CN105859736A - Glabridin Schiff alkaline derivative and preparation and application thereof - Google Patents

Glabridin Schiff alkaline derivative and preparation and application thereof Download PDF

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Publication number
CN105859736A
CN105859736A CN201610299250.9A CN201610299250A CN105859736A CN 105859736 A CN105859736 A CN 105859736A CN 201610299250 A CN201610299250 A CN 201610299250A CN 105859736 A CN105859736 A CN 105859736A
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glabridin
schiff
preparation
analog derivative
dmf
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CN105859736B (en
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石璐
王陈茹
袁继文
钟慧
易铭
魏元刚
杨永安
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Yili resistant bird Biotechnology Co. Ltd.
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JIANGSU NAIQUE BIOLOGICAL ENGINEERING TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Abstract

The invention discloses a glabridin Schiff alkaline derivative and preparation and application thereof. Glabridin subjected to treatment through DMF (dimethyl formamide) and phosphorus oxychloride for structure modification is acted in methyl alcohol with substituted aniline to obtain the glabridin Schiff alkaline derivative, and the glabridin Schiff alkaline derivative is applied in the preparation of antitumor drugs. By the arrangement, biological activity of Schiff alkaline in antitumor and antivirus is enhanced, obvious inhibitory effect in tumor cells is achieved, medical importance is significant, the preparation method is simple and practicable, preparation time is short, and practical value is remarkable.

Description

Glabridin Schiff analog derivative and preparation thereof and application
Technical field
The present invention relates to compound and preparation thereof, be specifically related to glabridin Schiff analog derivative and Preparation and application.
Background technology
Glabridin is one of Main Flavonoids constituents in Glycyrrhiza glabra L., within 1976, is separated and reflects for the first time Fixed.It has antioxidation, antiinflammatory, atherosclerosis, neuroprotective, regulation energy metabolism, antitumor, Multiple biological activity and the pharmacologically actives such as anti-nephritis and skin whitening, be referred to as " whitening gold ".It is reported, Glabridin has the strongest free radical resisting Oxidation, it is possible to substantially suppress to be produced in internal metabolic processes Raw free radical, can be effectively prevented free-radical oxidation cell wall and low density lipoprotein, LDL (LDL), The biomacromolecule to oxidation-sensitive such as DNA.
Schiff is primarily referred to as the class organic compound containing imines or azomethine characteristic group (-RC=N-) Thing, usual Schiff is to be condensed by amine and active carbonyl group to form.At medical domain, Schiff's base have antibacterial, Sterilization, antitumor, the biological activity of antiviral.
If the structure of glabridin can be modified, it is applied in the synthesis of Schiff analog derivative, To strengthen its anti-tumor activity, it it is problem highly significant.
Summary of the invention
Goal of the invention: glabridin is applied to Schiff class spreads out to overcome not have present in prior art The problem gone in biological synthesis, it is sweet that the present invention proposes a kind of light having obvious inhibitory action to tumor cell Grass determines Schiff analog derivative and preparation thereof and application.
Technical scheme: in order to solve above-mentioned technical problem, the technical solution adopted in the present invention is: glabridin Schiff analog derivative, formula is:
In formula, R is H, halogen, methyl, methoxyl group.
The invention allows for the preparation of above-mentioned glabridin Schiff analog derivative, comprise the following steps:
(1) in 20mL DMF, 15ml phosphorus oxychloride is dripped, ice bath, standby, to light Radix Glycyrrhizae after stirring 1h Add 20mL DMF in fixed, be slowly dropped into after mixing in the mixed solution of standby DMF and phosphorus oxychloride, 100 DEG C are heated to reflux, and react 2 hours；After reaction terminates, adding 200mL water EA extraction, silica gel column chromatography obtains White solid:
3-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2,6-dihydroxybenzal Dehyde, concrete reaction equation formula is as follows:
(2) take and step (1) obtains
3-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2,6-dihydroxybenzal Dehyde 100mg is added in 10mL methanol dissolve with the substituted aniline of the amount waiting material, reacts 4-6 little under room temperature Time, separate out white solid, filter, be dried, dehydrated alcohol recrystallization, i.e. obtain glabridin Schiff class Derivant, reaction equation is as follows:
Further, substituted aniline be aniline, chloroaniline, bromaniline, toluidines, aminoanisole, in One.
