Nothing Special   »   [go: up one dir, main page]

CN117946007A - Curcumin-amino acid methyl ester derivative and preparation method and application thereof - Google Patents

Curcumin-amino acid methyl ester derivative and preparation method and application thereof Download PDF

Info

Publication number
CN117946007A
CN117946007A CN202410105637.0A CN202410105637A CN117946007A CN 117946007 A CN117946007 A CN 117946007A CN 202410105637 A CN202410105637 A CN 202410105637A CN 117946007 A CN117946007 A CN 117946007A
Authority
CN
China
Prior art keywords
methyl ester
curcumin
formula
amino acid
acid methyl
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
Application number
CN202410105637.0A
Other languages
Chinese (zh)
Inventor
刘文清
徐志栋
杨莎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hebei University of Science and Technology
Original Assignee
Hebei University of Science and Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hebei University of Science and Technology filed Critical Hebei University of Science and Technology
Priority to CN202410105637.0A priority Critical patent/CN117946007A/en
Publication of CN117946007A publication Critical patent/CN117946007A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the technical field of pharmaceutical compounds, and particularly discloses a curcumin-amino acid methyl ester derivative, and a preparation method and application thereof. According to the invention, amino acid methyl ester is used as a modification group, the beta-diketone structure of curcumin is changed into an electron-rich five-membered pyrazole nitrogen heterocycle, a novel compound which takes pyrazole curcumin as a parent nucleus and succinic anhydride as a connecting arm and is connected with the amino acid methyl ester group is designed, and the cervical cancer resistance effect of the compound is obviously superior to that of curcumin, and even the anti-tumor effect equivalent to that of doxorubicin can be achieved. Meanwhile, the compound has the advantages of abundant raw material sources, low price, simple preparation process and convenient industrialized application. Therefore, the discovery of the compound is expected to provide a very promising treatment scheme for cervical cancer patients, and has great significance for breaking through the treatment bottleneck of cervical cancer.

Description

Curcumin-amino acid methyl ester derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical compounds, in particular to a curcumin-amino acid methyl ester derivative, and a preparation method and application thereof.
Background
Cancer is a global public health problem, has a great impact on human health and life, and currently cancer treatment remains a difficult task. The common clinical chemotherapeutic drugs have the defects of low curative effect on solid tumors, large toxic and side effects, easy generation of drug resistance and the like, so that the search for a proper lead compound with an anti-tumor effect from the active ingredients of natural plants is one of important research directions in the research and development of current medicines.
Curcumin (Curcumin, cur) is a plant polyphenol extracted from rhizome of Curcuma longa, and is collected in pharmacopoeia of the people's republic of China. Curcumin was listed by the national cancer institute (National Cancer Institute, NCI) as a third generation anti-cancer chemopreventive agent. Although curcumin has good anticancer prospect, the curcumin cannot fully exert pharmacological activity due to the problems of instability, low bioavailability and the like under in-vivo physiological conditions in clinical use, so that the clinical treatment effect of the curcumin is severely restricted, and the curcumin is a key reason that the curcumin is not yet developed into a medicament. In order to break the bottleneck, curcumin is used as a lead compound, and the curcumin is subjected to structural modification and reformation so as to improve the stability and bioavailability of the curcumin, so that the curcumin has very important significance in realizing the clinical application value of the curcumin.
Disclosure of Invention
Aiming at the technical problems of instability, low bioavailability and the like of curcumin under in-vivo physiological conditions in clinical use at present, the invention provides a curcumin-amino acid methyl ester derivative and a preparation method and application thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
A curcumin-amino acid methyl ester derivative has a structure shown in a formula (I):
Wherein R 1 is
In vivo and in vitro experiments prove that the diketone structure in the curcumin molecular structure is a key factor for causing the curcumin to be unstable under physiological conditions, and the stability of the curcumin can be effectively improved by modifying the diketone structure. Amino acid is a necessary nutrient for cancer cell proliferation, and has the advantages of good biocompatibility, wide pharmacological activity and the like. Therefore, the inventor creatively takes amino acid methyl ester substances as modification groups, changes the beta-diketone structure of curcumin into five-membered pyrazole nitrogen heterocycle rich in electrons, designs and obtains a novel compound which takes pyrazole curcumin as a parent nucleus, takes succinic anhydride as a connecting arm and connects the amino acid methyl ester groups, the anti-tumor effect of the compound is obviously superior to that of curcumin, even can reach the anti-tumor effect equivalent to that of doxorubicin, and provides a novel thought for development and utilization of novel anti-tumor drugs and curcumin, and the potential application value is higher.
Further, R 1 is
The invention also provides a preparation method of the curcumin-amino acid methyl ester derivative, which comprises the following steps:
Taking L-amino acid methyl ester and succinic anhydride as raw materials, and carrying out condensation reaction to obtain a compound shown in a formula (II); wherein the L-amino acid methyl ester hydrochloride is L-proline methyl ester hydrochloride, L-leucine methyl ester hydrochloride, L-alanine methyl ester hydrochloride, L-valine methyl ester hydrochloride, L-phenylalanine methyl ester hydrochloride or L-glutamic acid dimethyl ester hydrochloride;
the curcumin and hydrazine hydrate are taken as raw materials, and a compound shown in a formula (III) is obtained through cyclization reaction;
The compound shown in the formula (III) is subjected to acid-amine condensation reaction with the compound shown in the formula (II) after hydroxyl is protected, and deprotection is carried out to obtain the curcumin-amino acid methyl ester derivative shown in the formula (I);
Compared with the prior art, the preparation method of the curcumin-amino acid methyl ester derivative has the advantages of short synthesis steps, simplicity in operation, mild reaction conditions, high purity of the prepared product, good industrial utilization value and higher popularization and application values.
