CN119119148A - A curcumin glycosyl derivative and its preparation method and medical use - Google Patents
A curcumin glycosyl derivative and its preparation method and medical use Download PDFInfo
- Publication number
- CN119119148A CN119119148A CN202311794247.0A CN202311794247A CN119119148A CN 119119148 A CN119119148 A CN 119119148A CN 202311794247 A CN202311794247 A CN 202311794247A CN 119119148 A CN119119148 A CN 119119148A
- Authority
- CN
- China
- Prior art keywords
- curcumin
- reaction
- glycosyl derivative
- reacting
- glycosyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VFLDPWHFBUODDF-FCXRPNKRSA-N Curcumin Natural products 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 45
- 229940109262 curcumin Drugs 0.000 title claims abstract description 33
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 33
- 239000004148 curcumin Substances 0.000 title claims abstract description 33
- 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 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- JKWMSGQKBLHBQQ-UHFFFAOYSA-N diboron trioxide Chemical compound O=BOB=O JKWMSGQKBLHBQQ-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment 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
- 238000010992 reflux Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- SKPWEADPCJMLID-UHFFFAOYSA-N 4-fluoro-3-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(C=O)=C1 SKPWEADPCJMLID-UHFFFAOYSA-N 0.000 claims description 3
- OZUMXPOCHLGNQL-JAJWTYFOSA-N C(C)(=O)[C@@]1([C@@](O)(O[C@@H]([C@H]([C@@H]1O)O)CO)Br)O Chemical compound C(C)(=O)[C@@]1([C@@](O)(O[C@@H]([C@H]([C@@H]1O)O)CO)Br)O OZUMXPOCHLGNQL-JAJWTYFOSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 3
- 235000012141 vanillin Nutrition 0.000 claims description 3
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 208000032612 Glial tumor Diseases 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 6
- 210000005013 brain tissue Anatomy 0.000 abstract description 5
- 230000008499 blood brain barrier function Effects 0.000 abstract description 4
- 210000001218 blood-brain barrier Anatomy 0.000 abstract description 4
- 230000002503 metabolic effect Effects 0.000 abstract description 4
- 102000058063 Glucose Transporter Type 1 Human genes 0.000 abstract description 3
- 108091006296 SLC2A1 Proteins 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 2
- 230000009471 action Effects 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 230000004783 oxidative metabolism Effects 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 230000008034 disappearance Effects 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 210000001853 liver microsome Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000407170 Curcuma Species 0.000 description 1
- 235000014375 Curcuma Nutrition 0.000 description 1
- 244000163122 Curcuma domestica Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010051015 Radiation hepatitis Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000234299 Zingiberaceae Species 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001348 anti-glioma Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 235000003373 curcuma longa Nutrition 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a curcumin glycosyl derivative, a preparation method and medical application thereof, wherein the structure of the curcumin glycosyl derivative is shown as follows. According to the invention, the drug is modified through ester bond connection by using D-glucose, then targeted to GLUT1, and transported to reach brain tissues through a blood brain barrier, so that the targeting of the drug is remarkably improved. Furthermore, by F atom modification, this is due to its lower bond energy and reactivity than H atoms, smaller molecular weight than other blocking groups, and less impact on molecular size. The preparation can block the sites which are easy to generate oxidative metabolism, thereby improving the metabolic stability of the compound and prolonging the action time of the medicine in the body.
Description
Technical Field
The invention belongs to the technical field of curcumin glycosyl derivatives, and particularly relates to a curcumin glycosyl derivative, a preparation method and medical application thereof.
Background
Curcumin (curcumin) is a natural product separated from rhizome extracts of curcuma longa of curcuma genus of Zingiberaceae family, and researches show that curcumin has various activities such as anti-inflammatory, antioxidant and antiproliferative effects, and the antitumor effect is a research hotspot of scientific researchers. At present, numerous in vivo and in vitro experiments prove that curcumin has wide antitumor activity and low toxic and side effects on normal cells, and the results show that curcumin has great development potential in tumor treatment.
