CN109172564A - A kind of flavone compound is preparing the application in osteosporosis resistant medicament - Google Patents
A kind of flavone compound is preparing the application in osteosporosis resistant medicament Download PDFInfo
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- CN109172564A CN109172564A CN201811062879.7A CN201811062879A CN109172564A CN 109172564 A CN109172564 A CN 109172564A CN 201811062879 A CN201811062879 A CN 201811062879A CN 109172564 A CN109172564 A CN 109172564A
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Abstract
The invention discloses a kind of flavone compounds to prepare the application in osteosporosis resistant medicament.The Chinese of the compounds of this invention are as follows: 2- [6- (2; 4- dihydroxybenzoyl) -5- (2; 4- dihydroxy phenyl) -3- methyl cyclohexane -2- alkene -1- base] -1; 3; 8; parallel [3, the 2-b] chromone of 10a- tetrahydroxy -5a- isopentene group-[1] benzofuran, molecular formula are as follows: C40H36O12, molecular weight are as follows: 708.7.Cell assay in vitro shows that the compound can promote the proliferation of 14 cell of MC3T3-E1 Subclone, and inhibited to osteoclast.Internal animal experiment shows that the compound has significant therapeutic effect to the zebra fish osteoporosis that prednisone induces.
Description
Technical field
The present invention relates to a kind of flavone compounds, are that be related to a kind of flavone compound anti-in preparation more specifically
Application in medicine for treating osteoporosis.
Background technique
Osteoporosis is one kind caused by many reasons with the reduction of bone tissue content, and the microstructure degeneration of bone is spy
Sign causes the brittleness of bone to increase, strength reduction and causing is prone to a kind of systemic skeletal disease fractured.With mankind society
Aging can be progressed into, the illness rate of osteoporosis increases year by year.Osteoporosis not only seriously threatens people's health,
Thus bring fracture has also brought heavy burden.Currently, the medicament categories of clinical treatment osteoporosis have
Limit, and kind such as estrogen long-time service toxic side effect in part is larger.Therefore, it is badly in need of developing novel ALENDRONATE FOSAMAX
Object.
Bone is a dynamic activity tissue, it is maintained by lasting remodeling, and its mineralising balances and the structure of itself is complete
It is whole.Bone remodeling is a complicated biological process, and in this course, osteoclast (OC) completes the absorption function of bone, at
Osteocyte (OB) dominates the formation function of bone, and the two generates and active coordination is that bone remodeling process maintains skeletal structure complete
It is crucial.Healthy bone is in the state of OB bon e formation Yu the dynamic equilibrium of OC bone resorption, and this balance can lead to bone once being broken
A variety of bone metabolic diseases such as the loose, osteopetrosis of matter.
Flavone compound is a kind of compound of rich content in nature, more and more researches show that, flavones tool
There is the effects of phytoestrogen, anti-oxidant, anti-inflammatory, and these characteristics and anti-osteoporosis activity are closely related.2-[6-(2,4-
Dihydroxybenzoyl) -5- (2,4- dihydroxy phenyl) -3- methyl cyclohexane -2- alkene -1- base] -1,3,8,10a- tetrahydroxy -
5a- isopentene group-[1] benzofuran a pair of horses going side by side [3,2-b] chromone, is a kind of flavone compound, research shows that the compound has
There is the effects of anti-inflammatory, anti-oxidant, antitumor, but has no that the research in terms of its anti-osteoporosis is reported.
Summary of the invention
The purpose of the present invention is: discovery flavone compound is preparing the application in osteosporosis resistant medicament.
The present invention is implemented as follows: flavone compound is preparing the application in osteosporosis resistant medicament, Chinese
Are as follows: 2- [6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy phenyl) -3- methyl cyclohexane -2- alkene -1- base] -1,3,8,
Parallel [3, the 2-b] chromone of 10a- tetrahydroxy -5a- isopentene group-[1] benzofuran, molecular formula are as follows: C40H36O12, molecular weight are as follows:
708.7, the compound specific structure such as following formula (I).
