CN105801514A - Curcumin-amino acid conjugate and application - Google Patents
Curcumin-amino acid conjugate and application Download PDFInfo
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- CN105801514A CN105801514A CN201610325137.3A CN201610325137A CN105801514A CN 105801514 A CN105801514 A CN 105801514A CN 201610325137 A CN201610325137 A CN 201610325137A CN 105801514 A CN105801514 A CN 105801514A
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- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/16—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with only hydrogen or carbon atoms directly attached in positions 2 and 4
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses curcumin-amino acid conjugate and application.The curcumin-amino acid conjugate has the following structure (please see the structure in the description).Experiments show that the curcumin-amino acid conjugate can obviously reduce release of mouse mononuclear macrophage RAW264.7 inflammation model NO induced by lipopolysaccharide, and the curcumin-amino acid conjugate shows an excellent inflammation resisting effect, has the advantages of being simple in preparation method, low in production cost, high in inflammation resisting activity, low in toxicity, easy to dissolve in water and high in bioavailability, and has great potential value in the aspect of anti-inflammatory drug development.
Description
Technical field
The invention belongs to organic synthesis and drug world, be specifically related to a kind of curcumin for treating inflammation class disease-
Amino acid conjugates and purposes, particularly relate to curcumin-aminoacid binary conjugate application in preparing anti-inflammatory drug.
Background technology
Curcumin (Curcumin, chemical name: 1,7-bis-(4-hydroxy 3-methoxybenzene base)-1,6-heptadiene-3,5-bis-
Ketone) be from curcuma Rhizoma Curcumae Longae, Radix Curcumae, Rhizoma Curcumae dry rhizome extract separate a kind of polyphenol compound (change
Learn structure as shown in formula A), there is the pharmacological actions widely such as antiinflammatory, antioxidation, antitumor, regulation blood fat, fibrosis, can
For treating the clinical diseases such as tumor, diabetes, acquired immune deficiency syndrome (AIDS), rheumatic arthritis, atherosclerosis[1-7].Through a large amount of science
Research confirms, the inflammation that Different types of etiopathogenises is caused by curcumin all exists inhibitory action in various degree, and untoward reaction is few.With Yin
The traditional anti-inflammatory medicament such as diindyl U.S. is pungent, Phenylbutazone are compared[8], curcumin has that toxicity is low, human tolerance's degree is high the most excellent
Gesture, but there is also the defects such as poorly water-soluble, chemical constitution unstability, bioavailability be low[9].Therefore, prodrug design reason is used
Read the precursor structure to curcumin to modify, improve the dissolubility of curcumin, improve stability and bioavailability, strengthen raw
Thing activity becomes one of available strategy solving curcumin applied defect.
Formula A
Conventional researcher uses the mode of modified form to overcome the applied defect of curcumin mostly.Shahani etc.[10]System
For going out a kind of curcumin PLGA medicine carrying microballoons, hence it is evident that improve the water solublity of curcumin, and reach the sustained release slow release of 4 weeks effect
Really.Seo etc.[11]Be prepared for a kind of curcumin withThe solid dispersion of HS15, relatively Rhizoma Curcumae Longae have significantly bioavailability
Raising.Kahashi etc.[12]Prepare a kind of curcumin liposome, the infiltration rate of this liposome and degree the most relatively curcumin
Improving a lot, the particularly antioxidant activity in blood plasma highlights, and illustrates that liposome drug delivery technologies is to improve curcumin dissolubility,
Strengthen a kind of effective ways of its bioavailability.Additionally, also scholar's research microemulsion, clathrate, nanoparticle, polyphosphazene polymer
Compound micelle etc.[13]The water soluble drug delivery system of curcumin, they all can improve the water-soluble of curcumin to a certain extent
Property and bioavailability.