The structure of each L-amino acid methyl ester is shown in the following table:
Further, the preparation method of the curcumin-amino acid methyl ester derivative specifically comprises the following steps:
s1, adding L-amino acid methyl ester hydrochloride, 4-dimethylaminopyridine and organic base into succinic anhydride solution, performing condensation reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain a compound shown in a formula (II);
S2, dissolving curcumin in glacial acetic acid, adding hydrazine hydrate, performing cyclization reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain a compound shown in a formula (III);
S3, adding the compound shown in the formula (III) and organic base into the organic solvent a, uniformly mixing, adding a TBS hydroxyl protecting agent, and monitoring until the reaction is finished by thin-layer chromatography to obtain the compound shown in the formula (IV);
S4, adding a compound shown in a formula (II), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole into an organic solvent b, stirring and activating, adding a compound shown in a formula (IV), performing an acid-amine condensation reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain a compound shown in a formula (V);
s5, dissolving a compound shown in a formula (V) in an organic solvent c, adding glacial acetic acid, adding fluoride, performing deprotection reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain the curcumin-amino acid methyl ester derivative shown in the formula (I), wherein the specific synthetic route is as follows:
r in the above reaction equation represents L-proline methyl ester hydrochloride, L-leucine methyl ester hydrochloride, L-alanine methyl ester hydrochloride, L-valine methyl ester hydrochloride, L-phenylalanine methyl ester hydrochloride or L-glutamic acid dimethyl ester hydrochloride.
Further, in S1, the molar ratio of the 4-dimethylaminopyridine, the organic base, the succinic anhydride and the L-amino acid methyl ester hydrochloride is (0.5-5): 1.
Further, in S1, the organic base is at least one of triethylamine, ammonia water or diisopropylethylamine.
Further, in S1, the temperature of the condensation reaction is (20-40).
Further, in S2, the molar ratio of the curcumin to the hydrazine hydrate is 1 (1-10).
Further, in S2, the molar volume ratio of the curcumin to the glacial acetic acid is 1mmoL (1-50) mL.
In S2, the temperature of the cyclization reaction is (90-120).
In S3, the molar ratio of the organic base, TBS hydroxyl protecting agent and the compound shown in the formula (III) is (1-10): 1.
Further, in S3, the volume molar ratio of the organic solvent a to the compound represented by the formula (III) is (0.1-20) mL:1mmoL.
Further, in S3, the reaction temperature is (20 to 40).
Further, in S3, the organic solvent a is at least one of N, N-dimethylformamide, dimethyl sulfoxide or toluene.
Further, in S3, the organic base is at least one of imidazole, pyridine or triethylamine.
Further, in S3, the TBS hydroxyl protecting agent is one or two of TBDMS-Cl or TBSOTf.
In S4, the molar ratio of the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the 1-hydroxybenzotriazole, the compound shown in the formula (IV) and the compound shown in the formula (II) is (1-10): 1 (0.5-8).
Further, in S4, the organic solvent b is at least one of anhydrous dichloromethane, N-dimethylformamide or dimethyl sulfoxide.
Further, in S4, the volume molar ratio of the organic solvent b to the compound represented by the formula (II) is (1-20) mL/1 mmol.
Further, in S4, the temperature of the acid amine condensation reaction is (20-40).
In S5, the molar ratio of the glacial acetic acid, the fluoride and the compound shown in the formula (V) is (1-10): 1.
Further, in S5, the organic solvent c is anhydrous tetrahydrofuran.
Further, in S5, the fluoride is one or two of tetrabutylammonium fluoride or pyridine hydrogen fluoride complex.
Further, in S5, the volume molar ratio of the organic solvent c to the compound represented by the formula (V) is (10-50) mL:1mmoL.
Further, in S5, the temperature of the deprotection reaction is (-10 to 10) DEG C.
The above preferred reaction conditions are advantageous for improving the yield and purity of the target product.
The invention also provides application of the curcumin-amino acid methyl ester derivative in preparing an anti-cervical cancer drug.
The curcumin-amino acid methyl ester derivative provided by the invention has obvious activity of inhibiting the proliferation of cervical cancer cells Hela cells in vitro, has obviously better inhibiting activity on cervical cancer cells than curcumin, can even achieve the anti-cervical cancer activity equivalent to doxorubicin, and can be used for preparing medicaments for treating and preventing the anti-cervical cancer. Meanwhile, the compound has the advantages of abundant raw material sources, low price, simple preparation process and convenient industrialized application. Therefore, the discovery of the compound is expected to provide a very promising treatment scheme for cervical cancer patients, has important significance for breaking through the treatment bottleneck of cervical cancer and developing patent medicine of curcumin, and has wide potential application fields.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to better illustrate the present invention, the following examples are provided for further illustration.
Example 1
Compounds a to F were prepared according to the following scheme:
Preparation of Compound A:
L-proline methyl ester hydrochloride (1.50 g,9.05 mmol), 4-Dimethylaminopyridine (DMAP) (1.11 g,9.05 mmol) and triethylamine (Et 3 N) (1.2 mL) were added sequentially to a solution of succinic anhydride (1.08 g,10.87 mmol) in dichloromethane (20 mL). The progress of the reaction was monitored by thin layer chromatography, after stirring at room temperature for 17h, the reaction was quenched by addition of 10% aqueous NaHCO 3 (15 mL), the aqueous layer was acidified to pH 5-6 with 2N HCl and extracted with ethyl acetate (3X 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off under suction, and the filtrate concentrated under reduced pressure to give Compound A as a pale yellow viscous liquid, 1.28g, yield 61.7%.
