CN112645964B - Tyrosol-biotin small-molecule probe and preparation method and application thereof - Google Patents

Tyrosol-biotin small-molecule probe and preparation method and application thereof Download PDF

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CN112645964B
CN112645964B CN202011544003.3A CN202011544003A CN112645964B CN 112645964 B CN112645964 B CN 112645964B CN 202011544003 A CN202011544003 A CN 202011544003A CN 112645964 B CN112645964 B CN 112645964B
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王书芳
王毅
张兴贤
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Abstract

The invention discloses a tyrosol-biotin small molecular probe and a preparation method and application thereof. The tyrosol small molecular probe designed by the invention is subjected to in vitro activity test, and the result shows that the tyrosol small molecular probe has good activity on the protection of primary myocardial cell injury induced by hypoxia reoxygenation, can be used as a small molecular probe for researching the action mechanism of tyrosol, and has good application prospect in the medical field.

Description

Tyrosol-biotin small-molecule probe and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tyrosol-biotin small molecular probe and a preparation method and application thereof.
Background
Tyrosol (Tyrosol) is aglycone of salidroside, is one of main active ingredients in rhodiola plants, is one of main phenolic compounds in olive oil, and has strong antioxidant activity. Tyrosol has good pharmacological activity in preventing and treating nervous system diseases, protecting heart, liver and kidney, inhibiting inflammation, inhibiting oxidative stress, resisting thrombi, resisting atherosclerosis, resisting pathogenic microorganism, resisting tumor, etc. Oxidative stress is one of the important mechanisms of ischemia-reperfusion-induced myocardial injury, which leads to excessive accumulation of ROS and can trigger myocardial cell death, leading to heart failure. Research shows that tyrosol can activate SIRT1/AMPK/eNOS signal path, inhibit oxidative stress reaction and reduce myocardial ischemia-reperfusion injury of diabetic rat effectively. In addition, tyrosol can also promote Hsp70 expression, reduce caspase-8 level, inhibit ischemia reperfusion induced apoptosis and relieve myocardial cell injury by inhibiting ROS accumulation and activation of ERK and JNK.
In conclusion, although tyrosol has good antioxidant activity and effect of relieving myocardial cell injury in vitro, the structure-activity relationship research is less, the design and synthesis of active compounds are difficult points of research center, and the action target and action mechanism are not clear. Therefore, the design and synthesis of small molecular probes with biological activity are needed, and the method has important significance for researching the action target of tyrosol and the action mechanism for treating myocardial cell injury. As a common labeling group, biotin-tyrosol small molecular probes formed by biotin-tyrosol connection are not reported at present, so that an experimental report of an action target of biotin-tyrosol is obtained.
Disclosure of Invention
Aiming at the prior art, the invention provides a tyrosol-biotin small molecular probe and a preparation method and application thereof, aiming at overcoming the defects of the existing tyrosol action target and the research on the myocardial cell injury protection action mechanism.
In order to achieve the purpose, the invention adopts the technical scheme that: provides a tyrosol-biotin small molecular probe, the structure of the small molecular probe is shown as formula I,
Figure BDA0002855294030000021
wherein n is an integer of 1 to 5.
The tyrosol small molecule probe is preferably the following compound:
Figure BDA0002855294030000022
the preparation route of the tyrosol-biotin small molecule probe is as follows:
Figure BDA0002855294030000023
the preparation method comprises the following steps:
s1: mixing a compound shown as a formula II, a compound shown as a formula III and a base according to the proportion of 1: 2-5: 1-3, uniformly stirring, reacting for 10-20 h at 30-100 ℃, extracting, and concentrating to obtain an intermediate IV;
Figure BDA0002855294030000031
s2: and mixing the intermediate IV, the compound shown in the formula V and a base according to the proportion of 1: 0.6-1: 1-3, stirring uniformly, reacting for 10-20 h at 30-100 ℃, extracting, concentrating and purifying to obtain the product;
Figure BDA0002855294030000032
the preparation method can be further improved on the basis of the technical scheme as follows.
