CN105399640A - Aloe-emodin biquaternary ammonium salt with water solubility and anticancer activity and preparation thereof - Google Patents

Aloe-emodin biquaternary ammonium salt with water solubility and anticancer activity and preparation thereof Download PDF

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CN105399640A
CN105399640A CN201510966450.0A CN201510966450A CN105399640A CN 105399640 A CN105399640 A CN 105399640A CN 201510966450 A CN201510966450 A CN 201510966450A CN 105399640 A CN105399640 A CN 105399640A
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rhabarberone
ammonium salt
quaternary ammonium
ethanol
methylene dichloride
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CN105399640B (en
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王文峰
胡秀芳
苗军卫
谢世波
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Fuzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/24—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07C46/00—Preparation of quinones

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Abstract

The present invention belongs to the field of preparation of the quaternary ammonium salt anticancer drugs, and in particular to aloe-emodin biquaternary ammonium salt with water solubility and anticancer activity and a preparation method thereof. Aloe-emodin quaternary ammonium salt is first obtained, then aloe-emodin quaternary ammonium salt dibenzyl bromide is prepared, and finally aloe-emodin biquaternary ammonium salt is prepared. The preparation method has the advantages of simpleness, little side reaction and high product purity. The obtained biquaternary ammonium salt has better ability to inhibit leukemic cells while maintaining water solubility. The compound with water solubility and anti-cancer activity is expected to be developed into anti-cancer drugs, and has good application prospects.