Structural identification data ：1H NMR(500MHz,Methanol-d4)δ4.45(m,1H),3.73(s,3H),3.70-3.65(m,2H),2.75-2.59(m,6H),2.08-2.04(m,2H).
Preparation of compound B:
L-leucine methyl ester hydrochloride (1.50 g,8.26 mmol), 4-Dimethylaminopyridine (DMAP) (1.01 g,8.26 mmol) and triethylamine (Et 3 N) (1.1 mL) were added sequentially to a solution of succinic anhydride (0.99 g,9.91 mmol) in dichloromethane (20 mL), the progress of the reaction was monitored by thin layer chromatography, stirred at room temperature for 17h and then quenched by the addition of 10% aqueous NaHCO 3 (15 mL). The aqueous layer was acidified to pH 5-6 with 2N HCl and extracted with ethyl acetate (3X 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give Compound B as a yellow viscous liquid, 1.75g, 86.6% yield.
Structural identification data ：1H NMR(500MHz,CDCl3-d)δ8.34(br,1H),4.59-4.55(m,1H),3.70(s,3H),2.67-2.64(m,2H),2.55-2.52(m,2H),1.66-1.51(m,3H),0.91-0.88(m,6H).
Preparation of compound C:
L-alanine methyl ester hydrochloride (1.50 g,10.75 mmol), 4-Dimethylaminopyridine (DMAP) (1.31 g,10.75 mmol) and triethylamine (Et 3 N) (1.5 mL) were added sequentially to a solution of succinic anhydride (1.29 g,12.89 mmol) in dichloromethane (20 mL), the progress of the reaction was monitored by thin layer chromatography, after stirring at room temperature for 17h, 10% aqueous NaHCO 3 (15 mL) was added to quench the reaction, the aqueous layer was acidified to pH 5-6 with 2N HCl and extracted with ethyl acetate (3X 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate was concentrated under reduced pressure to give compound C as a pale yellow viscous liquid, 1.20g, yield 55.0%.
Structural identification data ：1H NMR(500MHz,Methanol-d4)δ5.02(br,1H).4.42(m,1H),3.74(s,3H),2.61-2.60(m,2H),2.57-2.53(m,2H),1.40(d,J＝7.3Hz,3H).
Preparation of compound D:
L-valine methyl ester hydrochloride (1.50 g,8.95 mmol), 4-Dimethylaminopyridine (DMAP) (1.09 g,8.95 mmol) and triethylamine (Et 3 N) (1.2 mL) were added sequentially to a solution of succinic anhydride (1.07 g,10.74 mmol) in dichloromethane (20 mL), the progress of the reaction was monitored by thin layer chromatography, and after stirring at room temperature for 17h, the reaction was quenched by addition of 10% aqueous NaHCO 3 (15 mL). The aqueous layer was acidified to pH 5-6 with 2N HCl and extracted with ethyl acetate (3X 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give compound D as a pale yellow viscous liquid, 1.48g, 71.5% yield.
Structural identification data ：1H NMR(500MHz,Methanol-d4)δ11.18(s,1H),6.88(d,J＝8.8Hz,1H),4.50(dd,J＝8.8,5.2Hz,1H),3.70(s,3H),2.69-2.62(m,2H),2.57-2.53(m,2H),2.14-2.07(m,1H),0.88(m,6H).
Preparation of Compound E:
L-phenylalanine methyl ester hydrochloride (1.50 g,6.95 mmol), 4-Dimethylaminopyridine (DMAP) (0.85 g,6.95 mmol) and triethylamine (Et 3 N) (1.0 mL) were added sequentially to a solution of succinic anhydride (0.83 g,8.34 mmol) in dichloromethane (20 mL), the progress of the reaction was monitored by thin layer chromatography, after stirring at room temperature for 17h, the reaction was quenched by addition of 10% aqueous NaHCO 3 (15 mL), the aqueous layer was acidified to pH 5-6 with 2N HCl and extracted with ethyl acetate (3X 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give compound E as a pale yellow viscous liquid, 1.51g, yield 72.4%.
Structural identification data ：1H NMR(500MHz,Methanol-d4)δ7.32-7.27(m,3H),7.12(d,J＝7.0Hz,2H),6.36(d,J＝7.8Hz,1H),4.93-4.89(m,1H),3.75(s,3H),3.19-3.09(m,2H),2.74-2.68(m,2H),2.54-2.51(m,2H).
Preparation of compound F:
Dimethyl L-glutamate hydrochloride (1.50 g,7.09 mmol), 4-Dimethylaminopyridine (DMAP) (0.87 g,7.09 mmol) and triethylamine (Et 3 N) (1.0 mL) were added sequentially to a solution of succinic anhydride (0.85 g,8.50 mmol) in dichloromethane (20 mL), the progress of the reaction was monitored by thin layer chromatography, after stirring at room temperature for 17h, the reaction was quenched by addition of 10% aqueous NaHCO 3 (15 mL), the aqueous layer was acidified to pH 5-6 with 2N HCl and extracted with ethyl acetate (3X 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give compound F as a pale yellow viscous liquid, 1.80g, yield 92.3%.
Structural identification data ：1H NMR(500MHz,Methanol-d4)δ8.06(br,1H),4.50(dd,J＝8.8,5.2Hz,1H),3.69(s,3H),3.63(s,3H),2.67-2.58(m,4H),2.53(d,J＝6.6Hz,2H),2.39-2.35(m,2H). structural formulas of the compounds a to F prepared in this example are shown in table 1 below.
