CN105859777B - Suppress aloe-emodin quaternary alkylphosphonium salt of group and preparation method thereof containing glycolysis - Google Patents
Suppress aloe-emodin quaternary alkylphosphonium salt of group and preparation method thereof containing glycolysis Download PDFInfo
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- CN105859777B CN105859777B CN201610303228.7A CN201610303228A CN105859777B CN 105859777 B CN105859777 B CN 105859777B CN 201610303228 A CN201610303228 A CN 201610303228A CN 105859777 B CN105859777 B CN 105859777B
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- YDQWDHRMZQUTBA-UHFFFAOYSA-N Aloe emodin Chemical compound C1=CC=C2C(=O)C3=CC(CO)=CC(O)=C3C(=O)C2=C1O YDQWDHRMZQUTBA-UHFFFAOYSA-N 0.000 title claims abstract description 124
- 150000003839 salts Chemical class 0.000 title claims abstract description 32
- 230000034659 glycolysis Effects 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloro-acetic acid Natural products OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims abstract description 44
- 229960005215 dichloroacetic acid Drugs 0.000 claims abstract description 33
- -1 salt dichloroacetic acid ester Chemical class 0.000 claims abstract description 33
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 201000011510 cancer Diseases 0.000 claims abstract description 16
- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 claims abstract description 5
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 238000010828 elution Methods 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 229910020667 PBr3 Inorganic materials 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 5
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 230000001093 anti-cancer Effects 0.000 description 8
- 230000002414 glycolytic effect Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 241001116389 Aloe Species 0.000 description 4
- 235000011399 aloe vera Nutrition 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 4
- 210000005265 lung cell Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- KKAJSJJFBSOMGS-UHFFFAOYSA-N 3,6-diamino-10-methylacridinium chloride Chemical compound [Cl-].C1=C(N)C=C2[N+](C)=C(C=C(N)C=C3)C3=CC2=C1 KKAJSJJFBSOMGS-UHFFFAOYSA-N 0.000 description 2
- 239000010282 Emodin Substances 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 101100109871 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aro-8 gene Proteins 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 240000004980 Rheum officinale Species 0.000 description 2
- 235000008081 Rheum officinale Nutrition 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- RHMXXJGYXNZAPX-UHFFFAOYSA-N emodin Chemical compound C1=C(O)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O RHMXXJGYXNZAPX-UHFFFAOYSA-N 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000007761 synergistic anti-cancer Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000006682 Warburg effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000010304 tumor cell viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5456—Arylalkanephosphonium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester for suppressing group containing glycolysis and preparation method thereof;Aloe-emodin first reacts to obtain bromo aloe-emodin with phosphorus tribromide, and octyl group reacts generation aloe-emodin quaternary alkylphosphonium salt with tri-n-octyl phosphine again, and esterification finally, which occurs, with dichloroacetyl chloride obtains aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester:.The cancer cell in vitro of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester suppresses experiment and shows there is inhibitory activity to a variety of cancer cells, has larger application prospect in terms of antineoplastic is prepared.
Description
Technical field
The invention belongs to the preparation field of cancer therapy drug, and in particular to a kind of aloe rheum officinale for suppressing group containing glycolysis
Su quaternary alkylphosphonium salt dichloroacetic acid esters and preparation method thereof.
Background technology
Cancer cell is with " Warburg effect ", i.e. cancer cell still tend to sugar under conditions of oxygen supply is sufficient
Glycolysis, thus by suppress cancer cell glycolysis suppress tumor cell viability be current pharmaceutical chemistry circle generally acknowledge it is extremely important
Anti-Cancer Drug Design thinking.Physician generally studies medicine by the way of chemotherapeutic and glycolytic inhibitor drug combination at present
Anticancer mechanism.
Aloe-emodin(AE)It for the antibiotic effective ingredient of rheum officinale, can be extracted from aloe, there is antitumor activity, antibacterial
Activity and immunosuppressive action isoreactivity.But the activity of aloe-emodin in itself is weaker, and therefore, aloe-emodin is tied
Structure modification improves its activity, has great application prospect.This seminar earlier studies have shown that, aloe-emodin quaternary alkylphosphonium salt(AP)
With good active anticancer.It can be pressed down with glycolytic inhibitor 2-DG combinations by reducing the mitochondrial membrane potential of cancer cell
Cancer cell mitochondrial function processed, strengthen the active anticancer of rheum emodin quaternary alkylphosphonium salt.But found during drug combination, 2-DG
Dosage it is bigger than normal, be also easy to produce toxic side effect;Drug combination is difficult to ensure that medicine while reaches cancer location simultaneously, it is also difficult to
Ensure that medicine can produce Synergistic anti-cancer effect with suitable concentration.
