-acetyl-para-fluoroaniline (3-21)
The same 3-1 of synthetic method.Compound 3-21 is faint yellow solid, yield 35.7%.
M.p: 265.7~267.6 ℃； 1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H,5-OH), 10.95 (s, 1H,7-OH), 10.31 (d, J = 12.7 Hz, 1H,NH), 9.85 (s, 1H,4′-OH), 9.42 (s, 1H,3′-OH), 7.70 (dd, J = 9.0, 5.0 Hz, 2H,2′-H,6′-H), 7.59 – 7.52 (m, 2H, 2×ph-H), 7.18 (t, J = 8.9 Hz, 2H, 2×ph-H), 6.91 (d, J = 9.0 Hz, 1H,5′-H), 6.46 (d, J = 1.9 Hz, 1H,8-H), 6.24 (d, J = 1.9 Hz, 1H,6-H), 4.58 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.05, 167.11, 164.85, 161.59, 156.87, 156.37, 149.42, 145.81, 137.18, 135.16, 135.14, 121.91, 121.83, 121.55, 120.93, 116.25, 115.92, 104.45, 99.25, 94.23, 71.64.
embodiment 22: the synthesis of Quercetin-3-O-acetyl-methyl naphthylamine (3-22)
The same 3-1 of synthetic method.Compound 3-23 is faint yellow solid, yield 48.3%.
M.p: 143.1~145.2 ℃； 1H NMR (400 MHz, DMSO) δ 12.53 (s, 1H,5-OH), 10.97 (s, 1H,7-OH), 10.41 (s, 1H,NH), 9.89 (s, 1H,4′-OH), 9.46 (s, 1H,3′-OH), 8.13 (dd, J = 5.9, 3.6 Hz, 1H,2′-H), 7.97 (dd, J = 5.9, 3.5 Hz, 1H, 6′-H), 7.82 (d, J = 8.2 Hz, 1H,), 7.74 (d, J = 7.3 Hz, 1H, ph-H), 7.65 – 7.51 (m, 5H,5×ph-H), 6.95 (d, J = 9.0 Hz, 1H,5′-H,ph-H), 6.49 (d, J = 1.9 Hz, 1H,8-H), 6.26 (d, J = 1.9 Hz, 1H,6-H), 4.75 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.19, 167.91, 164.89, 161.64, 156.92, 156.46, 149.47, 145.88, 137.30, 134.18, 133.27, 128.63, 128.31, 126.60, 126.49, 126.13, 126.06, 122.96, 122.17, 121.61, 120.98, 116.29, 116.01, 104.50, 99.26, 94.27, 79.65, 71.97.
embodiment 23: the synthesis of Quercetin-3-O-acetyl-phenylhydrazine (3-23)
The same 3-1 of synthetic method.Compound 3-23 is faint yellow solid, yield 52.4%.
M.p: 203.7~205.5 ℃； 1H NMR (400 MHz, DMSO) δ 12.59 (s, 1H,5-OH), 10.93 (s, 1H,7-OH), 10.00 (d, J = 2.6 Hz, 1H,CONH), 9.88 (s, 1H, 4′-OH), 9.39 (s, 1H,3′-OH), 7.80 (d, J = 2.5 Hz, 1H,NH), 7.62 – 7.53 (m, 2H, 2′-H, 6′-H), 7.14 (t, J = 7.9 Hz, 2H,2×ph-H), 6.92 (d, J = 8.5 Hz, 1H, 5′-H), 6.79 – 6.69 (m, 3H,3×ph-H), 6.45 (d, J = 1.9 Hz, 1H, 8-H), 6.24 (d, J = 1.9 Hz, 1H, 6-H), 4.61 (s, 2H,COCH 2).
13C NMR (101 MHz, DMSO) δ 178.00, 167.99, 164.76, 161.67, 156.81, 156.29, 149.55, 149.35, 145.79, 136.75, 129.12, 121.70, 121.06, 119.01, 116.13, 115.96, 112.71, 104.51, 99.18, 94.14, 70.41.
embodiment 24: the synthesis of Quercetin-3-O-acetyl-leucine (3-24)
the preparation of leucine benzyl ester tosilate
By leucine 1.31g (10 mmol), a water tosic acid 2.09g (11 mmol) joins in the round-bottomed flask of 100mL, adds phenylcarbinol 20mL, in 90-100 DEG C of backflow 24h.To most of leucine reaction, stopped reaction, is chilled to room temperature.Stir in cryosel bath is lower, then slowly drip ethyl acetate 50mL with constant pressure funnel, have a large amount of white solid to separate out.Filter, and use ethyl acetate rinse.After filtration cakes torrefaction, with anhydrous diethyl ether/dehydrated alcohol recrystallization, obtain the leucine tosilate 3.29g of benzyl protection, white solid, yield 83.7%.
