CN110981909B - Copper-containing aloe-emodin quaternary phosphonium salt and synthetic method and application thereof - Google Patents
Copper-containing aloe-emodin quaternary phosphonium salt and synthetic method and application thereof Download PDFInfo
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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 87
- 150000004714 phosphonium salts Chemical group 0.000 title claims abstract description 40
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229910052802 copper Inorganic materials 0.000 title claims abstract description 21
- 239000010949 copper Substances 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 14
- 230000000719 anti-leukaemic effect Effects 0.000 claims abstract description 12
- 208000032839 leukemia Diseases 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 8
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 239000010282 Emodin Substances 0.000 claims description 5
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- RMZAYIKUYWXQPB-UHFFFAOYSA-N trioctylphosphane Chemical compound CCCCCCCCP(CCCCCCCC)CCCCCCCC RMZAYIKUYWXQPB-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 5
- 229910001431 copper ion Inorganic materials 0.000 description 5
- 102000003915 DNA Topoisomerases Human genes 0.000 description 4
- 108090000323 DNA Topoisomerases Proteins 0.000 description 4
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 4
- 150000004056 anthraquinones Chemical class 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- QBPFLULOKWLNNW-UHFFFAOYSA-N chrysazin Chemical compound O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O QBPFLULOKWLNNW-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000003470 mitochondria Anatomy 0.000 description 3
- 210000001700 mitochondrial membrane Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003254 radicals Chemical group 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 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
- MWCQWHQZNMTRIF-UHFFFAOYSA-N [Cu].OC1=CC=CC=2C(C3=CC=CC(=C3C(C12)=O)O)=O Chemical compound [Cu].OC1=CC=CC=2C(C3=CC=CC(=C3C(C12)=O)O)=O MWCQWHQZNMTRIF-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229960001577 dantron Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035806 respiratory chain Effects 0.000 description 2
- RZVHIXYEVGDQDX-UHFFFAOYSA-N 9,10-anthraquinone Chemical group C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 RZVHIXYEVGDQDX-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- -1 ion free radical Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses copper-containing aloe-emodin quaternary phosphonium salt with leukemia resisting activity and a preparation method and application thereof. In vitro cancer cell inhibition experiments show that the compound can effectively inhibit the proliferation of leukemia cells and is expected to be developed into anti-leukemia drugs.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of copper-containing aloe-emodin quaternary phosphonium salt with anti-leukemia activity.
Background
The potential of the cancer cell mitochondrial membrane is obviously higher than that of a normal cell membrane, so that the lipophilic cation can show targeted toxicity to the cancer cell mitochondria at a certain concentration, and the targeting property is high and the toxic and side effects are small. Aloe-emodin itself has a quinoid planar structure, can be embedded into DNA, and has the ability to inhibit the activity of DNA topoisomerase, which is an enzyme highly expressed specifically by cancer cells. In addition, the quinoid structure can form a redox couple with the semiquinone free radical structure, thereby having electron transfer capability, and transferring electrons leaked from the respiratory chain to O2Reactive Oxygen Species (ROS) are generated, and copper ions can stabilize a semiquinone free radical structure (semiquinone free radical is a negative ion free radical, and copper ions can stabilize negative ions therein), so that ROS generating ability of the quinoid structure can be enhanced. The invention introduces copper ions into the quinoid structure of aloe-emodin, and aims to enhance the ROS generating capacity of the medicine, inhibit the activity of cancer cell DNA topoisomerase and reduce the cancer cell mitochondrial membrane potential in various waysImproving the anticancer activity of the drug molecules.