Dichloroacetic acid(DCA)It is famous glycolytic inhibitor, pyruvic dehydrogenase kinase activity can be activated, make pyruvic acid
It is converted into acetylcoenzyme and enters aerobic metabolism approach, so as to suppresses anaerobic metabolism approach (i.e. glycolytic pathway).The present invention will be big
Flavine quaternary alkylphosphonium salt is coupled with dichloroacetic acid by esterification, forms aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester(AP- DCA).On the one hand strengthen the active anticancer of aloe-emodin quaternary alkylphosphonium salt;On the other hand the dosage of glycolytic inhibitor is made
Reduce, reduce toxic side effect.
The content of the invention
It is an object of the invention to provide a kind of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid for suppressing group containing glycolysis
Ester and preparation method thereof.It is used as lipophilic cation targetted mitochondria by introducing long carbochain quaternary alkylphosphonium salt on aloe-emodin,
A dichloroacetic acid ester is re-introduced into, to produce dichloroacetic acid after hydrolyzing as glycolytic inhibitor, so as to greatly improve aloe
The active anticancer of rheum emodin.
To achieve the above object, the present invention adopts the following technical scheme that:
A kind of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester for suppressing group containing glycolysis, its structural formula are as follows:
。
The preparation method of described aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester, is concretely comprised the following steps:
1)The synthesis of bromo aloe-emodin:3.70 mmol aloe-emodins are dissolved in 100 mLCCl4In, add at room temperature
Enter 10.8 mmol PBr3, 65 DEG C are warming up to, stirred at reflux reacts 24 h;Revolving removes solvent, and residue is through silica gel column layer
Analysis purifying, obtains bromo aloe-emodin;
2)The synthesis of aloe-emodin quaternary alkylphosphonium salt:1.00 mmol bromo aloe-emodins are dissolved in 15 mL acetone, room temperature
1.12 mmol tri-n-octyl phosphines of lower addition, are warming up to 50 DEG C, react 6 h, and solvent is spin-dried for by reaction after terminating, and uses dichloromethane
Wet method loading, aloe-emodin quaternary alkylphosphonium salt is obtained through silica gel column chromatography gradient elution;
3)The synthesis of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester:By 0.14 mmol aloe-emodins quaternary alkylphosphonium salt and 1.09
Mmol potassium carbonate is dissolved in there-necked flask with 20 mL acetone, is warming up to 37 DEG C of 0.5 h of stirring, is added 1.05 mmol dichloroacetyls
Chlorine, the h of stirring reaction 3;Stop removing solvent with Rotary Evaporators after reacting, with dichloromethane wet method loading, gradient elution is carried out
Column chromatography purifies, and obtains aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester.
Step 1)Middle silica gel column chromatography purifying eluant, eluent used is CH2Cl2。
Step 2)The order of middle gradient elution is:V(CH2Cl2):V(C2H5OH)= 40:1→30:1→25:1→20:1。
Step 3)The eluting order of middle gradient elution is:V(CH2Cl2):V(C2H5OH)=40:1→30:1→25:1→20:
1。
A kind of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester for suppressing group containing glycolysis as described above is controlled in preparation
Treat the application in cancer drug;Described cancer includes lung cancer and liver cancer.
The remarkable advantage of the present invention is:
Glycolytic inhibitor is introduced aloe-emodin quaternary alkylphosphonium salt by the present invention by the method for chemical bonding, utilizes cancer cell
The high feature of hydrolytic enzyme activities, it is ensured that chemotherapeutic aloe-emodin quaternary alkylphosphonium salt can arrive simultaneously with glycolytic inhibitor dichloroacetic acid
Up to cancer cell position and produce Synergistic anti-cancer effect;Active anticancer test shows that the medicine has preferable active anticancer, and it is to more
Kind cancer cell has inhibited proliferation, and it is broad-spectrum anti-cancer drug to be expected to exploitation.
