CN103896790A - Aloe emodin quaternary ammonium salt as well as preparation and application thereof - Google Patents

Aloe emodin quaternary ammonium salt as well as preparation and application thereof Download PDF

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CN103896790A
CN103896790A CN201410176299.6A CN201410176299A CN103896790A CN 103896790 A CN103896790 A CN 103896790A CN 201410176299 A CN201410176299 A CN 201410176299A CN 103896790 A CN103896790 A CN 103896790A
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rhabarberone
quaternary ammonium
ammonium salt
deoxy
bromo
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CN103896790B (en
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邵敬伟
向利平
姜美红
杨祥
王文峰
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Fuzhou University
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Abstract

The invention relates to an aloe emodin quaternary ammonium salt with bioactivity of resisting hepatic carcinoma, melanoma, colon cancer and the like as well as a synthetic method and an application thereof. In-vitro cancer cell inhibition experiments show that the aloe emodin quaternary ammonium salt can effectively inhibit the growth of cells of hepatic carcinoma HepG2, melanoma A375 and colon cancer SW620; in-vitro anticancer activity experiments in combination with a glycolysis inhibitor 2-deoxy-D-glucose show that the inhibiting effects of a composition of the aloe emodin quaternary ammonium salt and the 2-deoxy-D-glucose on the three kinds of different tumor cells are increased with different degrees compared with the single agents of the same dose, and compounds AE-4 and AE-5 have significant synergic proliferation inhibition effects on the three kinds of different tumor cells after being combined with the 2-deoxy-D-glucose respectively. The composition can be used as a broad-spectrum agent for treating multiple malignant tumors, is particularly suitable for treating solid tumors such as the hepatic carcinoma, and has a great application prospect.

Description

A kind of rhabarberone quaternary ammonium salt and preparation and application
Technical field
The present invention relates to rhabarberone quaternary ammonium salt and preparation and application that a class has antitumour activity.
Background technology
Rhabarberone (1.8-dihydroxyl-3-methylol anthraquinone, Aloeemodin, AE) be the class anthraquinone analog compound being extensively present in the plants such as rheum officinale, aloe, Semen Cassiae, senna, there is the multiple biological activitys such as antitumor, antibacterial, immunosuppression and discharge function.But the activity of rhabarberone own is good not, therefore taking rhabarberone as parent, it is very necessary that its structure is modified to transformation, and the rhabarberone after modified shows better antitumour activity, has great application prospect.
2-deoxy-D-glucose (2-DG) is a kind of glycolytic inhibitor, and it is easily transported in cell by glucose transporter, thereby easily enrichment in tumour cell, power generation and picked-up while affecting cell self-regeneration.In addition, 2-deoxy-D-glucose can inhibition tumor cell in the generation of ATP, thereby tumour cell is killed in the energy metabolism of blocking-up tumour cell.The chemotherapeutic such as the Zorubicin of the use 2-deoxy-D-glucose such as Maschek associating in recent years, docetaxel act on tumour cell, and result shows that 2-deoxy-D-glucose has sensitization to chemotherapeutics.
By glycolytic inhibitor and chemotherapy drugs in combination medication, glycolytic inhibitor can effectively suppress to breed the energy metabolism and the lethal effect that enliven tumour cell on the one hand; Glycolysis-agent inhibitor can carry out enhanced sensitivity to chemotherapeutics on the other hand, thereby further entirety improves the effect for the treatment of tumour.Therefore, drug combination has great application prospect equally for the treatment of tumour.
Summary of the invention
The present invention relates to rhabarberone quaternary ammonium salt and preparation and application that a class has antitumour activity.
Concrete:
A kind of rhabarberone quaternary ammonium salt, its structure is suc as formula shown in I;
Figure 2014101762996100002DEST_PATH_IMAGE001
Wherein, work as R 1for CH 3time, R 2for C 8h 17, C 9h 19or C 14h 29straight chained alkyl;
When R1 is C 8h 17straight chained alkyl time, R 2for C 9h 19straight chained alkyl;
When R1 is C 10h 21straight chained alkyl time, R 2for C 10h 21straight chained alkyl.
Its preparation method comprises the following steps:
1) rhabarberone (representing with AE) with phosphorus tribromide at CCl 4in solvent, under room temperature, there is bromo-reaction and generate bromo rhabarberone;
2) bromo rhabarberone and a series of tertiary amine generation nucleophilic substitution reaction generate corresponding rhabarberone quaternary ammonium salt (using respectively AE-1 ~ AE-5 to represent).
