CN107473978B - Curcumin derivative and preparation method and application thereof - Google Patents

Curcumin derivative and preparation method and application thereof Download PDF

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CN107473978B
CN107473978B CN201710479059.7A CN201710479059A CN107473978B CN 107473978 B CN107473978 B CN 107473978B CN 201710479059 A CN201710479059 A CN 201710479059A CN 107473978 B CN107473978 B CN 107473978B
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curcumin
curcumin derivative
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beta
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陈惠雄
张万正
余群英
叶飞飞
杜志云
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Guangdong University of Technology
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Abstract

The curcumin derivative has a novel structure, good water solubility, high sensitivity, good selectivity, good photostability and high bioavailability, has good affinity with Abeta 1-42 aggregates, and can well inhibit the self-polymerization of beta-amyloid protein

Description

curcumin derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a curcumin derivative and a preparation method and application thereof.
Background
alzheimer's Disease (AD) is a malignant neurodegenerative disease, the etiology is unknown so far, and no specific medicine or method for curing is available at present. AD is characterized by a gradual decline in cognitive functions, such as memory, thought, understanding, computing, language, learning, and judgment abilities, that when reduced enough to affect an individual's daily living behavior is diagnosed as dementia. Although the worldwide incidence of AD is 4.7%, the incidence in industrially developed countries is as high as about 6.5%. The incidence rate rises to 8% above 65 years and up to 45% above 85 years. According to statistics, the number of Chinese patients exceeds 560 ten thousand at present, and the situation of rapid increase is presented along with the aging process of population. AD not only seriously harms the health of old people, but also brings heavy mental burden to family members of patients, brings huge health crisis to the society, and further has huge influence on economy, thereby arousing the general attention of people.
1-40 1-42more and more researches show that pathological changes in the brain occur as early as 10-20 years before the symptoms of AD occur, and the pathological mechanisms of AD mainly include 3 hypotheses, namely amyloid deposition, neurofibrillary tangles (neurofibrillary plaques) and cholinergic neuron degenerative changes, wherein the 'amyloid cascade hypothesis' is widely accepted.
curcumin is a chemical component extracted from the rhizome of some plants in the families of Zingiberaceae and Araceae. The medical research shows that the curcumin has the functions of reducing blood fat, resisting tumor, resisting inflammation, benefiting gallbladder and resisting oxidation, and also has the effect of resisting AD. Many studies have been made in recent years, both in vitro and in vivo, on the interaction of curcumin with β -amyloid. These included studies of the neuroprotective effects of curcumin on beta-amyloid-induced toxicity in cultured neuronal cells. Several mechanisms for this protective effect have been proposed. In human neuroblastoma cells, curcumin blocks kappa B nuclear factor, thus preventing beta-amyloid-induced cell death. Curcumin inhibited β -amyloid-mediated caspase-3 increase in rat frontal cortical neurons and protected nerves by activation of the Akt signaling pathway. Curcumin also reduced β -amyloid toxicity in APPswe transfected SY5Y cells by reducing GSK-3 β activity and stimulating the protective Wnt/β -catenin pathway. Therefore, curcumin can ameliorate neuronal damage caused by inflammation, oxidative stress or β -amyloid at many levels. In addition, curcumin can also affect the production and deposition of β -amyloid, which has long been recognized as one of the causes of neurodegeneration in AD. Curcumin studies have now entered the human testing phase (http:// www.clinicaltrials.gov). However, the current result is that the therapeutic effect is not yet significant. The reason for this analysis is probably that curcumin has poor water solubility and bioavailability and thus is produced in the brain at too low a level after oral absorption.
disclosure of Invention
In order to overcome the defects and shortcomings of curcumin in the prior art, the first object of the invention is to provide a curcumin derivative which can be better used for a fluorescent molecular probe for imaging of Alzheimer's disease amyloid beta plaque, and can also have an inhibiting effect on beta-amyloid protein polymerization so as to be used for treating Alzheimer's disease.
another object of the present invention is to provide a method for producing the curcumin derivative.
still another object of the present invention is to provide use of the curcumin derivative.