Further, the compound of formula II, the compound of formula III and the base are as follows 1: 3: 2 are co-dissolved in an organic solvent a.
Further, the intermediate IV, the compound of formula V and the base are as follows: 0.8: 2 in an organic solvent B.
Further, the base is at least one of triethylamine, diisopropylethylamine, pyridine, 2, 6-methylpyridine, piperidine, 1, 8-diazabicycloundecen-7-ene, 1, 4-diazabicyclo [2.2.2] octane, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide.
Further, the organic solvent A is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, dioxane and acetone. The dosage of the organic solvent A is 5-15 mL/g, preferably 10-12 mL/g, calculated by the compound shown in the formula II.
Further, the organic solvent B is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, dioxane, acetone, dichloromethane, 1, 2-dichloroethane and chloroform. The amount of the organic solvent B is 5-15 mL/g, preferably 7-9 mL/g, based on the compound shown in the formula II.
Further, the preparation route of the compound represented by the formula V is as follows:
Figure BDA0002855294030000041
the preparation method comprises the following steps:
SS 1: reacting a compound of formula VI, an iodine reagent, and a nitrate salt in the ratio of 1: 0.1-0.5: 0.1-1 mass ratio, stirring uniformly, reacting at room temperature for 5-10 h, extracting, and concentrating to obtain a compound shown in a formula VII;
Figure BDA0002855294030000042
SS 2: dissolving a compound shown as a formula VII in an organic solvent D, and then adding a hydrogenation catalyst, wherein the mass ratio of the hydrogenation catalyst to the compound shown as the formula VII is 1-4: 20; and introducing hydrogen into the reaction device at the temperature of 20-60 ℃, reacting for 4-10 hours, and then filtering and concentrating to obtain the catalyst.
Further, the iodine reagent is bis (tert-butylcarbonyloxy) iodobenzene, [ bis (trifluoroacetyloxy) iodo ] benzene, [ bis (trifluoroacetyloxy) iodo ] pentafluorobenzene or diacetoxyiodobenzene; the nitrate is zinc nitrate hexahydrate, ferric nitrate nonahydrate or cupric nitrate trihydrate.
Further, the organic solvent C is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, chloroform, dimethyl sulfoxide, methanol, ethanol, acetonitrile and trifluoroethanol, and the dosage of the organic solvent C is 10-20 mL/g, preferably 12-15 mL/g based on the compound shown in the formula VI; the organic solvent D is at least one of methanol, ethanol, isopropanol, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran, and the dosage of the organic solvent D is 30-60 mL/g, preferably 40-50 mL/g based on the compound shown in the formula VII.
Further, the hydrogenation catalyst is Raney nickel or Pd/C with the mass fraction of 5%.
The tyrosol-biotin small molecular probe prepared by the invention has good prevention and treatment effects on primary myocardial cell injury induced by hypoxia reoxygenation, and can be used for preparing corresponding treatment medicines.
The invention has the beneficial effects that:
1. a novel tyrosol small molecular probe which takes alkane as a connecting chain and biotin as a report group is synthesized.
2. The tyrosol small molecular probe has good water solubility and a protective effect on myocardial cell injury, provides a basis and a template molecule for 'fishing' a target spot and researching an action mechanism of tyrosol, and has important academic research value and application prospect.
3. The synthetic method has the advantages of short route, simple and convenient operation, mild reaction conditions and high selectivity, and provides a better method for designing the molecular probe of a complex natural product.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound I obtained in example 14;
FIG. 2 is a nuclear magnetic carbon spectrum of Compound I obtained in example 14;
FIG. 3 is a graph of the protective effect of small molecule probes on hypoxia-reoxygenation-induced primary cardiomyocyte injury.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
Example 1: preparation of 2-nitrotyrosol (VII)
Figure BDA0002855294030000051
In a 50mL round bottom flask, 934mg diacetoxyiodobenzene acetate, 1.3g zinc nitrate hexahydrate, and 25mL acetonitrile were added, followed by 2.0g 2-aminobutyric alcohol (VI). The reaction solution was reacted at room temperature overnight, the TLC detection of the starting material was essentially complete, water was added, extraction was carried out with ethyl acetate and the organic phase was concentrated to give a tan solid 1.67g with a yield of 63%.
Example 2: preparation of 2-nitrotyrosol (VII)