1H NMR (400 MHz, DMSO) δ 8.35 (s, 3H,NH 2 SO 3H), 7.49 (d, J = 8.0 Hz, 2H, 2×ph-H), 7.40 (dd, J = 12.3, 3.9 Hz, 5H,OBn), 7.13 (d, J = 7.9 Hz, 2H, 2×ph-H), 5.25 (s,2H,Ar-CH 2), 4.08 (t, J = 7.0 Hz, 1H,NH 2CH), 2.30 (s, 3H,Ar-CH 3), 1.75 – 1.57 (m, 3H,CH 2,CH), 0.88 (d, J = 6.1 Hz, 6H, 2×CH 3).
3 ', 4 ', 7-O-tribenzyl Quercetin-3-O-acetyl-leucic synthesis
1.26g (2mmol) compound 2,40mL anhydrous methylene chloride is added successively, 454mg(2.2mmol in round-bottomed flask 1) DCC and 297mg(2.2mmol) HOBt, stirs 1h under ice bath.Meanwhile, in round-bottomed flask 2, add the leucine tosilate of 865mg (2.2mmol) benzyl protection, 20mL anhydrous methylene chloride, 2.8mL (20mmol) anhydrous triethylamine, stirring at room temperature.After 1h, be slowly added drop-wise in bottle 1 by the solution in bottle 2 with constant pressure funnel, 20min drips off, and turns stirring at room temperature gradually 24 hours.After reaction terminates, as refrigerator cold-storage half an hour.Cross and filter most of by product DCU, filtrate extracted, add a small amount of dilute hydrochloric acid, removing HOBt, uses saturated sodium bicarbonate, saturated aqueous common salt successively, and distillation washing, organic over anhydrous dried over sodium sulfate is spent the night.Filter, concentrated by rotary evaporation, adds a small amount of acetone, has a small amount of white granular solid to separate out, and filter, filtrate is spin-dried for.With chloroform/methanol recrystallization, obtain faint yellow solid.Compound 3-24 is obtained again through shortening debenzylation.
Compound 3-24 is faint yellow solid, yield 53.7%.
M.p: 164.4~166.5 ℃； 1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H,COOH), 12.52 (s, 1H,5-OH), 10.94 (s, 1H,7-OH), 9.84 (s, 1H, 4′-OH), 9.41 (s, 1H, 3′-OH), 8.31 (s, 1H, NH), 7.57 – 7.48 (m, 2H, 2′-H, 6′-H), 6.89 (d, J = 8.4 Hz, 1H, 5′-H), 6.44 (d, J = 2.0 Hz, 1H,8-H), 6.23 (d, J = 2.0 Hz, 1H,6-H), 4.51 (d, J = 14.6 Hz, 1H,NHCH), 4.37 (d, J = 14.7 Hz, 2HCOCH 2), 1.63 (dt, J = 14.3, 4.4 Hz, 2H,NHCHCH 2), 1.58 – 1.51 (m, 1H,CH 3CHCH 3), 0.88 (dd, J = 19.0, 6.3 Hz, 6H,2×CH 3).
13C NMR(101MHz, DMSO) δ 178.06(C=O),174.13(COOH),168.21 (CH 2C=O), 164.81, 161.65, 156.84, 156.44, 149.41, 145.85, 137.05, 121.64, 120.91, 116.23, 115.82, 104.44, 99.19, 94.17, 71.28, 50.34(NHCH), 24.73(NHCHCH 2), 23.33(CH 3CH), 21.74(2CH 3).
embodiment 25: the synthesis of Quercetin-3-O-acetyl-glycine (3-25)
The same 3-24 of synthetic method.Compound 3-25 is faint yellow solid, yield 62.8%.
M.p: 267.3~269.2 ℃； 1H NMR (400 MHz, DMSO) δ12.56 (s, 1H,COOH), 12.52 (s, 1H,5-OH), 10.95 (s, 1H,7-OH), 9.83 (s, 1H,4′-OH), 9.42 (s, 1H, 3′-OH) , 8.43 (t, J = 5.9 Hz, 1H,NH)7.56 – 7.47 (m, 2H, 2′-H, 6′-H), 6.91 (d, J = 8.3 Hz, 1H, 5′-H), 6.44 (d, J = 2.0 Hz, 1H,8-H), 6.22 (d, J = 2.0 Hz, 1H,6-H), 4.45 (s, 2H,COCH 2), 3.87 (d, J = 5.9 Hz, 2H,NHCH 2).