In addition to modified form, scholars also attempt having synthesized the homologs of a series of curcumin, to seeking
Water solublity is more preferable, the higher curcumin derivate of biological activity.There is multiple decorating site in curcumin parent, such as: phenyl ring replacement,
Phenolic hydroxyl group replaces, active methylene group replaces, the modification etc. of 1,6-heptadiene-3,5-diketone connection chain[14-15].In recent years, Rhizoma Zingiberis Recens
The research introducing the little molecules of endogenous such as aminoacid, piperine, glucose on the phenolic hydroxyl group position of flavin causes research work
The extensive concern of person, wherein, the amino acid derivativges of curcumin has good water solublity, can be at the tissues such as tumor or thin
Born of the same parents are enriched with, and degrade, discharge curcumin, have given play to antioxidation, mutation, antitumor action etc.[16-19]。
Parvathy etc.[14]The aminoacid using tertbutyloxycarbonyl (t-Boc) to protect prepares a series of aminoacid Rhizoma Curcumae Longae
Element derivant, their water solublity all has raising (1～10mg/mL) in various degree compared with curcumin, and antioxidant activity is also simultaneously
Have clear improvement.Mishra etc.[16]It is prepared for the glycine derivative 1 of curcumin, has and well promote apoptosis of tumor
Activity.Lu Peng etc.[17]Synthesize 2 (N-maleoyl-glycine derivatives) and 3 (N-maleoyl-Valine derivants), but
Their anti-tumor activity relatively curcumin is the poorest.Dubey etc.[18]By curcumin with valine, glycine by macromolecule solid phase
Vector resin (CPG-LCAA) reaction obtains the monoester derivates 4-5, diester derivatives 6-7 of curcumin and distinguishes the most in the solution
React with glutamic acid and valine and to obtain.These curcumin derivates have good water solublity, slowly metabolic process with
And good cell absorbs, anti-tumor experiment shows that these derivants have higher work than alone curcumin under phase same level
Property, and monoester derivates is than diester derivatives activity more preferably (1-7 chemical constitution is as shown in formula B).
Formula B
Mishra etc.[16]The piperine derivate of design synthesis curcumin is as anti-tumor predrug, it is desirable to pass through piperine
Introduce improve curcumin bioavailability.Dubey etc.[18]By by the Fructus Piperis acyl chlorides of curcumin and de-methylene at pyridine
Middle reaction obtains a diester derivatives.Owing to having multiple phenolic hydroxyl group on this derivant structure, therefore the compound than Mishra
There is more preferable antimutagenic activity.Therefore, contributed to clearly by design synthesis polyhydric phenols structure and amplify the biology of curcumin
Activity, particularly anti-tumor activity.Arafa[19]Report curcumin β-glycosides derivatives to Caco-2, HT29 and the T84 mankind
The cytotoxicity of tumor cell line, result shows that it can be in conjunction with beta-glycosidase and activate apoptotic proteins enzyme, by activating
Caspase-3 and caspase-9 promotes apoptosis of tumor cells.
In sum, conventional curcumin structure of modification major part is to be esterified on phenolic hydroxyl group, needs first to amino
In acid, protection group carries out structural modification again, finally also needs to deprotection, therefore relates to multi-step chemical reaction, complex process.And this reality
Test the room structure by analysis curcumin, utilize Mannich reaction to synthesize a series of curcumin-aminoacid by single step reaction
Conjugate, this series conjugate has that preparation method is simple, production cost is low, anti-inflammatory activity is strong, toxicity is low, soluble in water, raw
The feature that thing availability is high, has great potential value in terms of exploitation anti-inflammatory drug.
List of references
[1]Aggarwal B B,Sundaram C,Malani N,et al.Curcumin:the Indian solid
gold[J].Adv Exp Med Biol,2007,595:1-75.
[2]Anand P,Kunnumakkara A B,Newman R A,et al.Bioavailability of
curcumin:problems and promises[J].Mol Pharm,2007,4(6):807-818.
[3]Anand P,Sundaram C,Jhurani S,et al.Curcumin and cancer:an“old-age”
disease with an“age-old”solution[J].Cancer Lett,2008,267(1):133-164.
[4]Goel A,Kunnumakkara A B,Aggarwal B B.Curcumin as“Curecumin”:from
kitchen to clinic[J].Biochem Pharmacol,2008,75(4):787-809.
[5]Shishodia S,Chaturvedi M M,Aggarwal B B.Role of curcumin in cancer
therapy[J].Curr Probl Cancer,2007,31(4):243-305.