Be shown below:
Figure 2014101762996100002DEST_PATH_IMAGE002
Concrete is:
1) bromo rhabarberone is synthetic: get rhabarberone and be dissolved in CCl 4in, add the phosphorus tribromide of 10 times of quality; At 65 DEG C, after stirring reaction 48h, be cooled to room temperature, revolve steaming except desolventizing obtains orange red crude product, through silica gel column chromatography separating purification, obtain bromo rhabarberone; When described silica gel column chromatography separates, eluent used is methylene dichloride;
2) rhabarberone quaternary ammonium salt is synthetic: get the bromo rhabarberone that step 1) makes and be dissolved in CHCl 3, after heating for dissolving, add the ratio of 0.1ml tertiary amine to add tertiary amine with every 0.3mmol bromo rhabarberone at approximately 50 DEG C; Reflux after lower stirring reaction 6h, be chilled to room temperature; Revolve to steam except after desolventizing and obtain garnet solid through silica gel column chromatography gradient elution, i.e. described rhabarberone quaternary ammonium salt; The order of described silica gel column chromatography gradient elution is: methylene dichloride → methylene dichloride: ethanol (v/v)=100:1 → methylene dichloride: ethanol (v/v)=50:1 → methylene dichloride: ethanol (v/v)=20:1.
Above-mentioned rhabarberone quaternary ammonium salt is in the application of preparing on antitumor drug.
The composition of above-mentioned rhabarberone quaternary ammonium salt and 2-deoxy-D-glucose composition is in the application of preparing on antitumor drug; Wherein said rhabarberone quaternary ammonium salt is characterized in that with the composition of 2-deoxy-D-glucose composition rhabarberone quaternary ammonium salt mixes with 1-25:50000 molar ratio with 2-deoxy-D-glucose.Wherein said rhabarberone quaternary ammonium salt is preferably AE-4 and AE-5.
The invention has the advantages that:
1. the rhabarberone quaternary ammonium salt described in has good antitumour activity.Cancer cell in vitro suppresses experiment and shows effectively killing hepatoma HepG2, melanoma A375 and the colorectal carcinoma SW620 cancer cells of 5 kinds of rhabarberone quaternary ammonium salts the present invention relates to, and has a good application prospect for the treatment of tumour.
2. further, by described rhabarberone quaternary ammonium salt and glycolytic inhibitor 2-deoxy-D-glucose drug combination, possess better antitumour activity.Both drug combinations have remarkable synergistic effect, and the increment action effect that suppresses liver cancer HepG2, melanoma A375 and colorectal carcinoma SW620 cancer cells is obvious, has great application prospect for the treatment of tumour.
Brief description of the drawings
Fig. 1 2DG and rhabarberone and 5 kinds of quaternary ammonium salt couplings act on the MTT experimental result of HepG2 cell
Fig. 2 2DG and rhabarberone and 5 kinds of quaternary ammonium salt couplings act on the MTT experimental result of A375 cell
Fig. 3 2DG and rhabarberone and 5 kinds of quaternary ammonium salt couplings act on the MTT experimental result of SW620 cell.
Embodiment
In order to make content of the present invention more be convenient to understand, below in conjunction with embodiment, technical solutions according to the invention are described further, but the present invention is not limited only to this.