Earlier studies have shown that curcumin derivative DMC-BH has a certain therapeutic effect on gliomas (Aging (Albany NY). 2020,12 (23): 23795-23807; aging (Albany NY): 2020,12 (14): 14718-14735.), but its ability to cross the blood brain barrier is not strong enough, and plasma stability is poor and easy to metabolize. Improving the metabolic stability of DMC-BH and the ability of DMC-BH to penetrate the blood brain barrier is hopeful to develop curcumin derivatives with better drug properties and develop curcumin derivatives into clinical anti-glioma effective drugs.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a curcumin glycosyl derivative, a preparation method and medical application thereof. The curcumin derivative with better metabolic stability and GLUT1 transport activity is obtained by structural modification of curcumin, and the preparation method and the application of the curcumin derivative in the field of anti-tumor are provided.
The technical scheme adopted by the invention is as follows in order to achieve the aim of the invention:
a curcumin glycosyl derivative and pharmaceutically acceptable salts thereof, the structure of the curcumin glycosyl derivative being as follows:
The invention also provides a preparation method of the curcumin glycosyl derivative, which comprises the following steps:
(1) Reacting 4-fluoro-3-formylbenzoic acid with N, O-dimethylhydroxylamine hydrochloride to generate an intermediate 1;
(2) Intermediate 1 reacts with tetrahydropyrrole to form intermediate 2;
(3) Compound 2 is reacted with a reducing agent to form intermediate 3;
(4) Reacting vanillin with acetyl bromo-alpha-D-glucose under alkaline conditions to yield intermediate 4;
(5) Acetylacetone reacts with intermediate 4 to form intermediate 5;
(6) Reacting intermediate 3 with intermediate 5 to form intermediate 6;
(7) And (3) reacting the intermediate 6 under an acidic condition to obtain the curcumin glycosyl derivative.
Preferably, the reaction formula is as follows:
Preferably, in the step (1), the reaction system also comprises 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 4-Dimethylaminopyridine (DMAP) and methylene dichloride, wherein the reaction is carried out for 10-14h under the condition of stirring at room temperature;
Preferably, the reaction is carried out in methanol, and the reaction system also comprises sodium triacetoxyborohydride and glacial acetic acid, and the reaction is carried out for 10-14h at 60-70 ℃.
Preferably, the reaction is carried out in anhydrous diethyl ether, the reducing agent is selected from lithium aluminum hydride, and the reaction is carried out under ice bath conditions for 1-3h;
Preferably, in the step (4), the alkali under the alkaline condition is selected from anhydrous potassium carbonate, and the reaction is carried out in N, N-dimethylformamide at 40-60 ℃ for 1-3h.
Preferably, in the step (5), the reaction method comprises the steps of dissolving acetylacetone and diboron trioxide in ethyl acetate, heating to 80-90 ℃ for reflux, reacting for 0.5-1.5h, cooling to 45-55 ℃, adding an intermediate 4 and tri-n-butyl borate, dissolving n-butylamine in ethyl acetate, slowly dropwise adding, keeping the temperature at 50+/-2 ℃, reacting for 1.5-2.5h, and adding hydrochloric acid solution to regulate the pH.
Preferably, in the step (6), the reaction method comprises the steps of dissolving the intermediate 5 and the diboron trioxide in ethyl acetate, heating to 80-90 ℃ for reflux, reacting for 0.5-1.5h, cooling to 45-55 ℃, adding 4-fluoro-3- (pyrrolidin-1-ylmethyl) benzaldehyde and tri-n-butyl borate, slowly dropwise adding n-butylamine in ethyl acetate, keeping the temperature at 50+/-2 ℃, reacting for 1.5-2.5h, and adding hydrochloric acid solution to regulate the pH.
Preferably, in the step (7), the acidic condition is selected from 2N HCl solution, the reaction is carried out in dichloromethane, the temperature is 55-65 ℃ and the reaction time is 1.5-2.5 hours, and after the reaction is finished, the crude product is recrystallized by dichloromethane and petroleum ether to obtain the curcumin glycosyl derivative pure product.
The invention also provides a pharmaceutical composition, which contains the curcumin glycosyl derivative and/or pharmaceutically acceptable salt thereof.
The invention finally provides the curcumin glycosyl derivative and/or pharmaceutically acceptable salt thereof, and application of the pharmaceutical composition in preparing medicines for treating tumors.
Further, the tumor is lung cancer or brain glioma.