the purpose of the invention is realized by the following technical scheme:
A curcumin derivative which is a compound of formula I or a pharmaceutically acceptable salt thereof, and a solvate, enantiomer, diastereomer, tautomer or mixture thereof in any proportion of said compound of formula I or a pharmaceutically acceptable salt thereof, including a racemic mixture:
Wherein, R 1 and R 3 are preferably one of-OH, -OCOCH 2 CH 2 NHCH (NH) NH 2 or-OCOCH 2 CH 2 NH 2, R 2 ═ R 4, R 2 is preferably one of-H or-OCH 3;
The pharmaceutically acceptable salt is preferably at least one of hydrochloride, acetate and trifluoroacetate prepared by the compound shown in the formula I in an alcoholic solution with hydrochloric acid, acetic acid and trifluoroacetic acid;
The curcumin derivative preferably has the following structure:
the preparation method of the curcumin derivative comprises the following steps:
(1) preparation of intermediate 1: starting from commercial β -alanine, the amino group of β -alanine was converted to a guanidino group by reaction with N, N' -2-tert-butoxycarbonyl-1-guanidinopyrazole using N, N-diisopropylethylamine as the base and a mixed solution of acetonitrile and water as the solvent, thus giving intermediate 1, the reaction formula shown below:
(2) Preparation of compounds 2,3, 4, 5: starting from commercial curcumin or bisdemethoxycurcumin, respectively carrying out esterification condensation reaction with intermediate 1 by using dehydrated acetonitrile or tetrahydrofuran as a solvent and N, N-diisopropylethylamine as a base under the condition of adding a Kate condensing agent, and purifying the obtained product by adopting a column chromatography method to obtain an intermediate 2(2a, 2b) and an intermediate 3(3a, 3 b); carrying out deprotection reaction on the obtained intermediates 2a, 2b, 3a and 3b under the acidic condition of trifluoroacetic acid and with dichloromethane as a solvent at normal temperature, and purifying by adopting a recrystallization method to obtain final products 4a, 4b, 5a and 5b, wherein the using amount of the kat condensing agent is preferably 2-4 equivalents, and the amount of the curcumin or demethoxycurcumin is 1 equivalent; the reaction chemical equation is as follows:
(3) Preparation of compounds 6, 7, 8, 9: similarly, starting from commercial curcumin or demethoxycurcumin, the esterification condensation reaction is carried out with beta-tert-butoxycarbonylalanine, and then deprotection reaction is carried out to obtain final products 8a, 8b, 9a and 9b, wherein the reaction chemical formula is shown as follows:
The curcumin derivative is applied to the field of fluorescent molecular probes;
The curcumin derivative is applied to a fluorescent molecular probe for imaging the amyloid beta plaque of the Alzheimer's disease;
The curcumin derivative is applied to the preparation of the medicine for treating the Alzheimer disease;
The medicine refers to the medicine containing at least one of the curcumin derivative or the medicinal salt and the solvate thereof. It is well known that the solvated forms and salts of a compound do not generally affect the biological activity of the compound itself;
The medicament may contain one or more pharmaceutically acceptable carriers or excipients;
Compared with the prior art, the invention has the following advantages and effects:
(1) The maximum absorption and fluorescence emission spectrum values of the curcumin derivative provided by the invention are respectively between 410-450 nm and 510-580 nm, and a blue shift phenomenon (10-80 nm) can occur after the curcumin derivative is combined with an A beta 1-42 self-polymer, so that the curcumin derivative is suitable for the characteristics of an Alzheimer's disease amyloid beta plaque imaging fluorescent molecular probe.
(2) In addition, in the test of the self-aggregation inhibition activity of the in vitro compound and beta-amyloid, the compound has better inhibition effect on the self-aggregation of A beta 1-42, the inhibition effect of the compound is stronger than that of a control curcumin or bisdemethoxycurcumin, and the IC 50 value reaches the range of 10 -5 -10 -6 M, so the compound also has the potential of treating the Alzheimer disease.
(3) The curcumin derivative provided by the invention has the advantages of novel structure, good water solubility, high sensitivity, good selectivity, good photostability and high bioavailability.