Brief description of the drawings
The synthetic route of Fig. 1 aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid esters;
Inhibitory activity (the IC to lung cell A549 such as Fig. 2 dichloroacetic acid and aloe-emodin and its derivative50, μ
M);
Inhibitory activity (the IC to hepatocellular carcinoma H22 such as Fig. 3 dichloroacetic acid and aloe-emodin and its derivative50, μ
M)。
Embodiment
In order that content of the present invention easily facilitates understanding, with reference to embodiment to of the present invention
Technical scheme is described further, but the present invention is not limited only to this.
Embodiment 1
A kind of preparation method of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester, is concretely comprised the following steps:
1)The synthesis of bromo aloe-emodin
The mmol of aloe-emodin 3.70 is dissolved in 100 mLCCl4In, 10.8 mmol PBr are added at room temperature3, it is warming up to
65 DEG C, stirred at reflux reacts 24 h;After revolving removes solvent, residue purifies through silica gel column chromatography(Eluant, eluent CH2Cl2)
Obtain orange/yellow solid bromo aloe-emodin;Characterization of The Products data are as follows:
Yield 72.1%;m.p. 72-73℃;Rf(CH2Cl2)=0.74; 1H NMR (400 MHz, CDCl3) δ:
12.09 (s, 1H, ArOH), 12.06 (s, 1H, ArOH), 7.89 (d, J=5.2 Hz, 1H, ArH), 7.88
(s, 1H, ArH), 7.73 (t, J=7.6 Hz, 1H, ArH), 7.36 (s, 1H, ArH), 7.35 (d, J=6.4
Hz, 1H, ArH), 4.51 (s, 2H, ArCH2Br); ESI-MS m/z 331.1 (M-H)-; HRMS m/z
330.9619 theoretical value (M-H)- 330.9611.
2)The synthesis of aloe-emodin quaternary alkylphosphonium salt
By step 1)The mmol of bromo aloe-emodin 1.00 of synthesis is dissolved in 15 mL acetone, adds 1.12 at room temperature
Mmol tri-n-octyl phosphines, 50 DEG C are warming up to, react 6 h, solvent is spin-dried for by reaction after terminating, with dichloromethane wet method loading, warp
Silica gel column chromatography gradient elution obtains aloe-emodin quaternary alkylphosphonium salt;Characterize data is as follows:
Yield 51.2%;m.p. 54-56℃;Rf(CH2Cl2:C2H5OH=20:1) = 0.21;1H NMR (400 MHz,
CDCl3) δ: 11.75 (br, 2H, OH), 7.63 (t, J=7.6Hz, 1H, Ar-H), 7.58 (m, 1H, Ar-
H), 7.57 (m, 2H, Ar-H), 7.17 (m, 1H, Ar-H), 4.67 [s, 1H, ArCH 2P+(C8H17)3], 4.63
[s, 1H, ArCH 2P+(C8H17)3], 2.38 (m, 6H, P+(CH 2C7H15)3), 1.49-1.21 [m, 36H, 3×CH2
(C6 H 12CH3)3], 0.81 (t, 9H, CH3); 13C NMR (400 MHz, CDCl3) δ: 192.1, 180.4,
162.7, 162.5, 140.5, 137.4, 133.8, 132.9, 126.0, 124.9, 120.7, 120.1, 115.3,
115.1, 31.7, 31.6, 31.2, 31.1, 30.8, 30.7, 29.0, 28.9, 28.8, 22.6, 22.5,
21.9, 21.6, 19.5, 19.0, 14.0; LC-MS( ESI) m/z: 623.67(M-Br)+.
