CN103044443A - Active curcumin derivative and preparation method thereof - Google Patents
Active curcumin derivative and preparation method thereof Download PDFInfo
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- CN103044443A CN103044443A CN2012105252122A CN201210525212A CN103044443A CN 103044443 A CN103044443 A CN 103044443A CN 2012105252122 A CN2012105252122 A CN 2012105252122A CN 201210525212 A CN201210525212 A CN 201210525212A CN 103044443 A CN103044443 A CN 103044443A
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Abstract
The invention discloses an active curcumin derivative and a preparation method thereof. The active curcumin derivative is the biotinylated curcumin obtained by jointing purely-natural and nonhazardous biotin with curcumin by virtue of a prodrug design principle, wherein a biotin molecule contains two nitrogen atoms and one sulphur atom; the active curcumin derivative is good in stability, high in bioavailability and low in toxic and side effects; and the specific structural formula of the active curcumin derivative is as shown in the specification.
Description
Technical field
The present invention relates to a kind of curcumin derivate, particularly relate to a kind of active curcumin derivate and preparation method thereof.
Background technology
Curcumine (Curcumin) is one of main effective constituent of per nnial herb turmeric, is that a kind of yellow shows slightly acid phenylbenzene hydrocarbon materials in heptan.In recent years, large quantity research finds that curcumine has anti-oxidant, antibiotic and physiology and the pharmacological actions such as immunomodulatory, antitumor, atherosclerosis.And curcumine is as a kind of natural drug, and almost non-toxic to people and animals, and its pharmaceutical use has been extended to the every field of modern medicine and has received much attention.And both at home and abroad the research of curcumin derivate mainly concentrated on the active methylene group, to the research of phenolic hydroxyl group also seldom, therefore great to this blank Research Significance.
Vitamin H is vitamin H, except being used for all right adjuvant therapy of diabetes of the treatment of egg-white injury disease, and good tolerance and bio-compatibility is arranged aspect medical.Even find that by people and various experimentation on animals a large amount of medications can not have side effects yet.Wang Xuefeng, Ding Shaomin is once respectively to acute, subchronic toxicity administration situation is tested, the result shows, vitamin H on heart rate, blood pressure, circulation of blood, breathing and stomachial secretion all less than impact (Wang XF (Wang Xuefeng), The total synthesis of biotin.[D] Beijing:Beijing Institute of Technology University.2003).In addition, the research of vitamin H mainly concentrated on biotin-avidin system both at home and abroad, and in the development of novel material.Recently research finds that vitamin H has played energetically effect to the biosynthesizing of lincomycin, its biological value is original 136.62%(LiX (Li Xiao), ChuJ (Chu Ju) etal, Effects of biotinandaminoacids on biosynthesisof lincomycin, Chinese Journal of Antibiotics (Chinese antibiosis long-cherished will) [J] .2009,33 (1): 6-10); The biotinylation trans-resveratrol has kept original antitumour activity and has had dose-dependence (FengL (Feng Lei) etal, Preparation and Pharmacodynamic Evaluation of Biotinylated Resveratrol, NatProd ResDev (research and development of natural products) .[J] .2009 (21): 988-991).According to the literature, contain heteroatomic curcumin ester compound and be better than curcumine (HuangSF (Huang Shufang) itself in drug effect, etal. Synthesis and antitumor activity study of nitrogen containing curcumin derivatives.Chinese Journal of Medicinal Chemistry (Chinese pharmaceutical chemistry magazine) [J] .2011 21, (2): 88-95).
Summary of the invention
The object of the invention is to, a kind of new active curcumin derivate and preparation method thereof is provided, the present invention is on the basis that guarantees security, has no side effect, strengthen the biological activity of curcumine, to obtain good stability, bioavailability is high, the newtype drug that toxic side effect is little.
Technical scheme of the present invention is: a kind of active curcumin derivate is the biotinylation curcumine, and it has following structural:
The preparation of vitamin H curcumine is that raw materials used all can the purchase obtains take vitamin H, curcumine etc. as raw material among the present invention, and experimental principle is as follows:
Vitamin H vitamin H acyl chlorides
The preparation method of the active curcumin derivate among the present invention may further comprise the steps:
1) biotin acyl chlorination: take by weighing the 5mmol curcumine, be dissolved in the trichloromethane of 30-60mL, add the 3-5mL acylating reagent, 35-50 ℃ of reaction 4-10 hour, obtain the wax yellow product;
2) impurity elimination: will wash for several times with trichloromethane after the desolventizing of above-mentioned product usefulness Rotary Evaporators, rotary evaporation is removed solvent and impurity;
3) preparation of biotinylation curcumine: take by weighing the 2mmol curcumine, be dissolved in the trichloromethane of 30-50mL, add the 2-4mL organic bases, previous step is obtained the vitamin H acyl chlorides be dissolved in and drop in the 15-35mL trichloromethane in the curcumine solution, 35-45 ℃ of reaction 15-30 hour;
4) filter drying: filter, filtrate is spin-dried for, drying obtains crude product biotinylation curcumine;
5) purifying: the crude product of above-mentioned biotinylation curcumin derivate is transferred in the silicagel column, uses methyl alcohol and the trichloromethane wash-out of 1:10, collect target product, vacuum-drying gets the biotinylation curcumine.