The compound is 2- [(1S, 5S, 6R) -6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy benzenes
Base) -3- methyl cyclohexane -2- alkene -1- base] -1,3,8,10a- tetrahydroxy -5a- isopentene group-[1] benzofuran a pair of horses going side by side [3,2-b]
Chromone, i.e. sanggenon C (II)；Its structure formula (II) is as follows:
The compound is 2- [(1R, 5S, 6R) -6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy benzenes
Base) -3- methyl cyclohexane -2- alkene -1- base] -1,3,8,10a- tetrahydroxy -5a- isopentene group-[1] benzofuran a pair of horses going side by side [3,2-b]
Chromone, i.e. Saliggenon D (III)；Its structure formula (III) is as follows:
For clear " 2- [6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy phenyl) -3- methyl cyclohexane -2-
Alkene -1- base] parallel [3,2-b] chromone of -1,3,8,10a- tetrahydroxy -5a- isopentene group-[1] benzofuran " anti-osteoporosis
Activity, inventor have carried out following experiment:
14 cell of MC3T3-E1Subclone is cultivated, which is studied to the shadow of osteoblastic proliferation using mtt assay
It rings.Osteoclast and bone marrow cell are isolated from newborn rabbit shin bone and femur, with 1 α, 25- (OH)2 VitD3To bone marrow cells
It is induced, using the osteoclast model of this primary separation building, studies effect of the compound to osteoclast activity.Knot
Fruit shows that the compound can promote the proliferation of 14 cell of MC3T3-E1 Subclone, and inhibited to osteoclast.
3dpf wild type AB strain zebra fish is randomly selected in 6 orifice plates, prednisone processing is given and establishes osteoporosis
Model.After 28 DEG C of incubators are handled 5 days, zebra fish is dyed with 0.2% calcein, takes pictures after dyeing and acquires number
According to zebra fish, first three fluorescence intensity for saving vertebrae evaluates therapeutic effect of the compound to zebra fish osteoporosis.Knot
Fruit shows that the compound can dramatically increase the bone density of zebra fish, has to the osteoporosis of prednisone induction and significantly controls
Treatment effect.
Present invention firstly discloses the compounds to the active function of osteoblast, osteoclast, and to zebra fish sclerotin
The therapeutic effect of osteoporosis is studied, and illustrates that this compound can be used for preventing and treating the bone loss disease such as osteoporosis.
Detailed description of the invention
Attached drawing 1: compound structure figure；
Attached drawing 2: Normal group does not give prednisone processing；
Attached drawing 3: model control group gives prednisone processing；
Attached drawing 4: positive controls give prednisone+disodium etidronate processing；
Attached drawing 5: experimental group gives prednisone+sanggenon C processing；
Attached drawing 6: experimental group gives prednisone+Saliggenon D processing.
Specific embodiment
The present invention is further described by the following examples, but embodiment is not delimit the scope of the invention.
Embodiment 1: the research that sanggenon C acts on osteoblast activity
MC3T3-E1Subclone l4 cell is inoculated into 96 orifice plates with the density in 5000/hole, changes drug containing afterwards for 24 hours
Culture medium, 10 μ L MTT (5mg/mL) are added in every hole after 48h, continue after being incubated for 4h, inhale and abandon each culture hole supernatant, be separately added into
150 μ L dimethyl sulfoxides vibrate 10min, measure OD value at 490nm wavelength with microplate reader, calculate proliferation rate, the results are shown in Table 1.
1 sanggenon C of table to 14 cell Proliferation of MC3T3-E1Subclone influence (N=5)
Compared with blank group, P < 0.01 *
The result shows that 10-5~10-8Compared with blank control group, absorbance increased and has aobvious mol/L sanggenon C
It writes sex differernce (p < 0.01), 10-5Mol/L sanggenon C proliferation rate illustrates that sanggenon C can promote MC3T3- up to 25.96%
The proliferation of E1Subclone l4 cell.
