CN111481536A - New use of aureoamidyl alcohol ester as MMP-9 inhibitor - Google Patents
New use of aureoamidyl alcohol ester as MMP-9 inhibitor Download PDFInfo
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- CN111481536A CN111481536A CN202010068528.8A CN202010068528A CN111481536A CN 111481536 A CN111481536 A CN 111481536A CN 202010068528 A CN202010068528 A CN 202010068528A CN 111481536 A CN111481536 A CN 111481536A
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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Abstract
The invention discloses a new application of aureoamid alcohol ester as an MMP-9 inhibitor, which can remarkably inhibit the differentiation capability of RAW264.7 cells induced by RANK L to osteoclasts under the condition of no cytotoxicity to osteoclast precursor cells RAW264.7 and has certain concentration dependence, and the subsequent research finds that the aureoamid alcohol ester can remarkably reduce the expression of MMP-9 in the osteoclast formation process so as to exert the capability of inhibiting the differentiation and formation of the osteoclasts, discloses the application of the aureoamid alcohol ester in the prevention and treatment of osteolytic diseases, can be used as a medicament prepared from a conventional medicinal carrier, and can prevent and treat the osteolytic diseases such as bone destruction, osteoporosis and the like.
Description
Technical Field
The invention belongs to the technical field of biological medicine extraction. More particularly, it relates to a new use of aureamide alcohol esters as MMP-9 inhibitors.
Background
The present literature indicates that the function of osteoclasts mediated by RANK L is closely related to various types of pathological osteolysis, such as tumor-induced bone destruction, inflammatory osteolysis, aseptic prosthesis loosening after artificial joint replacement, postmenopausal osteoporosis, pages's disease, psoriatic arthritis, ankylosing spondylitis, and the like, as the population of the world ages increases, the proportion of osteoporosis is increasing, particularly in developed countries, osteoporosis is a systemic skeletal metabolic disease characterized by a decrease in bone mass, a deterioration in bone tissue microstructure, an increase in bone fragility, and is liable to occur, epidemiological investigations show that in people over 50 years old, osteoporosis in men is 14.4%, women are 20.7%, bone fractures with low bone mass, and urinary bone fractures in women are more than 6.6%, and urinary osteoporosis is induced by more than 3.4% of patients after urinary tract diseases, and urinary tract diseases are more than 6.6.
There are two main known causes of osteoporosis: peak Bone Mineral Density (BMD), which is generally achieved around the age of 30, is low, and the rate of bone loss, which occurs especially after menopause and during natural aging, is high. Bone loss occurs with age, in part because the rate of bone resorption exceeds the rate of bone formation. Osteoblasts and osteoclasts are the basic regulatory units for bone remodeling, and the balance between osteoblast bone formation and osteoclast bone resorption is critical for maintaining normal bone density and mineral balance in vivo. Osteoclasts are the major bone-resorbing cells, and when osteoclast activity is enhanced, leading to excessive resorption of bone, osteoporosis will occur. In the bone resorption process, osteoclasts are firstly attached to the surface of bones to form a relatively closed bone resorption microenvironment, and protons and proteolytic enzymes are secreted to firstly dissolve bone mineral substances and then degrade bone matrixes, so that bone cavities are formed. At present, bisphosphonate medicines are used as an effective bone resorption inhibitor and are widely used for treating bone diseases with high turnover rate clinically. However, treatment of osteoporosis with bisphosphonates inhibits bone resorption and bone formation and inactivates the anabolic effects of parathyroid hormone (PTH).
The Matrix Metalloproteinase (MMP) is a calcium-containing and zinc-dependent endopeptidase which is secreted from cells such as polymorphonuclear neutrophils, macrophages, fibroblasts and osteocytes, acts at neutral pH, and has various extracellular matrices as matrices. Cell matrix metalloproteinases are not only involved in many physiological processes such as embryogenesis, tissue formation, salivary gland formation and teeth, but also in pathological processes and a variety of diseases such as wounds, cancer metastasis, dental diseases, rheumatoid arthritis, inflammation, diabetes, corneal ulceration, osteoporosis, gastric ulceration, trauma, skin wrinkles and aging, injuries, burns and the like. In particular, the MMPs of collagenase IV (MMP-2 and MMP-9), namely the 72-kD and 92-kD collagenases, are the most important enzymes in cancer cell infiltration and metastasis, since they break down collagenase IV, which is the main structural component of the basement membrane. Therefore, the collagenase inhibitor is expected to be used for the prevention and treatment of osteoporosis as a function of a drug.
The traditional Chinese medicine plays a very important role in the prevention and treatment process of various chronic diseases, and has the advantages of multiple target points, small toxic and side effects, wide application and the like. Therefore, searching new drug lead compounds from traditional Chinese medicines or finding new molecular targeting mechanisms of known molecules is one of the important approaches for drug development. In addition, the discovery of new drugs can also rely on the extensive activity screening of target proteins on existing compounds, and can also be used for de novo design and synthesis of corresponding combinable new entity molecules based on protein structures, but such high-throughput biological activity screening and drug design and synthesis processes often have the disadvantages of high cost, time consumption and labor consumption. Another method for finding new medicines is that old medicines are used newly, and 84 medicines listed in 2013 are 20% of the existing medicines and have new indications. Since it is found that drugs often act not only on one protein target in complex disease regulatory pathways, but act together by targeting multiple targets. Therefore, especially in the present day that big data and computer technology are continuously developed, the drug is relocated or a novel target is discovered through a virtual technology, and the new drug discovery method is an efficient and reliable new drug discovery way when reliable in-vivo or in-vitro biological verification is carried out.
Golden amide alcohol ester (AA) is a natural dipeptide micromolecule with a special structure, is obtained by condensing benzoyl phenylalanine and phenylalaninol, is extracted from Piper aurantiacam plants at first, is also obtained by separating important Chinese herbal medicines such as sweet wormwood herb, red flower polygonum, clematis and the like, and has better anti-inflammatory, analgesic and antioxidant activities. However, other pharmacological activities of AA and possible new targeting mechanisms are not known. There is no report of the use of aureoylamide esters for the treatment of osteoporosis.
Disclosure of Invention
The object of the present invention is to provide a new use of aureoamidyl esters as MMP-9 inhibitors.
The purpose of the invention is realized by the following technical scheme:
the invention, through extensive and intensive creative work, clearly reports the application of aureoyl amide ester in preparing the medicament of the MMP-9 inhibitor for the first time.
The aureamide alcohol ester has the following structural formula:
furthermore, the application of the aureoyl amide ester in inhibiting the protein expression of MMP-9 has a significant inhibiting effect on the protein expression of MMP-9.
Further, the golden amidoalcohol ester can be obtained commercially or isolated from natural products.
Further, the golden amidoalcohol ester is used as an MMP-9 inhibitor for preparing the medicine for preventing and treating the osteolytic disease. The drug takes MMP-9 as a target.
Further, the osteolytic disease is a bone disease caused by an increase in the number and/or activity of osteoclasts.
Further, the osteolytic disease is osteoporosis.
Further, the aureoamidol ester is used for preventing and treating osteoporosis by inhibiting the activity and/or the number of osteoclasts, or inhibiting the formation, growth, proliferation and/or differentiation of the osteoclasts.
Further, the golden amidoalcohol ester is used in the application as the only active ingredient or one of the active ingredients. The aureamide alcohol ester can be used as the only active ingredient, and can also be combined with other pharmaceutically allowable substances.
Further, the concentration of the golden amidoalcohol ester is greater than or equal to 5.0 μ M, preferably 5 to 100 μ M, more preferably 25 to 75 μ M, and still more preferably 40 to 75 μ M.
The invention also provides a pharmaceutical preparation for preventing and treating osteoporosis, which contains effective dose of aureoyl amide ester and pharmaceutically acceptable carriers or auxiliary materials. The aureamide alcohol ester can be used as the only active ingredient, and can also be combined with other pharmaceutically allowable substances.
Further, the osteoporosis comprises primary osteoporosis and secondary osteoporosis.
Specifically, the pharmaceutical preparation can be in the form of tablet, dispersible tablet, buccal tablet, orally disintegrating tablet, sustained release tablet, capsule, soft capsule, dripping pill, granule, injection, powder for injection, unguent, gel, emulsion, lotion or aerosol. Ointments, gels and emulsions may be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying, dispersing, suspending, thickening or coloring agents. The powder may be formed with the aid of any suitable powder base. The droplets and solutions may be formulated with an aqueous or non-aqueous base and also include one or more dispersing, dissolving or suspending agents. Aerosols are conveniently delivered from pressurized packs using a suitable propellant.
The carrier refers to a drug carrier which is conventional in the field of pharmacy.
The pharmaceutical preparation can be added with one or more of wetting agent, emulsifier, excipient, stabilizer, surfactant, pH regulator, antiseptic and carrier.
Available humectants such as glycerin, sodium lauryl sulfate, etc.; emulsifying agents such as lecithin, sorbitan monooleate, acacia; suitable excipients include lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, microcrystalline cellulose, and/or polyvinylpyrrolidone, and the like; surfactants such as cetyl alcohol; lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, and the like; preservatives such as p-hydroxybenzoic acid methyl ester, propyl p-hydroxybenzoate, sorbic acid; examples of antioxidants include, but are not limited to, amino acids, vitamins, minerals, carotenoids, peptides, thiols, sulfoximine compounds, chelators, unsaturated fatty acids, phenolic compounds, plant extracts, stilbenes, uric acid, mannose, chlorogenic acids, imidazoles (e.g., imidazoleacrylic acid), furfurylidene sorbitol, coenzymes, ubiquinones, plastoquinones, phytosterols and derivatives thereof (e.g., salts, esters, ethers, sugars, nucleosides, peptides, and/or lipid derivatives), and the like.
Compared with the prior art, the invention has the beneficial effects that:
the invention tests the activity of golden amidoalcohol ester for inhibiting osteoclast differentiation, and the results show that the golden amidoalcohol ester has the capacity of obviously inhibiting the differentiation of RAW264.7 cells induced by RANK L to osteoclasts when the concentration of golden amidoalcohol ester is 5 mu M, 10 mu M and 25 mu M, the forming capacity and the quantity of osteoclasts are obviously inhibited, and the golden amidoalcohol ester has certain concentration dependence, researches show that the golden amidoalcohol ester has no cytotoxicity to osteoclast precursor RAW264.7 cells by obviously reducing the expression of MMP-9 (P <0.05) in the osteoclast process, and in addition, the golden amidoalcohol ester has no cytotoxicity when the concentration of golden amidoalcohol ester is less than 25 mu M, and discloses the application of the golden amidoalcohol ester in preventing and treating osteolytic diseases, the golden amidoalcohol ester can be used with medicines prepared from conventional medicinal carriers, and can be used for preventing and treating osteolytic diseases including bone destruction, osteoporosis and the invention provides a new medicine for preventing and treating osteoporosis, and has great clinical application value.
Drawings
FIG. 1 is a molecular docking binding of aureoamidyl esters to MMP-9 protein.
FIG. 2 shows the effect of aureoamidol alcohol esters on Raw cells; wherein, A shows that the aureol amide is nontoxic, B shows that the differentiation of Raw cells to osteoclasts is obviously inhibited under the nontoxic dosage, and C shows the influence of the aureol amide on the Raw cells under different dosages.
FIG. 3 is the effect of aureoamid alcohol ester on RANK L in inducing osteoclast MMP-9 protein expression.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 molecular docking binding experiment of aureoamidyl alcohol ester with MMP-9 protein
As shown in FIG. 1, computer-assisted molecular docking experiments between drug ligands and protein receptors were performed on aureoamideol esters and MMP-9 protein to further analyze the ligand-receptor interaction mechanism; calculating the binding energy and action energy, and carrying out binding pattern analysis.
Through molecular docking and binding energy calculation, compared with the original ligand inhibitor, the key docking site is consistent, the binding energy is-72.0206 kcal/mol, and the result shows that the aureoamide alcohol ester and the MMP-9 protein have better drug-protein molecular docking binding capacity.
EXAMPLE 2 in vitro golden Anilide alcohol ester Activity
1. In vitro osteoclastogenesis assay
The RAW264.7 cells were cultured in DMEM medium containing fetal bovine serum 10%, penicillin-streptomycin 5%, temperature 37 deg.C, and CO2For induction of osteoclasts, RAW264.7 cells were cultured in 96-well plates in the presence of RANK L at a concentration of 50ng/M L, and 5, 10, 25 μ M aurora acylamide alcohol, the cells were fixed on day 7, and then the TRAP activity was stained according to the protocol of the kit.
2. Western blot analysis
Western blot for determining levels of protein expression RAW264.7 cells were plated on 60mm dishes, 5 × 105Cells/dish, incubated overnight, then treated with RANK L (50ng/M L) in the absence or presence of gold amidoalcohol ester (12.5, 25 or 50 μ M) for 48 hours, cell lysates prepared using RIPA buffer (Solarbio, beijing, china), cell extracts were normalized by BCA method to determine protein concentration the proteins were separated by 10% or 12% SDS-PAGE and then transferred onto PVDF membranes (EMD michigan, merck life science, KGaA, dalschatatt, germany), after blocking were incubated overnight at primary 4 ℃ using primary antibody, washed 3 times with TBST buffer, 10 minutes each, the membranes were incubated 1h at room temperature with horseradish peroxidase-coupled secondary antibody, washed 3 times 10 minutes each using TBST buffer, and bands were detected using Pro-light HRP chemiluminescence kit (Tiangen bioh, saint, beijing) obtained by the cheulor system (california).
3. Results
(1) Golden amide alcohol esters inhibit RANK L-induced osteoclast differentiation in vitro without cytotoxicity
As shown in FIG. 2, the present invention first tested the effect of gold amidol lipids on osteoclast precursor cells. Cell viability of macrophages (Raw 264.7) after 48 hours of action of the golden amidol lipid on macrophages (Raw 264.7) was used to determine which doses produced toxic effects.
As a result, it was found that, at a dose of less than 25. mu.M, the gold color amide alcohol ester had no cytotoxic effect. IC of golden amidol ester50Value 61.08 μ M (FIG. 2, panel A.) to determine the effect of aureamide alcohol esters on RANK L-induced osteoclast differentiation, the present invention treated Raw264.7 cells with RANK L in the presence of 5 μ M, 10 μ M, 25 μ M aureamide alcohol esters, significantly inhibited the formation of multi-nuclear osteoclasts positive for tartrate-resistant acid phosphatase (TRAP) in a dose-dependent manner, as shown in panel B of FIG. 2, by 35.7%, 51.2%, and 80.26%, respectively (FIG. 2, panel C.) indicating that aureamide alcohol esters are effective in inhibiting osteoclast formation overall without cytotoxic effects.
(2) Golden amidoalcohol ester inhibits protein expression of RANK L induced osteoclast MMP-9
To further investigate the inhibitory effect of aureoamidol ester on MMP-9, the expression of MMP-9 in different concentrations or in the absence of aureoamidol ester in RANK L-induced osteoclasts was examined.
As shown in FIG. 3, the result shows that the golden amidoalcohol ester concentration of 25.0 μ M can significantly reduce the expression of MMP-9 protein in osteoclasts (P <0.05), and the inhibition rates are 22.7%, 44.1% and 95.4%, respectively, which indicates that the golden amidoalcohol ester can inhibit the expression of MMP-9 protein in osteoclasts.
In addition, the golden amidoalcohol ester has no cytotoxicity, reveals the application of the golden amidoalcohol ester in preventing and treating the osteolytic diseases, can be used as a medicament prepared from a conventional medicinal carrier, and can prevent and treat the osteolytic diseases including bone destruction, osteoporosis and the like.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, so that any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are within the scope of the technical solution defined by the claims of the present invention, unless departing from the technical solution of the present invention.
Claims (10)
1. The application of aureoamidol ester in preparing medicines for MMP-9 inhibitor.
2. The use according to claim 1, wherein the golden amidoalcohol ester is used to inhibit protein expression of MMP-9.
3. The use according to claim 2, wherein the aureamide alcohol ester is used as an MMP-9 inhibitor in the manufacture of a medicament for the prevention and treatment of osteolytic diseases.
4. Use according to claim 3, wherein the osteolytic disease is a bone disease resulting from an increased number and/or activity of osteoclasts.
5. Use according to claim 3 or 4, wherein the osteolytic disease is osteoporosis.
6. The use according to claim 5, wherein the aureoamidol ester is used for the prevention or treatment of osteoporosis by inhibiting the viability and/or number of osteoclasts, or inhibiting osteoclast formation, growth proliferation and/or differentiation.
7. The use according to claim 3, wherein the osteolytic disease is induced by RANK L.
8. Use according to any one of claims 1 to 7, wherein the aureamide alcohol ester is used as the sole active ingredient in said use.
9. Use according to any one of claims 1 to 7, wherein the golden amidoalcohol ester is used as one of the active ingredients in the use.
10. Use according to claim 8 or 9, wherein the golden amidoalcohol ester is present in a concentration of greater than or equal to 5.0 μ M.
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Application publication date: 20200804 |