[6]Kunnumakkara A B,Diagaradjane P,Guha S,et al.Curcumin sensitizes
human colorectal cancer xenografts in nude mice to gamma-radiation by
targeting nuclear factor-kappaB–regulated gene products[J].Clin Cancer Res,
2008,14(7):2128-2136.
[7]Jagetia G C,Aggarwal B B.“Spicing up”of the immune system by
curcumin[J].J Clin Immunol,2007,27(1):19-35.
[8]Shahani K,Panyam J.Highly loaded,sustained-release microparticles
of curcumin for chemoprevention[J].J Pharm Sci,2011,100(7):2599-2609.
[9]Seo S W,Han H K,Chun M K,et al.Preparation and pharmacokinetic
evaluation of curcumin solid dispersion usingHS15as a carrier[J].Int J
Pharm,2012,424(1):18-25.
[10]Takahashi M,Uechi S,Takara K,et al.Evaluation of an oral carrier
system in rats:bioavailability and antioxidant properties of liposome-
encapsulated curcumin[J].J Agric Food Chem,2009,57(19):9141-9146.
[11] Yang Rulei, Wang Zheng. the progress [J] of the water soluble drug delivery system of curcumin. Inpharm is studied
Magazine, 2012,39 (4): 303-306.
[12] Wu Jie, Liu Guozhen, Ye Juan, etc. the structural modification progress [J] of curcumin. China Dispensary, 2014,25
(35): 3346-3350.
[13] Tu Yongyuan, Xu Xianxiang, Qiu Fei. the progress [J] of curcumin prodrug. organic chemistry, 2011,32 (5):
852-859.
[14]Parvathy K S,Negi P S,Srinivas P.Curcumin-amino acid conjugates:
Synthesis,antioxidant and antimutagenic attributes[J].Food Chem,2010,120(2):
523-530.
[15]Kapoor N,Narain U,Misra K.Bio-active conjugates of curcumin
having ester,peptide,thiol and disulfide links[J].J Sci Ind Res,2007,66(8):
647.
[16]Mishra S,Kapoor N,Mubarak Ali A,et al.Differential apoptotic and
redox regulatory activities of curcumin and its derivatives[J].Free Radic
Biol Med,2005,38(10):1353-1360.
[17] Lu Peng, Tong Qiangsong, Jiang Fengchao, etc. the synthesis of curcumin prodrug and anti tumor activity in vitro research thereof
[J]. Chinese Pharmacological Bulletin, 2006,22 (3): 321-324.
[18]Dubey S K,Sharma A K,Narain U,et al.Design,synthesis and
characterization of some bioactive conjugates of curcumin with glycine,
glutamic acid,valine and demethylenated piperic acid and study of their
antimicrobial and antiproliferative properties[J].Eur J Med Chem,2008,43(9):
1837-1846.
[19]Arafa H M.Possible contribution of beta-glycosidases and caspases
in the cytotoxicity of novel glycoconjugates in colon cancer cells[J].Invest
New Drugs,2010,28(3):306-317.
Summary of the invention
It is an object of the invention to overcome the deficiencies in the prior art, it is provided that a kind of there is efficient anti-inflammatory activity curcumin-
Amino acid conjugates.
Second object of the present invention is to provide a kind of curcumin-amino acid conjugates purposes as anti-inflammatory drug.
The purpose of the present invention is achieved through the following technical solutions:
A kind of curcumin-amino acid conjugates has a structure in which
Wherein, R=H or CH3Or
The application in preparing anti-inflammatory drug of a kind of curcumin-amino acid conjugates.
Curcumin-amino acid conjugates involved in the present invention has significant effect in terms of antiinflammatory, can be used for prevention and
The clinical common inflammatory class disease such as treatment of arthritis, colitis, pneumonia, hepatitis, pancreatitis.
Accompanying drawing explanation
Fig. 1 is the preparation technology flow chart of curcumin in the embodiment of the present invention 1.
Fig. 2 is the mass spectrum of curcumin in the embodiment of the present invention 1.
Fig. 3 is the infrared spectrum of curcumin in the embodiment of the present invention 1.
Fig. 4 is the proton nmr spectra of curcumin in the embodiment of the present invention 1.
Fig. 5 is the preparation technology flow chart of curcumin-glycine conjugates in the embodiment of the present invention 2.
