CN115944622A - Isoluplin compound and application and pharmaceutical composition thereof - Google Patents
Isoluplin compound and application and pharmaceutical composition thereof Download PDFInfo
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- CN115944622A CN115944622A CN202211063779.2A CN202211063779A CN115944622A CN 115944622 A CN115944622 A CN 115944622A CN 202211063779 A CN202211063779 A CN 202211063779A CN 115944622 A CN115944622 A CN 115944622A
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- isolupulin
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- androgen receptor
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- 229940002612 prodrug Drugs 0.000 claims description 6
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an isolupulin compound serving as an androgen receptor stimulant, a pharmaceutical composition comprising the isolupulin compound and application of the isolupulin compound. In addition, the isoluplin compound has strong affinity with androgen receptor through molecular docking calculation method by combining with the content of the embodiment part of the specification, and the isoluplin compound can be used as an androgen receptor agonist.
Description
Technical Field
The invention relates to the field of medicines, in particular to an isohop compound serving as an androgen receptor agonist, and application and a pharmaceutical composition thereof.
Background
Androgens are the major sex hormones responsible for the development and regulation of the male reproductive system and secondary sexual characteristics. Androgens also play a role in protein synthesis, blood coagulation, lipid homeostasis, gastrointestinal tract function, cognition, nervous system function, immune response, and heart disease. The biological activity of androgens is mediated primarily through the nuclear receptor Androgen Receptor (AR). The androgen receptor is an important nuclear receptor superfamily member, can be combined with an Androgen Response Element (ARE) in a target gene promoter region, regulates and controls the DNA transcription of a target gene, thereby regulating and controlling the expression level of the target gene and playing an important role in the processes of growth, development and metabolism of organisms.
When androgen level in body is disordered, androgen receptor activation can cause reproductive system disease, immune dysfunction, metabolic disease, prostatic cancer, nerve degenerative disease, alopecia and dermatosis, etc. Therefore, androgens are an important class of drugs.
Isolupulin (isoxanthohumol, isoxanthohumic acid) exists in Chinese medicinal materials such as radix Sophorae Flavescentis, etc., and is a natural product micromolecular compound with relatively mild properties. Isolupulin has good medicinal value, for example, it inhibits the development of lung metastases in tumor animals, and it has antiviral activity against herpes viruses (HSV 1 and HSV 2) and Bovine Viral Diarrhea Virus (BVDV). Isoluplin has the characteristics of obvious efficacy, small toxic and side effects and the like, and is gradually applied to the industries of Chinese patent medicine preparations, health-care products, cosmetics and the like. In the prior art, no report is available on whether the isolupulin and the analogues thereof can be used as androgen receptor agonists.
Disclosure of Invention
Based on this, it is necessary to provide isolupulin compounds which can be used as androgen receptor agonists.
In addition, a pharmaceutical composition comprising the isohop compound and an application of the isohop compound are also needed to be provided.
An isolupulin compound as an androgen receptor agonist, the isolupulin compound having the formula:
wherein, -R is-H, -CH 3 、-CH 2 CH 3 、-CH=CH 2 or-CH 2 CH 2 CH 3 。
In one embodiment, the isolupulin compound is isolupulin having the following chemical formula:
in one embodiment, the effective concentration of the isolupulin is from 0.25 μ M to 2 μ M.
A pharmaceutical composition comprising the above isolupulin compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
In one embodiment, the pharmaceutical composition is used for the prevention and treatment of neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, diseases of the reproductive system, skin diseases, alopecia, cancer and for contraception.
The isoluplin compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof or the prodrug thereof can be applied to the fields of medicines, health-care foods and cosmetics.
In addition, the isoluplin compound has strong affinity with androgen receptor through molecular docking calculation method by combining with the content of the embodiment part of the specification, and the isoluplin compound can be used as an androgen receptor agonist.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Wherein:
FIG. 1 is a diagram showing the bonding between isohop compounds and androgen receptors.
FIG. 2 is a graph showing the effect of isolupulin compounds on the expression of androgen reporter gene by HEK-293T in example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention discloses an isohop compound used as an androgen receptor stimulant, which has the following chemical formula:
wherein, -R is-H, -CH 3 、-CH 2 CH 3 、-CH=CH 2 or-CH 2 CH 2 CH 3 。
Specifically, the isolupulin compounds exist in traditional Chinese medicinal materials such as radix sophorae flavescentis and the like, and are natural product micromolecule compounds with relatively mild properties.
The isohop compounds have the function of enhancing the expression of androgen receptor reporter genes by combining the contents of the embodiment parts of the specification.
In order to research the androgen activity of the natural product small molecule compound, the invention analyzes the binding conformation between the androgen receptor and the natural product small molecule compound through a molecular docking software, and further analyzes the interaction conformation between the small molecule and the androgen receptor.
FIG. 1 shows that isolupulin compounds form hydrogen bonds with key amino acid residue Asn705 of androgen receptor, indicating that it can bind to androgen receptor through hydrogen bonding interaction.
The hydrogen bond is a chemical bond in the form of X — H formed by bonding a hydrogen atom to an atom X having a large electronegativity and a small radius by a specific intermolecular force.
Therefore, the natural product small molecular compound is verified to have strong affinity with the androgen receptor by combining the data of the embodiment part and the molecular docking calculation method, thereby indicating that the natural product small molecular compound can be used as an agonist of the androgen receptor.
