CN105111054B - A kind of curcumin analogue of conjugated system increase and its preparation method and application - Google Patents
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Abstract
The invention discloses a kind of curcumin analogue of conjugated system increase and its preparation method and application.Have such as the architectural feature of logical formula (I), wherein R1For hydrogen, methoxyl group, R2For hydrogen, hydroxyl, methoxyl group, two naphthalene nucleus are by the connection of 1,6 heptadiene, 3,5 diketone connects chain.The present invention synthesizes with the naphthalene nucleus Curcuminoids analog to hepatocellular carcinoma H22 cell propagation with advantageous activity, and its activity is superior to natural product curcumin using naphthols as raw material.The curcumin analogue of the conjugated system increase of the present invention is to instructing the discovery of prodrug and the design of lead compound, significant.
Description
Technical field
The present invention relates to a kind of naphthalene nucleus Curcuminoids analog of conjugated system increase, is especially that a kind of conjugated system increases
Big curcumin analogue and its preparation method and application.
Background technology
Curcumin is to extract a kind of plant pigment for obtaining from the rhizome of Rhizoma Curcumae Longae, is the main active of Rhizoma Curcumae Longae.It
There is the characteristics such as color stability, low toxicity, therefore, extensively eat in Asian countries such as India, China.Meanwhile, World Health Organization (WHO)
Permit which with FDA (Food and Drug Adminstration) to use as food additive.Pharmacological research confirms that the molecule has extensive life
Thing activity, has significant prevention to multiple physiological deceases such as cancer, nervous system disease, cardiovascular disease, metabolic disease, inflammation
And therapeutic effect.Its active anticancer receives much concern, and clinical experiment also well afoot.
Research finds, curcumin as a multiple-effect molecule, by covalent bond, hydrophobic interaction and hydrogen bond formation directly or
The regulation and control multi-signal molecule for connecing.These modulated molecules include inflammation-related factor (COX-1, COX-2, TNF-a etc.), egg
White kinases (GSK-3, PKC etc.), reduction albumen (TrxR, ALR2 etc.), transporter (HSA, BSA, Casein etc.), metal ion
(Mn, Cu, Fe etc.) and other molecules (MMP, Bcl-2, Keap1 etc.).The chemical fundamentalss of curcumin and these molecules depend on which
Construction unit：The methylated phenol of two neighbours, two unsaturated carbonyls and a central active methylene.
A lot of docking researchs show that curcumin can be by the hydrophobic interaction (Van der Waals force) of benzene ring structure and multiple amino
Sour residue is combined.And its adjacent hydroxymethoxy functional group and carbonyl structure are easy to hydrogen bond be formed with amino acid residue, increase which
Adhesion with target molecule.For example, curcumin can be by suppressing COX-1, docking experiment to show its benzene directly in conjunction with mode
Ring is enclosed in Leu384, Phe518, Met522, and in the hydrophobic environment of Leu357 compositions, and its methoxy group can be with
Ser530 forms hydrogen bond, increases its binding ability.And its unsaturated carbonyl construction unit can not only complexed transition metal ion, subtract
The damage that few excess metal ion is caused to body, additionally it is possible to the metal ion in conjugated protein active center, suppresses protein active.
In the effect of HIV1 albumen, curcumin is in connection not to only exist hydrophobic and hydrogen bond action, also by unsaturated carbonyl structure list
The magnesium ion in first its active center of complexation.What is more important, unsaturated carbonyl construction unit can be received as Michael additions
There is covalent modification with albumen in body.Fang etc. find curcumin can with TrxR be exposed to surface active center Cys 496 and
There is covalent reaction in Sec497, by improving the activity of nadph oxidase, promote the generation of ROS, and then it is anti-to cause which to cascade
Should, final inducing cell apoptosis.
Used as natural antitumor active component, the unique molecular structure of curcumin enables curcumin with multi-signal point
Son is combined, and may act on each stage of tumor, with small toxicity, the advantages of molecular structure is simple, is caused in recent years vast
The interest of researcher.But as its bioavailability is low, difficult, the reason such as metabolism is fast is absorbed, its clinical practice is hindered.Pin
Disadvantage mentioned above to curcumin, carries out appropriate modification to its structure, has obtained much pleasurable achievement, including five carbon
Seven carbochain analog that chain (straight chain or cyclic analogs) or configuration are fixed etc..However, at present both at home and abroad for conjugation
The research of the curcumin analogue of system increase and its preparation method and application is compared with shortage.
Content of the invention
Present invention aim at using naphthols as raw material, synthesizing the naphthalene nucleus class Rhizoma Curcumae Longae to liver cancer treatment with advantageous activity
Plain analog, and its activity is superior to natural product curcumin.
The present invention seeks to realized by technical scheme below：
A kind of curcumin analogue of conjugated system increase, with below formula (I)：
Wherein R1For hydrogen, methoxyl group, R2For hydrogen, hydroxyl, methoxyl group, two naphthalene nucleus are by 1,6- heptadiene -3,5- diketone company
Chain link connects.