Embodiment 1
Synthesizing of bromo rhabarberone
Get 1.4g (5.19mmol) rhabarberone and, in 250 there-necked flasks, add CCl 4180ml adds phosphorus tribromide 5ml (excessive) after rhabarberone dissolves again.Then be warming up to 65 DEG C and stir 48h, stopped reaction, is cooled to room temperature.Be spin-dried for solvent, obtain orange red crude product, silica gel column chromatography separates and obtains bromo rhabarberone 1.55g (4.67mmol), eluent methylene dichloride.Characterization of The Products data are as follows:
Yield:90%; 1H NMR (400MHz, CDCl 3) δ: 12.09 (s, 1H, Ar-OH), 12.06 (s, 1H, Ar-OH), 7.89 (d, J=5.2H z, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.73 (t, J=7.6H z, J=8.4H z, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.35 (d, J=6.4H z, 1H, Ar-H), 4.51 (s, 2H, Ar-CH 2-Br);
Embodiment 2: rhabarberone quaternary ammonium salt ( aE-1 ~ AE-5) synthetic
Get the synthetic bromo rhabarberone 100mg (0.30mmol) of embodiment 1 and be dissolved in 25mlCHCl 3be heated to add N after backflow (bathing 65 DEG C of temperature), N-dimethyl octylame (N, N-dimethyl nonyl amine, N, N-dimethyl tetradecy lamine, N-methyl-N-octyl group nonyl amine, N-methyl-N-decyl decyl amine) 0.1ml (excessive) backflow (bathing 65 DEG C of temperature) 6h, stopped reaction is cooled to room temperature.Revolve and steam except after desolventizing, residue separates gradient elution through silica gel column chromatography and obtains garnet product.Gradient elution order: methylene dichloride; Methylene dichloride: ethanol (v/v)=100:1; Methylene dichloride: ethanol (v/v)=50:1; Methylene dichloride: ethanol (v/v)=20:1.Corresponding Characterization of The Products data are as follows:
N-[(4,5-dihydroxyl-9,10-anthraquinone-2-yl) methyl]-N, N-dimethyl octane-1-brometo de amonio ( aE-1): Yield, 70%; 1h NMR (400MHz, CDCl 3) δ: 11.91 (s, 1H, Ar-OH), 11.83 (s, 1H, Ar-OH), 7.86 (s, 2H, Ar-H), 7.77 (d, j=8.0H z, 1H, Ar-H), 7.71 (d, j=8.0H z, 1H, Ar-H), 7.33 (d, j=8.0H z, 1H, Ar-H), 5.32 (s, 2H, ArCH 2n +), 3.42 (s, 8H, +nC h 2c 7h 15+ 2 × +nC h 3), 1.90 (m, 2H, +nCH 2c h 2c 6h 13), 1.28-1.23 (m, 10H, (C h 2) 5cH 3), 0.89 (t, j=8.0,3H ,-(CH 2) 7c h 3); Ultimate analysis C 25h 32brNO 4h 2o calculated value: C 59.06, H 6.74, N 2.75; Experimental value: C 59.02, H 6.59, N 2.72.
N-[(4,5-dihydroxyl-9,10-anthraquinone-2-yl) methyl]-N, N-dimethyl nonane-1-brometo de amonio ( aE-2): Yield, 80%; 1h NMR (400MHz, CDCl 3) δ: 11.94 (s, 1H, Ar-OH), 11.86 (s, 1H, Ar-OH), 7.89 (d, j=1.6H z, 1H, Ar-H), 7.85 (d, j=2.0H z, 1H, Ar-H), 7.81 (d, j=7.6H z, 1H, Ar-H), 7.72 (t, j=7.6H z, 1H, Ar-H), 7.35 (d, j=8.4H z, 1H, Ar-H), 5.32 (s, 2H, ArCH 2n +), 3.65-3.61 (m, 2H, +nC h 2c 8h 17), 3.43 (s, 6H, 2 × +nCH 3), 1.93-1.84 (m, 2H, +nCH 2c h 2c 7h 15), 1.44-1.24 (m, 12H ,-(C h 2) 6cH 3), 0.89 (t, j=6.0H z, j=7.2H z, 3H ,-(CH 2) 8c h 3); Ultimate analysis C 26h 34brNO 4h 2o calculated value: C 59.77, H 6.95, N 2.68; Experimental value: C 59.78, H 7.06, N 2.93.
N-[(4,5-dihydroxyl-9,10-anthraquinone-2-yl) methyl]-N, the N-dimethyl tetradecane-1-brometo de amonio ( aE-3): Yield, 90%; 1h NMR (400MHz, CDCl 3) δ: 11.93 (s, 1H, Ar-OH), 11.85 (s, 1H, Ar-OH), 7.88 (s, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.80 (d, j=7.2H z, 1H, Ar-H), 7.72 (t, j=8.4H z, 1H, Ar-H), 7.34 (d, j=8.4H z, 1H, Ar-H), 5.33 (s, 2H, ArCH 2n +), 3.43 (m, 8H, +nC h 2c 13h 27, 2 × +nC h 3), 1.93-1.84 (m, 2H, +nCH 2c h 2c 12h 25), 1.39-1.19 (m, 22H ,-(C h 2) 11cH 3), 0.90 (t, j=7.2H z, 3H ,-(CH 2) 13c h 3); Ultimate analysis C 31h 44brNO 41.2H 2o calculated value: C 62.45, H 7.84, N 2.35; Experimental value: C 62.47, H 7.71, N 2.25.