Description

There is rhabarberone bi-quaternary ammonium salt and the preparation thereof of water-soluble and antitumour activity
Technical field
The invention belongs to the preparation field of quaternary ammonium salt cancer therapy drug, be specifically related to a kind of to there is rhabarberone bi-quaternary ammonium salt of water-soluble and antitumour activity and preparation method thereof.
Background technology
Quaternary ammonium salt cancer therapy drug has the mitochondrial function of target cancer cell, because the mitochondrial membrane potential of cancer cells is generally higher than normal cell, so positively charged quaternary ammonium salt cancer therapy drug is easily enriched in the mitochondrial matrix of cancer cells.Plastosome is the main cell device performing apoptosis program, but mitochondrial inner membrance is fat-soluble comparatively strong, and water-soluble strong medicine is difficult to play cancer cell specific induction of apoptosis function through mitochondrial inner membrane usually.Drug molecule is because enhance water-soluble and example that is that lose antitumour activity can be found everywhere.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, provide a kind of and there is rhabarberone bi-quaternary ammonium salt of water-soluble and antitumour activity and preparation method thereof.The present invention introduces the short carbon chain quaternary ammonium salt that has very strong water-soluble again in containing the molecule of long carbon chain quaternary ammonium salt, obtains bi-quaternary ammonium salt.Wherein short carbon chain quaternary ammonium salt plays hydrophile function, long carbon chain quaternary ammonium salt plays and carries the function of rhabarberone through mitochondrial inner membrane, make this bi-quaternary ammonium salt can keep water miscible while, cancer cells mitochondrial inner membrane can be passed through smoothly and enter matrix, thus keep the ability of good anticancer activity.
For achieving the above object, the present invention adopts following technical scheme:
Have a water-soluble and rhabarberone bi-quaternary ammonium salt that is antitumour activity, its molecular structural formula is:
。
A kind of method preparing the rhabarberone bi-quaternary ammonium salt as mentioned above with water-soluble and antitumour activity: first obtained rhabarberone mono-quaternaries: , the more two benzyl bromine of obtained rhabarberone quaternary ammonium salt: , finally obtained rhabarberone bi-quaternary ammonium salt.
Described have preparation method that is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity, and its concrete steps are:
1) synthesis of rhabarberone mono-quaternaries: by rhabarberone and PBr 3the obtained bromo rhabarberone of reaction: , bromo rhabarberone reacts obtained rhabarberone mono-quaternaries again with N-methyl-N-n-octyl n-octyl amine;
2) synthesis of the two benzyl bromine of rhabarberone quaternary ammonium salt: obtain the two benzyl bromine of rhabarberone quaternary ammonium salt by rhabarberone mono-quaternaries and to dibenzyl bromine reaction;
3) synthesis of rhabarberone bi-quaternary ammonium salt: two for rhabarberone quaternary ammonium salt benzyl bromine and trolamine are reacted obtained rhabarberone bi-quaternary ammonium salt.
More specifically, step 1) is: added by rhabarberone in there-necked flask, add CCl 4make it dissolve, then add excessive PBr 3, after back flow reaction 48h, revolve and steam except desolventizing, solid residue obtains bromo rhabarberone through purification by silica gel column chromatography (eluent is methylene dichloride/sherwood oil=2:1 (v/v)); With CHCl 3for solvent, after bromo rhabarberone and N-methyl-N-n-octyl n-octyl amine back flow reaction 6h, revolve and steam except desolventizing, solid residue obtains rhabarberone mono-quaternaries on silica gel column chromatography after gradient elution; Gradient elution order is: methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1.
More specifically, step 2) be specially: to dibenzyl bromine with adding in there-necked flask, acetone will be added and make it dissolve, then adding K 2cO 3, stirring and refluxing; By rhabarberone mono-quaternaries and K 2cO 3with acetone solution, be heated to after solution becomes red-purple, slowly drop in the reaction system of there-necked flask by constant pressure funnel, after reaction 2h, revolve and steam except desolventizing; Solid residue linear gradient elution method is crossed column purification and is obtained the two benzyl bromine of rhabarberone mono-quaternaries; Elution order is: methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1 → methylene dichloride/ethanol=20:1.
More specifically, step 3) is specially: add in there-necked flask by two for rhabarberone mono-quaternaries benzyl bromine, add chloroform and make it dissolve, add in there-necked flask after being dissolved by trolamine chloroform, have yellow floss to separate out, stopped reaction after reaction 3h; Be spin-dried for solvent, solid residue linear gradient elution method crosses column purification, obtains rhabarberone bi-quaternary ammonium salt; The order of gradient elution is methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1 → methylene dichloride/ethanol=20:1 → methylene dichloride/ethanol=10:1.