TABLE 1 structural formulas of Compounds A through F
Example 2
Compound CCM-1 was prepared according to the following route:
Hydrazine hydrate (2.80 g,55.8 mmol) is slowly dripped into glacial acetic acid (100 mL) solution of curcumin (10.00 g,27.1 mmol) at room temperature, after the addition, stirring, heating and refluxing are carried out, the reaction liquid changes from orange yellow suspension to reddish brown clear, the reaction progress is monitored by thin layer chromatography, the reaction is stopped after 8h, the solvent is evaporated, the crude product is dissolved in ethyl acetate, pure water (3X 15 mL) and saturated saline (3X 15 mL) are sequentially used for washing, the organic phase is dried by anhydrous sodium sulfate, suction filtration is carried out, the filtrate is concentrated under reduced pressure, absolute ethyl alcohol (20 mL) is added for pulping and purification, suction filtration is carried out, and the compound CCM-1, light yellow solid, 5.50g and the yield 55.0% are obtained after the filter cake is dried.
Structural identification data ：m.p.＝(212.7-215.1)℃;1H NMR(500MHz,DMSO-d6)δ12.78(s,1H,NH),9.16(s,2H,2×Ar-OH),7.14(s,2H),7.04(d,2H),6.94-6.90(m,4H),6.77(d,J＝8.1Hz,2H),6.58(s,1H),3.83(s,6H,2×Ar-OCH3).LC-MS(ESI,m/z)Calcd for:C21H20N2O4[M+H+]:365.4,found:365.1.
Example 3
Compound CCM-2 was prepared according to the following route:
The compound CCM-1 (8.00 g,22.0 mmol) prepared in example 2 was added to a 100mL flask at room temperature, imidazole (3.74 g,54.9 mmol) and N, N-Dimethylformamide (DMF) (16 mL) were added thereto, TBDMS-Cl (8.25 g,54.9 mmol) was added after stirring for 30min, the progress of the reaction was monitored by thin layer chromatography, after 5h at room temperature, 10mL of pure water was added to quench the reaction, extraction was performed with ethyl acetate (3X 30 mL), the organic phases were combined, washed successively with pure water (3X 30 mL), saturated aqueous sodium bicarbonate (3X 30 mL) and saturated brine (3X 30 mL), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, slurried with anhydrous ethanol (16 mL), filtered, and the filter cake was dried to give compound CCM-2 as a white solid powder, 12.01g, yield 92.2%.
Structural identification data ：m.p.＝(219.3-223.1)℃;1H NMR(500MHz,DMSO-d6)δ12.94(s,1H,NH),7.26-7.06(m,5H),7.03-6.95(m,3H),6.83(dd,J＝17.5,8.0Hz,2H),6.69(s,1H),3.84(s,6H,2×Ar-OCH3),0.98(s,18H,2×SiC(CH3)3),0.15(s,12H,2×Si(CH3)2).LC-MS(ESI,m/z)Calcd for:C33H48N2O4Si2[M+H]+:593.3,found:593.4.
Example 4
CCM-4A to CCM-4F were prepared according to the following route:
synthesis of CCM-4A compound:
To a 25mL single-necked flask, compound A (0.35 g,1.18 mmol) prepared in example 1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.27 g,1.41 mmol), 1-Hydroxybenzotriazole (HOBT) (0.19 g,1.41 mmol) and anhydrous dichloromethane (10 mL) were sequentially added under ice-water bath, the ice-bath was removed after stirring and activation for 1h in the ice-water bath, CCM-2 (0.71 g,1.18 mmol) prepared in example 3 was added, the progress of the reaction was monitored by thin layer chromatography, after 24h of reaction at room temperature, 10mL of pure water was added to quench the reaction, an organic layer was separated, the aqueous phase was extracted with ethyl acetate (3X 10 mL), the organic phase was combined, washed with pure water (3X 10 mL), saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by suction chromatography (eluent: 150:1.05 g: 1.55% of the compound was obtained by silica gel, and the yield was 1.55% to 0.05 g.
To a flask containing compound CCM-3A (0.50 g,0.62 mmol) was successively added anhydrous tetrahydrofuran (6 mL) and glacial acetic acid (0.07 mL), the reaction was placed in an ice bath, tetrabutylammonium fluoride (TBAF) (1.3 mL) was slowly added dropwise thereto, after the dropwise addition, the ice bath was kept warm and stirred for 30min, 10mL of pure water was added to quench the reaction, ethyl acetate (3X 10 mL) was extracted, the organic phases were combined, washed successively with pure water (3X 10 mL), saturated aqueous sodium bicarbonate (3X 10 mL) and saturated brine (3X 10 mL), the organic phases were collected, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent dichloromethane and methanol, volume ratio 80:1 to 60:1) to obtain compound CCM-4A as a yellow viscous liquid, 0.23g, yield 65%, purity 98.89%.
Structural identification data ：m.p.＝(104.2-106.7)℃;1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),9.30(s,1H),7.65(d,J＝16.4Hz,1H),7.31-7.27(m,4H),7.11(d,J＝1.8Hz,1H),7.07(d,J＝16.5Hz,1H),7.03-7.00(m,2H),6.82(dd,J＝11.9,8.1Hz,2H),4.31(dd,J＝8.7,4.1Hz,1H),3.86(s,3H),3.85(s,3H),3.61(s,3H),3.44-3.40(m,1H),3.33-3.27(m,1H),2.53(s,2H),2.51(s,2H),2.23-1.96(m,2H),1.96-1.84(m,2H).LC-MS(ESI,m/z)Calcd for:C31H33N3O8[M+Na]+:598.2,found:598.4.