In a 50mL round bottom flask, 1.47g of bis (tert-butylcarbonyloxy) iodobenzene, 1.3g of zinc nitrate hexahydrate and 25mL of acetonitrile were charged, and 2.0g of tyrosol was added. The reaction solution was reacted at room temperature overnight, the TLC detection of the starting material was essentially complete, water was added, extraction was carried out with ethyl acetate and the organic phase was concentrated to give 1.59g of a tan solid with a yield of 60%.
Example 3: preparation of 2-nitrotyrosol (VII)
In a 50mL round bottom flask, 1.25g of [ bis (trifluoroacetoxy) iodo ] benzene, 1.3g of zinc nitrate hexahydrate and 25mL of acetonitrile were charged, and 2.0g of tyrosol was added. The reaction solution is reacted at room temperature overnight, the TLC detection shows that the raw materials are basically completely reacted, water is added, ethyl acetate is used for extraction, and the organic phase is concentrated to obtain 2.12g of brown yellow solid with the yield of 80%.
Example 4: preparation of 2-nitrotyrosol (VII)
In a 50mL round bottom flask, 1.51g of [ bis (trifluoroacetoxy) iodo ] pentafluorobenzene, 1.3g of zinc nitrate hexahydrate and 25mL of acetonitrile were added, and 2.0g of tyrosol was added. The reaction solution was reacted at room temperature overnight, the TLC detection of the starting material was essentially complete, water was added, extraction was carried out with ethyl acetate and the organic phase was concentrated to give 2.01g of a tan solid with a yield of 76%.
Example 5: preparation of 2-nitrotyrosol (VII)
In a 50mL round bottom flask, 1.87g of [ bis (trifluoroacetoxy) iodo ] benzene, 2.63g of ferric nitrate nonahydrate and 40mL of acetonitrile were added, and 3.0g of tyrosol was added. The reaction solution was reacted at room temperature overnight, the TLC detection of the starting material was essentially complete, water was added, extraction was carried out with ethyl acetate and the organic phase was concentrated to give a tan solid 3.38g with a yield of 85%.
Example 6: preparation of 2-nitrotyrosol (VII)
In a 50mL round bottom flask, 1.56g of [ bis (trifluoroacetoxy) iodo ] benzene, 1.23g of copper nitrate trihydrate and 30mL of acetonitrile were added, 2.0g of tyrosol was added. The reaction solution was reacted at room temperature overnight, the TLC detection of the starting material was essentially complete, water was added, extraction was carried out with ethyl acetate and the organic phase was concentrated to give a tan solid 1.99g with a yield of 75%.
Example 7: preparation of 2-aminobutyric alcohol (V)
Figure BDA0002855294030000071
Dissolving 2-nitrotyrosol (4g) in 95% ethanol, adding 400mg of 5 wt% Pd-C (containing 50% of water), hydrogenating at 40 ℃ under normal pressure, reacting for 6h, completely reacting the raw materials, performing suction filtration, and concentrating the filtrate to obtain dark green solid 2-aminobutyric alcohol (3.21 g), wherein the yield is 96%.
Example 8: preparation of 2-aminobutyric alcohol (V)
Dissolving 2-nitrotyrosol (2g) in tetrahydrofuran, adding 250mg of 5 wt% Pd-C (containing 50% of water), hydrogenating at 50 ℃ under normal pressure, reacting for 8h, completely reacting the raw materials, performing suction filtration, and concentrating the filtrate to obtain dark green solid 2-aminobutyric alcohol (1.57 g), wherein the yield is 94%.
Example 9: preparation of 2-aminobutyric alcohol (V)
Dissolving 2-nitrotyrosol (3g) in methanol, adding 320mg of 5 wt% Pd-C (containing 50% of water), hydrogenating at 30 ℃ under normal pressure, reacting for 6h, completely reacting the raw materials, performing suction filtration, and concentrating the filtrate to obtain 2.48g of dark green solid 2-aminobutyric alcohol, wherein the yield is 99%.
Example 10: preparation of Compound (IV)
Figure BDA0002855294030000072
976mg of biotin represented by the formula II, 2.6g of 1, 4-dibromobutane and 1.1g of potassium carbonate were put into 10mL of N, N-dimethylformamide, and the reaction was stirred at 60 ℃ for 10 hours. After the reaction is finished, adding water, extracting by dichloromethane, concentrating an organic phase to obtain a jelly, and performing silica gel column chromatography, wherein dichloromethane and methanol are mixed according to a volume ratio of 15: 1 as eluent, and evaporating the eluent to obtain 1.07g of light yellow solid with a yield of 70%.
Example 11: preparation of Compound (IV)
732mg of biotin represented by the formula II, 1.95g of 1, 4-dibromobutane and 912mg of 1, 8-diazabicycloundecen-7-ene (DBU) were put into 8mL of N, N-dimethylformamide and reacted with stirring at 55 ℃ for 16 hours. After the reaction is finished, adding water, extracting by dichloromethane, concentrating an organic phase to obtain a jelly, and performing silica gel column chromatography, wherein dichloromethane and methanol are mixed according to a volume ratio of 15: 1 as eluent, and evaporating the eluent to obtain 624mg of light yellow solid with a yield of 55%.