13C NMR (101 MHz, DMSO) δ 182.67 (s,C=O), 176.15 (s,COOH), 173.32 (s, CO-NH), 169.52 (s), 166.39 (s), 161.58 (s), 161.15 (s), 154.12 (s), 150.55 (s), 141.42 (s), 126.32 (s), 125.66 (s), 121.05 (s), 120.55 (s), 109.24 (s), 103.93 (s), 98.91 (s), 75.67 (s, OCH 2),45.68 (s,NHCH 2).
embodiment 26: the synthesis of Quercetin-3-O-acetyl-phenylalanine (3-26)
The same 3-24 of synthetic method.Compound 3-26 is faint yellow solid, yield 46.5%.
M.p: 189.7~191.6 ℃； 1H NMR (400 MHz, DMSO) δ12.55 (s, 1H, COOH), 12.49 (s, 1H,5-OH), 11.04 (s, 1H,7-OH), 9.91 (s, 2H, 4′-OH, 3′-OH), 8.32 – 8.26 (m, 1H,NH), 7.52 – 7.45 (m, 2H,2′-H, 6′-H), 7.26 – 7.17 (m, 5H,5×ph-H), 6.89 (d, J = 8.4 Hz, 1H, 5′-H), 6.44 (d, J = 1.7 Hz, 1H,8-H), 6.23 (d, J = 1.7 Hz, 1H,6-H), 4.52 (dd, J = 13.0, 8.0 Hz, 1H,NHCH), 4.38 (d, J = 2.0 Hz, 2H,COCH 2), 3.15 – 2.97 (m, 2H,NHCHCH 2).
13C NMR (101 MHz, DMSO) δ 177.88(C=O), 173.15(COOH), 167.95 (CH 2C=O), 164.87, 161.64, 156.83, 156.34, 149.45, 145.87, 137.93, 136.73, 129.68, 128.56, 126.85, 121.42, 120.87, 116.31, 115.85, 104.41, 99.21, 94.16, 71.02(COCH 2), 53.82(NHCH), 37.29(PhCH 2).
3 anti-tumor activity experiments
3.1 instrument and equipment
XD-101 type inverted microscope, Anting Scientific Instrument Factory, Shanghai
Integrated enzyme reaction detector, Bio Tek company of the U.S.
BCM-1000A type biological clean bench, SuZhou Antai Air Tech Co., Ltd.
CO 2incubator, Thermo Forma company of the U.S.
101 type electrically heated drying cabinets, Beijing Zhong Xing great achievement Instrument Ltd.
Micropipet, German Eppendorf company
Analytical balance, German Sai Duolisi
Refrigerator, Qingdao HaiEr Co., Ltd
Mili-Q Hyperpure water manufacturing systems, French MilliPore company
96 orifice plates, 75cm2 culturing bottle, Corning company of the U.S.
SYQ-DSX-280B stainless steel pressure steam sterilizer, Shenan Medical Appliances Factory, Shanghai
PH counts, Shanghai Lei Ci instrument plant
3.2 cell strains and reagent
Dimethyl sulfoxide (DMSO) (DMSO), Sigma company
Methyl thiazoly tetrazolium assay (MTT), Sigma company
RPMI-1640 substratum, Sai Mo flies generation that biological chemistry goods (Beijing) company limited
Foetal calf serum, Sai Mo flies generation that biological chemistry goods (Beijing) company limited
Trypsinase, Hangzhou Ji Nuo biological medicine technology company limited
Human esophageal squamous cell cancer cell EC109, Human esophageal squamous cell cancer cell EC9706, gastric carcinoma cells SGC7901 and B16 mouse melanoma cell line-F10, buy in Shanghai Life Sciences Research Institute, Chinese Academy Of Sciences's cell bank.
Substratum: get RPMI-1640 substratum, add 10% foetal calf serum, penicillin 100U/mL, Streptomycin sulphate 100 μ g/mL, mix, 4 DEG C store for future use.
Cells frozen storing liquid: add DMSO to the substratum containing 10% foetal calf serum, make DMSO concentration be 10%, now with the current.
Trysinization liquid (0.25% trypsinase+0.02%EDTA): take trypsinase powder 0.25g, EDTA0.02g, PBS fully dissolves, and is settled to 100mL, 0.22 μM of millipore filter filtration sterilization ,-20 DEG C of preservations after packing.
PBS:KCl 0.2g, NaCl 8.0g, Na 2hPO 41.56g, KH 2pO 40.2g is dissolved in 1000mL distilled water, and after high pressure steam sterilization, 4 DEG C store for future use;
MTT liquid: get MTT 250mg and add 50mL PBS, on magnetic stirring apparatus, lucifuge stirring 1h fully dissolves, and final concentration is 50mg/mL, and 0.22 μM is air filter filtration sterilization, and after packing, ﹣ 20 DEG C keeps in Dark Place.
Quercetin and derivative aqua sterilisa thereof are made into the original liquid body of 10mg/mL, and 4 DEG C save backup, and face the used time with the dilution of RPMI-1640 substratum, and with 0.22 μM of filtering with microporous membrane.