Preparation of CCM-4B Compound:
To a 25mL single-necked flask, compound B (0.35 g,1.42 mmol) prepared in example 1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.27 g,1.42 mmol), 1-Hydroxybenzotriazole (HOBT) (0.19 g,1.42 mmol) and N, N-dimethylformamide (10 mL) were sequentially added under ice-water bath, the ice bath was removed after stirring and activating for 1 hour in the ice-water bath, CCM-2 (0.71 g,1.18 mmol) prepared in example 3 was added, the progress of the reaction was monitored by thin layer chromatography, after a reaction was carried out at room temperature for 24 hours, 20mL of pure water was added to quench the reaction, an organic layer was separated, the aqueous phase was extracted with ethyl acetate (3X 10 mL), the organic phase was combined, washed with pure water (3X 20 mL), a saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the crude product was purified by chromatography (ethyl acetate: 693:693 volume% ethyl acetate, and the compound was obtained by volume ratio of 1:1.693.693.1.60% to yield.
To a flask containing compound CCM-3B (0.39 g,0.48 mmol) was successively added anhydrous tetrahydrofuran (6 mL) and glacial acetic acid (0.06 mL), the reaction was placed in an ice bath, tetrabutylammonium fluoride (TBAF) (1.0 mL) was slowly added dropwise thereto, after the dropwise addition, the ice bath was kept warm and stirred for 30min, 10mL of pure water was added to quench the reaction, ethyl acetate (3X 10 mL) was extracted, the organic phases were combined, washed successively with pure water (3X 10 mL), saturated aqueous sodium bicarbonate (3X 10 mL) and saturated brine (3X 10 mL), the organic phases were collected, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent dichloromethane and methanol, volume ratio 100:1 to 60:1) to give compound CCM-4B as a pale yellow solid powder, 0.21g, yield 75.0%, purity 98.59%.
Structural identification data :m.p.＝(113.6-116.4)℃;1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),9.30(s,1H),8.38-8.36(m,1H),7.68-7.63(m,1H),7.31-7.24(m,4H),7.11(d,J＝1.7Hz,1H),7.08-7.00(m,3H),6.82(dd,J＝12.3,8.1Hz,2H),4.34-4.29(m,1H),3.86(s,3H),3.85(s,3H),3.63(s,3H),2.78-2.73(m,2H),2.66-2.58(m,2H),1.70-1.55(m,2H),1.53-1.50(m,1H),0.88-0.85(m,6H).LC-MS(ESI,m/z)Calcd for:C32H37N3O8[M+H]+:592.2,found:592.2.
Preparation of CCM-4C compound:
To a 25mL single-necked flask, compound C (0.26 g,1.30 mmol) prepared in example 1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.27 g,1.42 mmol), 1-Hydroxybenzotriazole (HOBT) (0.19 g,1.42 mmol) and anhydrous dichloromethane (10 mL) were sequentially added under ice-water bath, the ice bath was removed after stirring and activation in ice-water bath, compound CCM-2 (0.71 g,1.18 mmol) prepared in example 3 was added, the progress of the reaction was monitored by thin layer chromatography, after reaction at room temperature for 24h, 10mL of pure water was added to quench the reaction, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (3X 10 mL), the organic phase was combined, washed with pure water (3X 10 mL), saturated aqueous sodium bicarbonate (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by silica gel chromatography (ethyl acetate and ethyl acetate volume: 15:1.50 g, the compound was obtained as a 1.50% of the compound by volume ratio of 15:3.50.55).
To a flask containing compound CCM-3C (0.50 g,0.90 mmol) was successively added anhydrous tetrahydrofuran (10 mL) and glacial acetic acid (0.2 mL), the reaction was placed in an ice bath, tetrabutylammonium fluoride (TBAF) (1.9 mL) was slowly added dropwise thereto, after the addition, 10mL of pure water was added to quench the reaction, ethyl acetate (3X 10 mL) was extracted, the organic phase was combined, washed successively with pure water (3X 10 mL), saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane and methanol at a volume ratio of 100:1 to 60:1) to obtain compound CCM-4C as a yellow solid powder, 0.25g, yield 51.2% and purity 98.45%.
Structural identification data :m.p.＝(121.5-123.2)℃;1H NMR(500MHz,DMSO-d6)δ9.38(s,1H),9.30(s,1H),8.43(d,J＝7.0Hz,1H),7.65(d,J＝16.4Hz,1H),7.31-7.27(m,3H),7.12(d,J＝1.8Hz,1H),7.05-7.01(m,3H),6.96-6.94(m,1H),6.83(dd,J＝13.0,8.1Hz,2H),4.32-4.26(m,1H),3.87(s,3H),3.85(s,3H)3.64(s,3H),2.53(m,2H),2.51(m,2H),1.31(d,J＝7.3Hz,3H).LC-MS(ESI,m/z)Calcd for:C29H31N3O8[M+Na]+:572.2,found:572.1.
Preparation of CCM-4D compound:
To a 25mL single-necked flask, compound D (0.23 g,1.01 mmol) prepared in example 1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.19 g,1.01 mmol), 1-Hydroxybenzotriazole (HOBT) (0.14 g,1.01 mmol) and dimethyl sulfoxide (10 mL) were sequentially added under ice-water bath, the ice bath was removed after stirring and activation in ice-water bath, compound CCM-2 (0.50 g,0.82 mmol) prepared in example 3 was added, the progress of the reaction was monitored by thin layer chromatography, after reaction at room temperature for 24h, 20mL of pure water was added to quench the reaction, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (3X 10 mL), the organic phase was combined, washed with pure water (3X 20 mL), saturated aqueous sodium bicarbonate (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by silica gel chromatography (ethyl acetate and ethyl acetate volume: 7:39 g, 1.39.6% of compound was obtained by volume to yield 1.39.6% of CCM.