Described have water-soluble and rhabarberone bi-quaternary ammonium salt that is antitumour activity and have good inhibit activities to hemopathy cell, is expected to be developed to broad-spectrum anti-cancer drug, has larger application prospect.
beneficial effect of the present invention is:
Rhabarberone bi-quaternary ammonium salt synthesis step obtained by the present invention is relatively simple, has good restraining effect to leukemia cell; Because it has water-soluble, easily transport in vivo, injection injection can be made and use; And lipophilic cation drug toxicity is less, be developed as having a bright future of cancer therapy drug, there is very high using value.
Accompanying drawing explanation
Fig. 1 Schuttgelb bi-quaternary ammonium salt synthetic route chart;
Fig. 2 is the water-soluble result of spectrophotometry test rhabarberone bi-quaternary ammonium salt.
Embodiment
The present invention's the following example further illustrates the present invention, but protection scope of the present invention is not limited to the following example.
embodiment 1
Have a preparation method that is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity, concrete steps are:
(1) synthesis of bromo rhabarberone
1.38g rhabarberone (5.11mmol) is used 150mLCCl 4be dissolved in 250mL there-necked flask, add 5mLPBr 3(excessive) be return stirring 48h afterwards; Revolve after cooling and steam except desolventizing, solid residue obtains orange solids 1.23g through silica gel column chromatography wash-out, i.e. bromo rhabarberone, and eluent is methylene dichloride/sherwood oil=2:1 (v/v); Characterization of The Products data are as follows: productive rate is 72.1%; M.p.72-73 DEG C; 1hNMR (400MH z, 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, ArCH 2br); ESI-MSm/z331.1 (M-H) -; HRMS (ESI -): calcdforC 15h 8brNO 4[M-H] -=330.9611; Found, 330.9619.
(2) synthesis of rhabarberone mono-quaternaries
In 50mL round-bottomed flask, add 25mLCHCl 3with 100mg bromo rhabarberone (0.30mmol), add 0.1mLN-methyl-N-n-octyl n-octyl amine (amount of skipping over) again after reflux, back flow reaction 6h; Stopped reaction, revolve and steam except desolventizing, residue obtains dark red solid 118mg through gradient elution on silica gel column chromatography, i.e. rhabarberone mono-quaternaries.Elution order is: methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1.Characterization of The Products data are as follows: productive rate is 67.4%; M.p.80-81 DEG C; 1hNMR (400MH z, CDCl 3) δ: 11.94 (s, 1H, Ar-OH), 11.88 (s, 1H, Ar-OH), 7.94 (s, 1H, Ar-H), 7.83 (d, j=7.6H z, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.73 (t, j=7.6H z, 1H, Ar-H), 7.35 (d, j=8.4H z, 1H, Ar-H), 5.29 (s, 2H, ArCH 2n +), 3.58-3.45 (m, 4H, 2 × NC h 2c 7h 5-n), 3.37 (s, 3H, NCH 3), 1.93-1.76 (m, 4H, 2 × NCH 2c h 2c 6h 13-n), 1.48-1.25 (m, 20H, 2 × (C h 2) 5cH 3), 0.91 (t, j=7.2H z, 6H, 2 × CH 3); ESI-MSm/z508.57 (M-Br) +; Anal.CalcdforC 32h 46brNO 40.5H 2o:C64.31, H7.93, N2.34; Found:C64.54, H7.86, N2.65.
(3) synthesis of the two benzyl bromine of rhabarberone mono-quaternaries
450mg is dissolved in there-necked flask to benzyl dibromo (excessive) with 15mL acetone, adds 100mgK 2cO 3(0.73mmol) post-heating is to backflow; By 100mg rhabarberone mono-quaternaries (0.17mmol) and 100mgK 2cO 3use 10ml acetone solution, be heated to after solution becomes red-purple, drip in the there-necked flask be equipped with benzyl dibromo lentamente by constant pressure funnel, stopped reaction after stirring and refluxing 2h, reaction solution becomes yellow and has yellow solid to generate; Directly reaction solution is spin-dried for together with solid, crosses post process by linear gradient elution method, obtain yellow solid product 60mg, be i.e. the two benzyl bromine of rhabarberone mono-quaternaries; Elution order is: methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1 → methylene dichloride/ethanol=20:1; Characterization of The Products data are as follows: productive rate is 36.2%; 1hNMR (400MH z, CDCl 3) δ: 8.31 (s, 1H, Ar-H), 7.77-7.71 (m, 4H, Ar-H), 7.59-7.54 (m, 3H, Ar-H), 7.45-7.43 (m, 2H, Ar-H), 7.38-7.36 (m, 2H, Ar-H), 7.24 (d j=8.4H z, 1H, Ar-H), 5.47 (s, 2H, ArCH 2n +), 5.25 (s, 2H, ArCH 2oAr), 5.20 (s, 2H, ArCH 2oAr), 4.58 (s, 2H, ArCH 2br), 4.54 (s, 2H, ArCH 2br), 3.38-3.30 (m, 4H, 2 × NC h 2c 7h 15-n), 2.99 (s, 3H, NCH 3), 1.83-1.72 (m, 4H, 2 × NCH 2c h 2c 6h 13-n), 1.38-1.28 (m, 20H, 2 × (C h 2) 5cH 3), 0.89 (t, j=7.2H z, 6H, 2 × CH 3); ESI-MSm/z874.43 (M-Br) +; HRMS (ESI +): calcdforC 48h 60br 2nO 4[M-Br] +=874.2869; Found, 874.2848.
(4) synthesis of rhabarberone bi-quaternary ammonium salt