3.3 cell cultures
(1) cultivate: each tumor cell line is incubated in the modified form RPMI-1640 substratum containing 10% foetal calf serum, 100 μ g/mL Streptomycin sulphates, 100U/mL penicillin, is placed in 37 DEG C, 5%CO 2, saturated humidity incubator in cultivate.
(2) recover: from liquid nitrogen, take out cryopreservation tube, in the 37 DEG C of water-baths of rapid input, melt in 1min, add 5mL perfect medium, the centrifugal 4min of 800rpm, abandons supernatant liquor, adds fresh complete medium 6mL re-suspended cell, cell suspension is moved in Tissue Culture Flask and put into incubator and cultivate, replaced medium after 24h.
(3) go down to posterity: inverted microscope observation of cell growing state, the had digestive transfer culture when cell is paved with 70% ~ 80% of bottle wall.The old substratum of sucking-off, adds PBS 3mL and washes twice, and then adds 1 ~ 2mL trysinization liquid.Basis of microscopic observation, add 3mL substratum when most cells becomes circle in raindrop shape and stop digestion, piping and druming makes it to become single cell suspension gently, and 8000rpm centrifugal 5min sedimentation cell adds after appropriate substratum re-suspended cell in 1:3 or 1:4 ratio Secondary Culture.
(4) frozen: the cell in vegetative period of taking the logarithm, PBS washs 2 times, add collected by trypsinisation, centrifugally abandon supernatant liquor, add cells frozen storing liquid (perfect medium containing 10%DMSO) and adjust cell density, proceed in 1.5mL cryopreservation tube, put into Virahol freezing storing box and be placed in ﹣ 80 DEG C of Ultralow Temperature Freezers, proceed in liquid nitrogen container after 48h and preserve.
3.4 cell growth inhibition assay
(1) with RPMI-1640 substratum, Quercetin and amide derivatives thereof are diluted to following concentration: 0.5,1,2,4,8,16,32,64 μ g/mL.Take the logarithm vegetative period, converge the cell that rate about reaches 80%, digestion collect, adjustment cell density be 2.0 × 10 4individual/mL, every hole 200 μ L is inoculated in 96 orifice plates, puts into incubator and cultivates.
(2) treat that cell attachment grows, experimental group adds the testing compound of above-mentioned each concentration.Control group replaces testing compound with perfect medium, and every hole adds volume 200 μ L, and often group arranges 6 multiple holes, cultivates 72 hours.200 μ L PBS are added to reduce because substratum volatilizees the experimental error caused in 96 orifice plate periphery holes.
(3), after drug intervention terminates, the MTT 20 μ L of every hole 5mg/mL, after hatching 4 ~ 6h in incubator, solution in careful sucking-off hole, adds DMSO 150 μ L, shakes up and precipitation is fully dissolved in every hole.Enzyme linked immunological microplate reader detects each hole, 570nm place absorbance value (A value).Experiment is independent in triplicate, averages.And by following formulae discovery growth inhibition ratio:
GI (growth inhibition ratio)=1-(medicine group avalue/control group avalue) × 100%
According to acquired results, SPPS19.0 is utilized to calculate IC 50value.
3.5 result
Quercetin and derivative thereof to the restraining effect of Human esophageal squamous cell cancer cell EC109, Human esophageal squamous cell cancer cell EC9706, gastric carcinoma cells SGC7901 and B16 mouse melanoma cell line-F10 four kinds of tumour cells in table 1.By data analysis in his-and-hers watches, we draw following result:
(1) Quercetin has certain restraining effect to EC109 and EC9706, and obvious not as good as front two strain cells to the restraining effect of SGC7901, B16-F10.All in all, the restraining effect of target compound to EC109 is better than other three strains tumour cell.
(2) reference substance Fluracil (5-FU) has good restraining effect, EC109 (IC to wherein two strain tumour cells 50=5.426 μ g/mL) and B16-F10 (IC 50=8.133 μ g/mL); Female medicine Quercetin is only to the restraining effect comparatively significantly (IC of EC109 cell 50=9.629 μ g/mL), undesirable to the restraining effect of other three strains tumour cell.Though the restraining effect of Quercetin to EC109 cell is less than 5-FU, its toxic side effect is less, so be a very potential antitumor drug candidate.
(3) five compounds are had to be better than Quercetin (IC to EC9706 cyto-inhibition in target compound 50=42.941 μ g/mL), be compound 3-14,3-15,3-18,3-19,3-22 respectively;
table 1 target compound to four strain inhibiting tumour cells effects ( ± SD)
In a word, carry out structural modification by chemical process to Quercetin, its anti tumor activity in vitro significantly strengthens.We will study its pharmacologically active further, wish for the exploitation of natural antitumor medicine and the searching of novel Quercetin prodrug are given a clue.

Claims (1)

1. a Quercetin amide derivatives, described compound is following five particular compound:
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