To a flask containing the compound CCM-3D (0.38 g,0.47 mmol), anhydrous tetrahydrofuran (10 mL) and glacial acetic acid (0.06 mL) were sequentially added, the reaction was placed in an ice bath, tetrabutylammonium fluoride (TBAF) (1.0 mL) was slowly added dropwise thereto, after the addition, 10mL of pure water was added to quench the reaction, ethyl acetate (3X 10 mL) was extracted, the organic phases were combined, washed with pure water (3X 10 mL), saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL) in this order, the organic phases were collected, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane and methanol at a volume ratio of 100:1 to 60:1) to obtain compound CCM-4D as a yellow solid powder, 0.17g, yield 63.1% and purity 98.48%.
Structural identification data :m.p.＝(109.0-112.2)℃;1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),9.30(s,1H),8.30(d,J＝8.2Hz,1H),7.64(d,J＝16.4Hz,1H),7.31-7.27(m,4H),7.11(d,J＝1.8Hz,1H),7.05-7.00(m,3H),6.82(dd,J＝12.8,8.1Hz,2H),4.22-4.19(m,1H),3.86(s,3H),3.85(s,3H),3.65(s,3H),2.53-2.51(m,4H)2.07-2.03(m,1H),0.93(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H).LC-MS(ESI,m/z)Calcd for:C31H35N3O8[M+Na]+:600.2,found:600.3.
Preparation of CCM-4E compound:
To a 25mL single-necked flask, compound E (0.40 g,1.42 mmol) prepared in example 1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.27 g,1.42 mmol), 1-Hydroxybenzotriazole (HOBT) (0.19 g,1.42 mmol) and anhydrous dichloromethane (10 mL) were sequentially added under ice-water bath, the ice bath was removed after stirring and activation in ice-water bath, compound CCM-2 (0.70 g,1.18 mmol) prepared in example 3 was added, the progress of the reaction was monitored by thin layer chromatography, after reaction at room temperature for 24h, 10mL of pure water was added to quench the reaction, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (3X 10 mL), the organic phase was combined, washed with pure water (3X 10 mL), saturated aqueous sodium bicarbonate (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by methanol chromatography (volume eluent: 200:1.73.73 g, 1.873% of compound was obtained by volume).
To a flask containing compound CCM-3E (0.87 g,0.21 mmol), anhydrous tetrahydrofuran (10 mL) and glacial acetic acid (0.1 mL) were sequentially added, the reaction was placed in an ice bath, tetrabutylammonium fluoride (TBAF) (2.1 mL) was slowly dropped therein, after dropping, 10mL of pure water was added to quench the reaction, ethyl acetate (3X 10 mL) was extracted, the organic phase was combined, washed with pure water (3X 10 mL), saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL) in this order, the organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain compound CCM-4E as a yellow solid powder, 0.43g, yield 70.0% and purity 98.78% by silica gel column chromatography purification (eluent: dichloromethane and methanol: volume ratio 150:1).
Structural identification data :m.p.＝(132.1-133.6)℃;1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),9.30(s,1H),8.50(d,J＝7.7Hz,1H),7.65(d,J＝16.4Hz,1H),7.32-7.21(m,10H),7.12(d,J＝1.7Hz,1H),7.04-7.01(m,2H),3.86(s,3H),3.83(s,3H),4.51-4.47(m,1H),3.85(d,J＝12.3Hz,6H),3.61(s,3H),3.06-2.92(m,2H),2.57(m,2H),2.53(m,2H).LC-MS(ESI,m/z)Calcd for:C35H35N3O8[M+H]+:626.2,found:626.1.
Preparation of CCM-4F compound:
To a 25mL single-necked flask, compound F (0.39 g,1.42 mmol) prepared in example 1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.27 g,1.42 mmol), 1-Hydroxybenzotriazole (HOBT) (0.19 g,1.42 mmol) and anhydrous dichloromethane (10 mL) were sequentially added under ice-water bath, the ice-bath was removed after stirring and activation in ice-water bath, compound CCM-2 (0.70 g,1.18 mmol) prepared in example 3 was added, the progress of the reaction was monitored by thin layer chromatography, after a reaction time of 24 hours at room temperature, 10mL of pure water was added thereto to quench the mixture, an organic layer was separated, the aqueous phase was extracted with ethyl acetate (3X 10 mL), the organic phase was combined, washed with pure water (3X 10 mL), a saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (volume eluent: 150:1.673 g to 67.6% of dichloromethane, yield of compound was obtained by volume ratio of 150:1.673.673.
To a flask containing compound CCM-3F (0.67 g,0.79 mmol) was successively added anhydrous tetrahydrofuran (10 mL) and glacial acetic acid (0.1 mL), the reaction was placed in an ice bath, tetrabutylammonium fluoride (TBAF) (1.7 mL) was slowly dropped therein, after dropping, 10mL of pure water was added to quench the reaction, ethyl acetate (3X 10 mL) was extracted, the organic phases were combined, washed successively with pure water (3X 10 mL), saturated aqueous sodium bicarbonate solution (3X 10 mL) and saturated brine (3X 10 mL), the organic phases were collected, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane and methanol at a volume ratio of 100:1 to 60:1) to give compound CCM-4F as a pale yellow solid powder, 0.23g, yield 46.8%, purity 98.61%.