Two for 100mg rhabarberone mono-quaternaries benzyl bromine (0.11mmol) is dissolved in there-necked flask with 15ml chloroform, add in there-necked flask after 70mg trolamine (0.47mmol) being dissolved with 1ml chloroform under stirring and refluxing, yellow floss is had to separate out after reaction 3h, stopped reaction; Revolve and steam except desolventizing, residue linear gradient elution method is crossed post and is separated, elution order is methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1 → methylene dichloride/ethanol=20:1 → methylene dichloride/ethanol=10:1, obtain yellow solid product 51mg, i.e. rhabarberone bi-quaternary ammonium salt.Characterization of The Products data are as follows: productive rate 50.1%; 1hNMR (400MH z, DMSO) and δ: 12.85 (s, 1H, OH), 8.04-7.59 (m, 9H, Ar-H), 5.51-5.41 (m, 6H, ArCH 2n+ArCH 2n+ArCH 2o), 4.84 (m, 6H, 3 × NCH 2c h 2oH), 3.97 (m, 6H, 3 × NCH 2cH 2oH), 3.48 (s, 3H, NCH 3), 3.22 (m, 4H, 2 × NC h 2c 7h 15), 1.98 (s, 3H, 3 × CH 2cH 2o h), 1.79-1.71 (m, 4H, 2 × NCH 2c h 2c 6h 13), 1.32-1.24 (m, 20H, 2 × (C h 2) 5cH 3), 0.86 (t, j=6.8H z, 6H, 2 × CH 3); ESI-MSm/z380.56 (M-2Br) 2+/ 2; HRMS (ESI +): calcdforC 46h 68n 2o 7[M-2Br] 2+/ 2=380.2514; Found, 380.2517.
Although trolamine is excessive in this synthesis, but experimental result shows that product is not three quaternary ammonium salts but bi-quaternary ammonium salt, and taken off one to dibenzyl bromine group, reason is in anthraquinone molecular 1, the locus of 8 is too near, is difficult to the quaternary ammonium salt group that accommodation two is larger.
application Example 1
(1) rhabarberone bi-quaternary ammonium salt is to leukemia cell growth inhibition assay
Using rhabarberone bi-quaternary ammonium salt as test medicine, with substratum by drug dilution; The density of leukemia (HL60 and K562) cell is adjusted to 1 × 10 5individual/mL, is inoculated in 96 orifice plates, and every hole 100 μ L, is placed in 37 DEG C, 5%CO 224h is cultivated in incubator; Remove old substratum, add test medicine, every hole 100 μ L, separately establishes blank group, and often group establishes 3 multiple holes.After drug effect 48h, 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 cultivating; Supernatant liquor in 96 orifice bores is abandoned in careful suction, and every hole adds 100 μ LDSMO, and vibration 10min, microplate reader measures each hole absorbance value (OD value) in 570nm wavelength place, calculation of half inhibitory concentration IC 50value.Result is as shown in table 1.
The various compound of table 1 is to the inhibit activities (IC of leukemia cell 50, μm ol/L)
Experimental result shows, rhabarberone bi-quaternary ammonium salt has all showed certain inhibit activities to two kinds of leukemia cells (HL60 and K562), and its antitumour activity about improves 1-2 doubly than water-fast primer rhabarberone.
(2) the water-soluble test of rhabarberone bi-quaternary ammonium salt and mono-quaternaries
The rhabarberone bi-quaternary ammonium salt taking 2.1mg is made into the aqueous solution of 8mL, and concentration is 2.858 × 10 -4m.Measure 50 μ L, 75 μ L respectively, the aqueous solution that 100 μ L, 125 μ L, 150 μ L, 175 μ L, the above-mentioned solution dilution of 200 μ L become 3mL, concentration of aqueous solution is respectively 4.764 × 10 -6m, 7.146 × 10 -6m, 9.528 × 10 -6m, 1.191 × 10 -5m, 1.429 × 10 -5m, 1.667 × 10 -5m, 1.9056 × 10 -5m.By ultraviolet test, they are respectively 0.1685,0.2085,0.2484,0.3022,0.3268,0.3758,0.4318 at the ultraviolet absorptivity at 260nm place.Absorbancy according to the known solution of langbobier law is directly proportional to concentration, therefore obtains straight-line equation y=0.07977+18035.56435x according to above data fitting, R 2=0.99346.
The preparation of saturated solution, gets relatively large rhabarberone bi-quaternary ammonium salt, and by a small amount of water dissolution, make it as often as possible dissolve in rear guarantee solution to also have solid by ultrasonic, after leaving standstill an evening, the supernatant liquor that do not disappear of solid is saturated solution.Recording its uv-absorbing at 260nm place after the saturated solution getting 20 μ L is diluted to 3mL is 0.2457, bringing the saturated solution concentration that above-mentioned gained equation can obtain rhabarberone bi-quaternary ammonium salt into is 0.00138M (1.27mg/mL), and this concentration is much larger than IC 50, show that this medicine can play drug effect in aqueous.Test result as shown in Figure 2.
In contrast, also test rhabarberone mono-quaternaries simultaneously 3water-soluble.Rhabarberone mono-quaternaries 3do not have water-soluble, be difficult to prepare the corresponding aqueous solution.Get 100mL redistilled water, add 1mg rhabarberone mono-quaternaries 3, sonic oscillation is placed after 30 minutes and is spent the night.Yellow solid rhabarberone mono-quaternaries after second day 3still high-visible, show rhabarberone mono-quaternaries 3be water-solublely less than 1mg/100mL, show that the introducing of second short carbon chain quaternary ammonium salt can make the water-soluble raising more than 100 times of rhabarberone quaternary ammonium salt.
The foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.