Present invention also offers a kind of preparation method of the curcumin analogue of conjugated system increase, including following reaction
Formula：
The preparation method comprises the steps：
A () naphthols is reacted with dimethyl sulfate, at hydroxyl introduce methyl；
B () is in the CH for newly steaming3COCl/AlCl3/CH2Cl2Under the conditions of, methoxynaphthalene introducing acetyl group is obtained 6,7- diformazans
Epoxide 2- acetonaphthone；
C () is in NaOH/Br2Under the conditions of 6,7- dimethoxy 2- acetonaphthones are oxidized to by 6,7- dimethoxies by haloform reaction
Base 2- naphthoic acids；
D () 6,7- dimethoxy 2- naphthalene acetic acids with concentrated sulphuric acid as catalyst, are introduced at the carboxyl of 2- positions in methanol solution
Ester group；
E () is in LiAlH4Under the conditions of/THF, ester group is reduced to alcohol；
F 6,7- dimethoxy 2- naphthalene methanol is oxidized to 6,7- dimethoxy 2- naphthaldehydes by DDQ oxidants by ()；
G () is in CH3COOH/Br2Under the conditions of/Sn, bromine is introduced in the 6- positions of beta naphthal, obtain the bromo- beta naphthals of 6-；
Under the conditions of -78 DEG C of (h), the bromine in bromo- for 6- beta naphthal is changed into aldehyde radical with n-BuLi/DMF/THF；
I (), under the conditions of boron oxide/butyl borate/n-butylamine, naphthaldehyde is condensed to yield naphthalene nucleus class Rhizoma Curcumae Longae with acetylacetone,2,4-pentanedione
Element.
A kind of preparation method of the curcumin analogue of conjugated system increase of the present invention can be with by technical scheme below
Realize：
A kind of preparation method of the curcumin analogue of conjugated system increase, in the step (a), the methoxyl group of product is made
For hydroxyl protecting group.
A kind of preparation method of the curcumin analogue of conjugated system increase, the step (b) is with aluminum chloride as drawing
Enter the lewis acid of acetyl group；Acetylation reagent in acetylization reaction is preferably new steaming chloroacetic chloride；Solvent is preferably dichloromethane
Alkane；The quencher is preferably cryosel acid；In the column chromatography purification solvent of eluting be preferably petroleum ether, ethyl acetate,
One or more of mixture in dichloromethane, normal hexane, hexamethylene.
A kind of preparation method of the curcumin analogue of conjugated system increase, in step (c) haloform reaction, solvent is excellent
Elect tetrahydrofuran, water as；Quencher is preferably frozen water, sodium sulfite.
A kind of preparation method of the curcumin analogue of conjugated system increase, the beta naphthal bromination reaction of the step (g)
Middle reagent is preferably glacial acetic acid.
A kind of preparation method of the curcumin analogue of conjugated system increase, the naphthaldehyde and acetylacetone,2,4-pentanedione of the step (i)
The chelating agent that condensation reaction occurs is preferably boron oxide, and solvent is preferably ethyl acetate, and alkali is preferably n-butylamine, and quencher is preferred
For 4N hydrochloric acid.
A kind of preparation method of the curcumin analogue of conjugated system increase, comprises the steps：
2,3- bisnaphthols (5g, 31.25mmol) are dissolved in 75mL by the preparation of 2,3- dimethoxys-naphthalene in the step (a)
In acetone, K is added2CO3(9.5g, 68.75mmol), then Deca dimethyl sulfate (6.65mL, 68.75mmol), backflow 12 are little
When, cooling is filtered, and acetone is washed, and is concentrated to give 2,3- dimethoxy-naphthalenes；
The preparation of 6- methoxyl groups -2- bromonaphthalenes in the step (a), bromo- for 6- beta naphthal (18.4g, 82.5mmol) is dissolved in
In 200mL acetone, K is added2CO3(25.1g, 181.5mmol), then Deca dimethyl sulfate (17.6mL, 181.5mmol), backflow
12 hours, cooling was filtered, and acetone is washed, and is concentrated to give 6- methoxyl group -2- bromonaphthalenes；
The preparation of 6,7- dimethoxys -2- acetonaphthones in the step (b), by 2,3- dimethoxy-naphthalenes (1.1g,
5.85mmol) it is dissolved in 1, the 2- dichloroethanes of 17mL dryings, the new chloroacetic chloride (0.5mL, 7.0mmol) for steaming of addition, then in batches
Add AlCl3(2.1g, 15.75mmol), stirs 12 hours at 0 DEG C, adds 15g ice and 5mL concentrated hydrochloric acid, organic phase separation, water
Extracted with dichloromethane, organic faciess anhydrous sodium sulfate drying, filtering and concentrating, CH2Cl2Rapid column chromatography is separated, and obtains 6,7- bis-
Methoxyl group -2- acetonaphthones；
The preparation of 6,7- dimethoxys -2- naphthalene acetic acids in the step (c), will be molten for sodium hydroxide (1.75g, 43.5mmol)
In 6mL water, 0 DEG C of Deca bromine (0.68mL, 13.3mmol) Deca 6 again, 7- dimethoxy -2- acetonaphthones (1.0g,
2mL tetrahydrofuran solutions 4.35mmol), are warmed to room temperature stirring 8 hours, and organic faciess extract, and water is added 10g ice and 20%
NaSO3Solution 5mL, the hydrochloric acid with 37% are acidified to pH=3, stirring a period of time, filter, and 60 DEG C of dryings obtain 6,7- dimethoxies
Base -2- naphthoic acids；
The preparation of 6,7- dimethoxys -2- 2-methyl naphthoates in the step (d), by 6,7- dimethoxy -2- naphthoic acids
(0.464g, 2mmol) is dissolved in 37mL methanol, adds concentrated sulphuric acid (0.74mL) to flow back 5 hours, methanol is removed under reduced pressure, and sucking filtration is obtained
6,7- dimethoxy -2- 2-methyl naphthoates；
The preparation of 6,7- dimethoxys -2- naphthalene methanol in the step (e), by LiAlH4(55.4mg) 4mL tetra- is suspended in
In hydrogen furan, Deca 6 at 0 DEG C, the 2mL tetrahydrofuran solutions of 7- dimethoxys -2- naphthoic acids (0.27g, 1.1mmol), 0 DEG C is stirred
