CN111763139B - Pinocembrin, application of pinocembrin and preparation method of pinocembrin - Google Patents

Pinocembrin, application of pinocembrin and preparation method of pinocembrin Download PDF

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CN111763139B
CN111763139B CN202010417626.8A CN202010417626A CN111763139B CN 111763139 B CN111763139 B CN 111763139B CN 202010417626 A CN202010417626 A CN 202010417626A CN 111763139 B CN111763139 B CN 111763139B
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pinosylvin
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孙斐
王成牛
龚胜男
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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Abstract

The invention provides pinosylvin which is a crystalline compound and has a temperature of m.p.153-155 ℃; EI-MS M/Z:212 (M +). The pinosylvin is used for preparing the medicine for treating oligospermia, and can also be used for preparing medically acceptable oral preparations, injections, granules, pills, capsules, powder, sustained-release preparations, controlled-release preparations, targeted preparations and other preparations for administration. The inventor of the invention finds that pinosylvin has obvious effect on oligoasthenozoospermia through long-term research, and further finds that: the pinosylvin has obvious therapeutic action on oligozoospermia model mice in the mice, the number and the concentration of sperms of the oligozoospermia model mice are obviously improved after two weeks of continuous administration, and the pinosylvin has promotion action on the concentration and the vitality of the sperms of the mice under different concentrations.

