CN109762161A - The preparation method of water-soluble isoxazole curcumin derivate and its application in anti-tumor aspect - Google Patents
The preparation method of water-soluble isoxazole curcumin derivate and its application in anti-tumor aspect Download PDFInfo
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- CN109762161A CN109762161A CN201910024837.2A CN201910024837A CN109762161A CN 109762161 A CN109762161 A CN 109762161A CN 201910024837 A CN201910024837 A CN 201910024837A CN 109762161 A CN109762161 A CN 109762161A
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- curcumin
- isoxazole
- water
- curcumin derivate
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 135
- 229940109262 curcumin Drugs 0.000 title claims abstract description 70
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 70
- 239000004148 curcumin Substances 0.000 title claims abstract description 70
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 70
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000007942 carboxylates Chemical class 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 235000003373 curcuma longa Nutrition 0.000 claims description 6
- 235000003392 Curcuma domestica Nutrition 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 235000013976 turmeric Nutrition 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 229920001451 polypropylene glycol Polymers 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000020717 oral cavity carcinoma Diseases 0.000 claims description 3
- 201000001275 rectum cancer Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 230000005961 cardioprotection Effects 0.000 claims description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 244000008991 Curcuma longa Species 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 150000002545 isoxazoles Chemical class 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 244000163122 Curcuma domestica Species 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000001384 succinic acid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 150000002576 ketones Chemical group 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000006886 Zingiber officinale Nutrition 0.000 description 3
- -1 curcumin compound Chemical group 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 235000008397 ginger Nutrition 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 241000234314 Zingiber Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229920001427 mPEG Polymers 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000551547 Dione <red algae> Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 244000273928 Zingiber officinale Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 150000004676 glycans Chemical class 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of preparation method of water-soluble isoxazole curcumin derivate and its in the application of anti-tumor aspect.The present invention has been designed and synthesized a series of using the Isoxazole derivative of curcumin as the water-soluble curcumin derivate of parent based on the Isoxazole derivative of curcumin in conjunction with polyethylene glycol water-soluble structure unit.The water solubility of the compound improves 245 times than curcumin.The inhibitor against colon carcinoma cells activity of the compound enhances 5 times or more than curcumin.The present invention solves the poorly water-soluble of curcumin, and bioavilability is low and the weak technical problem of anti-tumor activity.
Description
Technical field
The present invention relates to the preparation methods and purposes of water-soluble isoxazole curcumin derivate, in particular in different evil
One or two peg molecule is introduced in azoles curcumin structure parent nucleus.
Background technique
Research background:
Curcumin (Curcumin) be extracted from the rhizome of zingiberaceous plant turmeric (Curcuma longa) one kind it is orange
Color crystalline material, is natural diones chemical component, and structure is as shown in Figure 2.
Curcumin in (Vogel and Pelletier) plant turmeric most earlier than 1818 by separating, in Turmeric
Content proves that curcumin has extensive physiological activity in 2%-5%, a large amount of pharmaceutical research, comprising: inoxidizability resists
Scorching, antitumor, cardioprotection and liver, anti-inflammatory etc..Especially its anti-tumor activity causes the emerging of numerous researchers
Interest.Research finds that curcumin has suppression to Several Kinds of Malignancy such as breast cancer, carcinoma of mouth, gastric cancer, the carcinoma of the rectum, lung cancer, liver cancer etc.
Production is used.
However, due to the factor of curcumin compound structure itself, in addition to Turmeric is widely applied in Chinese prescription
In addition, the application of curcumin clinically itself is not extensive.Numerous studies and clinical test show monomer curcumin in cell
There are excellent results, but ineffective in human clinical trial in horizontal and Research of Animal Model for Study.Trace it to its cause mainly with
The property of curcumin itself is related with bioavilability.Curcumin compound itself is water-soluble very poor (20 μ g/ml), limits it
It absorbs, intravenous injection is caused to have very big difficulty.Due to the presence of curcumin double ketone structure, cause curcumin to light, heat, acid, alkali
It is unstable, it is easy to degrade in enteron aisle.Curcumin is taken orally according to the study enters blood generally in 1%-2%, oral administration biaavailability
It is low.To solve these problems, liposome embedded nanotechnology, curcumin bonding glycan molecule derivative and curcumin are bonded water
Dissolubility amino acid, water soluble sidechains derivative etc. are developed in succession.Due to curcumin structure anti-tumor activity itself it is low with
And the reasons such as unstable, in addition to liposome embedded curcumin nano technology has been applied to clinic, other derivatives are not yet applied
In clinic.