Detailed Description
the present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
EXAMPLE 1 Synthesis of 3- (2, 3-bis (tert-butoxycarbonyl-1-methylguanidino) propionic acid 1
750mg of β -alanine (8.4mmol, 4eq) are dissolved in a 6: 1 volume ratio acetonitrile/water (30mL/5mL) solution, followed by the addition of 627mg of N, N-di-tert-butoxycarbonylguanidinopyrazole (2.0mmol, 1eq) and 870 μ L N, N-diisopropylethylamine (3.36mmol, 2.5eq), the mixture is stirred at 55 ℃ for 2H, the reaction is followed by TLC until the starting material disappears, the organic solvent is dried, then extracted three times with DCM, the organic phase is washed three times with 5% (mass fraction) hydrochloric acid solution, dried over magnesium sulfate, filtered, dried to give the crude product, which is then isolated via silica gel column to give compound 1(401mg), a colorless liquid, yield 58%, 1 H NMR (400MHz, CDCl 3): δ 11.38(s,1H),8.81(s,1H),3.67(t, J ═ 8.0Hz,2H), 2.71J ═ 8.71 (t, 8.18H), and the synthesis is as shown below:
EXAMPLE 2 Synthesis of ethyl 4- ((1E, 6E) -7- (4-hydroxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) phenyl 3- (2, 3-bis (tert-butoxycarbonyl) methylguanidino) propionate 2a and ((1E, 6E) -3, 5-dioxohept-1, 6-dien-1, 7-diyl) bis (4, 1-phenylene) bis (3- (2, 3-bis (tert-butoxycarbonyl) methylguanidino) propionate) 3a
262mg of bisdemethoxycurcumin (0.85mmol, 1eq), 565mg of intermediate 1(1.7mmol, 2eq) obtained in example 1, 444. mu. L N, N-diisopropylethylamine (2.55mmol, 3eq) and 1.5g of a Kate condensing agent (3.4mmol, 4eq) were added to acetonitrile (30mL) solvent and stirred at room temperature for 12 to 16 h. The reaction was followed by TLC until the starting material disappeared, the reaction solvent was dried by spinning, dissolved in DCM, washed three times with water, the organic phase was collected, dried over magnesium sulfate, filtered, and dried to give crude product, which was purified by column chromatography to give compounds 2a (216mg) and 3a (347mg), the synthetic routes are as follows:
Yellow solid, melting point 168-170 deg.C, yield 41%, 1 H NMR (400MHz, DMSO): delta 10.50(s,1H),10.01(s,1H),8.57(s,1H),7.77(d, J ═ 8.0Hz,2H),7.59(m,3H),7.23(d, J ═ 8.0Hz,2H),6.92(d, J ═ 16.2Hz,1H),6.82(d, J ═ 8.0Hz,2H),6.55(d, J ═ 16.2Hz,1H),6.12(s,1H),3.67(t, J ═ 8.0Hz,4H),2.88(t, J ═ 8.0Hz,4H),1.48(s,9H),1.41(s,9H).
yellow solid, melting point 170-172 deg.C, yield 44%, 1 H NMR (400MHz, CDCl 3): delta 10.46(s,1H),8.74(s,1H),7.62(d, J ═ 17.5Hz,2H),7.54(d, J ═ 8.0Hz,4H),6.91(d, J ═ 8.0Hz,4H),6.55(d, J ═ 17.5Hz,2H),5.81(s,1H),3.81(t, J ═ 8.0Hz,4H),2.87(t, J ═ 8.0Hz,4H),1.49(s,9H),1.47(s,9H).
EXAMPLE 3 Synthesis of Ethyl 4- ((1E, 6E) -7- (4-hydroxy-3-methoxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) -2-methoxyphenyl 3- (2, 3-di-tert-butoxycarbonyl) -1-methylguanidino) propionate 2b and ((1E, 6E) -3, 5-dioxohept-1, 6-dien-1, 7-diyl) bis (2-methoxy-4, 1-phenylene) bis (3- (2, 3-bis-butoxycarbonyl) -1-methylguanidino) propionate) 3b
The method comprises the following steps: 150mg of curcumin (0.41mmol, 1eq) was dissolved in 8mL of acetonitrile solution, and 170mg of intermediate 1(0.50mmol, 1.3eq) obtained in example 1, 210. mu. L N, N-diisopropylethylamine (1.2mmol, 3eq) and 580mg of Kate condensing agent (1.3mmol, 3eq) were added to obtain compounds 2b (117mg, yield 42.1%) and 3b (30mg, yield 7.4%) according to the procedure of example 2.