3)The synthesis of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester
By step 2)The mmol of aloe-emodin quaternary alkylphosphonium salt 0.14 of synthesis and 1.09 mmol potassium carbonate are molten with 20 mL acetone
In there-necked flask, 37 DEG C of 0.5 h of stirring are warming up to, add 1.05 mmol dichloroacetyl chlorides, the h of stirring reaction 3;Stop reaction
Solvent is removed with Rotary Evaporators afterwards, with dichloromethane wet method loading, gradient elution carries out column chromatography purification, obtains rufous and glue
Thick solid, i.e. aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester;Characterization of The Products data are:
Yield 36.6%;m.p. 46-48℃;Rf(CH2Cl2:C2H5OH=20:1) = 0.20; 1H NMR (400 MHz,
CDCl3) δ: 7.70 (d, J=7.6Hz, 1H, Ar-H), 7.60 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-
H), 7.37 (s, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 6.06 (s, 1H, COCHCl2), 4.32 [s,
1H, ArCH 2P+(C8H17)3], 4.30 [s, 1H, ArCH 2P+(C8H17)3], 2.24 [m, 6H, ArCH2 P+
(CH 2C7H15)3] , 1.60-1.50 [m, 6H, 3×P+(CH2CH 2C6H13)3], 1.46-1.24 [m, 30H, 3×P+
(C2H4C5 H 10CH3)3], 0.86(t, J=7.2Hz, 9H, CH3); 13C NMR (400 MHz, CDCl3) δ: 192.3,
181.1, 167.4, 162.9, 162.7, 138.7, 137.7, 134.4, 133.1, 125.5, 125.3, 120.51,
120.47, 115.7, 115.6, 65.4, 37.1, 31.9, 31.7, 31.6, 31.0, 30.8, 30.6, 30.0,
29.7, 29.4, 29.0, 28.9, 28.8, 22.7, 22.6, 21.6, 21.3, 19.1, 18.6,14.1; LC-MS
(ESI) m/z: (M-Br)+ 733.67.
Application Example 1
Aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester is to lung cell A549 proliferation inhibition test
By the A549 cells of logarithmic phase, after being digested with pancreatin, cell count, 5 × 10 are made into4-1×105/ ml cell is dense
Degree, by obtained cell suspension, 96 orifice plates are inoculated into per the μ L of hole 100, are put in 37 DEG C, 5% CO224 h are cultivated in incubator, are abandoned
Fall old culture medium, add the various concentrations aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester medicine prepared, act on 24 h respectively
Afterwards, inhale and abandon pastille culture medium, the 0.5 mg/ml MTT μ L of solution 100 are added in every hole, continue after being incubated 4 h, terminate training
Support;Careful inhale abandons supernatant in 96 orifice bores, and 100 μ L DSMO are added per hole, vibrates 10min, is in enzyme in 570 nm wavelength
Each hole absorbance value is determined on mark instrument(OD values), calculate cell survival rate(%)=(Medication group mean OD value/blank control group is average
OD values)×100%.Data processing and calculation of half inhibitory concentration IC are carried out with GraphPad Prism softwares50Value, as a result as schemed
Shown in 2.
Application Example 2
Aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester is to hepatocellular carcinoma H22 proliferation inhibition test
By the HepG2 cells of logarithmic phase, after being digested with pancreatin, cell count, 5 × 10 are made into4-1×105/ ml cell is dense
Degree, by obtained cell suspension, 96 orifice plates are inoculated into per the μ L of hole 100, are put in 37 DEG C, 5% CO224 h are cultivated in incubator, are abandoned
Fall old culture medium, add the various concentrations aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester medicine prepared, act on 24 h respectively
Afterwards, inhale and abandon pastille culture medium, the 0.5 mg/ml MTT μ L of solution 100 are added in every hole, continue after being incubated 4 h, terminate
Culture;Careful inhale abandons supernatant in 96 orifice bores, and 100 μ L DSMO are added per hole, vibrates 10 min, is in 570 nm wavelength
Each hole absorbance value is determined on ELIASA(OD values), calculate cell survival rate(%)=(Medication group mean OD value/blank control group is put down
Equal OD values)×100%.Data processing and calculation of half inhibitory concentration IC are carried out with GraphPad Prism softwares50Value.As a result such as
Shown in Fig. 3.
The dichloroacetic acid of table 1 and aloe-emodin and its derivative etc. are to lung cell A549 and hepatocellular carcinoma H22
IC50Value(μM).
It is above-mentioned test result indicates that, aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester is because can to produce aloe big after hydrolysis
Flavine quaternary alkylphosphonium salt and glycolytic inhibitor dichloroacetic acid, the mitochondria energy supply and glycolysis energy supply of cancer cell can be destroyed simultaneously,
Good anticancer is shown to kinds of tumor cells such as HL-60 cells, lung cell A549 and hepatocellular carcinoma H22 etc.