In vitro and in vivo experiments confirm that the presence of the double ketone structure in curcumin molecular structure is curcumin in physiological condition
Under unstable key factor.Further research confirmation, can be effective by the transformation to double ketone structure in curcumin structure
Its stability is improved, and the structural modification of curcumin diketone part does not have significant impact to the bioactivity of curcumin
(Olivera, A. wait Int.Immunopharmacol.2012,12,368-377.Liang, G., etc.,
Bioorg.Med.Chem.2009,17,2623-2631.).Soumyananda etc. (Soumyananda C., etc.,
Biochemistry, 2013,52,7449-7460) Isoxazole derivative (Fig. 3) for having synthesized curcumin, not only increases such
Compound also effectively improves its activity for inhibiting tumour cell in physiological conditions to the stability of light, heat, PH etc..Ginger
The characteristic of flavine double ketone structure transformation provides direction for exploitation curcumin drug, but since the compound water soluble is poor, sternly
Ghost image rings its bioavilability and application pharmaceutically.Therefore developing a kind of water-soluble isoxazole curcumin derivate will
Greatly improve its medical value.
Summary of the invention
It is a series of derivative by the water-soluble curcumin of parent of curcumin isoxazole the purpose of the present invention is designing and synthesizing
Object, and its anti-tumor activity is evaluated.
To achieve the goals above, the first aspect of the present invention provides a series of isoxazole curcumin shown in logical formula (I)s
One of them is hydrogen by derivative and its pharmaceutically acceptable salt, R1 and R2, one of them is the carboxylate of polyethylene glycol；Or
Both for the carboxylate of polyethylene glycol.R3 is methyl or ethyl.Methylene radix (m) in dicarboxylic acids is 0-4.Ethylene glycol
Unit number (n) is 2-2000.
Further, the hydrophilic radical (R1 and R2) one of them for glycerol or polypropylene glycol carboxylate；Or both
It is the carboxylate of glycerol or polypropylene glycol.
The second aspect of the present invention provides a kind of drug made of the isoxazole curcumin derivate and analog
Compound and its medicinal composition that pharmaceutically acceptable salt is prepared as pharmacy activity component, individually or combine it is a kind of or
Several pharmaceutically acceptable, inert, nontoxic excipient or carrier.
The third aspect of the present invention provides a kind of drug made of the isoxazole curcumin derivate and analog
Dosage form, the pharmaceutical dosage form include powder, tablet, granule, capsule, solution, emulsion, suspension, injection, freeze-dried powder
Injection.
The fourth aspect of the present invention provides the side for preparing above-described isoxazole curcumin derivate and its analog
Method, including the following steps:
Using curcumin as Material synthesis isoxazole curcumin；
Using methoxy poly (ethylene glycol) and succinic anhydride as Material synthesis succinic acid polyethylene glycol monoesters；
Terminal carboxyl group and the n-hydroxysuccinimide reaction of succinic acid polyethylene glycol monoesters generate active ester；
The active ester of succinic acid polyethylene glycol monoesters reacts isoxazole ginger shown in the logical formula (I) of generation with isoxazole curcumin
Flavin derivatives.
It is multiple to provide drug made of above-described isoxazole curcumin derivate and analog for the fifth aspect of the present invention
Close object and its pharmaceutically application of the acceptable salt in inhibition growth of cancer cells.
In embodiments of the present invention, the water solubility of the compound improves 245 times than curcumin.The compound
The inhibitor against colon carcinoma cells activity of (IC50=18.2 μM) enhances 5 times or more than curcumin (100 μM of IC50 >).The present invention solves ginger
The poorly water-soluble of flavine, bioavilability is low and the weak technical problem of anti-tumor activity.