Claims (10)

1. there is a water-soluble and rhabarberone bi-quaternary ammonium salt that is antitumour activity, it is characterized in that: its molecular structural formula is:
。
2. prepare a method for the rhabarberone bi-quaternary ammonium salt as claimed in claim 1 with water-soluble and antitumour activity, it is characterized in that: first obtained rhabarberone mono-quaternaries: , the more two benzyl bromine of obtained rhabarberone quaternary ammonium salt: , finally obtained rhabarberone bi-quaternary ammonium salt.
3. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 2, it is characterized in that: concrete steps are:
1) synthesis of rhabarberone mono-quaternaries: by rhabarberone and PBr 3the obtained bromo rhabarberone of reaction: , bromo rhabarberone reacts obtained rhabarberone mono-quaternaries again with N-methyl-N-n-octyl n-octyl amine;
2) synthesis of the two benzyl bromine of rhabarberone quaternary ammonium salt: obtain the two benzyl bromine of rhabarberone quaternary ammonium salt by rhabarberone mono-quaternaries and to dibenzyl bromine reaction;
3) synthesis of rhabarberone bi-quaternary ammonium salt: two for rhabarberone quaternary ammonium salt benzyl bromine and trolamine are reacted obtained rhabarberone bi-quaternary ammonium salt.
4. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 3, it is characterized in that: step 1) is specially: rhabarberone is added in there-necked flask, add CCl 4make it dissolve, then add excessive PBr 3, after back flow reaction 48h, revolve and steam except desolventizing, solid residue obtains bromo rhabarberone through purification by silica gel column chromatography; With CHCl 3for solvent, after bromo rhabarberone and N-methyl-N-n-octyl n-octyl amine back flow reaction 6h, revolve and steam except desolventizing, solid residue obtains rhabarberone mono-quaternaries on silica gel column chromatography after gradient elution.
5. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 4, it is characterized in that: gradient elution order is: methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1.
6. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 3, it is characterized in that: step 2) be specially: to dibenzyl bromine with adding in there-necked flask, acetone will be added and make it dissolve, then adding K 2cO 3, stirring and refluxing; By rhabarberone mono-quaternaries and K 2cO 3with acetone solution, be heated to after solution becomes red-purple, slowly drop in the reaction system of there-necked flask by constant pressure funnel, after reaction 2h, revolve and steam except desolventizing; Solid residue linear gradient elution method is crossed column purification and is obtained the two benzyl bromine of rhabarberone mono-quaternaries.
7. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 6, it is characterized in that: elution order is: methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1 → methylene dichloride/ethanol=20:1.
8. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 3, it is characterized in that: step 3) is specially: two for rhabarberone mono-quaternaries benzyl bromine is added in there-necked flask, adding chloroform makes it dissolve, add in there-necked flask after trolamine chloroform is dissolved, yellow floss is had to separate out after reaction 3h, stopped reaction; Be spin-dried for solvent, solid residue linear gradient elution method crosses column purification, obtains rhabarberone bi-quaternary ammonium salt.
9. there is water-soluble and the rhabarberone bi-quaternary ammonium salt of antitumour activity preparation method according to claim 8, it is characterized in that: the order of gradient elution is methylene dichloride/ethanol=50:1 → methylene dichloride/ethanol=40:1 → methylene dichloride/ethanol=35:1 → methylene dichloride/ethanol=30:1 → methylene dichloride/ethanol=25:1 → methylene dichloride/ethanol=20:1 → methylene dichloride/ethanol=10:1.
10. bi-quaternary ammonium salt as claimed in claim 1 is preparing the application in anticancer medicine, and described cancer cells comprises HL-60 cells and K562.
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Cited By (3)

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CN109970570A (en) * 2019-03-16 2019-07-05 福建医科大学附属协和医院 One kind, which has, inhibits the active preparation method to dibenzyl bromine bi-quaternary ammonium salt of leukaemia cell
CN110981909A (en) * 2019-12-27 2020-04-10 福州大学 Copper-containing aloe-emodin quaternary phosphonium salt and synthetic method and application 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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