Mix 0.5 hour, add water and reaction is quenched, add dilute hydrochloric acid, ethyl acetate to extract, washing, anhydrous sodium sulfate drying, filtering and concentrating are obtained
6,7- dimethoxy -2- naphthalene methanol；
The preparation of 6,7- dimethoxys -2- naphthaldehydes in the step (f), by 6,7- dimethoxy -2- naphthalene methanol
(0.40g, 1.83mmol) is dissolved in 80mL Isosorbide-5-Nitraes-dioxane, adds DDQ (720mg, 3.2mmol), and stirring at normal temperature 0.5 is little
When, sucking filtration, concentration, n-hexane/ethyl acetate (8:1) column chromatography for separation obtains 6,7- dimethoxy -2- naphthaldehydes；
Beta naphthal (14.4g, 100mmol) is dissolved in 40mL glacial acetic acids by the preparation of the bromo- beta naphthals of 6- in the step (g)
In, the 10mL glacial acetic acid solution of Deca bromine (32g, 200mmol) under ice bath adds 10mL water, is heated to boiling, is cooled to 100 DEG C,
2.5g metallic tins are added, is boiled and is dissolved to metallic tin；Again plus 2.5g stannum is boiled to molten, be eventually adding 10g stannum, boil 3 hours cold
To 50 DEG C, filter, washed with the cold glacial acetic acids of 10mL, solid adds cold water stirring, filters, and solid is added in cold water and stirred, and is filtered,
100 DEG C of dryings.Obtain the bromo- beta naphthals of pink 6-；
The preparation of 6- hydroxyls -2- naphthaldehydes in the step (h), bromo- for 6- beta naphthal (0.91g, 4.1mmol) is dissolved in
In the anhydrous THF of 20mL, nitrogen is protected, Deca n-BuLi (3.4mL, 8.2mmol) at -78 DEG C, is stirred 1 hour, at -78 DEG C
Deca dry DMF (0.941mL, 12.3mmol), continues reaction 1 hour at -78 DEG C, is warmed to room temperature, is acidified to pH with 2N hydrochloric acid
=5, ethyl acetate is extracted, and washing, saturated common salt are washed, anhydrous sodium sulfate drying, filtering and concentrating, n-hexane/ethyl acetate (8:
1) column chromatography for separation must obtain 6- hydroxyl -2- naphthaldehydes；
The preparation of 6- methoxy-2-naphthaldehydes in the step (h), by 6- methoxyl groups -2- bromonaphthalenes (0.97g, 4.1mmol)
It is dissolved in the anhydrous THF of 20mL, nitrogen is protected, Deca n-BuLi (3.4mL, 8.2mmol) at -78 DEG C, stirs 1 hour, then at -78
Deca dry DMF (0.941mL, 12.3mmol) at DEG C, continues reaction 1 hour at -78 DEG C, is warmed to room temperature, and is acidified with 2N hydrochloric acid
To pH=5, ethyl acetate is extracted, and washing, saturated common salt are washed, anhydrous sodium sulfate drying, filtering and concentrating, normal hexane/acetic acid second
Ester (15:1) column chromatography for separation must obtain 6- methoxy-2-naphthaldehydes；
The preparation of 6,7- dimethoxys -2- naphthalene curcumin analogues in the step (i), by acetylacetone,2,4-pentanedione (0.5g,
5mmol) it is dissolved in 5mL ethyl acetate with boron oxide (0.25g, 3.5mmol), 40 DEG C are stirred 0.5 hour, add 6,7- dimethoxies
Base -2- naphthaldehydes (2.16g, 10mmol) and butyl borate (2.3g, 10mmol), stir 0.5 hour, then Deca n-butylamine
(0.5mL) 5mL ethyl acetate solutions, 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N hydrochloric acid 7mL to hydrolyze 1 hour, cold
But, ethyl acetate extraction, washing, anhydrous sodium sulfate drying；Filtering and concentrating, n-hexane/ethyl acetate (7:1) column chromatography for separation is obtained
6,7- dimethoxy -2- naphthalene curcumin analogues are a kind of curcumin analogue 1 of conjugated system increase；
Preparation in step (i) 6- hydroxyls -2- naphthalene curcumin analogues, by acetylacetone,2,4-pentanedione (0.5g, 5mmol) and oxygen
Change boron (0.25g, 3.5mmol) to be dissolved in 5mL ethyl acetate, 40 DEG C are stirred 0.5 hour, add 6- hydroxyl -2- naphthaldehydes
(1.72g, 10mmol) and butyl borate (2.3g, 10mmol), stirs 0.5 hour, then the 5mL of Deca n-butylamine (0.5mL)
Ethyl acetate solution, 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N hydrochloric acid 7mL to hydrolyze 1 hour, and cooling, ethyl acetate extract
Take, wash, anhydrous sodium sulfate drying；Filtering and concentrating, n-hexane/ethyl acetate (4:1) column chromatography for separation obtains 6- hydroxyl -2- naphthalene Rhizoma Zingiberis Recens
Flavin analog is a kind of curcumin analogue 2 of conjugated system increase；
The preparation of 6- methoxyl groups -2- naphthalene curcumin analogues in the step (i), by acetylacetone,2,4-pentanedione (0.5g, 5mmol) and
Boron oxide (0.25g, 3.5mmol) is dissolved in 5mL ethyl acetate, and 40 DEG C are stirred 0.5 hour, add 6- methoxy-2-naphthaldehydes
(1.86g, 10mmol) and butyl borate (2.3g, 10mmol), stirs 0.5 hour, then the 5mL of Deca n-butylamine (0.5mL)
Ethyl acetate solution, 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N hydrochloric acid 7mL to hydrolyze 1 hour, and cooling, ethyl acetate extract
Take, wash, anhydrous sodium sulfate drying；Filtering and concentrating, n-hexane/ethyl acetate (7:1) column chromatography for separation obtains 6- methoxyl group -2- naphthalenes
Curcumin analogue is a kind of curcumin analogue 3 of conjugated system increase；
The preparation of 2- naphthalenes curcumin analogue in the step (i), by acetylacetone,2,4-pentanedione (0.5g, 5mmol) and boron oxide
(0.25g, 3.5mmol) is dissolved in 5mL ethyl acetate, 40 DEG C stir 0.5 hour, add 2- naphthaldehydes (1.56g, 10mmol) and
Butyl borate (2.3g, 10mmol), stirs 0.5 hour, then the 5mL ethyl acetate solutions of Deca n-butylamine (0.5mL), 40 DEG C
Stirring 4 hours, stands overnight, and adds 0.4N hydrochloric acid 7mL to hydrolyze 1 hour, and cooling, ethyl acetate are extracted, washing, anhydrous sodium sulfate
Dry；Filtering and concentrating, n-hexane/ethyl acetate (7:1) column chromatography for separation obtains i.e. a kind of conjugated system of 2- naphthalenes curcumin analogue
The curcumin analogue 4 of increase.