The invention allows for the application of above-mentioned glabridin Schiff analog derivative, for antitumor drug Preparation.
Beneficial effect: a kind of glabridin Schiff analog derivative of present invention offer and preparation thereof and application, By light grass sweet fixed by the process of DMF, phosphorus oxychloride carry out structurally-modified after react in methanol with substituted aniline Obtain glabridin Schiff analog derivative, and apply it to the preparation of antitumor drug, enhance Schiff Antitumor that alkali itself has, the biological activity of antiviral, have obvious inhibitory action to tumor cell, doctor Meaning is notable, and preparation method simple possible, and preparation time is short, and practical value is notable.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail:
Embodiment 1:
Glabridin Schiff analog derivative
4-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2-((phenylimino)met Hyl) preparation of benzene-1,3-diol:
(1) in 20mL DMF, 15ml phosphorus oxychloride is dripped, ice bath, standby, to light Radix Glycyrrhizae after stirring 1h Add 20mL DMF in fixed, be slowly dropped into after mixing in the mixed solution of standby DMF and phosphorus oxychloride, 100 DEG C are heated to reflux, and react 2 hours；After reaction terminates, adding 200mL water EA extraction, silica gel column chromatography obtains White solid:
3-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2,6-dihydroxybenzal Dehyde, concrete reaction equation formula is as follows:
(2) 100mg obtained in step (1) is taken
3-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2,6-dihydroxybenzal Dehyde is added in 10mL methanol dissolve with the aniline of the amount waiting material, reacts 4-6h under room temperature, separates out white Solid, filters, and is dried, dehydrated alcohol recrystallization, obtains target compound, productivity 95%, Mp104-105 DEG C；1H NMR (300MHz, DMSO-d6): δ 9.37 (s, 1H, OH), 9.11 (s, 1H, OH), 8.36 (s, 1H, CH), 7.97-7.95 (d, J=6.06Hz, 1H, ArH), 7.75-7.74 (d, J=1.23Hz, 1H, ArH), 7.73 (m, 3H, ArH), 6.86 (d, 1H, J=12.5Hz, Ar-H), 6.38 (d, 1H, J=10Hz, Ar-H), 6.55 (d, 1H, J=12.5Hz, Ar-H), 6.34 (d, 1H, J=3Hz, Ar-H), 6.19 (dd, 1H, J=3Hz, C=CH), 5.64 (d, 1H, J=12.5Hz, C=CH), 4.23 (d, 1H, J=15Hz, CH2),3.92(m,1H,CH2),2.89(m, 1H,CH),2.70(m,1H,CH2),2.70(m,1H,CH2),2.50(m,1H,CH2),1.32(m,1H, CH3) .MS (ESI): 427.50 (C27H25NO4, [M+H]+) and .Anal.Calcd for C27H25NO4: C, 75.86； H,5.89；N, 3.28%.Found:C, 75.63；H,5.93；N, 3.47%
Embodiment 2:
Glabridin Schiff analog derivative
2-(((4-chlorophenyl)imino)methyl)-4-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f] Chromen-3-yl) preparation of benzene-1,3-diol