Description

Pinocembrin, application of pinocembrin and preparation method of pinocembrin
Technical Field
The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to pinosylvin, application of pinosylvin and a preparation method of pinosylvin.
Background
Pinosylvin is a derivative of natural trans-1, 2-stilbene, is found in wood pulp of pine and eucalyptus, tea oil and herbal medicine, and is stilbene.
Since pinosylvin exists in natural pine nuts and pine needle plants, the content of pinosylvin is very small, and the pinosylvin is very difficult to purify in a laboratory, at present, no wide pharmacological research is carried out on the pinosylvin, but a stilbene derivative is eliminated by a non-urinary way and is widely subjected to glucuronidation in vivo, so that the pinosylvin has a good antioxidation effect, and a great deal of research support is provided. Other stilbene derivatives such as resveratrol have been widely used in pharmacological research, and are hot spots for research and development of various antioxidant products. The pinosylvin has very effective antibacterial activity on a plurality of fungi, and when trees are infected by fungi, the trees can secrete the pinosylvin as a phytoalexin, so that the pinosylvin has wide research and development prospects on the antioxidant and antibacterial effects of animals. However, other more efficient and definite action targets, mechanisms and the like of pinosylvin have not been discovered so far.
At present, the resveratrol has no obvious effect on the oligoasthenospermia patients clinically, and the scientific research shows that the resveratrol has promotion effect on the oligoasthenospermia but has an unstable structure.
Disclosure of Invention
The invention aims to solve the technical problem of providing pinosylvin, application of pinosylvin and a preparation method thereof, and experiments prove that pinosylvin crystals can resist oxidation and have the effect of improving the sperm motility concentration.
To solve the above technical problems, an embodiment of the present invention provides pinosylvin, which is a crystalline compound having a formula (i), (ii), (iii) and (iv)
Figure 621932DEST_PATH_IMAGE001
) The chemical formula shown is as follows:
Figure 527571DEST_PATH_IMAGE002
formula (A), (B)
Figure 623703DEST_PATH_IMAGE001
）；
The crystalline compound is colorless needle crystal, and is m.p.153 to 155 ℃; EI-MS M/Z:212 (M +).
The invention also provides application of the pinosylvin in preparation of a medicine for treating oligospermia.
Wherein, when the pinosylvin is used for preparing the medicine for treating oligospermia, the effective dose range is 0.01ug/mL-10ug/mL.
The pinosylvin can be further used for preparing medically acceptable oral preparations, injections, granules, pills, capsules, powders, sustained release agents, controlled release preparations, targeting preparations and other preparations for administration.
The invention also provides a preparation method of pinosylvin, and the preparation equation is as shown in the formula (A)
Figure 256679DEST_PATH_IMAGE003
) Shown in the figure:
Figure 387446DEST_PATH_IMAGE004
formula (A), (B) and
Figure 526303DEST_PATH_IMAGE003
）；
the preparation method comprises the following steps:
(1) Adding 0.2mmol of compound A0.025mmol of bis (1, 5-cyclooctadiene) iridium (I) chloride dimer and 0.04mmol of 1, 2-bis (diphenylphosphino) ethane into a 15mL pressure resistant tube under the protection of nitrogen, adding 4mmol of EtOH and 1.5mL of THF, and stirring the reaction solution at 120 ℃ for 22h; after the reaction is finished, cooling to room temperature, and adding 10ml of ethyl acetate for dilution; washing the reaction mixed solution with saturated saline solution for 3 times, extracting with organic phase ethyl acetate, drying with organic phase anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain white product B, white solid 38 mg, and reaction yield 80%;
(2) Adding 0.2mmol of white product B into 6mL of anhydrous dichloromethane under the protection of nitrogen to dissolve, stirring at-20 ℃, slowly dropwise adding 1.34mmol of boron tribromide, stirring under the protection of mixed liquid nitrogen, slowly heating to room temperature to react for 4-5 h, adding 10mL of water after the reaction is finished, extracting for 3 times by using dichloromethane, washing by using salt water, and then drying by using anhydrous sodium sulfate; and (3) concentrating the crude product under reduced pressure, and purifying by column chromatography to obtain pinosylvin, wherein the white solid is 35mg, and the reaction yield is 83%.
Preferably, the compound A is (1- (2- (3, 5-dimethoxyphenyl) ethynyl)) benzene with the chemical formula of (A) (
Figure 47414DEST_PATH_IMAGE005
）：
Figure 297130DEST_PATH_IMAGE006
Formula (A), (B) and
Figure 282404DEST_PATH_IMAGE005
）；
the white product B is (E-1, 2-bis (4-methoxyphenyl) vinyl) benzene and has a chemical formula shown in the formula (
Figure 782043DEST_PATH_IMAGE007
）：
Figure 852767DEST_PATH_IMAGE008
Formula (A), (B) and
Figure 30807DEST_PATH_IMAGE007
）。
wherein, when column chromatography purification is carried out in the step (1), the volume ratio of the ethyl acetate to the petroleum ether is 1/4. And (3) during column chromatography purification in the step (2), the volume ratio of n-hexane to acetone is 6/4.
The technical scheme of the invention has the following beneficial effects:
the inventor of the invention finds that pinosylvin has obvious effect on oligoasthenozoospermia through long-term research, and further finds that: the pinosylvin has obvious therapeutic action on oligozoospermia model mice in the mice, the number and the concentration of sperms of the oligozoospermia model mice are obviously improved after two weeks of continuous administration, and the pinosylvin has promotion action on the concentration and the vitality of the sperms of the mice under different concentrations.
Drawings
FIG. 1 is a hydrogen spectrum of compound E-1, 2-bis (4-methoxyphenyl) vinyl) benzene of the present invention;
FIG. 2 is a carbon spectrum diagram of compound E-1, 2-bis (4-methoxyphenyl) vinyl) benzene of the present invention;
FIG. 3 is a chart of hydrogen spectrum of pinosylvin prepared by the invention;
FIG. 4 is a carbon spectrum of pinosylvin prepared by the present invention;
FIG. 5 is a graph showing the experimental results of the effects of pinosylvin and its crystals on the promotion of oligoasthenospermia in mice.
Detailed Description
In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to the accompanying drawings and specific embodiments.
The inventor of the invention finds that pinosylvin has obvious effect on oligoasthenozoospermia through long-term research, and further finds that: the pinosylvin has obvious therapeutic action on oligozoospermia model mice in the mice, the number and the concentration of sperms of the oligozoospermia model mice are obviously improved after two weeks of continuous administration, and the pinosylvin has promotion action on the concentration and the vitality of the sperms of the mice under different concentrations. At present, the resveratrol has no obvious effect on patients with oligoasthenospermia clinically, the scientific research shows that the resveratrol has a promoting effect on oligoasthenospermia, and the pinosylvin has a structure similar to that of the resveratrol and has a more stable secondary structure.