Specifically, in this embodiment, the isoluplin compound as the androgen receptor agonist is isoluplin (isoxanthohumol, isoxanthohumic acid, CAS number: 521-48-2), and the chemical formula of isoluplin is as follows:
preferably, the concentration of effective action of the isohop compound is 0.25. Mu.M to 2. Mu.M.
The invention also discloses a pharmaceutical composition of an embodiment, which comprises the isolupulin compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof.
When the androgen level of the body is reduced and the androgen receptor can not be normally activated, diseases or problems such as neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, reproductive system diseases, skin diseases, alopecia, cancers, infertility and the like are easy to occur.
Based on this, isoluplin compounds which are agonists of androgen receptor could theoretically be used for the prevention and treatment of the above-mentioned related diseases.
In particular, the pharmaceutical composition is used for preventing and treating neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, diseases of the reproductive system, skin diseases, alopecia, cancer and for contraception.
The invention also discloses an application of the isoluplin compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof or the prodrug thereof in the fields of medicines, health-care foods and cosmetics.
The following are specific examples. In the specific embodiment, HEK-293T cells ARE purchased from Chinese academy of sciences, fetal bovine serum is a product of Hangzhou Sijiu bio-corporation in China, plasmid pcDNA3.1-AR (synthesized by Jinweizhi corporation and inserted with a sequence shown in SEQ ID NO.1, plasmid pGL3-ARE-Luc (synthesized by Jinweizhi corporation and inserted with a sequence shown in SEQ ID NO. 2) and luciferase reporter gene kit (Bilun, cargo number RG 006).
Example 1
Effect test of Isohop on 293T cell reporter Gene
(1) Activated carbon treatment of four season clear fetal calf serum:
1) Adding 1g of activated carbon into a beaker filled with 100mL of fetal calf serum, placing the beaker in a water bath condition at 56 ℃ for continuously stirring for 2 hours, and then centrifuging the beaker for 20 minutes at 17000rpm by an ultracentrifuge;
2) Collecting the supernatant in a new beaker, adding 1g of activated carbon, placing in a water bath at 37 ℃ for continuously stirring for 2 hours, and centrifuging for 20min at 17000rpm of an ultracentrifuge;
3) Collecting the supernatant in a new beaker, adding 1g of activated carbon, placing the beaker under the ice bath condition of 4 ℃ for continuously stirring for 3 hours, and then centrifuging the beaker for 30min at 17000rpm by using an ultracentrifuge;
4) Finally, filtering the collected supernatant by using a sterile filter membrane of 0.22 mu m, and subpackaging and storing the filtrate in a refrigerator at minus 80 ℃ for later use.
(2) Determination of androgen reporter gene of 293T cell by isolupulin:
the plasmid pcDNA3.1-AR and the plasmid pGL3-ARE-Luc ARE transfected into HEK-293T cells, the pcDNA3.1-AR plasmid can express an androgen receptor AR, the pGL3-ARE-Luc is a reporter gene element, and the activated AR can be combined with an ARE reaction element to start the expression of downstream Luciferase Luciferase (Luc) genes.
Then, isolupin (isoxanthohumol) and 20nM Testosterone (Testosterone) were added to the culture medium (RPMI 1640 medium added with 10% activated carbon-treated serum) as positive controls at different concentrations, and after culturing the cells for 24 hours, the cells were lysed, the reporter activity was measured using a luciferase reporter kit, and the chemiluminescence intensity was measured with a microplate reader, and the protein concentration of the sample per well was determined, and the chemiluminescence intensity was divided by the protein concentration and by the value of the solvent Control (Control) to obtain fig. 2.
As can be seen from FIG. 2, isohop has a significant effect of enhancing the expression of androgen receptor reporter gene.
Specifically, the effective concentration of isolupulin is 0.25. Mu.M to 2. Mu.M, and the maximum activation effect is significantly higher than 20nM testosterone (testosterone).
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the claims. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
3. the isohop compound according to claim 1, wherein the effective concentration of the isohop compound is 0.25 to 2 μ M.
4. A pharmaceutical composition comprising the isolupulin compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof or prodrug thereof according to claim 1, 2 or 3.
5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is used for the prevention and treatment of neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, diseases of the reproductive system, skin diseases, alopecia, cancer and for contraception.
6. An isoluplin compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof according to claim 1, 2 or 3 for use in the fields of pharmaceuticals, health foods and cosmetics.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101170991A (en) * | 2005-03-12 | 2008-04-30 | 荷兰联合利华有限公司 | Hair and/or scalp care compositions incorporating amino-oxo-indole-ylidene compounds |
CN110974812A (en) * | 2019-08-16 | 2020-04-10 | 泰州医药城国科化物生物医药科技有限公司 | GPR35 receptor new agonist and application thereof |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101170991A (en) * | 2005-03-12 | 2008-04-30 | 荷兰联合利华有限公司 | Hair and/or scalp care compositions incorporating amino-oxo-indole-ylidene compounds |
CN110974812A (en) * | 2019-08-16 | 2020-04-10 | 泰州医药城国科化物生物医药科技有限公司 | GPR35 receptor new agonist and application thereof |
Non-Patent Citations (1)
Title |
---|
ANNA KATARZYNA ŻOŁNIERCZYK ET AL: "Isoxanthohumol-Biologically active hop flavonoid", 《FITOTERAPIA》, vol. 103, 30 June 2015 (2015-06-30), pages 71 - 82, XP029187975, DOI: 10.1016/j.fitote.2015.03.007 * |
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