Preparation method with embodiment 1, replaces aniline with parachloroanilinum, obtains target compound, white powder, Productivity 92%, Mp174-175 DEG C；1HNMR (300MHz, DMSO-d6): δ 9.37 (s, 1H, OH), 9.11 (s, 1H, OH), 8.36 (s, 1H, CH), 7.97-7.95 (d, J=6.06Hz, 1H, ArH), 7.75-7.74 (d, J=1.23 Hz, 1H, ArH), 7.73 (m, 2H, ArH), 6.86 (d, 1H, J=12.5Hz, Ar-H), 6.38 (d, 1H, J=10 Hz, Ar-H), 6.55 (d, 1H, J=12.5Hz, Ar-H), 6.34 (d, 1H, J=3Hz, Ar-H), 6.19 (dd, 1H, J=3Hz, C=CH), 5.64 (d, 1H, J=12.5Hz, C=CH), 4.23 (d, 1H, J=15Hz, CH2), 3.92(m,1H,CH2),2.89(m,1H,CH),2.70(m,1H,CH2),2.70(m,1H,CH2),2.50(m, 1H, CH2), 1.32 (m, 1H, CH3) .MS (ESI):
461.14(C27H24ClNO4, [M+H]+) and .Anal.Calcd for C27H24ClNO4: C, 70.20；H,5.24；N, 3.03%.Found:C, 70.48；H,5.19；N, 3.06%
Embodiment 3:
Glabridin Schiff analog derivative
2-(((4-bromophenyl)imino)methyl)-4-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f] Chromen-3-yl) preparation of benzene-1,3-diol
Preparation method, with embodiment 1, replaces aniline with para-bromoaniline, obtains target compound.White powder, Productivity 91%, Mp182-183 DEG C；1HNMR (300MHz, DMSO-d6): δ 9.37 (s, 1H, OH), 9.11 (s, 1H, OH), 8.36 (s, 1H, CH), 7.97-7.95 (d, J=6.06Hz, 1H, ArH), 7.75-7.74 (d, J=1.23 Hz, 1H, ArH), 7.73 (m, 2H, ArH), 6.86 (d, 1H, J=12.5Hz, Ar-H), 6.38 (d, 1H, J=10 Hz, Ar-H), 6.55 (d, 1H, J=12.5Hz, Ar-H), 6.34 (d, 1H, J=3Hz, Ar-H), 6.19 (dd, 1H, J=3Hz, C=CH), 5.64 (d, 1H, J=12.5Hz, C=CH), 4.23 (d, 1H, J=15Hz, CH2), 3.92(m,1H,CH2),2.89(m,1H,CH),2.70(m,1H,CH2),2.70(m,1H,CH2),2.50 (m,1H,CH2),1.32(m,1H,CH3) .MS (ESI): 505.09 (C27H24BrNO4, [M+H]+) and .Anal. Calcd for C27H24BrNO4:C,64.04；H,4.78；N, 2.77%.Found:C, 64.52；H,4.88；N, 2.43%
Embodiment 4:
Glabridin Schiff analog derivative
4-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2-((p-tolylimino)met Hyl) preparation of benzene-1,3-diol
Preparation method, with embodiment 1, replaces aniline with para-totuidine, obtains target compound.White powder, Productivity 94%, Mp169-170 DEG C；1HNMR (300MHz, DMSO-d6): δ 9.37 (s, 1H, OH), 9.11 (s, 1H, OH), 8.36 (s, 1H, CH), 7.97-7.95 (d, J=6.06Hz, 1H, ArH), 7.75-7.74 (d, J=1.23 Hz, 1H, ArH), 7.73 (m, 2H, ArH), 6.86 (d, 1H, J=12.5Hz, Ar-H), 6.38 (d, 1H, J=10 Hz, Ar-H), 6.55 (d, 1H, J=12.5Hz, Ar-H), 6.34 (d, 1H, J=3Hz, Ar-H), 6.19 (dd, 1H, J=3Hz, C=CH), 5.64 (d, 1H, J=12.5Hz, C=CH), 4.23 (d, 1H, J=15Hz, CH2), 3.92(m,1H,CH2),2.89(m,1H,CH),2.70(m,1H,CH2),2.70(m,1H,CH2),2.50(m, 1H, CH2), 2.36 (s, 1H, CH3), 1.32 (m, 1H, CH3) .MS (ESI:441.19 (C28H27NO4, [M+H]+).Anal.Calcd for C28H27NO4:C,76.17；H,6.16；N, 3.17%.Found:C, 76.56；H, 6.23；N, 3.08%.