The present invention can also be applied to the following technical measures to achieve further:
Acylating reagent refers to thionyl chloride, trichloromethylchloroformate or phosphorus pentachloride in the step 1).
Adopt nitrogen protection in the step 3), by TLC detection reaction process.
Organic bases described in the step 3) is triethylamine or pyridine.
Curcumin derivate is to utilize the prodrug principle of design among the present invention, selects the vitamin H of pure natural toxicological harmless and curcumine to carry out amalgamation, and biotin molecule contains two nitrogen-atoms and a sulphur atom, the biotinylation curcumine that obtains, its good stability, bioavailability is high, and toxic side effect is little.
Description of drawings
Fig. 1 infrared detection spectrogram of the present invention;
Fig. 2 magnetic resonance detection collection of illustrative plates of the present invention;
Fig. 3 mass-spectrogram of the present invention.
Embodiment
The biotinylation curcumine, its preparation method may further comprise the steps:
1) biotin acyl chlorination: take by weighing the 5mmol curcumine, be dissolved in the trichloromethane of 30-60mL, add the 3-5mL thionyl chloride, 35-50 ℃ of reaction 4-10 hour, obtain the wax yellow product;
2) impurity elimination: will wash for several times with trichloromethane after the desolventizing of above-mentioned product usefulness Rotary Evaporators, rotary evaporation is removed solvent and impurity;
3) preparation of biotinylation curcumine: take by weighing the 2mmol curcumine, be dissolved in the trichloromethane of 30-50mL, add the 2-4mL triethylamine, previous step is obtained the vitamin H acyl chlorides to be dissolved in and to drop in the curcumine solution in the 15-35mL trichloromethane, 35-45 ℃ of reaction 15-30 hour, system is carried out nitrogen protection, TLC detection reaction process;
4) filter drying: filter, filtrate is spin-dried for, drying obtains crude product biotinylation curcumine;
5) purifying: the crude product of above-mentioned biotinylation curcumin derivate is transferred in the silicagel column, uses methyl alcohol and the trichloromethane wash-out of 1:10, collect target product, vacuum-drying gets the biotinylation curcumine.
Measured vitamin H curcumine fusing point, specific rotatory power, its structure are by infrared spectra, and mass spectrum and nuclear magnetic resonance spectrum conclusive evidence data are as follows:
MP：174-175℃ [α]D22 = +87°
IR(KBr, ν/cm-1): 1762 (C=O), 1701 (C=O), 1628,1511(Ar-H), and 3536-3290(br, Ar-OH), its collection of illustrative plates is as shown in Figure 1;
1H NMR (500MHz, CDCl3): δ 0.89-1.37(m, 8H ,-CH2CH2CH2CH2-), 3.95 (s, 6H, 2 * OCH3), 4.21 (m, 1H, CH), 4.36 (m, 3H, CH-CH2), 4.81 (s, 1H, NH), (4.9 s, 2H, CH2), 5.92 (s, 1H, NH), 6.94 (d, 2H, J=15.0Hz, C2-C6), 7.11-7.26 (m, 6H, Ar-H), 7.64 (d, 2H, J=15.0Hz, C1-C7), 13.96(s, 1H, ArOH), its collection of illustrative plates is as shown in Figure 2;
MS (ESI, m/z): [M+H] +=595.2, its collection of illustrative plates as shown in Figure 3.
Embodiment 2
The biotinylation curcumine, its preparation method may further comprise the steps:
1) biotin acyl chlorination: take by weighing the 5mmol curcumine, be dissolved in the trichloromethane of 30-60mL, add the 3-5mL trichloromethylchloroformate, 35-50 ℃ of reaction 4-10 hour, obtain the wax yellow product;
2) impurity elimination: will wash for several times with trichloromethane after the desolventizing of above-mentioned product usefulness Rotary Evaporators, rotary evaporation is removed solvent and impurity;
3) preparation of biotinylation curcumine: take by weighing the 2mmol curcumine, be dissolved in the trichloromethane of 30-50mL, add the 2-4mL triethylamine, previous step is obtained the vitamin H acyl chlorides to be dissolved in and to drop in the curcumine solution in the 15-35mL trichloromethane, 35-45 ℃ of reaction 15-30 hour, system is carried out nitrogen protection, TLC detection reaction process;
4) filter drying: filter, filtrate is spin-dried for, drying obtains crude product biotinylation curcumine;
5) purifying: the crude product of above-mentioned biotinylation curcumin derivate is transferred in the silicagel column, uses methyl alcohol and the trichloromethane wash-out of 1:10, collect target product, vacuum-drying gets the biotinylation curcumine.