N-octyl group-N-[(4,5-dihydroxyl-9,10-anthraquinone-2-yl) methyl]-N-methylnonane-1-brometo de amonio ( aE-4): Yield, 78%; 1h NMR (400MHz, CDCl 3) δ: 11.86 (s, 1H, Ar-OH), 11.85 (s, 1H, Ar-OH), 7.90 (d, j=2.0H z, 1H, Ar-H), 7.81 (d, j=2.0H z, 1H, Ar-H), 7.80 (d, j=7.6H z, 1H, Ar-H), 7.71 (t, j=8.4H z, 1H, Ar-H), 7.33 (d, j=8.4H z, 1H, Ar-H), 5.31 (s, 2H, ArCH 2n +), 3.55-3.47 (m, 4H, 2 × +nC h 2-R), 3.37 (s, 3H, +nCH 3), 1.91-1.79 (m, 4H, 2 × +nCH 2c h 2r), 1.45-1.25 (m, 22H, (C h 2) 5cH 3+ (C h 2) 6cH 3), 0.90 (t, j=6.4H z, j=7.2H z, 6H, 2 × (CH 2) nc h 3); Ultimate analysis C 33h 48brNO 40.7H 2o calculated value: C 64.42, H 8.09; N 2.28; Experimental value: C 64.56, H 7.98, N 2.19.
N-decyl-N-[(4,5-dihydroxyl-9,10-anthraquinone-2-yl) methyl]-N-methyl decane-1-brometo de amonio ( aE-5): Yield, 85%; 1h NMR (400MHz, CDCl 3) δ: 11.90 (s, 1H, Ar-OH), 11.83 (s, 1H, Ar-OH), 7.90 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.78 (d, j=7.2H z, 1H, Ar-H), 7.70 (t, j=8.4H z, 1H, Ar-H), 7.32 (d, j=8.4H z, 1H, Ar-H), 5.31 (s, 2H, ArCH 2n +), 3.50 (t, j=8.4H z, 4H, 2 × +nC h 2c 9h 19), 3.36 (s, 3H, +nCH 3), 1.92-1.80 (m, 4H, 2 × +nCH 2c h 2c 8h 17), 1.48-1.19 (m, 28H, 2 ×-(C h 2) 7cH 3), 0.89 (t, j=6.8H z, 6H, 2 ×-(CH 2) 9c h 3); Ultimate analysis C 36h 54brNO 4h 2o calculated value: C 65.24, H 8.52; N 2.11; Experimental value: C 65.16, H 8.43, N 1.88.
Embodiment 3:5 kind rhabarberone quaternary ammonium salt is external tests Cytostatic to tumor cell
3 kinds of cancer cells density such as liver cancer HepG2, melanoma A375 and colorectal carcinoma SW620 cancer cells are adjusted into 1 × 10 5individual/ml, is inoculated in 96 orifice plates, and every hole 100 μ l, put 37 DEG C, 5% CO 2in incubator, cultivate 24 h; Remove old substratum, add tested medicine (5 kinds of rhabarberone quaternary ammonium salts) with substratum, tested medicament storage liquid to be diluted, set different concentration), every hole 100 μ l, separately establish blank group and rhabarberone group, establish 5 multiple holes for every group.After drug effect 24h, inhale and abandon pastille substratum, in every hole, add serum-free, without phenol red 1640 substratum 100 μ l, then add MTT solution 10 μ l, continue to hatch 4h, stop cultivation; Careful suction abandoned supernatant liquor in 96 orifice bores, and every hole adds 100 μ l DSMO, and vibration 10min is in and in microplate reader, measures each hole absorbance value (OD value), calculation of half inhibitory concentration IC50 value in 570nm wavelength.Result is as shown in table 1.