The invention has the beneficial effects that the D-glucose is utilized to modify the medicine through ester bond connection, then the medicine is targeted to GLUT1, and the medicine reaches brain tissues through the blood brain barrier by transportation, thereby remarkably improving the targeting of the medicine. Furthermore, by F atom modification, this is due to its lower bond energy and reactivity than H atoms, smaller molecular weight than other blocking groups, and less impact on molecular size. The preparation can block the sites which are easy to generate oxidative metabolism, thereby improving the metabolic stability of the compound and prolonging the action time of the medicine in the body.
Drawings
FIG. 1 is a schematic diagram of the design of the curcumin glycosyl derivative.
Detailed Description
The invention is further illustrated by the following examples. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention. The invention is further described below with reference to the accompanying drawings and examples:
example 1 preparation of intermediate 1
Dissolving 4-fluoro-3-formylbenzoic acid (1.0 g), N, O-dimethylhydroxylamine hydrochloride (0.87 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.7 g) and 4-dimethylaminopyridine (1.09 g) in 30ml of dichloromethane in this order, stirring at room temperature, reacting for 12H, detecting completion of the disappearance of the starting material by TLC, spin-drying the solvent, EA extraction, washing the organic layer with H 2 O and saturated saline for 3 times, drying with anhydrous sodium sulfate, standing, filtering, distilling off the solvent under reduced pressure, separating by silica gel column chromatography to obtain colorless oily liquid (intermediate 1) 0.94g (yield 75％).1H NMR(300MHz,DMSO-d6)δ10.23(s,1H),8.08(dd,J＝6.8,2.3Hz,1H),8.00(ddd,J＝8.7,5.1,2.3Hz,1H),7.51(dd,J＝10.5,8.6Hz,1H),3.55(s,3H),3.29(s,3H).ESI-MS m/z:212.1[M+H]+.
Example 2 preparation of intermediate 2
Dissolving intermediate 1 (0.7 g) in methanol, adding tetrahydropyrrole (0.35 g), sodium triacetoxyborohydride (0.84 g) and glacial acetic acid (0.02 ml), reacting at 65deg.C for 12H, TLC detecting completion of the disappearance of the starting material, spin-drying the solvent, EA extracting, washing the organic layer with H 2 O and saturated saline for 3 times, drying over anhydrous sodium sulfate, standing, filtering, distilling off the solvent under reduced pressure, separating by silica gel column chromatography to obtain yellow oily liquid (intermediate 2) 0.57g (yield) 65％).1H NMR(300MHz,DMSO-d6)δ7.67(dd,J＝7.2,2.3Hz,1H),7.56(ddd,J＝8.5,5.1,2.3Hz,1H),7.23(dd,J＝9.9,8.5Hz,1H),3.68-3.62(m,2H),3.53(s,3H),3.25(s,3H),2.48-2.43(m,4H),1.72-1.66(m,4H).ESI-MS m/z:267.1[M+H]+.
Example 3 preparation of [ intermediate 3 ]
Weighing (0.24 g) of lithium aluminum hydride, dissolving in 10ml of anhydrous diethyl ether, stirring at normal temperature for 30min, dissolving intermediate 2 (1.5 g) in 20ml of anhydrous diethyl ether solution, slowly dripping into the anhydrous diethyl ether solution of lithium aluminum hydride at-40 ℃, transferring the reaction to ice bath, stirring for 2H after dripping, detecting disappearance of raw materials by TLC, spin drying solvent, extracting by EA, washing organic layer with H 2 O and saturated saline for 3 times, drying with anhydrous sodium sulfate, standing, filtering, distilling under reduced pressure to remove solvent, separating by silica gel column chromatography to obtain 0.793g (intermediate 3) of yellow oily liquid (yield 68％).1H NMR(300MHz,DMSO-d6)δ9.99(s,1H),7.99(dd,J＝7.2,2.2Hz,1H),7.89(ddd,J＝7.8,5.2,2.2Hz,1H),7.41(dd,J＝9.8,8.4Hz,1H),3.69(d,J＝1.6Hz,2H),2.49(tdd,J＝6.7,4.0,1.7Hz,4H),1.70(h,J＝3.2Hz,4H).ESI-MS m/z:208.1[M+H]+.