Measured vitamin H curcumine fusing point, specific rotatory power, its structure are by infrared spectra, and mass spectrum and nuclear magnetic resonance spectrum conclusive evidence data are as follows:
MP：174-175℃ [α]D22 = +87°
IR(KBr, ν/cm-1): 1762 (C=O), 1701 (C=O), 1628,1511(Ar-H), and 3536-3290(br, Ar-OH), its collection of illustrative plates is as shown in Figure 1;
1H NMR (500MHz, CDCl3): δ 0.89-1.37(m, 8H ,-CH2CH2CH2CH2-), 3.95 (s, 6H, 2 * OCH3), 4.21 (m, 1H, CH), 4.36 (m, 3H, CH-CH2), 4.81 (s, 1H, NH), (4.9 s, 2H, CH2), 5.92 (s, 1H, NH), 6.94 (d, 2H, J=15.0Hz, C2-C6), 7.11-7.26 (m, 6H, Ar-H), 7.64 (d, 2H, J=15.0Hz, C1-C7), 13.96(s, 1H, ArOH), its collection of illustrative plates is as shown in Figure 2;
MS (ESI, m/z): [M+H] +=595.2, its collection of illustrative plates as shown in Figure 3.
Embodiment 3
The biotinylation curcumine, its preparation method may further comprise the steps:
1) biotin acyl chlorination: take by weighing the 5mmol curcumine, be dissolved in the trichloromethane of 30-60mL, add the 3-5mL phosphorus pentachloride, 35-50 ℃ of reaction 4-10 hour, obtain the wax yellow product;
2) impurity elimination: will wash for several times with trichloromethane after the desolventizing of above-mentioned product usefulness Rotary Evaporators, rotary evaporation is removed solvent and impurity;
3) preparation of biotinylation curcumine: take by weighing the 2mmol curcumine, be dissolved in the trichloromethane of 30-50mL, add the 2-4mL pyridine, previous step is obtained the vitamin H acyl chlorides to be dissolved in and to drop in the curcumine solution in the 15-35mL trichloromethane, 35-45 ℃ of reaction 15-30 hour, system is carried out nitrogen protection, TLC detection reaction process;
4) filter drying: filter, filtrate is spin-dried for, drying obtains crude product biotinylation curcumine;
5) purifying: the crude product of above-mentioned biotinylation curcumin derivate is transferred in the silicagel column, uses methyl alcohol and the trichloromethane wash-out of 1:10, collect target product, vacuum-drying gets the biotinylation curcumine.
Measured vitamin H curcumine fusing point, specific rotatory power, its structure are by infrared spectra, and mass spectrum and nuclear magnetic resonance spectrum conclusive evidence data are as follows:
MP：174-175℃ [α]D22 = +87°
IR(KBr, ν/cm-1): 1762 (C=O), 1701 (C=O), 1628,1511(Ar-H), and 3536-3290(br, Ar-OH), its collection of illustrative plates is as shown in Figure 1;
1H NMR (500MHz, CDCl3): δ 0.89-1.37(m, 8H ,-CH2CH2CH2CH2-), 3.95 (s, 6H, 2 * OCH3), 4.21 (m, 1H, CH), 4.36 (m, 3H, CH-CH2), 4.81 (s, 1H, NH), (4.9 s, 2H, CH2), 5.92 (s, 1H, NH), 6.94 (d, 2H, J=15.0Hz, C2-C6), 7.11-7.26 (m, 6H, Ar-H), 7.64 (d, 2H, J=15.0Hz, C1-C7), 13.96(s, 1H, ArOH), its collection of illustrative plates is as shown in Figure 2;
MS (ESI, m/z): [M+H] +=595.2, its collection of illustrative plates as shown in Figure 3.
Embodiment 4: the effect of vitamin H curcumine In Vitro Bacteriostatic
The preparation of bacterium liquid: gold-coloured staphylococci is accessed in the freshly prepared activation medium in optimum temperuture activation 2h again, and shaking table is cultivated 24h, and gained bacterium liquid is diluted to 10
8Cfu/mL.