Figure 2014101762996100002DEST_PATH_IMAGE003
Application SPSS17.0 software carries out data processing the value-added half-inhibition concentration of analytical calculation cancer cells (IC50), the results are shown in Table 1.As shown in table 1 result, 5 kinds of two hydroxyl rhabarberone quaternary ammonium salts of synthesized all have increment restraining effect in various degree to different types of tumour cell; To same tumour cell, to compare with rhabarberone parent, 5 kinds of two hydroxyl rhabarberone quaternary ammonium salts of synthesized all increase to tumour cell increment restraining effect, but have larger difference.Wherein, compd A E-4 and AE-5 are the strongest to three kinds of tumour cells increment restraining effect, and compd A E-3 takes second place, and compd A E-1 and AE-2 to the increment restraining effect of three kinds of tumour cells without significant raising.The IC50 minimum of compd A E-5 to liver cancer HepG2 be 5.207 μ Μ, and rhabarberone is 40.407 μ Μ to the IC50 of this cell, is 8 times of left and right of compd A E-5.
Embodiment 4:
The two hydroxyl rhabarberone quaternary ammonium salts of glycolytic inhibitor 2-deoxy-D-glucose and 5 kinds and the separately Anticancer Activity in vitro of composition---the inhibited proliferation of mtt assay detection of drugs to liver cancer HepG2, melanoma A375 and colorectal carcinoma SW620 cancer cells
Figure 2014101762996100002DEST_PATH_IMAGE004
get one bottle of tumour cell in logarithmic phase state, after digestion, make 1 × 10 5the cell suspension of individual/ml.
Figure 2014101762996100002DEST_PATH_IMAGE005
cell suspension is moved into 96 orifice plates, and every hole 100 μ l, put 37 DEG C, 5% CO 2in incubator, cultivate 24 h.
glycolytic inhibitor concentration is set as to 10mM; 5 kinds of two hydroxyl rhabarberone quaternary ammonium salts are divided into 0.2 μ M, 1 μ M and 3 groups of 5 μ M (tested drug level is all less than IC50) according to concentration; Drug combination group is mixed and is divided into 3 groups according to glycolytic inhibitor (2-DG) and 5 kinds of two hydroxyl rhabarberone quaternary ammonium salts.
Figure 2014101762996100002DEST_PATH_IMAGE007
remove substratum, add tested composition according to concentration gradient, every hole 100 μ l, separately establish blank group and rhabarberone group (rhabarberone concentration is divided into 1 μ M, 5 μ M and 25 μ M).Act on after 24 h, remove pastille substratum, in every hole, add serum-free, without phenol red medium 100 μ l, then add MTT solution 10 μ l, continue to hatch 4 h.
Figure 2014101762996100002DEST_PATH_IMAGE008
discard supernatant liquor in plate, every hole adds 100 μ l DMSO, vibration 10min, use microplate reader to detect each hole absorbance value (OD value), and calculate the proliferation inhibition rate of cell: inhibiting rate (%)=(the average OD value of the average OD value of 1-medication group ÷ blank group) × 100%, carry out data processing with GraphPad Prism software, the results are shown in figure below.
From Fig. 1, Fig. 2 and Fig. 3, the two hydroxyl rhabarberone quaternary ammonium salts of glycolytic inhibitor 2-deoxy-D-glucose and 5 kinds are combined when antitumor, its antitumour activity uses and compares the enhancing all having in various degree separately with the medicine of two kinds of Isodoses, there is the feature of broad spectrum anticancer activity, and the antitumour activity of 5 kinds of two hydroxyl rhabarberone quaternary ammonium salts is all certain dosage-concentration dependent.The aloe rheum officinale that antitumour activity is weak and plain quaternary ammonium salt AE-1-AE-3 thereof and 2-deoxy-D-glucose are combined after use, to the proliferation inhibiting effect of three kinds of tumour cells without obvious drug synergism; And stronger rhabarberone quaternary ammonium salt AE-4-AE-5 and the 2-deoxy-D-glucose of antitumour activity combined after use, the inhibited proliferation of three kinds of tumour cells is all had to significant synergistic function.
Table 2, table 3 and table 4 are 2DG(10mM) respectively with compd A E(25 μ M), AE-4(5 μ M), AE-5(5 μ M) combine use on the inhibiting impact of the increment of three kinds of tumour cells.

Claims (6)

1. a rhabarberone quaternary ammonium salt, its structure is suc as formula shown in I;
Figure 2014101762996100001DEST_PATH_IMAGE001
Wherein, work as R 1for CH 3time, R 2for C 8h 17, C 9h 19or C 14h 29straight chained alkyl;
Work as R 1for C 8h 17straight chained alkyl time, R 2for C 9h 19straight chained alkyl;
Work as R 1for C 10h 21straight chained alkyl time, R 2for C 10h 21straight chained alkyl.