Disclosure of Invention
The invention aims to provide a copper-containing aloe-emodin quaternary phosphonium salt with anti-leukemia activity and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a copper-containing aloe-emodin quaternary phosphonium salt with anti-leukemia activity has the following structural formula:
the preparation method of the copper-containing aloe-emodin quaternary phosphonium salt comprises the steps of carrying out substitution reaction on aloe-emodin and excessive phosphorus tribromide to generate brominated aloe-emodin; then carrying out nucleophilic substitution reaction on the bromo-aloe-emodin and tri-n-octylphosphine to obtain aloe-emodin quaternary phosphonium salt; and then reacting the aloe-emodin quaternary phosphonium salt with copper chloride dihydrate to obtain the copper-containing aloe-emodin quaternary phosphonium salt. The synthetic route is as follows:
the method comprises the following specific steps:
1) synthesis of bromo-aloe-emodin: dissolving aloe-emodin in CHCl3In the middle, phosphorus tribromide (PBr) is added at room temperature3) Stirring under reflux for 24 hr, removing solvent by rotary evaporation, and purifying the residue by silica gel column chromatography to obtain bromo-aloe-emodin;
2) synthesis of aloe-emodin quaternary phosphonium salt: dissolving the bromoaloe-emodin obtained in the step 1) in acetone, adding tri-n-octylphosphine at room temperature, refluxing for 6h, removing the solvent under reduced pressure, and using CH2Cl2And ethanol as eluent, passing through siliconPerforming gradient elution by gel column chromatography to obtain colorless viscous liquid, namely the aloe-emodin quaternary phosphonium salt;
3) synthesis of copper-containing aloe-emodin quaternary phosphonium salt: dissolving the aloe-emodin quaternary phosphonium salt obtained in the step 2) in a three-necked bottle filled with methanol, heating to 60 ℃, and stirring for 0.5 h; dissolving copper chloride dihydrate in methanol, transferring the solution to a separating funnel, slowly dropwise adding the solution into a three-necked bottle, and continuously stirring for 1h after dropwise adding; dissolving potassium hydroxide in methanol, transferring to separating funnel, slowly adding dropwise into three-necked bottle, stirring for reaction for 4 hr, removing solvent under reduced pressure, and adding CH2Cl2And using ethanol as an eluent, and performing gradient elution by silica gel column chromatography to obtain a red brown viscous liquid, namely the copper-containing aloe-emodin quaternary phosphonium salt.
The copper-containing aloe-emodin quaternary phosphonium salt can be used for preparing anti-cancer drugs, and is particularly suitable for treating cancer cells such as leukemia CA46 and K562.
The invention has the following remarkable advantages: cancer cells need to multiply frequently, so their DNA topoisomerases are highly expressed enzymes. The compound prepared by the invention contains three pharmacophores of aloe-emodin, long-carbon-chain quaternary phosphonium salt and copper ions. Wherein the aloe-emodin has a planar structure, and can be embedded into DNA of cancer cells to inhibit the activity of DNA topoisomerase; the long-carbon-chain quaternary phosphonium salt belongs to lipophilic cations, can preferentially enter the mitochondria of cancer cells by utilizing the characteristic that the cancer cells have high mitochondrial membrane potential, then is matched with a quinoid structure and copper ions to capture electrons leaked from the respiratory chain of the mitochondria to generate active oxygen, and inhibits the activity of the cancer cells by utilizing the characteristic that the cancer cells are less tolerant to the pressure of the active oxygen than normal cells. The compound synthesized by the invention has multiple anticancer mechanisms and high anticancer activity, thereby having higher application prospect in developing anti-leukemia drugs.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Example 1: synthesis of bromo-aloe-emodin
Dissolving aloe-emodin 1g (3.7 mmol) l in 100 mL CHCl3To the mixture was added 0.5 mL (5.3mmol) of PBr at room temperature3Stirring under heating reflux for 24 hr, rotary evaporating under reduced pressure to remove solvent, and adding CH2Cl2Purifying with silica gel column chromatography to obtain orange yellow solid of compound 2 (bromoaloe-emodin), with yield of 72.1%; product characterization data were as follows:
m.p. 72-73℃；δ: 12.09 (s, 1H, ArOH), 12.06 (s, 1H, ArOH), 7.89 (d, J=6.0 Hz, 1H, ArH), 7.88 (s, 1H, ArH), 7.73 (t, J=8.0 Hz, 1H, ArH), 7.36 (s, 1H, ArH), 7.34 (d, J=6.0 Hz, 1H, ArH), 4.51 (s, 2H, ArCH2Br)；ESI-MS m/z : 331.1 (M-H)-; HRMS (ESI+): calcd for C15H8BrO4 - [M-H]- = 330.9611; Found 330.9619。
example 2: synthesis of aloe-emodin quaternary phosphonium salt
150 mg (0.45 mmol) of the bromoaloe-emodin synthesized in example 1 was dissolved in 30 mL of acetone, 0.2 mL (0.45 mmol) of tri-n-octylphosphine was added at room temperature, the mixture was heated under reflux for 6 hours, the solvent was removed under reduced pressure, and CH was used2Cl2And using ethanol as an eluent to perform gradient elution through silica gel column chromatography, wherein the elution gradient is as follows: v (dichloromethane): v (ethanol) = 50:1 → 40:1 → 30:1 → 20:1, collect the second band, remove solvent to get compound 3 (i.e. aloe-emodin quaternary phosphonium salt) tan solid 212mg, yield 67.4%; the characterization data are as follows:
m.p. 54-56℃; 1H NMR (400 MHz, CDCl3) δ: 11.97 (s, 1H, OH), 11.94 (s, 1H, OH), 7.79 (d, J=7.2Hz, 1H, Ar-H), 7.69 (t, J=8.0Hz, 1H, Ar-H), 7.67 (s, 1H, Ar-H), 7.61 (s, 1H, Ar-H), 7.30 (d, J=8.0Hz, 1H, Ar-H), 4.67 (s, 1H, ArCH 2P(C8H17)3), 4.63 (s, 1H, ArCH 2P(C8H17)3), 2.47 (m, 6H, P(CH 2C7H15)3), 1.56-1.43 (m, 12H, 3×P(CH2C2 H 4)), 1.24 (m, 24H, 3×(C4 H 8CH3)), 0.86 (t, J=6.8Hz, 9H, 3×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)+; HRMS (ESI+): calcd for C39H60O4P+[M-Br]+= 623.4224; Found, 623.4213。
example 3: synthesis of copper-containing aloe-emodin quaternary phosphonium salt
Dissolving 100 mg (0.14 mmol) of the aloe-emodin quaternary phosphonium salt synthesized in the example 2 in a three-necked flask filled with 10 mL of methanol, heating to 60 ℃, and stirring for 0.5 h; dissolving 0.18 mmol of copper chloride dihydrate in 5mL of methanol, transferring the solution into a dropping funnel, slowly dropping the solution into a three-necked bottle, and continuously stirring for 1h after dropping; 56 mg (1.0 mmol) of potassium hydroxide are dissolved in 5mL of methanol and transferred to a dropping funnel, slowly added dropwise to a three-necked flask, and stirred under reflux for 4h after dropping. After the reaction was stopped, the solvent was removed under reduced pressure and CH was used2Cl2And ethanol is used as an eluent, gradient elution is carried out by silica gel column chromatography, and the elution gradient is as follows: v (dichloromethane): v (ethanol) = 50:1 → 40:1 → 30:1 → 20:1 → 10:1, collect the last band, get compound 4 (copper aloe emodin quaternary phosphonium salt) red brown viscous liquid, yield 43.8%; product characterization data were:
1H NMR (400 MHz, CDCl3) δ: 12.04-11.96 (m, 2H, Ar-OH), 7.80-7.13 (m, 10H, Ar-H), 5.05-4.45 (m, 4H, 2×ArCH 2P), 2.46-2.04 (m, 12H, 2×P(CH 2C7H15)3), 1.56-1.48 (m, 24H, 2×P(CH2C2 H 4)3), 1.30-1.25 (m, 48H, 2×P(C3H6C4 H 8CH3)3), 0.91-0.86 (m, 18H, 6×CH3); 13C NMR (400 MHz, CDCl3) δ: 192.3, 180.8, 162.9, 162.7, 147.1, 139.3, 138.5, 137.5, 134.1, 133.1, 129.9, 125.1, 124.5, 124.0, 120.3, 119.1, 115.5, 114.1, 37.1, 34.9, 33.8, 31.9, 31.7, 31.4, 30.2, 29.4, 29.0, 27.2, 22.7, 22.7, 14.1, 14.0; elemental analysis C78H120CuO10P2: 70.41 of C, 9.79 of H, 69.74 of C and 9.00 of H.
Comparative example Synthesis of copper Complex of 1, 8-dihydroxyanthraquinone
The synthetic route is as follows:
the method comprises the following specific steps:
dissolving 240mg (1 mmol) of 1, 8-dihydroxyanthraquinone in a three-necked flask with 30 mL of methanol, heating to 60 ℃, and stirring for 0.5 h; another 1.2mmol of CuCl is taken2·2H2Dissolving O in 10 mL of methanol, transferring the solution into a dropping funnel, slowly dropping the solution into a three-neck bottle under a reflux state, and continuously stirring for 1h after dropping. 112mg (2mmol) of KOH is dissolved in 5mL of methanol, the solution is transferred to a dropping funnel, the solution is slowly dropped into a three-neck flask under the reflux state, the stirring reaction is continued for 4 hours after the dropping, a large amount of solid is separated out, and the reaction is stopped. After cooling, the mixture was filtered by suction, and the filter cake was washed with dichloromethane and ethanol three times, respectively, to obtain compound 5 (1, 8-dihydroxyanthraquinone copper complex) as a reddish brown solid in a yield of 91.7%. Product characterization data were:
m.p>250℃; 1H NMR (400 MHz, DMSO) δ13.34(s, 1H, OH), 7.69-7.33(m, 6H, ArH), elemental analysis C28H18CuO10: 57.57, 2.60 percent of H, 58.19 percent of C and 3.14 percent of H.