Present invention also offers a kind of purposes of the curcumin analogue of conjugated system increase, the analog is applied to hepatocarcinoma
Drug therapy.
Beneficial effects of the present invention
The present invention synthesizes, with to hepatocellular carcinoma H22 cell propagation, there is advantageous activity using naphthols as raw material
Naphthalene nucleus Curcuminoids analog, and its activity is superior to natural product curcumin.The Rhizoma Curcumae Longae of the conjugated system increase of the present invention
Plain analog is to instructing the discovery of prodrug and the design of lead compound, significant.
Description of the drawings
Fig. 1 is the curcumin analogue general structure of the present invention.
Fig. 2 is the preparation method reaction equation of the curcumin analogue of the present invention.
Fig. 3 is the hydrogen spectrum of the curcumin analogue 1 of the present invention.
Fig. 4 is the hydrogen spectrum of the curcumin analogue 2 of the present invention.
Fig. 5 is the carbon spectrum of the curcumin analogue 2 of the present invention.
Fig. 6 is the hydrogen spectrum of the curcumin analogue 3 of the present invention.
Fig. 7 is the hydrogen spectrum of the curcumin analogue 4 of the present invention.
Fig. 8 is the carbon spectrum of the curcumin analogue 4 of the present invention.
Fig. 9 is concentration dependent curve chart of the curcumin analogue 1 of the present invention to HepG2 cell inhibitory effect activity.
Figure 10 is concentration dependent curve chart of the curcumin analogue 2 of the present invention to HepG2 cell inhibitory effect activity.
Figure 11 is concentration dependent curve chart of the curcumin analogue 3 of the present invention to HepG2 cell inhibitory effect activity.
Figure 12 is concentration dependent curve chart of the curcumin analogue 4 of the present invention to HepG2 cell inhibitory effect activity.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
Apply the specific material proportion described by example, process conditions and its result be merely to illustrate the present invention and not should also without limitation on
The present invention described in detail in claims.
Embodiment 1
A kind of curcumin analogue 1 of conjugated system increase, with following structural formula：
A kind of preparation method of the curcumin analogue 1 of conjugated system increase, comprises the steps：
The preparation of (a) 2,3- dimethoxys-naphthalene
2,3- bisnaphthols (5g, 31.25mmol) are dissolved in 75mL acetone, K is added2CO3(9.5g, 68.75mmol), then
Deca dimethyl sulfate (6.65mL, 68.75mmol), flows back 12 hours, and cooling is filtered, and acetone is washed, and is concentrated to give 2,3- dimethoxies
Base naphthalene, yield 90%.
The preparation of (b) 6,7- dimethoxy -2- acetonaphthones
2,3- dimethoxy-naphthalenes (1.1g, 5.85mmol) are dissolved in 1, the 2- dichloroethanes of 17mL dryings, new steaming is added
Chloroacetic chloride (0.5mL, 7.0mmol), then be dividedly in some parts AlCl3(2.1g, 15.75mmol), stirs 12 hours at 0 DEG C, adds
15g ice and 5mL concentrated hydrochloric acid, organic phase separation, water are extracted with dichloromethane, organic faciess anhydrous sodium sulfate drying, are filtered dense
Contracting, CH2Cl2Rapid column chromatography is separated, and obtains 6,7- dimethoxy -2- acetonaphthones, yield 83.6%.1H NMR 300MHz
(CDCl3), δ 8.33 (s, 1H), 7.89 (d, J=8.4Hz, 1H), 7.71 (d, J=8.1Hz, 1H), 7.23 (s, 1H), 7.15
(s,1H),4.03(s,6H),2.69(s,3H).
The preparation of (c) 6,7- dimethoxy -2- naphthalene acetic acids
Sodium hydroxide (1.75g, 43.5mmol) is dissolved in 6mL water, 0 DEG C of Deca bromine (0.68mL, 13.3mmol) is again
Deca 6, the 2mL tetrahydrofuran solutions of 7- dimethoxys -2- acetonaphthones (1.0g, 4.35mmol) are warmed to room temperature stirring 8 hours,
Organic faciess extract, and water is added 10g ice and 20% NaSO3Solution 5mL, the hydrochloric acid with 37% are acidified to pH=3, when stirring one section
Between, filter, 60 DEG C of dryings, obtain 6,7- dimethoxy -2- naphthoic acids, yield 90%.1H NMR 400MHz(CDCl3),δ8.41
(d, J=9.6Hz, 1H), 7.81 (s, 2H), 7.50 (s, 1H), 7.34-7.41 (m, 1H), 3.89-3.91 (s, 6H).