Detailed description of the invention
The attached drawing for constituting a part of the invention is used to provide further understanding of the present invention, so that of the invention is other
Feature, objects and advantages become more apparent upon.Illustrative examples attached drawing and its explanation of the invention is used to explain the present invention, not
Constitute inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is the structural diagrams of isoxazole curcumin derivate；
Fig. 2 is the structural diagrams of curcumin；
Fig. 3 is the structural diagrams of isoxazole curcumin；And
Fig. 4 is experimental result of the PEG- isoxazole curcumin to the inhibitory activity of colon cancer cell.
Specific embodiment
In order to enable those skilled in the art to better understand the solution of the present invention, below in conjunction in the embodiment of the present invention
Attached drawing, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is only
The embodiment of a part of the invention, instead of all the embodiments.Based on the embodiments of the present invention, ordinary skill people
The model that the present invention protects all should belong in member's every other embodiment obtained without making creative work
It encloses.
It should be noted that term " includes " and " tool in the description and claims of this application and above-mentioned attached drawing
Have " and their any deformation, it is intended that cover it is non-exclusive include, for example, containing a series of raw materials or step, no
Those of be necessarily limited to be clearly listed raw material or step, but may include be not clearly listed or for these raw materials or step
Rapid intrinsic other raw materials or step.
The specific embodiment of the preparation method of above-described isoxazole curcumin derivate is provided as follows:
Embodiment 1: the preparation of isoxazole curcumin
Curcumin 7.4g is weighed, 20ml dehydrated alcohol is dissolved in, measures 12ml glacial acetic acid, above-mentioned reaction solution is added at 50 DEG C,
It is stirred to react 30min；Then hydroxylamine hydrochloride 6.95g is added, increases temperature to 80 DEG C, is stirred to react 10h.It is residual to be filtered to remove solid
Slag, filtrate extract (15ml × 3) with methylene chloride, dry with anhydrous sodium sulfate, and solvent is evaporated off, obtains yellow solid product 3.59g,
Yield 49.2%.Structural Identification data: mp=171.9-173.7 DEG C；1H NMR (600MHZ, DMSO-d6): δ 3.85 (6H, s),
6.80 (2H, dd, J=7.8,4.2Hz), 6.86 (1H, s), 7.05 (1H, d, J=7.8Hz), 7.08-7.11 (3H, m), 7.27-
7.31 (4H, m), 9.35 (1H, s), 9.43 (1H, s) .LC-MS (ESI, m/z): Calcd for C21H19N05 ([M+H]+)
366.13, found:366.2.
Embodiment 2: the preparation of succinic acid polyethylene glycol monoesters
Methoxy poly (ethylene glycol) 5.53g is weighed, succinic anhydride 1.51g is dissolved in 20ml methylene chloride, takes 0.52ml triethylamine
It is added dropwise in above-mentioned reaction solution, in 60 DEG C of back flow reaction 8h, distills water washing 15ml × 3, the extraction of water phase methylene chloride (10ml ×
3), merge organic phase, saturated common salt wash (20ml × 3), anhydrous sodium sulfate dries, filters, organic phase be spin-dried for 5.8g is colourless
Transparent oil is directly used in the next step.
Embodiment 3: the synthesis of activated polyethylene glycol
It weighs succinic acid polyethylene glycol monoesters 5.0g to be dissolved in 20ml methylene chloride, is stirred in 0 DEG C, be separately added into NHS
1.04g and EDC 1.2g stirs 10min, 12h is then stirred at room temperature, is washed with distilled water (20ml × 3) after reaction,
Water phase is extracted with dichloromethane (10ml × 3), merges organic phase, and organic phase washes (20ml × 3) with saturated common salt, anhydrous slufuric acid
Sodium dries, filters, and organic phase is evaporated off solvent and obtains 5.14g white waxy solid, yield 92%.Structural Identification data:
1H NMR (600MHz, DMSO-d6)): δ 2.70 (2H, t, J=12.0Hz), 2.94 (2H, t, J=12.0Hz),
3.25 (3H, s), 3.44 (2H, t, J=6.0Hz), 3.62 (2H, t, J=6.0Hz), 3.45-3.60 (m, PEG), 4.15 (2H,
T, J=12.0Hz), 5.74 (4H, s) .LC-MS (ESI, m/z): Calcd for C41H75N022 ([M+H]+) 933.48,
A series of found: normal distribution peaks of mass difference 44.