Based on the theory, the invention provides pinosylvin which is a crystal compound and has a formula (A)
Figure 870587DEST_PATH_IMAGE001
) The chemical formula shown is as follows:
Figure 351247DEST_PATH_IMAGE002
formula (A), (B) and
Figure 706005DEST_PATH_IMAGE001
）；
the crystal compound is colorless needle crystal, and is m.p.153 to 155 ℃; EI-MS M/Z:212 (M +).
The invention also provides application of the pinosylvin in preparation of a medicine for treating oligospermia. When the pinosylvin is used for preparing the medicine for treating oligospermia, the effective dose range is 0.01ug/mL-10ug/mL.
The pinosylvin can also be used for preparing medically acceptable oral preparations, injections, granules, pills, capsules, powder, sustained release preparations, controlled release preparations, targeting preparations and other preparations for administration.
The invention also provides a preparation method of pinosylvin, and the preparation equation is as shown in the formula (A)
Figure 563103DEST_PATH_IMAGE003
) Shown in the figure:
Figure 257389DEST_PATH_IMAGE009
formula (A), (B) and
Figure 95901DEST_PATH_IMAGE003
）；
the preparation method comprises the following steps:
(1) Adding 0.2mmol of (1- (2- (3, 5-dimethoxyphenyl) ethynyl)) benzene, 0.005mmol of bis (1, 5-cyclooctadiene) iridium (I) chloride dimer and 0.04mmol of 1, 2-bis (diphenylphosphino) ethane to a 15mL pressure-resistant tube under the protection of nitrogen, adding 4mmol of EtOH (232 mL) and 1.5mL of THF, and stirring the reaction solution at 120 ℃ for 22h; after the reaction is finished, cooling to room temperature, and adding 10ml of ethyl acetate for dilution; washing the reaction mixed solution with saturated saline solution for 3 times, extracting organic phase ethyl acetate, drying the organic phase with anhydrous sodium sulfate, concentrating the crude product under reduced pressure, and purifying by column chromatography (ethyl acetate/petroleum ether = 1/4) to obtain a white product (E-1, 2-bis (4-methoxyphenyl) vinyl) benzene, wherein the white solid is 38 mg, and the reaction yield is 80%;1H NMR (400 MHz, CDCl 3) 7.51-7.49 (m, 2H), 7.37-7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.09 (d, J = 16.4 Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H), 6.7 (d, J = 2.4 Hz, 2H), 6.40 (t, J = 2.0 Hz, 1H), 3.82 (s, 6H); 13C NMR (100 MHz, CDCl 3): 161.1, 139.5, 137.3, 129.3, 128.8, 128.8, 127.9, 126.7, 104.7, 100.1, 55.5.
(2) Adding 0.2mmol of (E-1, 2-bis (4-methoxyphenyl) vinyl) benzene into 6mL of anhydrous dichloromethane under the protection of nitrogen to dissolve, stirring at-20 ℃, slowly dropwise adding 1.34mmol of boron tribromide (0.34 g, 30% of boron tribromide is dissolved in the anhydrous dichloromethane), stirring under the protection of nitrogen in a mixed solution, slowly heating to room temperature to react for 4 to 5 hours, adding 10mL of water after the reaction is finished, extracting for 3 times by using dichloromethane, washing by using salt water, and then drying by using anhydrous sodium sulfate; the crude product was concentrated under reduced pressure and purified by column chromatography (n-hexane/acetone = 6/4) to give pinosylvin as a white solid 35mg with a reaction yield of 83%. 1 H NMR (400 MHz, (CD3)2CO): 7.57 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.10 (s, 2H), 6.60 (d, J = 2.0 Hz, 2H), 6.32 (t, J = 2.4 Hz, 1H); 13 C NMR (100 MHz, (CD3)2CO): 159.6, 140.4, 138.4, 129.8, 129.5, 129.2, 128.3, 127.3, 105.9, 103.1。
The effect of pinosylvin and its crystals in ameliorating oligoasthenospermia is further demonstrated below with reference to specific examples.
The experimental procedure was as follows:
step one, after 40 mature ICR male mice of 8 weeks old are bred for 3 days, the ICR male mice are randomly divided into 8 groups of a model group, a blank group, a pinosylvin high-dose group, a pinosylvin medium-dose group, a pinosylvin low-dose group, a resveratrol high-dose control group, a resveratrol medium-dose control group and a resveratrol low-dose control group, and each group comprises 5 mice.
Step two, the Busulfan is prepared into a solution with the concentration of 6mg/mL, except that the blank group of mice is not treated, other groups of mice are injected into testis with the dose of 6mg/kg, and the mouse model with the oligoasthenospermia is formed. After two weeks, the high dose group, the medium dose group and the low dose group of the pinosylvin are respectively administered with different concentrations of pinosylvin for intragastric administration, the intragastric administration dose is respectively 100mg/kg of the weight of the high dose group, 10mg/kg of the weight of the medium dose group and 1mg/kg of the weight of the low dose group, the high dose control group, the medium dose control group and the low dose control group of the resveratrol are respectively administered with different concentrations of resveratrol for intragastric administration, the intragastric administration dose is respectively 100mg/kg of the weight of the high dose group, 10mg/kg of the weight of the medium dose group and 1mg/kg of the weight of the low dose group, and the model group and the blank group are both administered with 1mL of solvent per day for intragastric administration and each group is continuously administered for 14 days.
And step three, observing the general state (such as hair color, activity, body state and the like) of the mouse in the experimental process, and measuring the daily water intake and food intake.
Step four, killing the mice completely after the experiment is finished, taking blood from femoral artery, separating serum, picking testis, gonad and accessory gonad, weighing, extracting epididymis semen, and detecting the sperm density, sperm motility and forward movement sperm percentage of the mice by adopting a CASA computer-assisted sperm quality analysis system; detecting the weight of the mouse and the quality of the testis and the epididymis; an Elisa kit detects the levels of ROS, MDA and SOD1 in mouse testis; the Elisa kit detects the serum gonadotropin testosterone (T) and Luteinizing Hormone (LH) levels and Follicle Stimulating Hormone (FSH) of each group of mice.
The results are shown in FIG. 5:
compared with a model group, a blank group has a statistical significance (P < 0.05) in comparison of sperm count and sperm motility detection results, and compared with the model group, the sperm count and sperm motility of each drug treatment group of a pinosylvin high dose group, a pinosylvin medium dose group, a resveratrol high dose control group and a resveratrol medium dose control group are remarkably improved, the difference has a statistical significance (P < 0.05), the sperm count and sperm motility of the high dose group are remarkably higher than those of the medium dose group and the low dose group, and the difference has a statistical significance (P < 0.05). Compared with a blank group, the wet weight of the testis and the wet weight of the epididymis of each group of mice are reduced, the difference is significant and has statistical significance (P < 0.05), compared with a model group, a pinosylvin high-dose group, a pinosylvin medium-dose group, a resveratrol high-dose control group and a resveratrol medium-dose control group are all increased, the difference is significant and has statistical significance (P < 0.05), and compared with the model group, a low-dose group has no significant difference (P > 0.05).
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (3)