The mensuration of minimal inhibitory concentration: in culture dish, access 10
8The test strain 0.1mL of cfu/mL gold-coloured staphylococci, get the concentration gradient curcumine solution of 0.1-16mg/mL, and the biotinylation curcumine solution of 0.1-8mg/mL concentration gradient is applied to each culture dish, wherein each concentration is done three parallel laboratory tests, the experiment take stroke-physiological saline solution as blank is cultivated a growth cycle in the gold-coloured staphylococci optimum culturing temperature.
The mensuration of inhibition zone: with the positive contrast of collutory through sterile filtration, with the negative contrast of stroke-physiological saline solution.In each culture dish, access respectively 10
8Cfu/mL experimental strain 0.1mL dips respectively the curcumine solution of equivalent, biotinylation curcumine solution with the 6mm filter paper of sterilizing, collutory, stroke-physiological saline solution is affixed on to access on the flat board of test strain, cultivate a growth cycle in optimum culturing temperature, measure the diameter of each inhibition zone.
The bacteriostatic experiment result: curcumine concentration is 14mg/mL(0.038mmol/mL), biotinylation curcumine concentration is 4mg/mL(0.0067mmol/mL) time, gold-coloured staphylococci is had obvious fungistatic effect, and antibacterial circle diameter is 10mm and 12mm, and its bacteriostatic activity is 5.67 times of curcumine.
Claims (5)
1. active curcumin derivate, it is characterized in that: described derivative is the biotinylation curcumine, and it has following structural:
2. a method for preparing active curcumin derivate claimed in claim 1 is characterized in that, may further comprise the steps:
1) biotin acyl chlorination: take by weighing the 5mmol curcumine, be dissolved in the trichloromethane of 30-60mL, add the 3-5mL acylating reagent, 35-50 ℃ of reaction 4-10 hour, obtain the wax yellow product;
2) impurity elimination: will wash for several times with trichloromethane after the desolventizing of above-mentioned product usefulness Rotary Evaporators, rotary evaporation is removed solvent and impurity;
3) preparation of biotinylation curcumine: take by weighing the 2mmol curcumine, be dissolved in the trichloromethane of 30-50mL, add the 2-4mL organic bases, previous step is obtained the vitamin H acyl chlorides be dissolved in and drop in the 15-35mL trichloromethane in the curcumine solution, 35-45 ℃ of reaction 15-30 hour;
4) filter drying: filter, filtrate is spin-dried for, drying obtains crude product biotinylation curcumine;
5) purifying: the crude product of above-mentioned biotinylation curcumin derivate is transferred in the silicagel column, uses methyl alcohol and the trichloromethane wash-out of 1:10, collect target product, vacuum-drying gets the biotinylation curcumine.
3. the preparation method of active curcumin derivate according to claim 1, it is characterized in that: acylating reagent refers to thionyl chloride, trichloromethylchloroformate or phosphorus pentachloride in the step 1).
4. the preparation method of active curcumin derivate according to claim 1 is characterized in that: adopt nitrogen protection in the step 3), by TLC detection reaction process.
5. the preparation method of active curcumin derivate according to claim 1, it is characterized in that: organic bases described in the step 3) is triethylamine or pyridine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104418883A (en) * | 2013-08-26 | 2015-03-18 | 保定市龙瑞药物技术有限责任公司 | Curcumin phosphate compound and preparation method and application thereof |
| CN105566317A (en) * | 2016-01-13 | 2016-05-11 | 北京宜生堂医药科技研究有限公司 | Compound and preparation method thereof |
| CN106349330A (en) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | Lys-Glu modified curcumin and preparation thereof, as well as biological activity and application |
| CN113583018A (en) * | 2021-07-27 | 2021-11-02 | 山东第一医科大学(山东省医学科学院) | Curcumin derivative connected with biotin and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104418883A (en) * | 2013-08-26 | 2015-03-18 | 保定市龙瑞药物技术有限责任公司 | Curcumin phosphate compound and preparation method and application thereof |
| CN106349330A (en) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | Lys-Glu modified curcumin and preparation thereof, as well as biological activity and application |
| CN106349330B (en) * | 2015-07-13 | 2019-07-12 | 首都医科大学 | The curcumin of Lys-Glu modification, preparation, bioactivity and application |
| CN105566317A (en) * | 2016-01-13 | 2016-05-11 | 北京宜生堂医药科技研究有限公司 | Compound and preparation method thereof |
| CN113583018A (en) * | 2021-07-27 | 2021-11-02 | 山东第一医科大学(山东省医学科学院) | Curcumin derivative connected with biotin and preparation method and application thereof |
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