The second method comprises the following steps: 150mg of curcumin (0.41mmol, 1eq) was dissolved in 8mL of acetonitrile solution, 170mg of intermediate 1(1.2mmol, 3eq) prepared in example 1 was added, followed by further addition of 210. mu. L N, N-diisopropylethylamine (1.2mmol, 3eq) dropwise to the system, and finally 580mg of the Cartesian condensing agent (1.3mmol, 3eq) was added, and compounds 2b (32mg, yield 11.5%) and 3b (126mg, yield 31.1%) were isolated and purified according to the post-experimental workup method for compound 2 a. The synthetic route is as follows:
yellow solid, melting point 105-107 ℃, 1 H NMR (400MHz, CDCl 3): δ 10.47(s,1H),8.70(s, J ═ 4.0Hz,1H),7.60(d, J ═ 4.0Hz,1H),7.56(d, J ═ 4.0Hz,1H),7.06(m,5H),6.91(d, J ═ 8.0Hz,1H),6.52(d, J ═ 14.7Hz,1H),6.46(d, J ═ 14.7Hz,1H),5.90(s,1H),5.80(s,1H),3.93(s,3H),3.90(s,3H),3.82(t, J ═ 8.0Hz,2H),2.88(t, J ═ 8.0, 1H), 9.46H, 9H, 1H).
Yellow solid with melting point 118-120 deg.C, 1 H NMR (400MHz, CDCl 3): delta 10.47(s,1H),8.72(s,1H),7.61(d, J ═ 15.0Hz,2H),7.09(m,6H),6.54(d, J ═ 15.0Hz,2H),5.84(s,1H),3.83(t, J ═ 8.0Hz,4H),2.88(t, J ═ 8.0Hz,4H),1.56(s,18H),1.46(s,18H).
EXAMPLE 4 Synthesis of 4- ((1E, 6E) -7- (4-hydroxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) phenyl 3- (1-methylguanidino) propionate 4a
110mg of compound 2a (0.05mmol) obtained in example 2 was dissolved in 1mL of DCM, 500 μ L of trifluoroacetic acid was added dropwise, and the mixture was stirred at room temperature for 2 hours, and a yellow solid precipitated in the reaction system, a solid was produced by adding diethyl ether, and after filtration, compound 4a (94.7mg) was obtained as a yellow solid having a melting point of 146 to 148 ℃ and a yield of 100%, 1 H NMR (400MHz, DMSO): δ 10.13(s,1H),7.78(m,3H),7.60(m,3H),7.24(d, J ═ 8.0Hz,2H),6.92(d, J ═ 16Hz,1H),6.83(d, J ═ 8.0Hz,2H),6.74(d, J ═ 16Hz,1H),6.12(s,1H),3.47(t, J ═ 8.0Hz,2H),2.88(t, J ═ 8, J ═ 16Hz,2H), 2.32, 2H), 3.32 δ NMR (C, 3652.32, 32H), as shown in the following synthesis route:
EXAMPLE 5 Synthesis of 4- ((1E, 6E) -7- (4-hydroxy-3-methoxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) -2-methoxyphenyl 3- (1-methylguanidino) propionate 4b
35mg (0.05mmol) of the compound 2b obtained in example 3 was dissolved in DCM and trifluoroacetic acid, and according to the procedure of example 4, compound 4b (27mg) was obtained as a yellow solid with a melting point of 124 to 126 ℃ and a yield of 88.3%, 1 H NMR (400MHz, DMSO): δ 10.13(s,1H),7.60(m,3H),7.52(s,1H),7.34(m,2H),7.17(d, J ═ 8.0Hz,2H),6.97(d, J ═ 16Hz,1H),6.83(d, J ═ 8.0Hz,1H),6.79(d, J ═ 16Hz,1H),6.14(s,1H),3.85(s,3H),3.84(s,3H),3.47(t, J ═ 8.0, 2H),2.88(t, 8, J ═ 8, 2H), 3.56H), 3.35H, 3627.35H, 368, 3655, 368, 3655, 35H, 3655, 366335H:
EXAMPLE 6 Synthesis of ((1E, 6E) -3, 5-dioxohepta-1, 6-diene-1, 7-diyl) bis (4, 1-phenylene) bis (3- (1-methylguanidino) propionate) 5a