The preparation of (d) 6,7- dimethoxy -2- 2-methyl naphthoates
6,7- dimethoxys -2- naphthoic acids (0.464g, 2mmol) is dissolved in 37mL methanol, concentrated sulphuric acid is added
(0.74mL) flow back 5 hours, methanol is removed under reduced pressure, sucking filtration obtains 6,7- dimethoxy -2- 2-methyl naphthoates, yield 77.2%.1H
NMR 400MHz(CDCl3), δ 8.46 (s, 1H), 7.92 (dd, J=8.4Hz, 1.6Hz, 1H), 7.70 (d, J=8.4Hz, 1H),
7.21(s,1H),7.15(s,1H),4.03(s,3H),4.02(s,3H),3.96(s,3H).
The preparation of (e) 6,7- dimethoxy -2- naphthalene methanol
By LiAlH4(55.4mg) it is suspended in 4mL tetrahydrofurans, Deca 6 at 0 DEG C, 7- dimethoxy -2- naphthoic acids
The 2mL tetrahydrofuran solutions of (0.27g, 1.1mmol), 0 DEG C is stirred 0.5 hour, adds water and reaction is quenched, and adds dilute hydrochloric acid, acetic acid
Ethyl ester is extracted, washing, and anhydrous sodium sulfate drying, filtering and concentrating obtain 6,7- dimethoxy -2- naphthalene methanol, yield 91%.1H NMR
300MHz(CDCl3), δ 7.67 (d, 2H, J=8.7Hz), 7.33 (dd, J=8.1,1.2Hz, 1H), 7.11 (d, J=1.8Hz,
2H),4.00(s,6H).
The preparation of (f) 6,7- dimethoxy -2- naphthaldehydes
6,7- dimethoxys -2- naphthalene methanol (0.40g, 1.83mmol) is dissolved in 80mL Isosorbide-5-Nitraes-dioxane, is added
DDQ (720mg, 3.2mmol), stirring at normal temperature 0.5 hour, sucking filtration, concentration, n-hexane/ethyl acetate (8:1) column chromatography for separation is obtained
6,7- dimethoxy -2- naphthaldehydes, yield 73%.1H NMR 400MHz(CDCl3),δ10.0(s,1H),8.19(s,1H),
7.82 (dd, J=8.4,1.6Hz, 1H), 7.76 (d, J=8.4Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 4.00 (s,
6H).
The preparation of (i) 6,7- dimethoxy -2- naphthalene curcumin analogues
Acetylacetone,2,4-pentanedione (0.5g, 5mmol) and boron oxide (0.25g, 3.5mmol) are dissolved in 5mL ethyl acetate, 40 DEG C are stirred
Mix 0.5 hour, add 6,7- dimethoxys -2- naphthaldehydes (2.16g, 10mmol) and butyl borate (2.3g, 10mmol), stir
Mix 0.5 hour, then the 5mL ethyl acetate solutions of Deca n-butylamine (0.5mL), 40 DEG C are stirred 4 hours, are stood overnight, and are added
0.4N hydrochloric acid 7mL is hydrolyzed 1 hour, and cooling, ethyl acetate are extracted, washing, anhydrous sodium sulfate drying；Filtering and concentrating, normal hexane/second
Acetoacetic ester (7:1) column chromatography for separation obtains i.e. a kind of Rhizoma Curcumae Longae of conjugated system increase of 6,7- dimethoxy -2- naphthalenes curcumin analogue
Plain analog 1, yield 45%.1H NMR 400MHz(CDCl3), δ 7.79-7.83 (m, 4H), 7.68 (d, J=8.4Hz, 2H),
7.58 (d, J=8.4Hz, 2H), 7.13-7.15 (m, 4H), 6.70 (d, J=16Hz, 2H), 5.89 (s, 1H), 4.03 (s,
12H).
Embodiment 2
A kind of curcumin analogue 2 of conjugated system increase, with following structural formula：
A kind of preparation method of the curcumin analogue 2 of conjugated system increase, comprises the steps：
The preparation of the bromo- beta naphthals of (g) 6-
Beta naphthal (14.4g, 100mmol) is dissolved in 40mL glacial acetic acids, Deca bromine (32g, 200mmol) under ice bath
10mL glacial acetic acid solution, adds 10mL water, is heated to boiling, is cooled to 100 DEG C, adds 2.5g metallic tins, boils and dissolves to metallic tin；
Again plus 2.5g stannum is boiled to molten, it is eventually adding 10g stannum, boils 3 hours and be cooled to 50 DEG C, filter, washed with the cold glacial acetic acids of 10mL, Gu
Body adds cold water stirring, filters, and solid is added in cold water and stirred, and is filtered, 100 DEG C of dryings.The bromo- beta naphthals of pink 6- are obtained, is produced
Rate 88%.1HNMR(300MHz,CDCl3) δ 7.92 (s, 1H), 7.65 (d, J=9.3,1H), 7.47-7.54 (m, 2H), 7.10-
7.14(m,2H).
The preparation of (h) 6- hydroxyl -2- naphthaldehydes
Bromo- for 6- beta naphthal (0.91g, 4.1mmol) is dissolved in the anhydrous THF of 20mL, nitrogen is protected, Deca n- at -78 DEG C
BuLi (3.4mL, 8.2mmol), stirs 1 hour, then at Deca dry DMF (0.941mL, 12.3mmol) at -78 DEG C, -78 DEG C
Lower continuation reaction 1 hour, is warmed to room temperature, and is acidified to pH=5 with 2N hydrochloric acid, and ethyl acetate is extracted, and washing, saturated common salt are washed,
Anhydrous sodium sulfate drying, filtering and concentrating, n-hexane/ethyl acetate (8:1) column chromatography for separation must obtain 6- hydroxyl -2- naphthaldehydes, produce
Rate 78.6%；1HNMR(300MHz,CDCl3) δ 10.1 (s, 1H), 8.27 (s, 1H), 7.91 (d, J=6.9Hz, 2H), 7.75 (d,
J=8.1Hz, 1H), 7.19 (d, J=7.5Hz, 2H).