Fig. 6 is the preparation technology flow chart of curcumin in the embodiment of the present invention 3-alanine conjugate.
Fig. 7 is the preparation technology flow chart of curcumin in the embodiment of the present invention 4-valine conjugate.
Fig. 8 is the preparation technology flow chart of curcumin in the embodiment of the present invention 5-leucine conjugate.
Fig. 9 is the mass spectrum of curcumin in the embodiment of the present invention 5-leucine conjugate.
Figure 10 is the infrared spectrum of curcumin in the embodiment of the present invention 5-leucine conjugate.
Figure 11 is the proton nmr spectra of curcumin in the embodiment of the present invention 5-leucine conjugate.
Figure 12 be curcumin in the embodiment of the present invention 6-isoleucine conjugate preparation technology flow chart.
Figure 13 is the mass spectrum of curcumin in the embodiment of the present invention 6-isoleucine conjugate.
Figure 14 is the infrared spectrum of curcumin in the embodiment of the present invention 6-isoleucine conjugate.
Figure 15 is the proton nmr spectra of curcumin in the embodiment of the present invention 6-isoleucine conjugate.
Figure 16 is the preparation technology flow chart of curcumin in the embodiment of the present invention 7-phenylalanine conjugate.
Figure 17 is the preparation technology flow chart of curcumin-cysteine conjugate in the embodiment of the present invention 8.
Figure 18 is the preparation technology flow chart of curcumin in the embodiment of the present invention 9-threonine conjugate.
Figure 19 is the preparation technology flow chart of curcumin in the embodiment of the present invention 10-methionine conjugate.
Figure 20 is the preparation technology flow chart of curcumin in the embodiment of the present invention 11-serine conjugate.
Figure 21 is the preparation technology flow chart of curcumin in the embodiment of the present invention 12-food in one's mouth propylhomoserin conjugate.
Figure 22 is the preparation technology flow chart of curcumin in the embodiment of the present invention 13-glutamic acid conjugate.
Figure 23 is the preparation technology flow chart of curcumin in the embodiment of the present invention 14-aspartic acid conjugate.
Figure 24 is the standard curve of NO in the embodiment of the present invention 15.
Detailed description of the invention
Below by embodiment, the invention will be further described, and its purpose is only that and is better understood from present disclosure
Rather than limit the scope of the invention:
The preparation of embodiment 1 curcumin
Take 60g vanillin and 210mL butyl borate, add 200mL and be dried in ethyl acetate, stirring and evenly mixing；Add
20g acetylacetone,2,4-pentanedione and 10g boric anhydride, be stirred at room temperature 10min, and then dropping 1-n-butylamine catalytic reaction, is stirred at room temperature to reaction
Completely, add diluted hydrochloric acid aqueous solution 300mL, 60 DEG C of stirring 60min, separate ethyl acetate layer, concentrate, add proper amount of methanol precipitation
Product ,-4 DEG C of standings, filter, vacuum drying, obtain yellow curcumin solid 43.5g, (synthetic route is shown in Fig. 1 to yield 62%, characterizes
Fig. 2-4 is shown in by collection of illustrative plates).
The preparation of embodiment 2 curcumins-glycine conjugates
Take 0.68g (9.0mmol) glycine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 2 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-glycine conjugates 0.89g, yield 43.2% (synthetic route is shown in Fig. 5).
The preparation of embodiment 3 curcumins-alanine conjugate
Take 0.81g (9.0mmol) alanine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 3 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-alanine conjugate 0.98g, yield 44.8% (synthetic route is shown in Fig. 6).
The preparation of embodiment 4 curcumins-valine conjugate
Take 1.05g (9.0mmol) valine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 4 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-valine conjugate 1.15g, yield 47.2% (synthetic route is shown in Fig. 7).