117mg (0.13mmol) of the compound 3a obtained in example 2 was recrystallized and purified according to the procedure of example 4 to obtain 5a (95.4mg) as a brown solid with a melting point of 150 to 152 ℃ in 100% yield, 1 H NMR (400MHz, DMSO): δ 7.71(m,6H),7.22(d, J ═ 8.0Hz,4H),6.82(d, J ═ 16Hz,2H),6.10(s,1H),3.61(t, J ═ 8.0Hz,2H),2.96(t, J ═ 8.0Hz,4H), 13 C NMR (500MHz, DMSO): δ 183.6,169.5,152.1,139.1,133.1,130.1,125.0,122.9,102.4,35.0,32.2. the synthetic route is as follows:
EXAMPLE 7 Synthesis of ((1E, 6E) -3, 5-dioxohepta-1, 6-diene-1, 7-diyl) bis (2-methoxy-4, 1-phenylene) bis (3- (1-methylguanidino) propionate) 5b
26mg (0.13mmol) of the compound 3b obtained in example 3 was purified by recrystallization according to the procedure of example 4 to obtain compound 5b (21.5mg) as a yellow solid with a melting point of 145 to 147 ℃ in 100% yield, 1 H NMR (400MHz, DMSO): δ 7.81(s,6H),7.66(d, J ═ 16Hz,2H),7.52(s,2H),7.54(s,2H),7.19(d, J ═ 8.0Hz,2H),7.01(d, J ═ 16Hz,2H),6.21(s,1H),3.85(s,6H),3.48(t, J ═ 8.0Hz,2H),2.88(t, J ═ 8.0Hz,2H), 13 C NMR (500MHz, δ 183.7,169.6,157.4,151.6,141.1,140.3,134.3,125.2,123.8,121.9,112.6,102.2,56.5,37.1, 33.5) according to the following scheme:
EXAMPLE 8 Synthesis of 4- ((1E, 6E) -7- (4-hydroxyphenyl) -3, 5-dioxoheptan-1, 6-dien-1-yl) phenyl-3- ((tert-butoxycarbonyl) amino) 6a and ((1E, 6E) -3, 5-dioxoheptan-1, 6-dien-1, 7-diyl) bis (4, 1-phenylene) bis (3- ((tert-butoxycarbonyl) amino) 7a
The method comprises the following steps: 100mg of bisdemethoxycurcumin (0.32mmol, 1eq), 61mg of Boc-beta-alanine (0.32mmol, 1eq), 169. mu. L N, N-diisopropylethylamine (0.96mmol, 3eq), 287mg of Kate condensing agent (0.64mmol, 2eq), acetonitrile (6mL) as a reaction solvent, according to the procedure of example 2, were isolated and purified to give compounds 6a (87mg, yield 56%) and 7a (19mg, yield 9%).
The second method comprises the following steps: 50mg (0.16mmol, 1eq) of bisdemethoxycurcumin, 93mg of Boc-beta-alanine (0.48mmol, 3eq), 85. mu. L N, N-diisopropylethylamine (0.48mmol, 3eq), 215mg of a Kate condensing agent (0.48mmol, 3eq) and acetonitrile (5mL) as a reaction solvent were separated and purified by the procedure of example 2 to obtain compound 7a (75mg, yield 71%) and compound 6a (22mg, yield 28.3%). The synthetic route is as follows:
Yellow solid, melting point 180-182 ℃, 1 H NMR (400MHz, CDCl 3): δ 7.56(m,4H),7.41(d, J ═ 8.0Hz,2H),7.09(d, J ═ 8.0Hz,2H),6.82(d, J ═ 8.0Hz,2H),6.53(d, J ═ 15.0Hz,1H),6.46(d, J ═ 15.0Hz,1H),5.78(s,1H),5.05(s,1H),3.49(t, J ═ 8.0Hz,2H),2.78(t, J ═ 8.0Hz,2H),1.44(s,9H).
7a yellow solid with a melting point of 122-124 ℃, 1 H NMR (400MHz, DMSO). delta.7.86 (d, J-8.0 Hz,4H),7.72(d, J-16.7 Hz,2H),7.30(d, J-8.0 Hz,4H),7.09(s,2H),7.01(d, J-16.7 Hz,2H),6.25(s,1H),3.37(t, J-8.0 Hz,4H),2.78(t, J-8.0 Hz,4H),1.45(s,18H).