Example 4 preparation of intermediate 4
Dissolving vanillin (1.0 g), acetyl bromo-alpha-D-glucose (3.24 g) and potassium carbonate (2.72 g) in 50mL of N, N-dimethylformamide, heating to 50deg.C, reacting for 3H, TLC detecting complete disappearance of the raw material, extracting with EA, washing the organic layer with H 2 O and saturated saline for 3 times, drying with anhydrous sodium sulfate, standing, filtering, distilling under reduced pressure to remove the solvent, separating with silica gel column chromatography to obtain white solid (intermediate 4) 2.5g (yield 80％).1H NMR(300MHz,DMSO-d6)δ9.85(s,1H),7.51(dd,J＝7.6,1.6Hz,1H),7.39(d,J＝1.6Hz,1H),7.15(d,J＝7.5Hz,1H),5.30(t,J＝6.9Hz,1H),5.26(t,J＝6.9Hz,1H),5.16(t,J＝6.8Hz,1H),4.93(d,J＝6.8Hz,1H),4.28(dd,J＝12.2,6.9Hz,1H),4.15(dd,J＝12.2,7.0Hz,1H),4.09(q,J＝6.9Hz,1H),3.83(s,2H),2.06(dd,J＝6.8,1.5Hz,12H).ESI-MS m/z:483.1[M+H]+.
Example 5 preparation of intermediate 5
Acetylacetone (5 g) and diboron trioxide (2.5 g) were dissolved in 60ml of ethyl acetate, heated to 85 ℃ for reflux, cooled to 50 ℃ after 1 hour of reaction, compound 4 (4.0 g) and tri-n-butyl borate (4.8 g) were added, n-butylamine (1.0 g) was dissolved in 10ml of ethyl acetate and slowly added dropwise, the temperature was kept at 50 ℃ for 2 hours, TLC detection of the completion of the disappearance of the starting material, pH was adjusted by adding 1mol/L hydrochloric acid solution, EA extraction, the organic layer was washed 3 times with H 2 O and saturated brine, dried over anhydrous sodium sulfate, left standing, filtered, the solvent was removed by distillation under reduced pressure, and silica gel column chromatography was carried out to obtain 2.43g (intermediate 5) as pale yellow oily solid (yield) 52％).1H NMR(300MHz,DMSO-d6)δ7.51-7.44(m,1H),7.18-7.09(m,3H),6.66(d,J＝15.0Hz,1H),5.31(t,J＝6.9Hz,1H),5.26(t,J＝6.9Hz,1H),5.19(t,J＝6.9Hz,1H),4.93(d,J＝6.8Hz,1H),4.23(dd,J＝7.0,1.8Hz,2H),4.07(q,J＝7.0Hz,1H),3.89(s,2H),3.76(s,2H),2.21(s,2H),2.10-2.02(m,11H).ESI-MS m/z:565.2[M+H]+.
Example 6 preparation of intermediate 6
Dissolving compound 5 (0.5 g) and diboron trioxide (0.075 g) in 15ml of ethyl acetate, heating to reflux at 85 ℃, cooling to 50 ℃ after 1H of reaction, adding intermediate 3 (0.22 g) and tri-n-butyl borate (0.2 g), dissolving n-butylamine (0.07 g) in 5ml of ethyl acetate, slowly dropwise adding, keeping the temperature at 50 ℃, reacting for 12H, detecting the completion of the raw material disappearance reaction, adding 1mol/L hydrochloric acid solution to adjust the pH, extracting EA, washing an organic layer with H 2 O and saturated saline for 3 times, drying anhydrous sodium sulfate, standing, filtering, distilling under reduced pressure to remove the solvent, separating by silica gel column chromatography to obtain 0.226g of yellow solid (intermediate 6) (yield 34％).1H NMR(300MHz,DMSO-d6)δ7.57-7.43(m,4H),7.25(t,J＝7.9Hz,1H),7.18-7.10(m,3H),6.65(d,J＝15.1Hz,2H),5.31-5.23(m,2H),5.19-5.12(m,1H),4.97-4.90(m,1H),4.27-4.15(m,2H),4.07(q,J＝6.9Hz,1H),3.89(s,2H),3.70(dd,J＝12.3,1.0Hz,1H),3.65(dd,J＝12.4,0.9Hz,1H),3.48(s,2H),2.84(dddd,J＝7.6,4.9,2.8,0.8Hz,4H),2.10-2.03(m,11H),1.78-1.66(m,4H).ESI-MS m/z:754.3[M+H]+.