Structural identification data :m.p.＝(110.3-112.3)℃;1H NMR(500MHz,DMSO-d6)δ9.40(s,1H),9.31(s,1H),8.43(d,J＝7.6Hz,1H),7.65(d,J＝16.4Hz,1H),7.31-7.27(m,4H),7.12(d,J＝1.7Hz,1H),7.07(d,J＝16.5Hz,1H),7.03-7.01(m,2H),6.82(dd,J＝13.1,8.1Hz,2H),4.34-4.30(m,1H),3.86(s,3H),3.85(s,3H),3.64(s,3H),3.59(s,3H),2.73-2.72(m,2H),2.65-2.57(m,2H),2.45-2.42(m,2H),2.38-2.24(m,2H).LC-MS(ESI,m/z)Calcd for:C32H35N3O10[M+H]+:644.2,found:644.4.
The structural formula of the curcumin-amino acid methyl ester derivative prepared in this example is shown in the following table 2:
TABLE 2 structural formulas of target compounds CCM-4A-CCM-4F
The reaction materials in the above examples, and the amounts of each of the reaction materials added may be other reaction conditions defined by the present invention, and the compounds CCM-4A to CCM-4F having higher purity may be prepared as long as they are within the scope defined by the present invention.
Example 6
Proliferation effect on human cervical cancer cell Hela
The CCK-8 experiment is a commonly used cell proliferation and toxicity detection method, and the principle is that a WST-8 reagent is utilized to react with dehydrogenase in cells to generate formazan dye, and the proliferation condition of the cells and the toxic effect of the drug on the cells are quantitatively analyzed by measuring the absorbance value of the formazan dye in a culture medium. The effect of curcumin-amino acid methyl ester derivatives (CCM-4A-CCM-4F) with different concentrations on the proliferation activity of human cervical cancer cells Hela is detected by adopting a 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonyl benzene) -2H-tetrazolium monosodium salt) (CCK-8) method.
Spreading human cervical cancer Hela cells in logarithmic phase in 96-well plate, standing overnight, removing original culture solution, adding 90 μL of fresh culture solution containing curcumin-amino acid methyl ester derivatives (CCM-4A-CCM-4F) with different concentrations of 0 μM, 1 μM,5 μM, 10 μM, 20 μM, 50 μM and 100 μM, setting corresponding blank control group and curcumin positive control group, and doxorubicin positive control group, incubating at 37deg.C for 24 hr, adding CCK-8 reagent (10 μL per well), incubating 96-well plate in incubator for 4 hr, and measuring absorbance OD at 450nm with enzyme-labeled instrument after incubation. Cell growth rate was obtained by the following formula: cell growth (%) = (OD treatment/OD blank) ×100%. 3 parallel wells were set for each concentration and the test was repeated 3 times. The median inhibitory concentration (IC 50) values were calculated using GRAPHPAD PRISM software and the results are shown in table 3.
TABLE 3 IC 50 values of curcumin-amino acid methyl ester derivatives (CCM-4A-CCM-4F) on Hela cells
According to the experimental results of CCK-8 method shown in Table 3, the IC 50 values of the synthesized CCM-4A-CCM-4F on Hela cells are lower than those of the control curcumin (IC 50 = 13.990 mu M). Therefore, the CCM-4A-CCM-4F has better inhibition effect on human cervical cancer Hela cells, wherein the IC 50 values of the compounds CCM-4B, CCM-4D and CCM-4F are equivalent to the antitumor effect of the positive control drug doxorubicin.
In conclusion, the curcumin-amino acid methyl ester derivative provided by the invention has obvious inhibition activity on cervical cancer cells, provides a novel drug compound for preventing and treating cervical cancer, is simple and convenient to operate, has mild reaction conditions, is easy to obtain raw materials, is suitable for industrial scale production, and has higher potential application value.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims (10)

1. A curcumin-amino acid methyl ester derivative is characterized in that the structure is shown as a formula (I):
Wherein R 1 is
2. The curcumin-amino acid methyl ester derivative as claimed in claim 1, wherein R 1 is
3. A method for preparing the curcumin-amino acid methyl ester derivative as defined in claim 1 or 2, comprising the following steps:
Taking L-amino acid methyl ester and succinic anhydride as raw materials, and carrying out condensation reaction to obtain a compound shown in a formula (II); wherein the L-amino acid methyl ester hydrochloride is L-proline methyl ester hydrochloride, L-leucine methyl ester hydrochloride, L-alanine methyl ester hydrochloride, L-valine methyl ester hydrochloride, L-phenylalanine methyl ester hydrochloride or L-glutamic acid dimethyl ester hydrochloride;
the curcumin and hydrazine hydrate are taken as raw materials, and a compound shown in a formula (III) is obtained through cyclization reaction;
The compound shown in the formula (III) is subjected to acid-amine condensation reaction with the compound shown in the formula (II) after hydroxyl is protected, and deprotection is carried out to obtain the curcumin-amino acid methyl ester derivative shown in the formula (I);
4. The method for preparing curcumin-amino acid methyl ester derivatives as claimed in claim 3, comprising the following steps:
s1, adding L-amino acid methyl ester hydrochloride, 4-dimethylaminopyridine and organic base into succinic anhydride solution, performing condensation reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain a compound shown in a formula (II);
S2, dissolving curcumin in glacial acetic acid, adding hydrazine hydrate, performing cyclization reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain a compound shown in a formula (III);
S3, adding the compound shown in the formula (III) and organic base into the organic solvent a, uniformly mixing, adding a TBS hydroxyl protecting agent, and monitoring until the reaction is finished by thin-layer chromatography to obtain the compound shown in the formula (IV);
S4, adding a compound shown in a formula (II), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole into an organic solvent b, stirring and activating, adding a compound shown in a formula (IV), performing an acid-amine condensation reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain a compound shown in a formula (V);
S5, dissolving the compound shown in the formula (V) in an organic solvent c, adding glacial acetic acid, adding fluoride, performing deprotection reaction, and monitoring by thin layer chromatography until the reaction is finished to obtain the curcumin-amino acid methyl ester derivative shown in the formula (I).