EXAMPLE 9 Synthesis of Ethyl 4- ((1E, 6E) -7- (4-hydroxy-3-methoxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) -2-methoxyphenyl 3- ((tert-butoxycarbonyl) amino) propanoate 6b and Synthesis of ((1E, 6E) -3, 5-dioxohept-1, 6-dien-1, 7-diyl) bis (2-methoxy-4, 1-phenylene) bis (3- ((tert-butoxycarbonyl) propanoate) 7b
Method one 150mg curcumin (0.41mmol, 1eq), 77mg Boc-beta-alanine (0.41mmol, 1eq), 142. mu.L DIPEA (0.82mmol, 2eq), 270mg Carbot condensing agent (0.62mmol, 1.5eq) and dried tetrahydrofuran (10mL) as solvent were reacted at room temperature for 18h according to the procedure of example 2 to obtain compound 6b (118mg, yield 53.7%) and 7b (35mg, yield 12.1%) after isolation and purification.
method two, 200mg curcumin (0.54mmol, 1eq), 216mg Boc-beta-alanine (2.43mmol, 2.1eq), 291. mu.L DIPEA (1.67mmol, 3eq), 721mg Cartesian condensation agent (1.63mmol, 3eq) were weighed and reacted at room temperature for 18h with dry tetrahydrofuran (20mL) as solvent. Referring to the experimental workup procedure for compound 2a, after isolation and purification, compound 7b (138mg, yield 35.8%) and 6b (70mg, yield 23.9%) were obtained. The synthetic route is as follows:
Yellow solid, melting point 67-70 ℃, 1 H NMR (400MHz, CDCl 3): δ 7.63(d, J ═ 3.5Hz,1H),7.59(d, J ═ 3.5Hz,1H),7.21-7.05(m,4H),6.94(d, J ═ 8.0Hz,1H),6.56(d, J ═ 16Hz,1H),6.49(d, J ═ 16Hz,1H),5.89(s,1H),5.83(s,1H),5.30(s,1H),3.95(s,3H),3.91(s,3H),3.56(t, J ═ 8.0Hz,2H),2.81(t, J ═ 8.0Hz,2H),1.47(s,9H).
7b yellow solid, melting point 85-87 ℃, 1 H NMR (400MHz, DMSO): δ 7.65(d, J ═ 16.7Hz,2H),7.52(d, J ═ 3.5Hz,2H),7.18(d, J ═ 8.0Hz,2H),7.0(d, J ═ 16.7Hz,2H),6.95(s,2H),6.20(s,1H),3.85(s,6H),3.29(t, J ═ 8.0Hz,4H),2.71(t, J ═ 8.0Hz,4H),1.40(s,18H).
EXAMPLE 10 Synthesis of 4- ((1E, 6E) -7- (4-hydroxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) phenyl 3-aminopropionate 8a
28mg (0.058mmol) of the compound 6a obtained in example 8 was dissolved in DCM and trifluoroacetic acid and purified by recrystallization according to the procedure of example 4 to obtain compound 8a (25mg) as a brown solid with a melting point of 203 to 205 ℃ in 87% yield, 1 H NMR (400MHz, DMSO): delta 10.23(s,1H),8.07(s,3H),7.79(d, J ═ 8.0Hz,2H),7.59(m,4H),7.27(d, J ═ 8.0Hz,2H),6.92(d, J ═ 16Hz,1H),6.84(d, J ═ 8.0Hz,2H),6.74(d, J ═ 16Hz,1H),6.21(s,1H),3.85(s,6H),3.16(t, J ═ 8.0, 2H), 99.99 (t, J ═ 2H, t ═ 2H), DMSO, 36H, 3652H, 36 MHz, 3652H:
EXAMPLE 11 Synthesis of 4- ((1E, 6E) -7- (4-hydroxy-3-methoxyphenyl) -3, 5-dioxohept-1, 6-dien-1-yl) -2-methoxyphenyl-3-aminopropionate 8b
45mg of compound 6b from example 9 was dissolved in DCM and trifluoroacetic acid, and the procedure of example 4 was followed to obtain compound 8b (35mg) as a yellow solid with a melting point of 102-105 ℃ and a yield of 75.8%, 1 H NMR (400MHz, DMSO): Δ 9.74(s,1H),7.86(br,3H),7.62(d, J ═ 4.0Hz,1H),7.58(d, J ═ 4.0Hz,1H),7.54(s,1H),7.34(m,2H),7.19(m,2H),6.97(d, J ═ 16Hz,1H),6.83(d, J ═ 8.5Hz,1H),6.80(d, J ═ 16Hz,1H),6.13(s,1H),3.65(s,3H),3.64 (t ═ 8.5Hz,1H),6.80(d, J ═ 16Hz,1H), 6.56H, 368H, 19 (19, 3.56.56H), 3.56H, 19, 3H, 19, 3.7.7.7.7.7.7.7.7.7.6.7.7.6.6.7.7, 3H, 3:
EXAMPLE 12 Synthesis of ((1E, 6E) -3, 5-dioxohepta-1, 6-diene-1, 7-diyl) bis (4, 1-phenylene) bis (3-aminopropionate) 9a