The synthesis of embodiment 4:PEG- isoxazole curcumin
It weighs isoxazole curcumin 500mg and is dissolved in 10ml anhydrous methylene chloride, activated polyethylene glycol 850mg is then added,
DMAP 22mg is stirred at room temperature for 24 hours, and reaction terminates, 10ml water washing reaction solution twice, water phase be extracted with dichloromethane (15ml ×
3), merge organic phase, wash (10ml × 3) with saturated common salt, anhydrous sodium sulfate dries, filters, and organic phase is spin-dried for, Flash silica
Column chromatography for separation (DCM: MeOH=200: 1-20: 1) obtains light yellow oil 220mg, yield 20.4%.Structural Identification number
According to:
1H NMR (600MHz, CDCl3): δ 2.80 (2H, t, J=8.4Hz), 2.94 (2H, t, J=8.4Hz), 3.38
(3H, s), 3.55 (2H, t, J=9.0Hz), 3.63-3.72 (m, PEG), 3.88 (3H, d, J=4.8Hz), 3.95 (3H, d, J=
4.8Hz), 4.28 (2H, t, J=9.0Hz), 5.95 (1H, d, J=22.2Hz), 6.45 (1H, d, J=22.2Hz), 6.81 (1H,
D, J=18.0Hz), 6.91 (1H, d, J=18.0Hz), 6.93-6.97 (1H, m), 7.01 (1H, d, J=18.0Hz), 7.06-
7.09 (3H, m), 7.11-7.15 (2H, m), 7.31 (1H, d, J=18.0Hz) .LC-MS (ESI, m/z): Calcd for
C58H89N024 ([M+Na]+) 1206.57, found:1207.3；HRMS (ESI, m/z): Calcd for C58H89N024 ([M
+ Na]+) 1206.5673, ([M+H]+) 1184.5808, found:1206.5742,1184.5922.
Embodiment 5: solubility test
(1) configuration standard solution
With assay balance precise compound PEG- isoxazole curcumin 2.00mg, it is with methanol dissolution configuration concentration
Then the stock solution of 2mg/ml successively prepares such as 2.00,1.00,0.50,0.25,0.125,0.0625mg/ml with methanol dilution
The solution of concentration, solution are placed in spare in refrigerator.
(2) HPLC testing conditions
Chromatographic condition:
Chromatographic column: 5TC-C18 250*4.6mm
Detection wavelength: 400nm
Mobile phase: 70% methanol: 30% water
Sample volume: 20ul
Flow velocity: 1ml/min
(3) Specification Curve of Increasing
Standard solution is measured respectively under above-mentioned liquid-phase condition, records chromatographic peak area, with concentration (mg/ml) and
Peak area (A) linear regression, obtains working curve Y=87.34X+0.012 (R2=0.9999)
(4) PEG- isoxazole curcumin solubility test
In 2.0ml EP pipe, 200 μ l distilled water are added, at 30 DEG C in precise 1mg PEG- isoxazole curcumin
Vibrate 72h；10000 revs/min are centrifuged 5 minutes, take supernatant liquor to carry out liquid-phase chromatographic analysis, according to peak area and standard curve
Calculate the solubility of PEG- isoxazole curcumin in water.
Experimental result: the solubility of PEG- isoxazole curcumin in water is 4.9mg/mL.Compared to curcumin (20 μ g/
ML), water solubility improves 245 times.
The measurement of 6 Anti-tumor angiogenesis of embodiment
Colon-26 colon cancer cell is cultivated in 37 DEG C, 5%CO2 incubator.Culture solution is 1640 culture medium of RPMI,
Use 10% fetal calf serum of preceding addition (FBS) and 1% antibiotic-antimycotic mixing antibiotic.