The preparation of (i) 6- hydroxyl -2- naphthalene curcumin analogues
Acetylacetone,2,4-pentanedione (0.5g, 5mmol) and boron oxide (0.25g, 3.5mmol) are dissolved in 5mL ethyl acetate, 40 DEG C are stirred
Mix 0.5 hour, add 6- hydroxyls -2- naphthaldehydes (1.72g, 10mmol) and butyl borate (2.3g, 10mmol), stirring 0.5
Hour, then the 5mL ethyl acetate solutions of Deca n-butylamine (0.5mL), 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N hydrochloric acid
7mL is hydrolyzed 1 hour, and cooling, ethyl acetate are extracted, washing, anhydrous sodium sulfate drying；Filtering and concentrating, n-hexane/ethyl acetate
(4:1) column chromatography for separation obtains i.e. a kind of curcumin analogue 2 of conjugated system increase of 6- hydroxyl -2- naphthalenes curcumin analogue, produces
Rate 49%.1H NMR 400MHz(DMSO-d6),δ10.06(s,2H),8.08(s,2H),7.21-7.83(m,8H),7.13-
7.16 (m, 4H), 6.97 (d, J=16Hz, 2H) .6.20 (s, 1H)；13C NMR 100MHz(DMSO-d6),183.19,
156.91,140.76,135.70,130.39,130.28,129.26,127.51,126.88,124.19,122.96,119.34,
109.10,101.75.
Embodiment 3
A kind of curcumin analogue 3 of conjugated system increase, with following structural formula：
A kind of preparation method of the curcumin analogue 3 of conjugated system increase, comprises the steps：
The preparation of the bromo- beta naphthals of (g) 6-
Beta naphthal (14.4g, 100mmol) is dissolved in 40mL glacial acetic acids, Deca bromine (32g, 200mmol) under ice bath
10mL glacial acetic acid solution, adds 10mL water, is heated to boiling, is cooled to 100 DEG C, adds 2.5g metallic tins, boils and dissolves to metallic tin；
Again plus 2.5g stannum is boiled to molten, it is eventually adding 10g stannum, boils 3 hours and be cooled to 50 DEG C, filter, washed with the cold glacial acetic acids of 10mL, Gu
Body adds cold water stirring, filters, and solid is added in cold water and stirred, and is filtered, 100 DEG C of dryings.The bromo- beta naphthals of pink 6- are obtained, is produced
Rate 88%.1HNMR(300MHz,CDCl3) δ 7.92 (s, 1H), 7.65 (d, J=9.3,1H), 7.47-7.54 (m, 2H), 7.10-
7.14(m,2H).
The preparation of (a) 6- methoxyl group -2- bromonaphthalenes
Bromo- for 6- beta naphthal (18.4g, 82.5mmol) is dissolved in 200mL acetone, K is added2CO3(25.1g,
181.5mmol), then Deca dimethyl sulfate (17.6mL, 181.5mmol), flow back 12 hours, cooling is filtered, and acetone is washed, dense
Contract to obtain 6- methoxyl group -2- bromonaphthalenes, yield 92%.1HNMR(400MHz,CDCl3) δ 7.92 (d, J=1.6Hz, 1H), 7.59 (q, J
=8.8,9.2Hz, 2H), 7.49 (dd, J=8.8,2Hz, 1H), 7.15 (dd, J=8.8,2.4Hz, 1H), 7.09 (d, J=
2.4Hz,1H),3.92(s,3H).
The preparation of (h) 6- methoxy-2-naphthaldehydes
6- methoxyl groups -2- bromonaphthalenes (0.97g, 4.1mmol) is dissolved in the anhydrous THF of 20mL, nitrogen is protected, is dripped at -78 DEG C
Plus n-BuLi (3.4mL, 8.2mmol), stir 1 hour, then at Deca dry DMF (0.941mL, 12.3mmol) at -78 DEG C, -
Continuing reaction 1 hour at 78 DEG C, being warmed to room temperature, pH=5 is acidified to 2N hydrochloric acid, ethyl acetate is extracted, washing, saturated aqueous common salt
Wash, anhydrous sodium sulfate drying, filtering and concentrating, n-hexane/ethyl acetate (15:1) column chromatography for separation obtains 6- methoxyl group -2- naphthalene first
Aldehyde, yield 88.6%.1HNMR(300MHz,CDCl3)δ10.07(s,1H),8.22(s,1H),7.87-7.92(m,2H),7.76
(d, J=8.4Hz, 1H), 7.18-7.24 (m, 1H), 7.14-7.16 (m, 1H), 3.92 (s, 3H).
The preparation of (i) 6- methoxyl group -2- naphthalene curcumin analogues
Acetylacetone,2,4-pentanedione (0.5g, 5mmol) and boron oxide (0.25g, 3.5mmol) are dissolved in 5mL ethyl acetate, 40 DEG C are stirred
Mix 0.5 hour, add 6- methoxy-2-naphthaldehydes (1.86g, 10mmol) and butyl borate (2.3g, 10mmol), stirring
0.5 hour, then the 5mL ethyl acetate solutions of Deca n-butylamine (0.5mL), 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N
Hydrochloric acid 7mL is hydrolyzed 1 hour, and cooling, ethyl acetate are extracted, washing, anhydrous sodium sulfate drying；Filtering and concentrating, normal hexane/acetic acid second
Ester (7:1) column chromatography for separation obtains i.e. a kind of curcumin analogue of conjugated system increase of 6- methoxyl group -2- naphthalenes curcumin analogue
3, yield 51%.1H NMR 400MHz(DMSO-d6), δ 8.13 (s, 2H), 7.41-7.88 (m, 8H), 7.36 (d, J=1.8Hz,
2H), 7.18 (dd, J=8.7,5.4Hz, 2H), 6.99 (d, J=15.6Hz, 2H), 6.20 (s, 1H), 3.89 (s, 6H).