Activity.This result shows that it is good Anti-Cancer Drug Design that dichloroacetic acid and aloe-emodin quaternary alkylphosphonium salt are carried out into covalent bond
Thinking.
The foregoing is only presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, it should all belong to the covering scope of the present invention.
Claims (8)
- A kind of 1. aloe-emodin quaternary alkylphosphonium salt for suppressing group containing glycolysis, it is characterised in that:Its structural formula is as follows:。
- 2. a kind of preparation method for the aloe-emodin quaternary alkylphosphonium salt for suppressing group containing glycolysis as claimed in claim 1, its It is characterised by:Aloe-emodin and excessive phosphorus tribromide are reacted, obtain bromo aloe-emodin;Bromo aloe-emodin again with Tri-n-octyl phosphine carries out nucleophilic substitution and obtains aloe-emodin quaternary alkylphosphonium salt;Aloe-emodin quaternary alkylphosphonium salt is sent out with dichloroacetyl chloride Raw esterification obtains aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester.
- 3. the preparation method of the aloe-emodin quaternary alkylphosphonium salt according to claim 2 for suppressing group containing glycolysis, it is special Sign is:Specifically include following steps:1)The synthesis of bromo aloe-emodin:3.70 mmol aloe-emodins are dissolved in 100 mLCCl4In, add at room temperature 10.8 mmol PBr3, 65 DEG C are warming up to, stirred at reflux reacts 24 h;Revolving removes solvent, and residue is through silica gel column chromatography Purifying, obtains bromo aloe-emodin;2)The synthesis of aloe-emodin quaternary alkylphosphonium salt:1.00 mmol bromo aloe-emodins are dissolved in 15 mL acetone, added at room temperature Enter 1.12 mmol tri-n-octyl phosphines, be warming up to 50 DEG C, react 6 h, solvent is spin-dried for by reaction after terminating, with dichloromethane wet method Loading, aloe-emodin quaternary alkylphosphonium salt is obtained through silica gel column chromatography gradient elution;3)The synthesis of aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester:By 0.14 mmol aloe-emodins quaternary alkylphosphonium salt and 1.09 mmol Potassium carbonate is dissolved in there-necked flask with 20 mL acetone, is warming up to 37 DEG C of 0.5 h of stirring, is added 1.05 mmol dichloroacetyl chlorides, stir Mix 3 h of reaction;Stop removing solvent with Rotary Evaporators after reacting, with dichloromethane wet method loading, gradient elution carries out post layer Analysis purification, obtains aloe-emodin quaternary alkylphosphonium salt dichloroacetic acid ester.
- 4. the preparation method of the aloe-emodin quaternary alkylphosphonium salt according to claim 3 for suppressing group containing glycolysis, it is special Sign is:Step 1)Middle silica gel column chromatography purifying eluant, eluent used is CH2Cl2。
- 5. the preparation method of the aloe-emodin quaternary alkylphosphonium salt according to claim 3 for suppressing group containing glycolysis, it is special Sign is:Step 2)The order of middle gradient elution is:V(CH2Cl2):V(C2H5OH)= 40:1→30:1→25:1→20:1。
- 6. the preparation method of the aloe-emodin quaternary alkylphosphonium salt according to claim 3 for suppressing group containing glycolysis, it is special Sign is:Step 3)The eluting order of middle gradient elution is:V(CH2Cl2):V(C2H5OH)=40:1→30:1→25:1→20: 1。
- 7. a kind of aloe-emodin quaternary alkylphosphonium salt for suppressing group containing glycolysis as claimed in claim 1 is preparing treating cancer Application in medicine.
- 8. the aloe-emodin quaternary alkylphosphonium salt according to claim 7 for suppressing group containing glycolysis is preparing treating cancer medicine Application in thing, it is characterised in that:Described cancer includes lung cancer and liver cancer.
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CN103936788A (en) * | 2014-02-22 | 2014-07-23 | 福州大学 | Emodin quaternary phosphonium salt with antitumor activity, and preparation method thereof |
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CN103936788A (en) * | 2014-02-22 | 2014-07-23 | 福州大学 | Emodin quaternary phosphonium salt with antitumor activity, and preparation method thereof |
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