Example 12: preparation of Compound (I)
Figure BDA0002855294030000081
Dissolving 280mg of a compound shown as a formula IV in N, N dimethylformamide (2mL), adding 110mg of 2-aminobutyric alcohol and 100mg of sodium bicarbonate, and reacting the reaction solution at 55 ℃ for 16h after uniformly stirring; after the reaction is finished, performing silica gel column chromatography, wherein dichloromethane and methanol are mixed according to the volume ratio of 10: 1 as eluent, and evaporating the solvent from the eluent to obtain 257mg of yellow viscous oil with a yield of 77%.
Example 13: preparation of Compound (I)
Dissolving 300mg of a compound shown as a formula IV in N, N dimethylformamide (3mL), adding 98mg of 2-amino tyrosol and 221mg of potassium carbonate, uniformly stirring, and reacting the reaction solution at 55 ℃ for 20 h; after the reaction is finished, performing silica gel column chromatography, wherein dichloromethane and methanol are mixed according to the volume ratio of 10: 1 as eluent, and evaporating the solvent from the eluent to obtain 293mg of yellow viscous oil with the yield of 81%.
Example 14: preparation of Compound (I)
Dissolving 200mg of a compound shown as a formula IV in N, N dimethylformamide (2mL), adding 66mg of 2-amino tyrosol and 161mg of 1, 8-diazabicycloundecen-7-ene (DBU), uniformly stirring, and reacting the reaction solution at 55 ℃ for 10 hours; after the reaction is finished, performing silica gel column chromatography, wherein dichloromethane and methanol are mixed according to the volume ratio of 10: 1 as eluent, and evaporating the solvent from the eluent to obtain 157mg of yellow viscous oil with a yield of 66%.
The spectral data of the prepared compound I were resolved as follows:
1H NMR(CD3OD,500MHz)δ1.42-1.47(m,2H),1.56-1.78(m,8H),2.36(t,J＝7.35Hz,2H),2.68-2.72(m,3H),2.87-2.89(m,1H),3.16-3.18(m,3H),3.71(t,J＝7.25Hz,2H),4.14(t,J＝6.0Hz,2H),4.26-4.28(m,1H),4.44-4.47(m,1H),6.42(dd,J＝1.95,7.9Hz,1H),6.53(d,J＝1.9Hz,1H),6.62(d,J＝7.85Hz,1H)ppm.
13C NMR(CD3OD,125MHz)δ24.64,25.58,26.00,28.08,28.35,33.53,38.77,39.67,43.48,55.59,60.22,61.99,63.45,64.01,112.12,113.27,117.45,130.40,136.74,143.10,164.71,174.14ppm.
HRMS-ESI:calculated for C22H34N3O5S[M+H]+:452.2214,found:452.2227.
experimental example pharmacodynamic experiment of Salidroside-biotin small molecule probe
Protection activity test for hypoxia reoxygenation-induced primary myocardial cell injury
1. Drugs and reagents: test samples, DMEM, 10% Fetal Bovine Serum (FBS), dimethyl sulfoxide (DMSO), Lactate Dehydrogenase (LDH) cytotoxicity detection kit.
2. The instrument comprises the following steps: clean bench, CO2Incubator, multifunctional inverted microscope, centrifuge, and 96-well culture plate with automatic microplate reader.
3. Cell lines: primary suckling mouse cardiac muscle cells.
4. Preparing a sample: the tyrosol small molecular probe prepared by the invention is taken, a compound is dissolved by DMSO, ultrasonic dissolution is carried out, the concentration is 200mM, and the obtained medicine solution is stored at the temperature of minus 20 ℃.
5. The specific experimental method comprises the following steps: inoculating primary suckling mouse myocardial cells into a 96-well plate, culturing for 24H, and setting a control group, an anoxic reoxygenation model group (H/R) and an H/R + tyrosol-biotin group. Respectively pre-protecting cells with tyrosol-biotin micromolecules with different concentrations (50 and 100 mu mol/L), and culturing in a cell culture box for 12 h; then, the cells are subjected to hypoxia for 4 hours and reoxygenation for 2 hours to form a myocardial cell hypoxia reoxygenation injury model, the LDH release rate of each hole of cells is detected by using a Lactate Dehydrogenase (LDH) cytotoxicity detection kit, so that the protective effect of tyrosol-biotin small molecules on primary myocardial cell injury induced by hypoxia reoxygenation is observed, and the experimental result is shown in figure 3.
6. The experimental results are as follows: the tyrosol small molecular probe disclosed by the invention has better activity on protecting primary myocardial cell injury induced by hypoxia reoxygenation, has an application prospect of treating myocardial cell injury, and can be applied to research on tyrosol 'fishing' targets and action mechanisms thereof.
While the present invention has been described in detail with reference to the embodiments, it should not be construed as limited to the scope of the patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.