EXAMPLE 7 preparation of Compound DMC-GF ]
Compound 6 (0.1 g) was dissolved in 10ml of methylene chloride, 10ml of 2N HCl aqueous solution was added to react for 2 hours at 60℃and TLC was used to detect completion of the disappearance of the starting material, the solvent was dried by spin-drying, and recrystallized from methylene chloride and petroleum ether to give 0.06g of a yellow solid (Compound DMC-GF) (yield 77％).1H NMR(300MHz,DMSO-d6)δ7.58-7.49(m,3H),7.49(dd,J＝4.9,0.7Hz,1H),7.22-7.13(m,3H),7.15-7.09(m,1H),6.66(d,J＝15.1Hz,2H),5.12(d,J＝6.9Hz,1H),4.82(d,J＝10.1Hz,1H),4.78(d,J＝9.7Hz,1H),4.73(d,J＝10.1Hz,1H),4.47(t,J＝7.5Hz,1H),3.91-3.55(m,10H),3.48(s,2H),3.40(dtd,J＝9.7,6.9,1.8Hz,1H),2.89-2.79(m,4H),1.80-1.66(m,4H).ESI-MS m/z:586.2[M+H]+..
Experimental examples pharmacological and pharmaceutical substitution experimental results of the compounds of the present invention:
test of antitumor Activity
1. Cell digestion, counting, preparing cell suspensions at a concentration of 5X 10 4 cells/mL, adding 100. Mu.L of cell suspension per well (5X 10 3 cells per well) to 96-well plates;
2.96-well plates were placed in a 37℃and 5% CO 2 incubator for 24 hours;
3. Diluting the medicine with the complete culture medium to the required concentration, adding 100 mu L of corresponding medicine-containing culture medium into each hole, and simultaneously setting a negative control group, a solvent control group and a positive control group;
4.96-well plates were incubated at 37℃in a 5% CO 2 incubator for 72 hours;
5. The OD value was determined by MTT staining of 96-well plates, λ=490 nm.
1) Mu.L MTT (5 mg/mL) was added to each well, and the culture was continued in an incubator for 4 hours;
2) The culture medium was discarded, 150 mu LDMSO was added to each well for dissolution, the mixture was gently mixed in a shaker for 10 minutes, lambda=490 nm, and the OD value of each well was read by an ELISA reader, and the inhibition rate was calculated.
Cell inhibition ratio% = 100% × (negative control OD value-compound OD value)/negative control OD value
6. Experimental results
TABLE 1 antiproliferative activity of the compound DMC-GF on different tumor cell lines (IC 50: units. Mu.g/mL)
Liver microsome stability of DMC-GF (a) Compound
1. Experimental materials ITEM (VENDOR) mouse liver microsomes (RILD);BSA(Solarbio);TRIZMABASE(Sigma);MgCl2(Sigma);NADPH(Solarbio);Acetonitrile(Merck);Methanol
(Merck)。
2. Experimental equipment ：Mass Spectrometer(Waters 529);UPLC(UPLC H-Class,Waters);Temperature(Controlling System KK25V61TI,Seimens);Microplate Reader
(INFINITE 200PRO,TECAN)。
3. Incubation System liver microsomes were added to a 0.1M TRIS buffer solution pH7.4 (final concentration 0.33 mg/mL), co-incubation factor MgCl 2 (final concentration 5 mM) and test compound (final concentration 1. Mu.M, solvent (0.01%)
DMSO) and 0.005% fetal Bovine Serum (BSA)) for 10min at 37 ℃. NADPH (final concentration 1)
MM) and then aliquoted at 0,7,17,30and 60min and methanol (4 ℃) was added for termination of the reaction, followed by centrifugation (4000 rpm,5 min) and analysis of the compound content by LC-MS/MS.