1. The application of the pinosylvin is characterized in that the pinosylvin is used for preparing a medicine for treating oligospermia;
the pinosylvin is a crystalline compound and has the formula (A)
Figure 290203DEST_PATH_IMAGE001
) The chemical formula shown is as follows:
Figure 370155DEST_PATH_IMAGE002
formula (A), (B) and
Figure 458197DEST_PATH_IMAGE001
）；
the crystalline compound is colorless needle crystal, and is m.p.153 to 155 ℃; EI-MS M/Z:212 (M +).
2. The use of pinosylvin according to claim 1, wherein the effective dose of pinosylvin for the preparation of a medicament for the treatment of oligoasthenospermia is in the range of 0.01ug/mL to 10ug/mL.
3. The use of pinosylvin according to claim 1, for the preparation of medically acceptable oral formulations, injections, granules, pills, capsules, powders, sustained release formulations, controlled release formulations, targeted formulations and other routes of administration.
CN202010417626.8A 2020-05-18 2020-05-18 Pinocembrin, application of pinocembrin and preparation method of pinocembrin Expired - Fee Related CN111763139B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109758438A (en) * 2019-01-23 2019-05-17 南通大学 The purposes and preparation method of pinosylvin

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109758438A (en) * 2019-01-23 2019-05-17 南通大学 The purposes and preparation method of pinosylvin

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* Cited by examiner, † Cited by third party
Title
Ligand-controlled iridium-catalyzed semihydrogenation of alkynes with ethanol: highly stereoselective synthesis of E- and Z-alkenes;Jinfei Yang等;《Chem. Commun.》;20190124;1-4 *

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