2. a preparation method for rhabarberone quaternary ammonium salt as claimed in claim 1, comprises the following steps:
Rhabarberone and phosphorus tribromide are at CCl 4in solvent, under room temperature, there is bromo-reaction and generate bromo rhabarberone;
Bromo rhabarberone and a series of tertiary amine generation nucleophilic substitution reaction generate corresponding rhabarberone quaternary ammonium salt.
3. the preparation method's of rhabarberone quaternary ammonium salt as claimed in claim 2 concrete steps are:
Synthesizing of bromo rhabarberone: get rhabarberone and be dissolved in CCl 4in, add the phosphorus tribromide of 10 times of quality; At 65 DEG C, after stirring reaction 48h, be cooled to room temperature, revolve steaming except desolventizing obtains orange red crude product, through silica gel column chromatography separating purification, obtain bromo rhabarberone; When described silica gel column chromatography separates, eluent used is methylene dichloride;
Rhabarberone quaternary ammonium salt synthetic: get the bromo rhabarberone that step 1) makes and be dissolved in CHCl 3, after heating for dissolving, add the ratio of 0.1ml tertiary amine to add tertiary amine with every 0.3mmol bromo rhabarberone at 50 DEG C; Reflux after lower stirring reaction 6h, be chilled to room temperature; Revolve to steam except after desolventizing and obtain garnet solid through silica gel column chromatography gradient elution, i.e. described rhabarberone quaternary ammonium salt; The order of described silica gel column chromatography gradient elution is: methylene dichloride → methylene dichloride: ethanol (v/v)=100:1 → methylene dichloride: ethanol (v/v)=50:1 → methylene dichloride: ethanol (v/v)=20:1.
4. rhabarberone quaternary ammonium salt as claimed in claim 1 is in the application of preparing on antitumor drug.
5. the composition of rhabarberone quaternary ammonium salt as claimed in claim 1 and 2-deoxy-D-glucose composition is in the application of preparing on antitumor drug; Wherein said rhabarberone quaternary ammonium salt is characterized in that with the composition of 2-deoxy-D-glucose composition rhabarberone quaternary ammonium salt mixes with 1-25:50000 amount of substance ratio with 2-deoxy-D-glucose.
6. the composition of rhabarberone quaternary ammonium salt as claimed in claim 5 and 2-deoxy-D-glucose composition, in the application of preparing on antitumor drug, is characterized in that described rhabarberone quaternary ammonium salt is suc as formula the compound shown in II or formula III
Figure 639538DEST_PATH_IMAGE002
Figure 2014101762996100001DEST_PATH_IMAGE003
。
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CN104356014A (en) * 2014-11-07 2015-02-18 福州大学 Rheum emodin single-chain biquaternary ammonium salt with antitumor activity and preparation method thereof
CN105399640A (en) * 2015-12-22 2016-03-16 福州大学 Aloe-emodin biquaternary ammonium salt with water solubility and anticancer activity and preparation thereof
CN111039806A (en) * 2019-12-27 2020-04-21 福州大学 Hydroxy benzoquinone biquaternary ammonium salt and preparation and application thereof

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104356014A (en) * 2014-11-07 2015-02-18 福州大学 Rheum emodin single-chain biquaternary ammonium salt with antitumor activity and preparation method thereof
CN104356014B (en) * 2014-11-07 2016-03-30 福州大学 Schuttgelb strand bi-quaternary ammonium salt with antitumour activity and preparation method thereof
CN105399640A (en) * 2015-12-22 2016-03-16 福州大学 Aloe-emodin biquaternary ammonium salt with water solubility and anticancer activity and preparation thereof
CN105399640B (en) * 2015-12-22 2017-06-06 福州大学 Aloe-emodin bi-quaternary ammonium salt and its preparation with water-soluble and active anticancer
CN111039806A (en) * 2019-12-27 2020-04-21 福州大学 Hydroxy benzoquinone biquaternary ammonium salt and preparation and application thereof
CN111039806B (en) * 2019-12-27 2021-04-27 福州大学 Hydroxy benzoquinone biquaternary ammonium salt and preparation and application thereof

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