Embodiment 4
A kind of curcumin analogue 4 of conjugated system increase, with following structural formula：
A kind of preparation method of the curcumin analogue 4 of conjugated system increase, comprises the steps：
The preparation of (i) 2- naphthalene curcumin analogues
Acetylacetone,2,4-pentanedione (0.5g, 5mmol) and boron oxide (0.25g, 3.5mmol) are dissolved in 5mL ethyl acetate, 40 DEG C are stirred
Mix 0.5 hour, add 2- naphthaldehydes (1.56g, 10mmol) and butyl borate (2.3g, 10mmol), stir 0.5 hour, then
The 5mL ethyl acetate solutions of Deca n-butylamine (0.5mL), 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N hydrochloric acid 7mL hydrolysis
1 hour, cooling, ethyl acetate were extracted, washing, anhydrous sodium sulfate drying；Filtering and concentrating, n-hexane/ethyl acetate (7:1) post layer
Analysis separates to obtain i.e. a kind of curcumin analogue 4 of conjugated system increase of 6- methoxyl group -2- naphthalenes curcumin analogue, yield 51%.1H NMR 400MHz(CDCl3), δ 7.98 (s, 2H), 7.84-7.87 (m, 8H), 7.72-7.74 (dd, J=8.4,1.6Hz,
2H), 7.51-7.54 (m, 4H), 6.76 (d, J=16Hz, 2H), 5.94 (s, 1H).13C NMR100MHz(DMSO-d6),
206.2,184.6,137.7,134.9,133.1,132.5,131.5,129.8,128.0,127.8,127.3,126.7,
126.0,124.1.
Embodiment 5
The inhibitory action that the curcumin analogue of the present invention is bred to human hepatoma HepG2 cell
Experimental principle：
MTT full name are 3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides, are a kind of welds.MTT
Colorimetry is a kind of method for evaluating cell survival and growth.Its Cleaning Principle is the succinate dehydrogenase in living cells mitochondria
Exogenous MTT can be made to be reduced to water-fast bluish violet crystallization (first a ceremonial jade-ladle, used in libation, Formazan) and be deposited in cell, but dead thin
Born of the same parents do not have this kind of function.And dimethyl sulfoxide can dissolve the first a ceremonial jade-ladle, used in libation in cell, detected at 570nm with enzyme-linked immunosorbent assay instrument
Its light absorption value.In certain scope, the amount of the first a ceremonial jade-ladle, used in libation crystallization that MTT is formed is directly proportional cell number to viable count, so, this
Method can reflect the quantity of living cells indirectly.Cell survival rate is calculated by formula below：
Cell survival rate (%)=dosing group OD/ matched group OD × 100%
Experimental technique：
1) 3 × 10 are taken4Cells/mL HepG2 cell 100mL are inoculated in 96 orifice plates, in 5%CO2, under 37 DEG C of environment
24h is incubated with RPMI-1640 culture medium.
2) 90mL fresh cultures are exchanged for, the curcumin or curcumin analogue effect 48h of 10mL variable concentrations is added.
3) culture medium is discarded, 110mL MTT solution (5mg/mL, i.e. 0.5%MTT) continuation effect 4h is added per hole.
4) culture medium is discarded, is added 100mL DMSO to be placed in low speed concussion on shaking table, crystal is fully dissolved.In enzyme
The light absorption value in each hole of detection at connection immune detector 570nm.
Natural product curcumin (curcumin) is lived to the Proliferation Ability of HepG2 cells with the curcumin analogue of the present invention
Property experimental result is shown in Table 1.
Table 1
| Curcumin analogue | IC50/(μM) |
| 1 | >200 |
| 2 | 20.0±2.6 |
| 3 | 132.8±7.2 |
| 4 | >200 |
| Curcumin | 52.3±1.1 |
Conclusion：The curcumin analogue 2 of the present invention is 20.0M to the increment inhibitory activity of human hepatoma HepG2 cell, hence it is evident that
Natural product curcumin (52.3M) is superior to, and assumes good concentration dependent, can serve as the Rhizoma Curcumae Longae for treating hepatocarcinoma
Plain class primer.
The curcumin analogue 1 of the present invention is shown in Fig. 9 to the concentration dependant linearity curve of HepG2 cell inhibitory effect activity.
The curcumin analogue 2 of the present invention is shown in Figure 10 to the concentration dependant linearity curve of HepG2 cell inhibitory effect activity.
The curcumin analogue 3 of the present invention is shown in Figure 11 to the concentration dependant linearity curve of HepG2 cell inhibitory effect activity.
The curcumin analogue 4 of the present invention is shown in Figure 12 to the concentration dependant linearity curve of HepG2 cell inhibitory effect activity.
Embodiment of above technology design only to illustrate the invention and feature, its object is to allow and are familiar with technique
People understands present invention and is carried out, and can not be limited the scope of the invention with this, all real according to spirit of the invention
Equivalence changes or modification that matter is done, should all cover within the scope of the present invention.
Claims (6)
1. the curcumin analogue that a kind of conjugated system increases, it is characterised in that with below formula (I)：
Wherein R1For hydrogen, R2For hydroxyl, two naphthalene nucleus are by 1,6- heptadiene -3, the connection of 5- diketone connects chain.