Harvest index growth Colon-26 colon cancer cell, be layered in 96 orifice plates, concentration be 2 × 104 cells/
Hole.After being incubated for 24 hours at 37 DEG C, handled cell 72 hours with the curcumin and PEG- isoxazole curcumin of various concentration.
Then the MTT (5mg/mL) of 20 μ L is added into each hole, culture plate is incubated for 2 hours at 37 DEG C.Liquid is discarded supernatant, to each
100 μ L DMSO are added in hole.Absorbance is recorded in 490nm after 15 minutes.Cell growth rate: cell growth is obtained by following formula
Rate (%)=OD processing × 100%/OD blank control.Data report is the average value of independent experiment three times, and experiment every time is
Three times.
Experimental result: MTT experiment according to Fig.4, is as a result, PEG- isoxazole curcumin is thin to Colon-26 colon cancer
The half-inhibitory concentration of born of the same parents is 18.2 μM, and comparison medicine curcumin is greater than the half-inhibitory concentration of Colon-26 colon cancer cell
100μM。
From the experimental result of embodiment 6, it can be seen that the isoxazole curcumin derivate and analog and its
Pharmaceutically acceptable salt has the function of inhibiting growth of cancer cells.
Wherein the cancer cell can be colon cancer, breast cancer, carcinoma of mouth, gastric cancer, the carcinoma of the rectum, lung cancer, liver cancer etc..
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (8)
1. isoxazole curcumin derivate shown in a kind of logical formula (I) and its pharmaceutically acceptable salt, R1 and R2 wherein one
A is hydrogen, one of them is the carboxylate of polyethylene glycol；Or both be polyethylene glycol carboxylate.R3 is methyl or ethyl.
Methylene radix (m) in dicarboxylic acids is 0-4.The unit number (n) of ethylene glycol is 2-2000.
2. the analog of isoxazole curcumin derivate according to claim 1 and its pharmaceutically acceptable salt,
Be characterized in that, in the analog R1 and R2 one of them be hydrogen, one of them for glycerol or polypropylene glycol carboxylate；Or two
Person is glycerol or polypropylene glycol.
3. being formed by and being pharmaceutically subjected to formula (I) compound of 2 any one or these compounds according to claim 1
The medicinal composition that is prepared as pharmacy activity component of salt, individually or combine one or more of pharmaceutically acceptable, inertia
, nontoxic excipient or carrier.
4. isoxazole curcumin derivate according to claims 1 and 2 and analog and its pharmaceutically acceptable salt
The pharmaceutical dosage form generated for raw material, which is characterized in that the pharmaceutical dosage form includes powder, tablet, granule, capsule, solution
Agent, emulsion, suspension, injection, freeze drying powder injection.
5. the preparation method of isoxazole curcumin derivate according to claim 1.It is characterized in that, by isoxazole turmeric
Element prepares logical formula (I) compound with the ester condensation of diacid polyethyleneglycol.
6. isoxazole curcumin derivate according to any one of claim 1 to 3 and its preparation are in treatment tumour
Using.
7. application according to claim 6, which is characterized in that the tumour be colon cancer, breast cancer, carcinoma of mouth, gastric cancer,
The carcinoma of the rectum, lung cancer, liver cancer etc..
8. isoxazole curcumin derivate according to any one of claim 1 to 3 and its preparation answering in other purposes
It is inoxidizability, anti-inflammatory, cardioprotection and liver, anti-inflammatory etc. with, which is characterized in that the purposes.
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| CN101524546A (en) * | 2008-11-07 | 2009-09-09 | 浙江中医药大学 | Conjugate conjugated from polyethylene glycol and curcumin derivative |
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| CN101524546A (en) * | 2008-11-07 | 2009-09-09 | 浙江中医药大学 | Conjugate conjugated from polyethylene glycol and curcumin derivative |
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| DANIELE SIMONI，ET AL.: "Antitumor effects of curcumin and structurally b-diketone modified analogs on multidrug resistant cancer cells", 《BIOORG. MED. CHEM. LETT.》 * |
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| CN110859892A (en) * | 2019-12-20 | 2020-03-06 | 杭州劲驰医疗器械有限公司 | Preparation method of curcumin-tea product and application of curcumin-tea product in anti-tumor aspect |
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