Embodiment 5:
Glabridin Schiff analog derivative
4-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2-(((4-methoxyphen Yl) imino) methyl) preparation of benzene-1,3-diol
Preparation method, with embodiment 1, replaces aniline with P-nethoxyaniline, obtains target compound.White powder End, productivity 92%, Mp189-190 DEG C；1HNMR (300MHz, DMSO-d6): δ 9.37 (s, 1H, OH), 9.11 (s, 1H, OH), 8.36 (s, 1H, CH), 7.97-7.95 (d, J=6.06Hz, 1H, ArH), 7.75-7.74 (d, J=1.23Hz, 1H, ArH), 7.73 (m, 2H, ArH), 6.86 (d, 1H, J=12.5Hz, Ar-H), 6.38 (d, 1H, J=10Hz, Ar-H), 6.55 (d, 1H, J=12.5Hz, Ar-H), 6.34 (d, 1H, J=3Hz, Ar-H), 6.19 (dd, 1H, J=3Hz, C=CH), 5.64 (d, 1H, J=12.5Hz, C=CH), 4.23 (d, 1H, J=15Hz, CH2),3.92(m,1H,CH2),3.16(s,3H,OCH3),2.89(m,1H,CH),2.70(m,1H,CH2), 2.70(m,1H,CH2),2.50(m,1H,CH2),1.32(m,1H,CH3) .MS (ESI:
457.19(C28H27NO5, [M+H]+) and .Anal.Calcd for C28H27NO5:C,73.51；H,5.95；N, 3.06%.Found:C, 73.57；H,5.86；N, 3.08%.
Embodiment 6:
The research to tumors inhibition activity of the glabridin Schiff analog derivative:
MTT [3-(4,5)-bis-methyl-2-thiazoles-(2,5)-phenyl bromination tetrazole is blue] method is used to measure light The licoricidin Schiff compounds 503nhibiting concentration to HepG2, Hela, A549, i.e. IC50。
(1) preparation of culture fluid (calculating with every L):
1. suspension cell: RPMI-1640 cultivates one bag of powder (10.4g), new-born calf serum 100mL, penicillin solution (20 Ten thousand U/mL) 0.5mL, Streptomycin Solution (200,000 U/mL) 0.5mL, after adding tri-distilled water dissolving, with 5.6% NaHCO3Solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml, filtration sterilization；
2. attached cell: culture fluid compound method ibid, adds NaHCO3 2.00g, HEPES 2.38g simultaneously. (2) preparation of D-Hanks buffer (calculating with every L): NaCl8.00g, KCl 0.40g, Na2HPO4·12H2O 0.06g, KH2PO40.06g, NaHCO30.35g, autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks buffer to be made into concentration is 0.5% trypsin solution, filters Degerming.
(4) preparation of medicinal liquid is tested: by the glabridin Schiff analog derivative compound of test sample embodiment 1-5 Dissolving with tri-distilled water and be made into test medicinal liquid, empirically 10 times of maximum concentration are joined, different according to compound dissolution, Available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve, and DMSO is at culture fluid In concentration unsuitable excessive, in the every porocyte suspension after dosing, the final concentration of DMSO is usually no more than 0.05% 0.1%, it is stored in-20 DEG C of refrigerators standby after test drug solution preparing.
(5) cultivation of cell: for adherent growth cell, cellar culture in above-mentioned attached cell culture fluid, put 37 DEG C, 5%CO2Incubator is cultivated, passed on once every 3-4 days.First discard original fluid when passing on, then use D-Hanks buffer solution；Then digest about 30 seconds with 0.5% trypsin solution, add a small amount of fresh training Nutrient solution terminates digestion；Piping and druming, makes attached cell split away off from culture bottle wall；Pipette appropriate to fresh cultured In Ping, it is supplemented with fresh medium to original volume (culture fluid volume is about the 1/10 of culture bottle capacity).
(6) cell incubation: the above-mentioned tumor cell of trophophase of taking the logarithm, adjusting concentration of cell suspension is 2 × 104Individual/ml. In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 DEG C, 5%CO2Incubator is cultivated 24h.Cultivate After 24h, add medicinal liquid by design respectively.
(7) dosing: by test medicinal liquid according to 100 μMs, 10 μMs, 1 μM, the Concentraton gradient of 0.1 μM is added separately to each Kong Zhong, each concentration sets 6 parallel holes；Experiment is divided into drug test group (to be separately added into the test medicine of variable concentrations Liquid), matched group (only add culture fluid and cell, be not added with test medicinal liquid) and blank group (only add culture fluid, not refinement Born of the same parents and test medicinal liquid).96 orifice plates after dosing are placed in 37 DEG C, 5%CO2Incubator is cultivated 48h.
(8) mensuration of survivaling cell: in 96 orifice plates after having cultivated 48h, every hole adds MTT 40 μ l and (uses 40 μ lPBS are made into the MTT of 2.5mg/ml).After placing 4h at 37 DEG C, remove supernatant.Every hole adds 100 μ l Extracting solution (10%SDS-5% isobutanol-0.01M HCl).37 DEG C of overnight incubation, finally, utilize automatic enzyme mark Instrument detects the optical density (OD value) in each hole at 570nm wavelength.