Embodiment 2: the research that Saliggenon D acts on osteoblast activity
MC3T3-E1Subclone l4 cell is inoculated into 96 orifice plates with the density in 5000/hole, changes drug containing afterwards for 24 hours
Culture medium, 10 μ L MTT (5mg/mL) are added in every hole after 48h, continue after being incubated for 4h, inhale and abandon each culture hole supernatant, be separately added into
150 μ L dimethyl sulfoxides vibrate 10min, measure OD value at 490nm wavelength with microplate reader, calculate proliferation rate, the results are shown in Table 2.
2 Saliggenon D of table to 14 cell Proliferation of MC3T3-E1Subclone influence (R=5)
Compared with blank group, P < 0.01 *
The result shows that 10-5~10-8Compared with blank control group, absorbance increased and has aobvious mol/L Saliggenon D
It writes sex differernce (p < 0.01), 10-5Mol/L Saliggenon D proliferation rate illustrates that Saliggenon D can promote MC3T3- up to 42.34%
The proliferation of E1Subclone l4 cell.
Embodiment 3: the research that sanggenon C acts on osteoclast activity
By be born 48h within newborn rabbit break neck put to death, 75% alcohol disinfecting, in aseptic operating platform remove hind leg femur and
Shin bone is placed in PBS.It strips soft tissue to be placed in the α-MEM culture medium containing 10% fetal calf serum, cuts off backbone, gently scrape
Cell, whirlpool concussion, is sieved with 200 mesh cell sieves, is diluted to 2 × 106The cell suspension of a/mL is inoculated in 48 well culture plates
On, it is placed in incubator and cultivates.It is rinsed, is changed to containing 1 α, 25- (OH) with PBS afterwards for 24 hours2VitD3Pastille culture medium, then often
Change within 3 days a subculture, culture is aobvious to being dyed after the 8th day by Tartrate resistant acid phosphatase (TRAP) staining kit
To TRAP Positive Cell Counts under micro mirror.The result shows that sanggenon C can significantly inhibit the formation of osteoclast.
3 sanggenon C of table to osteoclast TRAP staining positive cells number influence (N=4)
Compared with blank group, P < 0.01 *
Embodiment 4: the research that Saliggenon D acts on osteoclast activity
By be born 48h within newborn rabbit break neck put to death, 75% alcohol disinfecting, in aseptic operating platform remove hind leg femur and
Shin bone is placed in PBS.It strips soft tissue to be placed in the α-MEM culture medium containing 10% fetal calf serum, cuts off backbone, gently scrape
Cell, whirlpool concussion, is sieved with 200 mesh cell sieves, is diluted to 2 × 106The cell suspension of a/mL is inoculated in 48 well culture plates
On, it is placed in incubator and cultivates.It is rinsed, is changed to containing 1 α, 25- (OH) with PBS afterwards for 24 hours2VitD3Pastille culture medium, then often
Change within 3 days a subculture, culture is aobvious to being dyed after the 8th day by Tartrate resistant acid phosphatase (TRAP) staining kit
To TRAP Positive Cell Counts under micro mirror.The result shows that Saliggenon D can significantly inhibit the formation of osteoclast.
4 Saliggenon D of table to osteoclast TRAP staining positive cells number influence (N=4)
Compared with blank group, P < 0.01 *
Embodiment 5: sanggenon C and Saliggenon D are to zebra fish osteoporosis therapy evaluation of effect
3dpf wild type AB strain zebra fish is randomly selected in 6 orifice plates, it is water-soluble to give prednisone processing to establish zebra
Fish Osteoporotic Model.It is water-soluble respectively to osteoporosis model zebra fish to give 10 μM of sanggenon Cs and 1 μM of Saliggenon D, sun
Property 300 μ g/mL concentration of comparison medicine disodium etidronate, while be arranged Normal group (the normal zebra fish of fish culture water processing) and
Model control group.After 28 DEG C of incubators are handled 5 days, zebra fish is dyed with 0.2% calcein, is clapped after dyeing
According to and analyze statistics zebra fish first three section vertebrae accumulation optical density, statistical procedures result with mean ± SE indicate.