The preparation of embodiment 5 curcumins-leucine conjugate
Take 1.18g (9.0mmol) leucine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 2 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-leucine conjugate 1.37g, and (synthetic route is shown in Fig. 8 to yield 53.7%, characterizes collection of illustrative plates and sees figure
9-11)。
The preparation of embodiment 6 curcumins-isoleucine conjugate
Take 1.18g (9.0mmol) isoleucine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water,
Add 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds 50mL methanol dilution above-mentioned instead
Answering liquid, be subsequently adding 1.11g (3.0mmol) curcumin, reaction 3 hour is stirred at room temperature, TLC monitoring is complete to curcumin reaction,
Dripping in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/ice second
Acid mixed solvent eluting, obtains curcumin-isoleucine conjugate 1.34g, and (synthetic route is shown in Figure 12, phenogram to yield 52.3%
Spectrum is shown in Figure 13-15).
The preparation of embodiment 7 curcumins-phenylalanine conjugate
Take 1.49g (9.0mmol) phenylalanine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water,
Add 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds 50mL methanol dilution above-mentioned
Reactant liquor, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 4 hour is stirred at room temperature, and TLC monitoring has been reacted to curcumin
Entirely, dripping in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/ice
Acetic acid mixed solvent eluting, obtains curcumin-phenylalanine conjugate 1.21g, yield 42.3% (synthetic route is shown in Figure 16).
The preparation of embodiment 8 curcumins-cysteine conjugate
Take 1.09g (9.0mmol) cysteine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water,
Add 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds 50mL methanol dilution above-mentioned instead
Answering liquid, be subsequently adding 1.11g (3.0mmol) curcumin, reaction 2 hour is stirred at room temperature, TLC monitoring is complete to curcumin reaction,
Dripping in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/ice second
Acid mixed solvent eluting, obtains curcumin-cysteine conjugate 1.26g, yield 51.2% (synthetic route is shown in Figure 17).
The preparation of embodiment 9 curcumins-threonine conjugate
Take 1.07g (9.0mmol) threonine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 3 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-threonine conjugate 1.18g, yield 48.3% (synthetic route is shown in Figure 18).
The preparation of embodiment 10 curcumins-methionine conjugate
Take 1.34g (9.0mmol) methionine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 4 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-methionine conjugate 1.29g, yield 47.5% (synthetic route is shown in Figure 19).
The preparation of embodiment 11 curcumins-serine conjugate
Take 0.95g (9.0mmol) serine and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 2 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-serine conjugate 1.13g, yield 48.9% (synthetic route is shown in Figure 20).
The preparation of embodiment 12 curcumin-food in one's mouth propylhomoserin conjugate
Take 1.04g (9.0mmol) and feed propylhomoserin and 0.76g sodium bicarbonate (9.0mmol), be dissolved in 6mL deionized water, add
Enter 0.75mL formalin (37%, 9.0mmol), reaction 2 hour is stirred at room temperature, adds the above-mentioned reaction of 50mL methanol dilution
Liquid, is subsequently adding 1.11g (3.0mmol) curcumin, and reaction 3 hour is stirred at room temperature, and TLC monitoring to curcumin reaction completely, is dripped
Adding in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/glacial acetic acid
Mixed solvent eluting, obtains curcumin-food in one's mouth propylhomoserin conjugate 1.02g, yield 45.1% (synthetic route is shown in Figure 21).
The preparation of embodiment 13 curcumins-glutamic acid conjugate
Take 1.33g (9.0mmol) glutamic acid and 1.52g sodium bicarbonate (18.0mmol), be dissolved in 10mL deionized water,
Add 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds 50mL methanol dilution above-mentioned instead
Answering liquid, be subsequently adding 1.11g (3.0mmol) curcumin, reaction 4 hour is stirred at room temperature, TLC monitoring is complete to curcumin reaction,
Dripping in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/ice second
Acid mixed solvent eluting, obtains curcumin-glutamic acid conjugate 1.23g, productivity 45.2% (synthetic route is shown in Figure 22).
The preparation of embodiment 14 curcumins-aspartic acid conjugate
Take 1.20g (9.0mmol) aspartic acid and 1.52g sodium bicarbonate (18.0mmol), be dissolved in 10mL deionized water
In, add 1.5mL formalin (37%, 18.0mmol), reaction 2 hour is stirred at room temperature, adds on 50mL methanol dilution
Stating reactant liquor, add 1.11g (3.0mmol) curcumin, reaction 2 hour is stirred at room temperature, TLC monitoring is complete to curcumin reaction,
Dripping in appropriate 0.5M dilute hydrochloric acid and sodium bicarbonate, product silica gel column chromatography separates, methylene chloride/methanol/ice second
Acid mixed solvent eluting, obtains curcumin-aspartic acid conjugate 1.23g, productivity 47.2% (synthetic route is shown in Figure 23).
