CN114057676A - Andrographolide compound and application and pharmaceutical composition thereof - Google Patents
Andrographolide compound and application and pharmaceutical composition thereof Download PDFInfo
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- -1 Andrographolide compound Chemical class 0.000 title claims abstract description 32
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- XMJAJFVLHDIEHF-CRBRZBHVSA-N 14-Deoxy-11,12-didehydroandrographolide Chemical compound C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@@H](O)[C@]2(CO)C)=C\C1=CCOC1=O XMJAJFVLHDIEHF-CRBRZBHVSA-N 0.000 claims abstract description 15
- YIIRVUDGRKEWBV-UHFFFAOYSA-N (E)-3-(2-((1R,4aS,5R,6R,8aS)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalen-1-yl)ethylidene)furan-2(3H)-one Natural products C=C1CCC2C(C)(CO)C(O)CCC2(C)C1CC=C1C=COC1=O YIIRVUDGRKEWBV-UHFFFAOYSA-N 0.000 claims abstract description 14
- XMJAJFVLHDIEHF-UHFFFAOYSA-N 14-deoxy-11, 12-didehydroandrographolide Natural products OCC1(C)C(O)CCC2(C)C1CCC(=C)C2C=CC1=CCOC1=O XMJAJFVLHDIEHF-UHFFFAOYSA-N 0.000 claims abstract description 14
- YIIRVUDGRKEWBV-YSDSKTICSA-N 14-deoxy-11,12-didehydroandrographolide Natural products C[C@@]1(CO)[C@H](O)CC[C@@]2(C)[C@H](CC=C/3C=COC3=O)C(=C)CC[C@H]12 YIIRVUDGRKEWBV-YSDSKTICSA-N 0.000 claims abstract description 14
- GVRNTWSGBWPJGS-YSDSKTICSA-N 4-[2-[(1r,4as,5r,6r,8as)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1h-naphthalen-1-yl]ethyl]-2h-furan-5-one Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)CC1=CCOC1=O GVRNTWSGBWPJGS-YSDSKTICSA-N 0.000 claims abstract description 14
- XMJAJFVLHDIEHF-YSDSKTICSA-N dehydroandrographolide Natural products C([C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@@H](O)[C@]2(CO)C)=CC1=CCOC1=O XMJAJFVLHDIEHF-YSDSKTICSA-N 0.000 claims abstract description 14
- GVRNTWSGBWPJGS-UHFFFAOYSA-N deoxyandrographolide Natural products C=C1CCC2C(C)(CO)C(O)CCC2(C)C1CCC1=CCOC1=O GVRNTWSGBWPJGS-UHFFFAOYSA-N 0.000 claims abstract description 14
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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Abstract
The invention discloses an andrographolide compound serving as an estrogen receptor agonist, which comprises the andrographolide compound and application of the andrographolide compound, wherein the andrographolide compound is deoxyandrographolide or 14-deoxy-11, 12-didehydro-andrographolide. In addition, the andrographolide compound is verified to have strong affinity with an estrogen receptor through a molecular docking calculation method by combining with a figure 1 and a figure 2, so that the andrographolide compound can be used as an agonist of the estrogen receptor.
Description
Technical Field
The invention relates to the field of medicines, in particular to an andrographolide compound serving as an estrogen receptor agonist and application and a pharmaceutical composition thereof.
Background
Estrogens are the primary female hormones responsible for the development and regulation of the female reproductive system and secondary female sexual characteristics. Estrogens also play a role in, inter alia, protein synthesis, coagulation, lipid balance, fluid balance, melanin, gastrointestinal function, pulmonary function, cognition, immune response, and heart disease.
Estrogen receptors are ligand-activated transcriptional regulatory proteins that mediate the induction of a variety of biological effects through interaction with endogenous estrogens.
Estrogens can bind to estrogen receptors in vivo, play an important physiological role by activating estrogen receptors, and play an important role in maintaining the functions of multiple systems such as reproductive system, endocrine system, skeletal system, nervous system, cardiovascular system, and the like. When the estrogen level of the organism is reduced and the estrogen receptor can not be normally activated, the diseases such as osteoporosis, irregular menstruation, infertility, climacteric syndrome, senile dementia and the like are easily caused. The estrogen receptor is an important nuclear receptor superfamily member, can be combined with an estrogen response element to regulate and control a DNA transcription process, plays an important regulating and controlling role in the growth, development and metabolic processes of a human body, and is an important drug action target for treating diseases such as osteoporosis, gynecological diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, skin diseases, alopecia, cancers and the like and resisting aging.