45mg (0.069mmol) of the compound 7a obtained in example 8, according to the procedure of example 4, gave compound 9a (40mg) as a brown solid with a melting point of 166 to 168 ℃ in 85.3%, 1 H NMR (400MHz, DMSO): delta 7.97(s,6H),7.82(d, J ═ 8.5Hz,4H),7.67(d, J ═ 16Hz,2H),7.28(d, J ═ 8.5Hz,4H),6.97(d, J ═ 16Hz,2H),6.19(s,1H),3.65(s,3H),3.64(s,3H),3.17(t, J ═ 8.0Hz,4H),2.98(t, J ═ 8.0Hz, 4H): 13 C NMR (500MHz, delta 183.6,170.1,157.5,152.2,139.0,133.0,130.1,125.0,122.9,102.4, 37.8. DMSO, 33.8. the following synthesis route:
EXAMPLE 13 Synthesis of ((1E, 6E) -3, 5-dioxohepta-1, 6-diene-1, 7-diyl) bis (2-methoxy-4, 1-phenylene) bis (3-aminopropionate) 9b
38mg (0.053mmol) of the compound 7b prepared in example 9 was synthesized according to the procedure of example 4, to obtain compound 9b (31mg) as a yellow solid having a melting point of 115 to 117 ℃ in a yield of 78.5% and 1 H NMR (400MHz, DMSO): delta 7.88(br,6H),7.66(d, J ═ 16Hz,2H),7.55(d, J ═ 1.5Hz,2H),7.36(dd, J ═ 8.5,1.5Hz,2H),7.22(d, J ═ 8.5Hz,2H),7.0(d, J ═ 16Hz,2H),6.20(s,1H),3.85(s,6H),3.15(t, J ═ 8.0Hz,4H),2.96(t, J ═ 8.0, 4H), 4H (C, 6.32, 32, 32.500.35 MHz, DMSO, 35.52. delta.: as follows:
effects of the embodiment
(1) absorption and emission wavelengths of curcumin and bisdemethoxycurcumin derivatives
the absorption spectra and emission wavelengths were measured with a multimode spectrophotometer (multifunctional microplate reader spectramax Paradigm, san francisco, california, usa);
(2) Testing the solubility of the curcumin derivative in water;
(3) binding assay with Abeta 1-42 aggregates
The aggregate of Abeta 1-42 was used to fix the concentration of 5. mu.M and to bind different concentrations of fluorescent compounds the fluorescence signal detection was determined from the excitation/emission spectra of the respective compounds the Kd values were calculated using Grafpad Prism software.
(4) method for testing self-aggregation inhibitory activity of beta-amyloid:
dissolving beta-amyloid (Abeta 1-42) freeze-dried powder in hexafluoroisopropanol, standing at room temperature for 16h for depolymerization, blowing off the hexafluoroisopropanol at room temperature by using nitrogen flow to obtain a depolymerized Abeta 1-42 monomer, dissolving with DMSO to prepare a solution with the concentration of 200 mu M, and storing at-20 ℃ for later use.
10L of each test compound and 10L of a 40M A β 1-42 monomer solution were added to 384 plates and incubated at 37 ℃ for 48 hours in the absence of light, after which 10L of a 5M ThT solution were added and after incubation for 30 minutes the fluorescence intensity was measured and recorded using a microplate reader.
The test results obtained were as follows:
As shown in Table 1, the maximum absorption and fluorescence emission spectrum values of the curcumin derivative provided by the invention are respectively between 410-440 nm and 510-580 nm. Compared with curcumin and bisdemethoxycurcumin, the curcumin derivative provided by the invention has greatly improved solubility in water, and the highest solubility is compounds 8a and 9a, and is 28 g/L.
TABLE 1 maximum absorption, fluorescence emission spectra and solubility of curcumin derivatives
from the results of the binding ability test of the compounds shown in table 2 for the a β 1-42 self-mer, they generally have slightly stronger binding ability to the a β self-mer than curcumin and bisdemethoxycurcumin.