The extracorporeal anti-inflammatory pharmacodynamics of the curcumin-amino acid conjugates of embodiment 15 embodiment of the present invention 1-14 gained is commented
Valency, comprises the steps:
(1) the cytotoxicity detection of medicine takes the mouse monokaryon being in growth logarithmic (log) phase that conventional culture methods cultivates and huge bites
Cell RAW264.7, cell scrapes, and piping and druming is uniformly.Cultivate with the DMEM in high glucose containing 10% heat-inactivated fetal bovine serum (HI-FBS)
Basigamy becomes single cell suspension, is seeded in 96 orifice plates and cultivates, and 5 × 105Individual cells/well, inoculates volume 100 μ l, puts CO2In incubator
Hatch 24h and make cell attachment；Incline culture fluid, and it is molten that every hole is sequentially added into the medicine that concentration is 0.5,1,5,10,25,50,100 μMs
Liquid 100 μ L, 5 secondary orifices of each concentration, CO2Incubator is hatched 24h；Every hole adds 10 μ L MTT (5mg/mL), continues to cultivate
4h.Terminating cultivating, careful suction abandons culture supernatant in hole, and every hole adds 100 μ L DMSO, and vibrate 5min, makes crystal fully melt
Solve；Each hole absorbance at 490nm wavelength is detected in microplate reader, right as blank using the cell cultivated without compound incubation
According to, calculating cell inhibitory rate, Reed-Meuench method calculates poisonous concentration TC of half50(being shown in Table 1).
Cell inhibitory rate (%)=(1-administration group OD value/blank group OD value) × 100%
(2) the anti-inflammatory activity detection of medicine takes the mouse monokaryon being in growth logarithmic (log) phase that conventional culture methods cultivates and huge bites
Cell RAW264.7, cell scrapes, and piping and druming is uniformly.Cultivate with the DMEM in high glucose containing 10% heat-inactivated fetal bovine serum (HI-FBS)
Basigamy becomes single cell suspension, is seeded in 96 orifice plates and cultivates, and 5 × 105Individual cells/well, inoculates volume 100 μ l, puts CO2In incubator
Hatch 24h and make cell attachment；Incline culture fluid, every hole be sequentially added into the concentration containing 0.2 μ g/mL LPS be 0.5,1,5,10,25,
50, the drug solution 100 μ L of 100 μMs, 5 secondary orifices of each concentration, CO2Incubator is hatched 24h；Use cell culture fluid DMEM+
5%HI-FBS dilution standard product NaNO2, compound concentration is followed successively by the standard solution of 0,1,2,5,10,20,40,60,100 μMs；
96 orifice plates add standard solution and cell supernatant, every hole 50 μ L, are then sequentially added into Griess reagent I 50 μ L/ hole,
Griess reagent II 50 μ L/ hole, room temperature is placed 10 minutes, is vibrated 5 minutes, microplate reader detects each hole and inhales at 540nm wavelength
Receipts value, with without compound and containing the cell supernatant of LPS as model group, without compound and do not contain the cell supernatant of LPS and be
Blank group, calculates NO concentration and NO suppression ratio (being shown in Table 2), linear equation: the y=in every hole according to standard curve (see Figure 24)
0.05652+0.00766x, correlation coefficient r2=0.9999.
Cytotoxicity (the TC of table 1 curcumin-amino acid conjugates50, μM)
The NO suppression ratio (%) of table 2 curcumins-amino acid conjugates
Claims (2)
1. curcumin-amino acid conjugates, is characterized in that having a structure in which
Wherein, R=H or CH3Or
Curcumin-the amino acid conjugates the most according to claim 1 application in preparing anti-inflammatory drug.
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| CN104610424A (en) * | 2011-12-13 | 2015-05-13 | 首都医科大学 | Lys(Pro-Ala-Lys) curcumin derivatives, synthesis thereof and application thereof in medical science |
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