2. the preparation method of the curcumin analogue of a kind of conjugated system increase according to claim 1, it is characterised in that
Including following reaction equation：
The preparation method comprises the steps：
G () is in CH3COOH/Br2Under the conditions of/Sn, bromine is introduced in the 6- positions of beta naphthal, obtain the bromo- beta naphthals of 6-；
Under the conditions of -78 DEG C of (h), the bromine in bromo- for 6- beta naphthal is changed into aldehyde radical with n-BuLi/DMF/THF；
I (), under the conditions of boron oxide/butyl borate/n-butylamine, naphthaldehyde is condensed to yield naphthalene nucleus Curcuminoids with acetylacetone,2,4-pentanedione.
3. the preparation method of the curcumin analogue of a kind of conjugated system increase according to claim 2, it is characterised in that
In the beta naphthal bromination reaction of the step (g), reagent is preferably glacial acetic acid.
4. the preparation method of the curcumin analogue of a kind of conjugated system increase according to claim 2, it is characterised in that
The chelating agent that the naphthaldehyde of the step (i) occurs condensation reaction with acetylacetone,2,4-pentanedione is preferably boron oxide, and solvent is preferably acetic acid second
Ester, alkali are preferably n-butylamine, and quencher is preferably 4N hydrochloric acid.
5. the preparation method of the curcumin analogue of a kind of conjugated system increase according to claim 2, it is characterised in that
Comprise the steps：
The preparation of the bromo- beta naphthals of 6- in the step (g), beta naphthal 14.4g is dissolved in 40mL glacial acetic acids, dropping liquid under ice bath
The 10mL glacial acetic acid solution of bromine 32g, adds 10mL water, is heated to boiling, is cooled to 100 DEG C, adds 2.5g metallic tins, boils to metal
Stannum dissolves；Again plus 2.5g stannum is boiled to molten, it is eventually adding 10g stannum, boils 3 hours and be cooled to 50 DEG C, filter, with the ice second that 10mL is cold
Pickling, solid add cold water stirring, filter, and solid is added in cold water and stirred, and is filtered, and 100 DEG C of dryings obtain the bromo- 2- of pink 6-
Naphthols；
The preparation of 6- hydroxyls -2- naphthaldehydes in the step (h), bromo- for 6- beta naphthal 0.91g is dissolved in the anhydrous THF of 20mL,
Nitrogen is protected, Deca n-BuLi 3.4mL at -78 DEG C, is stirred 1 hour, then at Deca dry DMF 0.941mL at -78 DEG C, -78
Continuing reaction 1 hour at DEG C, being warmed to room temperature, pH=5 is acidified to 2N hydrochloric acid, ethyl acetate is extracted, washing, saturated aqueous common salt
Wash, anhydrous sodium sulfate drying, filtering and concentrating, normal hexane is 8 with the amount ratio of ethyl acetate:1, column chromatography for separation obtain 6- hydroxyls-
2- naphthaldehydes；
The preparation of 6- hydroxyls -2- naphthalene curcumin analogues in the step (i), will be molten to acetylacetone,2,4-pentanedione 0.5g and boron oxide 0.25g
In 5mL ethyl acetate, 40 DEG C are stirred 0.5 hour, add 6- hydroxyl -2- naphthaldehydes 1.72g and butyl borate 2.3g, stirring
0.5 hour, then the 5mL ethyl acetate solutions of Deca 0.5mL n-butylamine, 40 DEG C are stirred 4 hours, are stood overnight, and add 0.4N salt
Sour 7mL is hydrolyzed 1 hour, and cooling, ethyl acetate are extracted, washing, anhydrous sodium sulfate drying；Filtering and concentrating, normal hexane and acetic acid second
The amount ratio of ester is 4:1 column chromatography for separation obtains i.e. a kind of curcumin of conjugated system increase of 6- hydroxyl -2- naphthalenes curcumin analogue
Analog 2.
6. the purposes of the curcumin analogue of a kind of conjugated system increase according to any one of Claims 1 to 5, its feature
It is, application of the analog in the medicine for preparing treatment hepatocarcinoma.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012164969A1 (en) * | 2011-05-30 | 2012-12-06 | 国立大学法人金沢大学 | Pharmaceutical composition for preventing and/or treating cancer, containing substituted phenanthrene compound as active ingredient |
| CN102911022A (en) * | 2012-10-25 | 2013-02-06 | 山东鲁诺动物药业有限公司 | Method for artificially synthesizing natural curcumin compound |
| CN102964192A (en) * | 2011-09-01 | 2013-03-13 | 中国科学院大连化学物理研究所 | Method for preparing aldehyde or ketone by alcohol oxidation |
| CN103214358A (en) * | 2013-03-12 | 2013-07-24 | 上海立科药物化学有限公司 | Synthetic method of 6-hydroxy-2-naphthaldehyde |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012164969A1 (en) * | 2011-05-30 | 2012-12-06 | 国立大学法人金沢大学 | Pharmaceutical composition for preventing and/or treating cancer, containing substituted phenanthrene compound as active ingredient |
| CN102964192A (en) * | 2011-09-01 | 2013-03-13 | 中国科学院大连化学物理研究所 | Method for preparing aldehyde or ketone by alcohol oxidation |
| CN102911022A (en) * | 2012-10-25 | 2013-02-06 | 山东鲁诺动物药业有限公司 | Method for artificially synthesizing natural curcumin compound |
| CN103214358A (en) * | 2013-03-12 | 2013-07-24 | 上海立科药物化学有限公司 | Synthetic method of 6-hydroxy-2-naphthaldehyde |
Non-Patent Citations (3)
| Title |
|---|
| 1-溴-6-氰基-2-萘酚的合成;朱园园等;《精细化工》;201401;第31卷(第1期);110-112、116 * |
| 付春.3,5-二羟基苯甲醇.《精细与专用化学品》.2001,(第18期), * |
| 姜黄素诱导人肝癌HepG2细胞发生凋亡及对细胞生长周期的影响;康永驰等;《中国医学工程》;200911;第17卷(第4期);243-246 * |
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