In addition, as shown in the results of the test on the self-aggregation inhibition activity of the compounds and beta-amyloid shown in the table 2, all the compounds have better inhibition effect on the self-aggregation of A beta 1-42, the inhibition effect is slightly stronger than that of control curcumin, curcumin and bisdemethoxycurcumin, particularly the compounds 5b and 9b, and the IC 50 value reaches the range of 10 -6 M.
table 2 binding ability of curcumin derivatives to a β 1-42 self-aggregates and assay of self-aggregation inhibitory activity against β -amyloid
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (9)

1. A curcumin derivative characterized by being a compound of formula I or a pharmaceutically acceptable salt thereof, or a tautomer of said compound of formula I or a pharmaceutically acceptable salt thereof, or a mixture thereof in any ratio:
wherein R 1 and R 3 are one of-OH, -OCOCH 2 CH 2 NHC (NH) NH 2 or-OCOCH 2 CH 2 NH 2, R 2 is R 4, and R 2 is one of-H or-OCH 3;
however, the curcumin derivative cannot be a compound having the following structure:
(1)R1＝R3＝-OH，R2＝R4＝-H；
(2)R1＝R3＝-OH，R2＝R4＝-OCH3。
2. a curcumin derivative according to claim 1, characterized in that:
The pharmaceutically acceptable salt is at least one of hydrochloride, acetate and trifluoroacetate prepared by reacting the compound of the formula I in an alcoholic solution with hydrochloric acid, acetic acid and trifluoroacetic acid, wherein the hydrochloride, the acetate and the trifluoroacetate are corresponding to the compound of the formula I in claim 1.
3. a curcumin derivative according to claim 1, characterized in that:
The curcumin derivative has the following structure:
4. A process for producing a curcumin derivative as claimed in any one of claims 1 to 3, characterized by comprising the steps of:
(1) Preparation of intermediate 1: starting from beta-alanine, converting the amino group of beta-alanine into a guanidino group by reaction with N, N' -di-tert-butoxycarbonyl-1-guanidinopyrazole using N, N-diisopropylethylamine as the base and a mixed solution of acetonitrile and water as the solvent, thus obtaining intermediate 1;
(2) Preparation of compounds 2,3, 4, 5: starting from curcumin or bisdemethoxycurcumin, taking dehydrated acetonitrile or tetrahydrofuran as a solvent, taking N, N-diisopropylethylamine as alkali, respectively carrying out esterification condensation reaction with the intermediate 1 under the condition of adding a Kate condensing agent, and purifying the obtained product by adopting a column chromatography method to obtain intermediates 2a and 2b and intermediates 3a and 3 b; carrying out deprotection reaction on the obtained intermediates 2a, 2b, 3a and 3b under the acidic condition of trifluoroacetic acid and with dichloromethane as a solvent at normal temperature, and purifying by adopting a recrystallization method to obtain final products 4a, 4b, 5a and 5 b;
(3) preparation of compounds 6, 7, 8, 9: similarly, starting from curcumin or demethoxycurcumin, carrying out esterification condensation reaction with beta-tert-butoxycarbonylalanine, and then carrying out deprotection reaction to obtain final products 8a, 8b, 9a and 9 b;
any one of the final products 4a, 4b, 5a, 5b, 8a, 8b, 9a and 9b is the target product curcumin derivative.
5. A curcumin derivative as claimed in any one of claims 1-3, and its application in the preparation of fluorescent molecular probe.
6. The application of the curcumin derivative in the field of preparing a fluorescent molecular probe according to claim 5, wherein the curcumin derivative is characterized in that:
the curcumin derivative is applied to preparing a fluorescent molecular probe for imaging the amyloid beta plaque of the Alzheimer's disease.
7. a curcumin derivative as claimed in any one of claims 1 to 3, for use in the preparation of a medicament for the treatment of Alzheimer's disease.
8. use of a curcumin derivative according to claim 7 in the preparation of a medicament for the treatment of alzheimer's disease, characterized in that:
The medicament contains at least one of curcumin derivatives or pharmaceutically acceptable salts and solvates thereof according to any one of claims 1 to 3.
9. Use of a curcumin derivative according to claim 7 in the preparation of a medicament for the treatment of alzheimer's disease, characterized in that: the medicament may contain one or more pharmaceutically acceptable carriers or excipients.
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A curcumin-based molecular probe for near-infrared fluorescence imaging of tau fibrils in Alzheimer"s disease;Park, Kwang-su等;《Organic & Biomolecular Chemistry》;20151231;第13卷(第46期);第11195页图1 *
Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol(acetaminophen) pharmacokinetics in healthy volunteers;Volak, Laurie P.等;《British Journal of Clinical Pharmacology》;20131231;第75卷(第2期);右栏第一段 *

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