5. The method for preparing curcumin-amino acid methyl ester derivative according to claim 4, wherein in S1, the molar ratio of 4-dimethylaminopyridine, organic base, succinic anhydride and L-amino acid methyl ester hydrochloride is (0.5-5): 0.5-5:1; and/or
In S1, the organic base is at least one of triethylamine, ammonia water or diisopropylethylamine; and/or
In S1, the temperature of the condensation reaction is (20-40).
6. The method for producing curcumin-amino acid methyl ester derivatives according to claim 4, wherein in S2, the molar ratio of curcumin to hydrazine hydrate is 1 (1-10); and/or
In S2, the molar volume ratio of the curcumin to the glacial acetic acid is 1mmoL (1-50) mL; and/or
In S2, the temperature of the cyclization reaction is (90-120).
7. The method for producing a curcumin-amino acid methyl ester derivative according to claim 4, wherein in S3, the molar ratio of the organic base, TBS hydroxyl protecting agent to the compound represented by the formula (III) is (1-10): 1; and/or
In S3, the volume mole ratio of the organic solvent a to the compound shown in the formula (III) is (0.1-20) mL, 1mmoL; and/or
S3, the reaction temperature is (20-40) DEG C; and/or
In S3, the organic solvent a is at least one of N, N-dimethylformamide, dimethyl sulfoxide or toluene; and/or
In S3, the organic base is at least one of imidazole, pyridine or triethylamine.
8. The method for producing a curcumin-amino acid methyl ester derivative according to claim 4, wherein in S4, the molar ratio of the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, the compound represented by the formula (IV) to the compound represented by the formula (II) is (1-10): 1 (0.5-8); and/or
In S4, the organic solvent b is at least one of anhydrous methylene dichloride, N-dimethylformamide or dimethyl sulfoxide; and/or
In S4, the volume molar ratio of the organic solvent b to the compound shown in the formula (II) is (1-20) mL, 1mmoL; and/or
In S4, the temperature of the acid amine condensation reaction is (20-40).
9. The method for producing a curcumin-amino acid methyl ester derivative according to claim 4, wherein in S5, the molar ratio of glacial acetic acid, fluoride to the compound represented by the formula (V) is (1-10): 1; and/or
S5, the organic solvent c is anhydrous tetrahydrofuran; and/or
In S5, the volume mole ratio of the organic solvent c to the compound shown in the formula (V) is (10-50) mL, 1mmoL; and/or
In S5, the temperature of the deprotection reaction is (-10) DEG C.
10. The use of curcumin-amino acid methyl ester derivatives as claimed in claim 1 or 2 in preparing anti-cervical cancer drugs.
CN202410105637.0A 2024-01-25 2024-01-25 Curcumin-amino acid methyl ester derivative and preparation method and application thereof Pending CN117946007A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202410105637.0A CN117946007A (en) 2024-01-25 2024-01-25 Curcumin-amino acid methyl ester derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202410105637.0A CN117946007A (en) 2024-01-25 2024-01-25 Curcumin-amino acid methyl ester derivative and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN117946007A true CN117946007A (en) 2024-04-30

Family

ID=90802590

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202410105637.0A Pending CN117946007A (en) 2024-01-25 2024-01-25 Curcumin-amino acid methyl ester derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN117946007A (en)

Similar Documents

Publication Publication Date Title
CN113150058B (en) Tripterine derivative and preparation method and application thereof
CN107286220B (en) 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof
CN111646941A (en) Sulfonamide derivative and preparation method and application thereof
CN111704646A (en) Steroid compound and preparation method and application thereof
CN113416189B (en) Beta-carbopol Lin Dangai derivative, preparation method and anti-tumor application
CN110642740B (en) Isostaviolamide derivative and preparation method thereof
CN112457365B (en) Functional molecules targeting proteolytic pathway, preparation and application thereof
CN117946007A (en) Curcumin-amino acid methyl ester derivative and preparation method and application thereof
CN111471080A (en) ocotillol type ginsengenin A-ring amino thiazole ring derivative and preparation method thereof
CN115246869B (en) Tripterine-thiazolidinedione derivative, and preparation method and application thereof
CN107522857A (en) A kind of tanshinone IIA high-molecular compound and its preparation and application
CN110240631A (en) Chiral isoindolone and cyclic hexapeptide derivatives, its preparation method and purposes
CN112225730B (en) Crystal form of condensed-cyclic compound, composition, preparation method and application thereof
CN111961048B (en) Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof
CN111362962B (en) Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof
CN102485735B (en) 6-fructosamine-4-arylamidoquinazoline derivative and purpose thereof
CN108329300B (en) Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof
CN113387963A (en) Beta-carboline compound and preparation method and application thereof
CN108276420B (en) 8, 13-dihydrobenzo [5,6] chromene [2,3-b ] indole compound and synthetic method thereof
CN115073355B (en) Cycloheptene-aza-oxaditerpenoid derivative, pharmaceutical composition thereof and application thereof in pharmacy
CN110804039A (en) Phthalimide-containing 1, 8-naphthalic anhydride derivatives, pharmaceutically acceptable salts thereof and application of anti-tumor drugs thereof
CN113563330B (en) 3-position derivative of beta-carbopol as well as preparation method and application thereof
CN116063230B (en) Sinomenine 1-position substituted derivative, and preparation method and application thereof
EP4357343A1 (en) Rna-binding molecules with a small core scaffold (r-score) and uses thereof
CN118290341B (en) Urea compound with anti-tumor activity, preparation method and application

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