The andrographolide compound has good effects of resisting inflammation, sterilizing, clearing heat and detoxicating, is widely applied clinically, and is often used as a component of a Chinese patent medicine preparation. There is no report in the prior art about whether andrographolide compounds can be used as estrogen receptor agonists.
Disclosure of Invention
Based on this, there is a need to provide andrographolide compounds which can be used as estrogen receptor agonists.
In addition, a pharmaceutical composition comprising the andrographolide compound and application of the andrographolide compound are also provided.
An andrographolide compound used as an estrogen receptor agonist, wherein the andrographolide compound is deoxyandrographolide or 14-deoxy-11, 12-didehydro-andrographolide, and the chemical formula is as follows:
in one embodiment, the effective concentration of the andrographolide compound is 0.01 μ M to 1 μ M.
A pharmaceutical composition comprises the andrographolide 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 preventing and treating osteoporosis, gynecological diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, skin diseases, alopecia, and cancer.
The andrographolide compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof or prodrug thereof can be applied to the fields of medicines, health-care foods and cosmetics.
In addition, the andrographolide compound is verified to have strong affinity with an estrogen receptor through a molecular docking calculation method by combining with a figure 1 and a figure 2, so that the andrographolide compound can be used as an agonist of the estrogen receptor.
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 of the bonding between deoxyandrographolide and estrogen receptor.
FIG. 2 is a diagram of the bonding between 14-deoxy-11, 12-didehydroandrographolide and estrogen receptor.
FIG. 3 is a graph showing the effect of deoxyandrographolide on the proliferation of MCF-7 cells in example 1.
FIG. 4 is a graph showing the effect of 14-deoxy-11, 12-didehydroandrographolide in example 2 on MCF-7 cell proliferation.
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 andrographolide compound used as an estrogen receptor stimulant, which is deoxyandrographolide or 14-deoxy-11, 12-didehydro-andrographolide and has the following chemical formula:
the andrographolide compound has a proliferation promoting effect on breast cancer cells MCF-7 (estrogen receptor positive cells) in combination with the content of the description.
In order to research the estrogenic activity of the andrographolide compounds, the conformation of the combination between the estrogen receptor and the andrographolide compounds is analyzed through molecular docking software, and the conformation of the interaction between small molecules and the estrogen receptor is further analyzed.
Combining fig. 1 and fig. 2, the oxygen atom of deoxyandrographolide and 14-deoxy-11, 12-didehydro andrographolide forms hydrogen bond with the hydrogen atom of key amino acid residue Arg394 of estrogen receptor, wherein the oxygen atom of 14-deoxy-11, 12-didehydro andrographolide can also form hydrogen bond with the hydrogen atom of key amino acid residue His524 of estrogen receptor, which indicates that the two can be combined with estrogen receptor through hydrogen bond 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 data in the embodiment section and the molecular docking calculation method verify that the andrographolide compound has strong affinity with an estrogen receptor, thereby indicating that the andrographolide compound can be used as an agonist of the estrogen receptor.
Preferably, the effective concentration of andrographolide compounds is 0.01 μ M to 1 μ M. The andrographolide compound has mild action concentration.
The invention also discloses a pharmaceutical composition which comprises the andrographolide compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof.
When the estrogen level of the organism is reduced and the estrogen receptor can not be normally activated, the diseases such as osteoporosis, irregular menstruation, infertility, climacteric syndrome, senile dementia and the like are easily caused.
Based on this, andrographolide compounds, which can be agonists of estrogen receptors, can 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 osteoporosis, gynecological diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, skin diseases, alopecia and cancer.
The invention also discloses an application of the andrographolide compound, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof in the fields of medicines, health-care foods and cosmetics.
The following are specific examples. In the specific embodiment, the breast cancer cell MCF-7 is purchased from cell banks of Chinese academy of sciences, the fetal bovine serum is a product of Hangzhou Sijiqing biology GmbH in China, and the double antibody is a product of Gibco in America.
Example 1
Effect of deoxyandrographolide on growth of breast cancer cells MCF-7
(1) Treating ilex purpurea Hassk fetal calf serum with activated carbon:
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 using 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 proliferation of breast cancer cells MCF-7 by deoxyandrographolide (Crystal Violet staining method):
1) culturing MCF-7 cells in phenol red-free RPMI1640 culture medium (containing 10% activated carbon-treated fetal calf serum and 1% double antibody) for 3 days; 2) digesting the cells at 5X 104Adding 100 mu L of MCF-7 cell suspension per mL into a 96-well plate, culturing for 24h, sucking cell culture fluid in the culture plate, adding deoxyandrographolide diluted by the cell culture fluid and having different concentrations, wherein each diluted concentration comprises 6 multiple wells, placing the mixture in a 37 ℃ carbon dioxide incubator for culturing for 72h, discarding the cell culture fluid, adding newly-configured cell culture fluid of deoxyandrographolide having different concentrations, and placing the mixture in a 37 ℃ carbon dioxide incubator for culturing for 72h again; 3) discarding the cell culture solution, adding 100 μ L of 1% glutaraldehyde, fixing for 30min, washing the cells with PBS for 3 times, placing at room temperature for complete drying, staining with 50 μ L of 0.5% crystal violet solution for 15min, discarding the staining solution, washing the redundant crystal violet with clear water, placing at room temperature for complete drying, dissolving 100 μ L of 0.5% 100X-Triton solution overnight, and detecting OD values of 405nm and 560nm by an enzyme-labeling instrument.
Calculating the proliferation effect of the deoxyandrographolide on the breast cancer cells MCF-7: the cell density was determined as OD (650) to OD (405), and the results are shown in fig. 3.
As can be seen from FIG. 3, deoxyandrographolide has a significant proliferation-promoting effect on breast cancer cells MCF-7.
Specifically, the effective action concentration of the deoxyandrographolide is 0.01-1 mu M, and the action concentration is mild.
Example 2
Test of Effect of 14-deoxy-11, 12-didehydroandrographolide on growth of breast cancer cells MCF-7
(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 using 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 proliferation of 14-deoxy-11, 12-didehydro andrographolide on breast cancer cells MCF-7 (Crystal Violet staining):
1) culturing MCF-7 cells in phenol red-free RPMI1640 culture medium (containing 10% activated carbon-treated fetal calf serum and 1% double antibody) for 3 days; 2) digesting the cells at 5X 104Adding 100 mu L of MCF-7 cell suspension per mL into a 96-well plate, culturing for 24h, sucking cell culture fluid in the culture plate, adding 14-deoxy-11, 12-didehydro andrographolide diluted by the cell culture fluid and having different concentrations, wherein each diluted concentration comprises 6 multiple wells, culturing for 72h in a 37 ℃ carbon dioxide incubator, discarding the cell culture fluid, adding newly configured cell culture fluid of 14-deoxy-11, 12-didehydro andrographolide having different concentrations, and culturing for 72h in the 37 ℃ carbon dioxide incubator; 3) discarding cell culture solution, adding 1% glutaraldehyde 100 μ L, fixing for 30min, washing cells with PBS 3 times, drying thoroughly at room temperature, dyeing with 0.5% crystal violet solution 50 μ L for 15min, discarding dye solution and washing redundant crystal with clear waterThe violet was thoroughly dried at room temperature, dissolved in 100. mu.L of 0.5% 100X-Triton solution overnight, and then measured for OD at 405nm and 560nm by a microplate reader.
Calculating the proliferation effect of 14-deoxy-11, 12-didehydro andrographolide on breast cancer cells MCF-7: the cell density was determined as OD (650) to OD (405), and the results are shown in fig. 4.
As can be seen from FIG. 4, 14-deoxy-11, 12-didehydro andrographolide has a significant effect on promoting proliferation of breast cancer cells MCF-7.
Specifically, the effective action concentration of the 14-deoxy-11, 12-didehydro andrographolide is 0.01-1 mu M, and the action concentration is mild.
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 (5)
1. An andrographolide compound used as an estrogen receptor agonist, which is characterized in that the andrographolide compound is deoxyandrographolide or 14-deoxy-11, 12-didehydroandrographolide, and the chemical formula is as follows:
2. the andrographolide compound according to claim 1, wherein the effective acting concentration of the andrographolide compound is 0.01 μ M to 1 μ M.
3. A pharmaceutical composition comprising the andrographolide compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof according to claim 1 or 2.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is used for preventing and treating osteoporosis, gynecological diseases, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, autoimmune diseases, skin diseases, alopecia and cancer.
5. An andrographolide compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof according to claim 1 or 2, for use in the fields of medicine, health food and cosmetics.
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| CN103739575A (en) * | 2014-01-09 | 2014-04-23 | 中国科学院昆明植物研究所 | 14-deoxy-11,12-dideoxyandrographolide derivative as well as drug composition and application thereof |
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