4. Experimental results
TABLE 2 stability results of liver microsomes
(III) Compound DMC-GF brain permeability study in ICR mice
1. Male ICR mice were fed with water freely during feeding and dosing, and fasted 12 hours before blood withdrawal.
2. The experiment groups are that 15 male ICR mice are divided into 5 time points (15 min,45min,2h,6h and 12 h), and 3 male ICR mice are respectively administered with medicines in I.V. at the dosage of 1.0mg/kg.
3. Blood collection, namely, after mice are dosed, blood plasma and brain tissues are collected according to the corresponding time points of each group, blood plasma samples are placed in an EDTA-K2 anticoagulated EP tube for ice bath after collection, centrifugation is carried out for 5 minutes at 4 ℃ and 8000rpm, and the blood plasma is transferred to-20 ℃ as soon as possible for preservation and measurement. The brain tissue is peeled off the surface blood vessel by filter paper and then is filled into a self-sealing bag with corresponding number, the brain tissue is preserved at-20 ℃ to be detected, 4 times of 20% MeOH by volume is added for homogenization treatment before detection, and a certain volume of sample is taken for pretreatment and then LC-MS/MS detection is carried out.
4. Detection the compound concentration in the collected plasma/brain homogenate sample is determined by using an established LC-MS/MS detection method. Pharmacokinetic parameters were calculated using Winnonlin 5.2.
5. Experimental results
TABLE 3 content (ng/mL) in plasma/brain homogenates after administration of the compound DMC-GF
While the embodiments of the present invention have been described in detail with reference to the drawings and the specific examples, the present invention is not limited to the above embodiments, and various changes may be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Claims (10)
1. A curcumin glycosyl derivative and pharmaceutically acceptable salt thereof, wherein the structure of the curcumin glycosyl derivative is as follows:
2. the method for producing a curcumin glycosyl derivative according to claim 1, comprising the steps of:
(1) Reacting 4-fluoro-3-formylbenzoic acid with N, O-dimethylhydroxylamine hydrochloride to generate an intermediate 1;
(2) Intermediate 1 reacts with tetrahydropyrrole to form intermediate 2;
(3) Compound 2 is reacted with a reducing agent to form intermediate 3;
(4) Reacting vanillin with acetyl bromo-alpha-D-glucose under alkaline conditions to yield intermediate 4;
(5) Acetylacetone reacts with intermediate 4 to form intermediate 5;
(6) Reacting intermediate 3 with intermediate 5 to form intermediate 6;
(7) And (3) reacting the intermediate 6 under an acidic condition to obtain the curcumin glycosyl derivative.
3. The method for preparing the curcumin glycosyl derivative according to claim 2, wherein in the step (1), the reaction system further comprises 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 4-Dimethylaminopyridine (DMAP) and methylene dichloride, wherein the reaction is carried out for 10-14 hours under the condition of stirring at room temperature;
in the step (2), the reaction is carried out in methanol, and the reaction system also comprises sodium triacetoxyborohydride and glacial acetic acid, and the reaction is carried out for 10-14h at 60-70 ℃.
4. The method for producing a curcumin glycosyl derivative according to claim 2, wherein in the step (3), the reaction is performed in anhydrous diethyl ether, the reducing agent is selected from lithium aluminum hydride, and the reaction is a stirred reaction under ice bath conditions for 1-3 hours;
In the step (4), the alkali under the alkaline condition is selected from anhydrous potassium carbonate, and the reaction is carried out in N, N-dimethylformamide at 40-60 ℃ for 1-3h.
5. The method for preparing the curcumin glycosyl derivative according to claim 2, wherein in the step (5), the method for the reaction comprises the steps of dissolving acetylacetone and diboron trioxide in ethyl acetate, heating to 80-90 ℃ for reflux, cooling to 45-55 ℃ after reacting for 0.5-1.5h, adding an intermediate 4 and tri-n-butyl borate, slowly dropwise adding n-butylamine in ethyl acetate, keeping the temperature at 50+/-2 ℃, and adding hydrochloric acid solution after reacting for 1.5-2.5h to regulate the pH.
6. The method for preparing the curcumin glycosyl derivative according to claim 2, wherein in the step (6), the method for the reaction comprises the steps of dissolving an intermediate 5 and diboron trioxide in ethyl acetate, heating to 80-90 ℃ for reflux, cooling to 45-55 ℃ after reacting for 0.5-1.5h, adding 4-fluoro-3- (pyrrolidin-1-ylmethyl) benzaldehyde and tri-n-butyl borate, slowly dropwise adding n-butylamine in ethyl acetate, keeping the temperature at 50+/-2 ℃, and adding hydrochloric acid solution to adjust the pH after reacting for 1.5-2.5 h.