The result shows that zebra fish vertebrae accumulation optical density (21702 pixel) of model control group and Normal group
(48195 pixel) compares p < 0.001, and hints model constructs successfully；The zebra fish vertebra of positive control drug disodium etidronate group
Bone accumulation optical density (45132 pixel) p < 0.001, zebra fish osteoporosis compared with model control group (21702 pixel) is controlled
Treatment effect is 88%, and positive drug is prompted to have significant therapeutic effect to the zebra fish osteoporosis that prednisone induces.
The zebra fish vertebrae accumulation optical density of sanggenon C group is 45460 pixels, the effect of zebra fish osteoporosis therapy
It is 90%, there is significant difference (p < 0.001) compared with model control group, illustrates the zebra fish that sanggenon C induces prednisone
Osteoporosis has significant therapeutic effect；The zebra fish vertebrae accumulation optical density of Saliggenon D group is 38686 pixels,
The effect of zebra fish osteoporosis therapy is 64%, has significant difference (p < 0.01) to illustrate Saliggenon D compared with model control group
There is significant therapeutic effect to the zebra fish osteoporosis of prednisone induction.See Table 5 for details.
The therapeutic effect (n=10) of 5 sanggenon C of table and Saliggenon D to zebra fish osteoporosis
Compared with model control group, p < 0.001 * p < 0.01, * *.
Claims (3)
1. a kind of flavone compound is preparing the application in osteosporosis resistant medicament, it is characterised in that: the compound Chinese name
Referred to as: 2- [6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy phenyl) -3- methyl cyclohexane -2- alkene -1- base] -1,3,
Parallel [3, the 2-b] chromone of 8,10a- tetrahydroxy -5a- isopentene groups-[1] benzofuran, molecular formula are as follows: C40H36O12, molecular weight
Are as follows: 708.7, specific structure such as following formula (I)；
2. flavone compound according to claim 1 is preparing the application in osteosporosis resistant medicament, it is characterised in that:
The compound is 2- [(1S, 5S, 6R) -6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy phenyl) -3- methyl
Hexamethylene -2- alkene -1- base] parallel [3, the 2-b] chromone of -1,3,8,10a- tetrahydroxy -5a- isopentene groups-[1] benzofuran, i.e. mulberry
Root ketone C (II)；Its structure formula (II) is as follows:
3. flavone compound according to claim 1 is preparing the application in osteosporosis resistant medicament, it is characterised in that:
The compound is 2- [(1R, 5S, 6R) -6- (2,4- dihydroxybenzoyl) -5- (2,4- dihydroxy phenyl) -3- methyl
Hexamethylene -2- alkene -1- base] parallel [3, the 2-b] chromone of -1,3,8,10a- tetrahydroxy -5a- isopentene groups-[1] benzofuran, i.e. mulberry
Root ketone D (III)；Its structure formula (III) is as follows:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051659A (en) * | 2019-06-14 | 2019-07-26 | 贵州理工学院 | Mulberrin is preparing the application in osteosporosis resistant medicament |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107206040A (en) * | 2014-06-16 | 2017-09-26 | 尤尼根公司 | For managing or improving bone disorders, cartilage disorder or combination thing and method |
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2018
- 2018-09-12 CN CN201811062879.7A patent/CN109172564A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107206040A (en) * | 2014-06-16 | 2017-09-26 | 尤尼根公司 | For managing or improving bone disorders, cartilage disorder or combination thing and method |
Non-Patent Citations (1)
| Title |
|---|
| 张静 等: "桑白皮不同部位对实验性高脂糖尿病小鼠的影响", 《中药新药与临床药理》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051659A (en) * | 2019-06-14 | 2019-07-26 | 贵州理工学院 | Mulberrin is preparing the application in osteosporosis resistant medicament |
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Application publication date: 20190111 |