Claims (10)

1. A tyrosol-biotin small molecule probe, which is characterized in that: the structure of the small molecular probe is shown as a formula I,
Figure FDA0002855294020000011
wherein n is an integer of 1 to 5.
2. The method for preparing tyrosol-biotin small molecule probes according to claim 1, comprising the steps of:
s1: mixing a compound shown as a formula II, a compound shown as a formula III and a base according to the proportion of 1: 2-5: 1-3, uniformly stirring, reacting for 10-20 h at 30-100 ℃, extracting, and concentrating to obtain an intermediate IV;
Figure FDA0002855294020000012
s2: and mixing the intermediate IV, the compound shown in the formula V and a base according to the proportion of 1: 0.6-1: 1-3, stirring uniformly, reacting for 10-20 h at 30-100 ℃, extracting, concentrating and purifying to obtain the product;
Figure FDA0002855294020000013
3. the method of claim 2, wherein: the alkali is at least one of triethylamine, diisopropylethylamine, pyridine, 2, 6-methylpyridine, piperidine, 1, 8-diazabicycloundeca-7-ene, 1, 4-diazabicyclo [2.2.2] octane, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide.
4. The method of claim 2, wherein: the organic solvent A is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N dimethylformamide, N-dimethylacetamide, dioxane and acetone.
5. The method of claim 2, wherein: the organic solvent B is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N dimethylformamide, N-dimethylacetamide, dioxane, acetone, dichloromethane, 1, 2-dichloroethane and chloroform.
6. The method according to claim 2, wherein the compound of formula V is prepared by the following steps:
SS 1: reacting a compound of formula VI, an iodine reagent, and a nitrate salt in the ratio of 1: 0.1-0.5: 0.1-1 mass ratio, stirring uniformly, reacting at room temperature for 5-10 h, extracting, and concentrating to obtain a compound shown in a formula VII;
Figure FDA0002855294020000021
SS 2: dissolving a compound shown as a formula VII in an organic solvent D, and then adding a hydrogenation catalyst, wherein the mass ratio of the hydrogenation catalyst to the compound shown as the formula VII is 1-4: 20; and introducing hydrogen into the reaction device at the temperature of 20-60 ℃, reacting for 4-10 hours, and then filtering and concentrating to obtain the catalyst.
7. The method of claim 6, wherein: the iodine reagent is bis (tert-butyl carbonyl oxygen) iodobenzene, [ bis (trifluoroacetoxy) iodine ] benzene, [ bis (trifluoroacetoxy) iodo ] pentafluorobenzene or diacetoxy iodobenzene; the nitrate is zinc nitrate hexahydrate, ferric nitrate nonahydrate or copper nitrate trihydrate.
8. The method of claim 6, wherein: the organic solvent C is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, chloroform, dimethyl sulfoxide, methanol, ethanol, acetonitrile and trifluoroethanol; the organic solvent D is at least one of methanol, ethanol, isopropanol, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran.
9. The method of claim 6, wherein: the hydrogenation catalyst is Raney nickel or Pd/C with the mass fraction of 5%.
10. The use of the tyrosol-biotin small molecule probe of claim 1 in the preparation of a medicament for the prevention and treatment of primary cardiomyocyte injury induced by hypoxia-reoxygenation.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
CN103476951A (en) * 2011-02-16 2013-12-25 海德威技术公司 Methods and compositions for the target-localized anchoring of detectable label

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Publication number Priority date Publication date Assignee Title
CN103476951A (en) * 2011-02-16 2013-12-25 海德威技术公司 Methods and compositions for the target-localized anchoring of detectable label

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Catechol Type Polyphenol Is a Potential Modifier of Protein Sulfhydryls: Development and Application of a New Probe for Understanding the Dietary Polyphenol Actions;Takeshi Ishii，等;《Chem. Res. Toxicol.》;20091009;第22卷;第1689-1698页 *

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