7. The method for preparing the curcumin glycosyl derivative according to claim 2, wherein in the step (7), the acidic condition is selected from 2N HCl solution, the reaction is carried out in methylene dichloride for 1.5-2.5 hours at 55-65 ℃, and after the reaction is finished, the crude product is recrystallized by methylene dichloride and petroleum ether to obtain the curcumin glycosyl derivative pure product.
8. A pharmaceutical composition comprising the curcumin glycosyl derivative and/or pharmaceutically acceptable salt thereof as claimed in claim 1.
9. Use of a curcumin glycosyl derivative and/or its pharmaceutically acceptable salt as claimed in claim 1, and a pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for treating tumors.
10. The use according to claim 9, wherein the tumour is lung cancer or glioma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311794247.0A CN119119148A (en) | 2023-12-25 | 2023-12-25 | A curcumin glycosyl derivative and its preparation method and medical use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311794247.0A CN119119148A (en) | 2023-12-25 | 2023-12-25 | A curcumin glycosyl derivative and its preparation method and medical use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN119119148A true CN119119148A (en) | 2024-12-13 |
Family
ID=93747078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311794247.0A Pending CN119119148A (en) | 2023-12-25 | 2023-12-25 | A curcumin glycosyl derivative and its preparation method and medical use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN119119148A (en) |
-
2023
- 2023-12-25 CN CN202311794247.0A patent/CN119119148A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102432663B (en) | Celastrol derivative and preparation method thereof and application of celastrol derivative to preparation of antitumor medicine | |
| CN113336765B (en) | Curcumol ester compound, preparation method and application thereof in medicine for treating colorectal cancer | |
| CN111499608B (en) | Benzo [ c ] benzopyrone derivatives and application thereof | |
| CN102153536A (en) | Mangiferin aglycon derivative, as well as preparation method and application of the mangiferin aglycon derivative | |
| CN103275051B (en) | A kind of 7,3 ', 4 '-trihydroxyflavone derivative and preparing the application in Hepatoma therapy medicine | |
| CN111484435B (en) | Tetrahydropyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| US8680251B2 (en) | Triterpenoid 2-deoxy glycosides, method of preparation thereof and use thereof as medicaments | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN108484632B (en) | Artemisinin-anilinoquinazoline derivatives, and preparation method and application thereof | |
| CN116789679A (en) | Cyclicariin 5-glycosylated derivatives and preparation methods and uses thereof | |
| CN117567392B (en) | A pterostilbene paeonol acetic acid compound, its preparation method and medical use | |
| CN106188209B (en) | A kind of melbine conjugate for having antitumor and activity of resisting tumor metastasis concurrently and its application | |
| CN108752404B (en) | A kind of berberine salt derivative and its preparation method and application that triazole is sugar-modified | |
| CN119119148A (en) | A curcumin glycosyl derivative and its preparation method and medical use | |
| CN104592091A (en) | Compound containing Indole acetic acid core structure and application of compound | |
| CN110078770B (en) | Compound with quinolinone tetravalent platinum structure, preparation method and application thereof in the preparation of antitumor drugs | |
| CN112094278B (en) | Aurovertin B derivatives and their preparation methods and applications | |
| CN109206469B (en) | Glycyrrhetinic acid derivative and preparation method and application thereof | |
| CN114805269A (en) | Eriocalyxin B derivative and application thereof in preparation of antitumor drugs | |
| CN110840880B (en) | Application of puerarin derivatives in the preparation of anticancer drugs and a drug for the treatment of cancer | |
| CN104292211A (en) | Desloratadine nitric oxide donor, and preparation method and application thereof | |
| CN109232710B (en) | Preparation method of special iso-steroid alkaloid and derivatives thereof | |
| CN102432603B (en) | Preparation method and pharmacological effect of mangiferin hexa-butyl-esterified derivative | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN101590035B (en) | Application of dehydrogenated silybin in preparing anti-lung-cancer medicament |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |