CN110664803B - Application of isoindolone compounds in preparation of medicines for preventing and treating osteolytic diseases - Google Patents
Application of isoindolone compounds in preparation of medicines for preventing and treating osteolytic diseases Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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 application of isoindolone compounds in preparing a medicament for preventing and treating osteolytic diseases. The isoindolone compound has a structure shown in a formula (I):the isoindolone compound can remarkably inhibit the capacity of bone marrow-derived macrophage BMMs induced by RANKL to differentiate into osteoclasts and the bone absorption capacity of the osteoclasts, and is concentration-dependent; subsequent mechanism researches show that the isoindolone compounds inhibit the expression of the transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, thereby downregulating the expression of the osteoclast related genes and exerting the capacity of inhibiting the differentiation and bone resorption of the osteoclast. In addition, the isoindolones do not affect the differentiation of osteoblasts, and the application of the isoindolones in preventing and treating osteolytic diseases is disclosed, and the isoindolones can be used for preventing and treating osteolytic diseases with a pharmaceutical composition prepared from the isoindolones and a conventional pharmaceutical carrier.
Description
Technical Field
The invention relates to the technical field of compounds and medicines, in particular to application of isoindolone compounds in preparation of medicines for preventing and treating osteolytic diseases.
Background
Osteolytic disease (osteolytic disease) is a systemic bone disease in which bone fragility increases due to decrease in bone density and bone quality and destruction of bone microstructure resulting from increase in the number of osteoclasts and enhancement of activity, and fracture is liable to occur. There is a great deal of literature currently showing that RANKL-mediated osteoclast function charging has a close relationship with various types of pathological osteolysis, such as: bone destruction caused by tumors, inflammatory osteolysis, aseptic prosthetic loosening after artificial joint replacement, postmenopausal osteoporosis, page's disease, psoriatic arthritis, ankylosing spondylitis, and the like. With the advent of the global aging society, bone destruction due to various osteolytic diseases has become a serious challenge for medical workers. In recent years, the drug treatment of osteolytic diseases mainly comprises drugs for inhibiting bone resorption, drugs for promoting bone formation and basic supplements, but the first-line drugs for inhibiting bone resorption are bisphosphate drugs for excessively promoting bone mineralization, and the long-term application also leads to increased bone fragility; bone formation promoting drugs often have adverse reactions such as palpitations and canceration. Therefore, the search for a safe and effective medicament for treating osteolytic diseases remains a difficult problem for the vast medical staff. Natural products are an important source of drug development and have been a precedent for some success, and natural compounds with osteoclast inhibitory activity have been reported, including lignin, diterpenes, sesquiterpene lactones, and the like.
Disclosure of Invention
The invention aims to overcome the defects or the shortcomings of the prior art and provides application of isoindolone compounds in preparing medicines for preventing and treating osteolytic diseases. The inventor of the invention researches and discovers that isoindolones with specific structures can remarkably inhibit the capacity of bone marrow-derived macrophages BMMs induced by RANKL to differentiate into osteoclasts and the bone absorption capacity of the osteoclasts and are concentration-dependent; subsequent mechanism researches show that the isoindolone compounds inhibit the expression of the transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, thereby downregulating the expression of the osteoclast related genes and exerting the capacity of inhibiting the differentiation and bone resorption of the osteoclast. In addition, the isoindolones do not influence the differentiation of osteoblasts, and the application of the isoindolones in preventing and treating osteolytic diseases is disclosed, and the isoindolones can be used for preventing and treating osteolytic diseases including osteoporosis, paged Ji Shi and the like with a pharmaceutical composition prepared from the isoindolones and a conventional pharmaceutical carrier. The invention provides a new medicine for osteolytic diseases and has great clinical application value.
In order to achieve the above object of the present invention, the present invention provides the following technical solutions:
the application of isoindolone compounds with a structure shown in a formula (I) in preparing medicines for preventing and treating osteolytic diseases:
the inventors of the present invention isolated a series of isoindolones from a fermentation broth of the marine fungus Diadorthe sp.SYSU-HQ 3. In order to better develop and utilize the series of isoindolones, the series of isoindolones are more widely and deeply studied.
The research shows that among the series of isoindolones, the isoindolones with a specific formula structure shown in the formula (I) can remarkably inhibit the capacity of bone marrow-derived macrophage BMMs induced by RANKL to differentiate into osteoclasts and the bone absorption capacity of the osteoclasts, and are concentration-dependent; subsequent mechanism researches show that the isoindolone compounds inhibit the expression of the transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, thereby downregulating the expression of the osteoclast related genes and exerting the capacity of inhibiting the differentiation and bone resorption of the osteoclast. In addition, the isoindolones do not influence the differentiation of osteoblasts, and the application of the isoindolones in preventing and treating osteolytic diseases is disclosed, and the isoindolones can be used for preventing and treating osteolytic diseases including osteoporosis, paged Ji Shi and the like with a pharmaceutical composition prepared from the isoindolones and a conventional pharmaceutical carrier.
The invention provides a new medicine for osteolytic diseases and has great clinical application value.
The isoindolone compounds can be prepared by referring to patent CN 107721990A.
The pharmaceutical composition prepared from isoindolone compounds serving as active ingredients and conventional medicinal carriers can be used for preventing and treating osteolytic diseases. Specifically, the pharmaceutical composition can be in the form of tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sustained release tablets, capsules, soft capsules, dripping pills, granules, injections, powder injections or aerosols and the like.
Preferably, the osteolytic disease is a bone disease resulting from an increased number and/or activity of osteoclasts.
More preferably, the osteolytic disease is one or more of bone destruction, inflammatory osteolysis, aseptic prosthetic loosening after artificial joint replacement, postmenopausal osteoporosis, page's disease, psoriatic arthritis, or ankylosing spondylitis.
Preferably, the isoindolone compounds are used for inhibiting the expression of the transcription factor NFATc 1.
Preferably, the isoindolones are useful in blocking RANKL-induced activation of MAPK and PI3K/AKT signaling pathways.
Compared with the prior art, the invention has the following advantages and effects:
the invention tests the activity of the isoindolone compounds for inhibiting the differentiation of the osteoclast, and the results show that the isoindolone compounds remarkably inhibit the capacity of bone marrow-derived macrophage BMMs induced by RANKL to differentiate into the osteoclast and the bone absorption capacity of the osteoclast and are concentration-dependent. Subsequent mechanism researches show that the isoindolone compounds inhibit the expression of the transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, thereby downregulating the expression of the osteoclast related genes and exerting the capacity of inhibiting the differentiation and bone resorption of the osteoclast. In addition, the isoindolones do not influence the differentiation of osteoblasts, and the application of the isoindolones in preventing and treating osteolytic diseases is disclosed, and the isoindolones can be used for preventing and treating osteolytic diseases including osteoporosis, paged Ji Shi and the like with a pharmaceutical composition prepared from the isoindolones and a conventional pharmaceutical carrier.
The invention provides a new medicine for osteolytic diseases and has great clinical application value.
Drawings
FIG. 1 is a graph of the isoindolone compounds inhibiting RANKL-induced BMMs differentiation into osteoclasts;
FIG. 2 is a graph of the bone resorption ability of isoindolones to inhibit osteoclasts;
FIG. 3 is a graph showing the effect of isoindolones on osteoblast differentiation;
FIG. 4 is a graph showing the down-regulation of RANKL-induced osteoclast marker genes by isoindolones;
FIG. 5 is a graph showing activation of the RANKL-induced PI3K/AKT and MAPK pathways downregulated by isoindolones.
Detailed Description
The present invention is further explained below with reference to examples and drawings, but the examples are not intended to limit the present invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
The reagents and materials used in the present invention are commercially available unless otherwise specified.
The isoindolone compounds selected in the examples of the present invention were prepared by referring to the methods described in CN 107721990 a.
Example 1
This example explores the inhibitory activity of isoindolones on osteoclast differentiation and was tested as follows.
(1) Cell culture: bone marrow-derived macrophage BMMs were isolated from femur and tibia of C57BL/6, cultured in a medium of alpha-MEM containing 10% fetal calf serum, streptomycin (100. Mu.g/mL), penicillin (100 units/mL), and subjected to conventional maintenance culture and passaging at 37℃and 5% carbon dioxide concentration.
(2) TRAP staining experiments: BMMs cells were spread in 96-well plates at a density of 3X 103/well, and after waiting 24 hours for cell attachment, different concentrations of isoindolones were dosed to test for inhibition of RANKL (50 ng/mL) and MCSF (30 ng/mL) induced osteoclast formation, and osteoclasts were stained with TRAP kit to calculate osteoclasts (TRAP + The number of nuclei > 3), reflecting the inhibitory activity of the compound on osteoclast formation.
(3) Cell viability test: BMMs cells are planted in a 96-well plate at the density of 5 multiplied by 103, and after the BMMs are attached to the wall, isoindolone compound solutions with different concentrations are added; after 72h, CCK-8 reagent was added at a concentration of 20. Mu.L/well, and the absorbance at 490mm was measured after 2h to calculate the effect of the compound on BMMs cell viability.
(4) Bone resorption ability test: BMMs cells were cultured in collagen plates at a density of 5X 104/well, BMMs were induced to differentiate into osteoclast precursor cells with RANKL (50 ng/mL) and MCSF (30 ng/mL), then the cells were digested and collected from the plates, seeded in bone resorption plates at a density of 6X 103/well, and after 48 hours of dosing, 24-well plates were washed 2-3 times with PBS, and the inhibition of bone resorption capacity by isoindolones was analyzed with IMAG J.
(5) Alkaline phosphatase (ALP) staining and Alizarin red (Alizarin S red) staining experiments: C3H10T1/2 cells were seeded in 24-well plates at a density of 3 x 103/well, after 24H adherence, induced differentiation into osteoblasts with osteogenic differentiation medium (complete medium DMEM, dexamethasone, β -sodium phosphate, L-ascorbic acid) and drug intervention, cells were fixed with 4% paraformaldehyde for 20min after 14 days, washed 2-3 times with pbs, stained with ALP staining kit, fixed and washed cells as described above after another 21 days, stained with Alizarin S red staining kit.
(6) Quantitative real-time polymerase chain reaction experiments: BMMs cells are planted in a six-hole plate according to the density of 5 multiplied by 104 per hole, after 24 hours of adherence, BMMs differentiation is induced by RANKL (50 ng/mL) and MCSF (30 ng/mL), medicine intervention is added, after 5 days of co-culture, cellular RNA is extracted by a TRIZOL method, the cellular RNA is reversely transcribed into cDNA by a Toyobo reverse transcription kit, and specific primers are quantified by utilizing a quantitative instant polymerase chain reaction experiment.
(7) Western blot experiment: RAW264.7 cells are planted in a six-hole plate at the density of 10 multiplied by 104 per hole, after the cells are attached on the next day, the cells are dosed in advance for 2 hours, then RANKL (50 ng/mL) is added for induction, the culture medium is discarded, the cells are washed for 2 to 3 times by precooled PBS, RIPA is added for cell lysis, after standing for 10 minutes, 13000rpm and 20 minutes, the supernatant is taken, and the expression levels of different proteins are analyzed by a western blot experiment.
As shown in fig. 1, isoindolones inhibited RANKL-induced BMMs from differentiating into osteoclasts. Wherein A is the chemical structure of the isoindolone, B is the chemical structure of the isoindolone for inhibiting the BMMs induced by RANKL from differentiating into osteoclasts (Mag=10×; scale bar:400 μm), C is the number of osteoclasts in each hole, D is the area of the osteoclasts in each hole, E is the cell viability test of the isoindolone on the BMMs, F-G are the inhibition effects of the isoindolone on the osteoclasts at different time points. From the figure, the compound significantly inhibited RANKL-induced osteoclast differentiation and exhibited concentration dependence; in addition, the time gradient test shows that the compounds show inhibition at the earliest of the first day of BMMs differentiation, and the cell viability test excludes the activity of the compounds in inhibiting osteoclast differentiation due to toxicity. .
FIG. 2 shows the bone resorption inhibition ability of the isoindolones. Wherein A-B are isoindolones for inhibiting bone resorption of osteoclast (Mag=4×; scale bar:100 μm). From the figure, it is clear that the compound significantly inhibits bone resorption by osteoclasts in the artificial bone fragment well plate and shows concentration dependence, and that the compound completely inhibits bone resorption function by osteoclasts at a concentration of 10 μm.
FIG. 3 is a graph showing the effect of isoindolones on osteoblast differentiation. From the figure, ALP and Alizarin S red staining showed that isoindolones did not affect osteoblast differentiation.
FIG. 4 is a graph showing the expression of the ranKL-induced osteoclast marker gene down-regulated by isoindolones. From the figure, the compounds significantly inhibit RANKL-induced osteoclast marker gene expression, including TRAP, CTSK, NFATc1, V (2), MMP-9, DC-stamp, and the like.
FIG. 5 is a graph showing activation of the RANKL-induced PI3K/AKT and MAPK pathways downregulated by isoindolones. From the figure, it can be seen that the compounds significantly inhibit RANKL-induced phosphorylation of key protein AKT, ERK, JNK, P38 in PI3K/AKT and MAPK pathways, thereby inhibiting activation of the downstream transcription factor NFATc1 by the pathway.
From the above, the isoindolone compounds can significantly inhibit the RANKL-induced bone marrow-derived macrophage BMMs differentiation ability to osteoclasts and the bone resorption ability of osteoclasts, and are concentration-dependent; subsequent mechanism researches show that the isoindolone compounds inhibit the expression of the transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, thereby downregulating the expression of the osteoclast related genes and exerting the capacity of inhibiting the differentiation and bone resorption of the osteoclast. In addition, the isoindolones do not influence the differentiation of osteoblasts, and the application of the isoindolones in preventing and treating osteolytic diseases is disclosed, and the isoindolones can be used for preventing and treating osteolytic diseases including osteoporosis, paged Ji Shi and the like with a pharmaceutical composition prepared from the isoindolones and a conventional pharmaceutical carrier.
Claims (3)
1. The application of the isoindolone compound with the structure shown in the formula (I) in preparing the medicine for treating osteolytic diseases is characterized in that the isoindolone compound inhibits the expression of a transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, thereby downregulating the expression of an osteoclast related gene, exerting the capacity of inhibiting the differentiation and bone resorption of the osteoclast, and in addition, not affecting the differentiation of the osteoblast;
formula (I).
2. The use according to claim 1, wherein the osteolytic disease is a bone disease caused by an increased number and/or an increased activity of osteoclasts.
3. The use according to claim 2, wherein the osteolytic disease is one or both of postmenopausal osteoporosis or Page's disease.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5925655A (en) * | 1996-04-10 | 1999-07-20 | Merck & Co., Inc. | αv β3 antagonists |
| WO2007047646A2 (en) * | 2005-10-14 | 2007-04-26 | Janssen Pharmaceutica, N.V. | Substituted dihydro-isoindolones useful in treating kinase disorders |
| CA2588369A1 (en) * | 2007-05-11 | 2008-11-11 | Thomas Jefferson University | Methods of treatment and prevention of metabolic bone diseases and disorders |
| WO2018016901A1 (en) * | 2016-07-20 | 2018-01-25 | 이화여자대학교 산학협력단 | Pharmaceutical composition for preventing or treating bone diseases |
| CN107721990A (en) * | 2017-08-25 | 2018-02-23 | 中山大学 | The iso-indole ketone compounds in a kind of marine fungi source and preparation method thereof and the application in anti-inflammatory drug is prepared |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2840302B1 (en) * | 2002-06-03 | 2004-07-16 | Aventis Pharma Sa | ISOINDOLONE DERIVATIVES, PREPARATION METHOD AND INTERMEDIARY THEREOF AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5925655A (en) * | 1996-04-10 | 1999-07-20 | Merck & Co., Inc. | αv β3 antagonists |
| WO2007047646A2 (en) * | 2005-10-14 | 2007-04-26 | Janssen Pharmaceutica, N.V. | Substituted dihydro-isoindolones useful in treating kinase disorders |
| CA2588369A1 (en) * | 2007-05-11 | 2008-11-11 | Thomas Jefferson University | Methods of treatment and prevention of metabolic bone diseases and disorders |
| WO2018016901A1 (en) * | 2016-07-20 | 2018-01-25 | 이화여자대학교 산학협력단 | Pharmaceutical composition for preventing or treating bone diseases |
| CN107721990A (en) * | 2017-08-25 | 2018-02-23 | 中山大学 | The iso-indole ketone compounds in a kind of marine fungi source and preparation method thereof and the application in anti-inflammatory drug is prepared |
Non-Patent Citations (1)
| Title |
|---|
| 炎症相关骨质疏松症的发病机制;夏婷等;《中国骨质疏松杂志》;20150120;第21卷(第01期);第117页右栏第2段、第118页右栏倒数第1段至第119页右栏第3段 * |
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