The calculating of suppression ratio: the suppression ratio of cell growth calculates according to the following formula:
Growth inhibition ratio=(1-survival rate) × 100%=[1-(OD experiment-OD is blank)/(OD comparison-OD is blank)] × 100% (OD experiment represent testing drug group average optical, OD comparison represent matched group average light close Degree, OD blank represents the average optical of matched group).
Half-inhibition concentration (IC50) it is defined as the drug level when the tumor cell survival of 50%.According to the light measured Density (OD value), makes the standard curve of inhibitory rate of cell growth, tries to achieve the medicine of its correspondence on standard curve Substrate concentration.
The glabridin Schiff analog derivative of embodiment 1-5 is to HepG2, Hela, A549 cell proliferation Inhibitory action is as shown in table 1 with the correction data of current clinical medicine Erlotinib, the wherein light of embodiment 1-5 Licoricidin Schiff analog derivative formula is as follows:
Table 1. active testing result (IC50, μm)
As can be known from Table 1, Hela cell and A549 cell are had preferably by glabridin Schiff analog derivative Inhibitory activity, inconspicuous to HepG2 Carbazole alkaloid.Wherein thin to Hela when R substituent is methoxyl group Born of the same parents and A549 cell inhibitory activity are best, and tracing it to its cause is that the electron donating group that methoxyl group is stronger adds light The active anticancer of licoricidin, and Cl, Br, H, be all electron donating group, thus activity is poor.With clinical medicine Thing Erlotinib is compared, and the Schiff analog derivative of embodiment 1-5 is relative to HepG2 cell, Hela cell It is respectively provided with obvious advantage with A549 cell inhibitory activity.
It should be pointed out that, that above detailed description of the invention is merely to illustrate the present invention rather than limits the model of the present invention Enclosing, after having read the present invention, the amendment of the various equivalent form of values of the present invention is all fallen by those skilled in the art In the application claims limited range.

Claims (4)

1. glabridin Schiff analog derivative, formula is:
In formula, R is H, halogen, methyl, methoxyl group.
2. the preparation of glabridin Schiff analog derivative as claimed in claim 1, it is characterised in that include Following steps:
(1) in 20mL DMF, 15ml phosphorus oxychloride is dripped, ice bath, standby, to light Radix Glycyrrhizae after stirring 1h Add 20mL DMF in fixed, be slowly dropped into after mixing in the mixed solution of standby DMF and phosphorus oxychloride, 100 DEG C are heated to reflux, and react 2 hours；After reaction terminates, adding 200mL water EA extraction, silica gel column chromatography obtains White solid:
3-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2,6-dihydroxybenzal Dehyde, concrete reaction equation formula is as follows:
(2) take and step (1) obtains
3-(8,8-dimethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromen-3-yl)-2,6-dihydroxybenzal Dehyde 100mg is added in 10mL methanol dissolve with the substituted aniline of the amount waiting material, reacts 4-6 little under room temperature Time, separate out white solid, filter, be dried, dehydrated alcohol recrystallization, i.e. obtained glabridin Schiff Bases derivant, reaction equation is as follows:
The preparation of glabridin Schiff analog derivative the most according to claim 2, it is characterised in that Substituted aniline is the one in aniline, chloroaniline, bromaniline, toluidines, aminoanisole.
4. the application of glabridin Schiff analog derivative as claimed in claim 1, it is characterised in that use Preparation in antitumor drug.
CN201610299250.9A 2016-05-06 2016-05-06 Glabridin Schiff analog derivative and its preparation and application Active CN105859736B (en)

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CN103030647A (en) * 2013-01-16 2013-04-10 山东省分析测试中心 Method for synthesizing glabridin
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JP2006008604A (en) * 2004-06-25 2006-01-12 Kuraray Co Ltd Method for producing isoflavan derivative
WO2007058480A1 (en) * 2005-11-16 2007-05-24 Md Bioalpha Co., Ltd. Composition having effect on treatment and prevention of diseases syndrome treatment with glabridin
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