Experiment for inhibiting proliferation of leukemia cells
Diluting the tested medicine with culture medium by using aloe-emodin quaternary phosphonium salt (compound 3), copper-containing aloe-emodin quaternary phosphonium salt (compound 4) and 1, 8-dihydroxy anthraquinone copper complex hydrate (compound 5); the density of leukemia cells K562 and CA46 was adjusted to 1X 105One cell/mL, inoculated in 96 wells, respectivelyPlates, 100. mu.L per well, at 37 ℃ with 5% CO2Culturing for 24 h in an incubator; the old medium was removed and the test drug (at a concentration of 0.63. mu.M-40. mu.M) was added at 100. mu.L per well, and a blank control was added and 3 replicate wells were set. After the drug acts for 48 hours, the drug-containing culture medium is removed by suction, 100 mu L of serum-free phenol red 1640 culture medium is added into each hole, 10 mu L of MTT solution is added, the incubation is continued for 4 hours, and the culture is terminated; carefully removing supernatant from 96-well plate wells, adding 100. mu.L of DSMO into each well, oscillating for 10min, measuring light absorption (OD) of each well at 570nm wavelength on microplate reader, and calculating half inhibitory concentration IC50The value is obtained. The results are shown in Table 1.
TABLE 1 inhibitory Activity of Compounds 3,4 and 5 on leukemia cells (IC)50, μmol/L)
The results in Table 1 show that Compound 5, which does not contain a long carbon chain quaternary phosphonium salt, shows moderate anti-leukemic activity on K562 cells and no anti-leukemic activity on CA 46. In contrast, compound 3 having a long carbon chain quaternary phosphonium salt showed good anti-leukemia activity, indicating that the long carbon chain quaternary phosphonium salt is a good pharmacophore for anthraquinone, and that the mere conversion of anthraquinone to a metal ion complex is not effective in improving the anti-leukemia cell proliferation effect of the compound.
Compared with the compound 3, the compound 4 shows better anti-leukemia activity, and shows that the long-carbon-chain quaternary phosphonium salt is introduced into anthraquinone and the anthraquinone forms a metal ion complex, so that the anti-leukemia activity of the anthraquinone can be synergistically increased, and the synthesized product has market potential for developing anti-cancer drugs.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (4)
1. A copper-containing aloe-emodin quaternary phosphonium salt with anti-leukemia activity, which is characterized in that: the structural formula is as follows:
2. the method of preparing the copper-containing aloe-emodin quaternary phosphonium salt of claim 1, wherein: the aloe-emodin and excessive phosphorus tribromide are subjected to substitution reaction to generate bromo-aloe-emodin; then carrying out nucleophilic substitution reaction on the bromo-aloe-emodin and tri-n-octylphosphine to obtain aloe-emodin quaternary phosphonium salt; and then reacting the aloe-emodin quaternary phosphonium salt with copper chloride dihydrate to obtain the copper-containing aloe-emodin quaternary phosphonium salt.
3. The method of preparing the copper-containing aloe-emodin quaternary phosphonium salt according to claim 2, wherein: the method comprises the following steps:
1) synthesis of bromo-aloe-emodin: dissolving aloe-emodin in CHCl3Adding phosphorus tribromide at room temperature, stirring under reflux for 24 h, performing rotary evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain bromo-aloe-emodin;
2) synthesis of aloe-emodin quaternary phosphonium salt: dissolving the bromoaloe-emodin obtained in the step 1) in acetone, adding tri-n-octylphosphine at room temperature, refluxing for 6h, removing the solvent under reduced pressure, and using CH2Cl2And ethanol as an eluent, and performing gradient elution by silica gel column chromatography to obtain colorless viscous liquid, namely the aloe-emodin quaternary phosphonium salt;
3) synthesis of copper-containing aloe-emodin quaternary phosphonium salt: dissolving the aloe-emodin quaternary phosphonium salt obtained in the step 2) in a three-necked bottle filled with methanol, heating to 60 ℃, and stirring for 0.5 h; dissolving copper chloride dihydrate in methanol, transferring the solution to a separating funnel, slowly dropwise adding the solution into a three-necked bottle, and continuously stirring for 1h after dropwise adding; dissolving potassium hydroxide in methanol, transferring to separating funnel, slowly adding dropwise into three-necked bottle, stirring for reaction for 4 hr, removing solvent under reduced pressure, and adding CH2Cl2And ethanol as eluent, performing gradient elution by silica gel column chromatography to obtain brown viscous liquid containing copper reedAloe-emodin quaternary phosphonium salts.
4. The use of the copper-containing aloe-emodin quaternary phosphonium salt according to claim 1 in the preparation of an anticancer drug, characterized in that: the cancer cells are leukemia CA46 and K562.
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