CN104415031A - Application of wedelolactone in preparation of medicaments or healthcare products for treating osteoporosis - Google Patents

Application of wedelolactone in preparation of medicaments or healthcare products for treating osteoporosis Download PDF

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Publication number
CN104415031A
CN104415031A CN201310410289.XA CN201310410289A CN104415031A CN 104415031 A CN104415031 A CN 104415031A CN 201310410289 A CN201310410289 A CN 201310410289A CN 104415031 A CN104415031 A CN 104415031A
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China
Prior art keywords
trihydroxy
benzo
methoxy
osteoporosis
wedelolactone
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CN201310410289.XA
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肖红斌
程孟春
刘艳秋
王莉
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Dalian Institute of Chemical Physics of CAS
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Dalian Institute of Chemical Physics of CAS
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    • A—HUMAN NECESSITIES
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides new use of wedelolactone and particularly relates to application of wedelolactone in preparation of medicaments or healthcare products for treating osteoporosis. Experiments show that wedelolactone is capable of obviously inhibiting proliferation of preosteoclast and inhibiting tartrate-resistant acid phosphatase activity of the preosteoclast; by inhibiting the proliferation and the differentiation of the preosteoclast, the bone loss is reduced, so that wedelolactone has anti-osteoporosis activity and can be used for preparing the medicaments or the healthcare products for treating the osteoporosis.

Description

The application of 1,8,9-trihydroxy-3-methoxy-benzo[4,5 in preparation prevention or treatment osteoporosis agents or health product
Technical field
The present invention relates to the application of 1,8,9-trihydroxy-3-methoxy-benzo[4,5.Namely 1,8,9-trihydroxy-3-methoxy-benzo[4,5 is preparing the application in Prevention and Curation osteoporosis agents and health product.
Background technology
Osteoporosis occupies the 7th in world's commonly encountered diseases, frequently-occurring disease, multiple in old people.According to Expert forecast, China's current more than 60 years old population osteoporosis incidence, women is approximately 50%, and male is 20%, existing patients with osteoporosis about 90,000,000 people.Along with increasingly sharpening of China's aging, the control of osteoporosis becomes a large engineering, although the control of expert to this disease is both at home and abroad attached great importance to, this disease still lacks effective Prevention and Curation medicine.
The medicine of osteoporosis is divided into bone resorption inhibitor and bone formation-promoter according to the mechanism of action.Estrogen is clinical comparatively common bone resorption inhibitor at present, has clear and definite curative effect, but its side effect is also comparatively obvious, and breast carcinoma, carcinoma of endometrium morbidity there is contact, and can myocardial infarction be caused, venous thrombosis, pulmonary infarction etc.Phytoestrogen is as the active substance of the natural heterocycle Polyphenols be present in plant of a class, its structure is similar to endogenous estrogen, can in conjunction with and activate mammal estrogen receptor, there is estrogenlike activity and without obvious estrogen-like side effect, be considered to estrogenic natural substitute.Current correlational study is verified, and osajin phytoestrogen has clear and definite function of resisting osteoporosis, and existing soybean isoflavone is medicine and the health product list marketing of main component.
1,8,9-trihydroxy-3-methoxy-benzo[4,5 (Wedelolactone) belongs to the coumarin kind compound in phytoestrogen, and molecular formula is C 16h 10o 7, molecular weight is 314.25, No. CAS is 524-12-9, and structural formula is shown in following formula 1, is the index components that in version pharmacopeia in 2010, Herba Ecliptae is newly-increased, is mainly present in Herba Ecliptae and Herbia Wedeliae.Herba Ecliptae, as kidney-nourishing tcm drug, has certain application (Lin Xionghao, Wu Jinzhong in tcm clinical practice treatment osteoporosis.The chemical composition of Chinese medicine compound ERZHI WAN and osteoporosis progress.PLA's Acta Pharmaceutica Sinica, 25(5): 421.) also there is reported in literature Herbia Wedeliae ethanol extraction to the function of resisting osteoporosis of Ovariectomized rat model obviously (Annie S, Prabhu RG, Malini S.Activity of Wedelia calendulacea Lessin post-menopausal osteoporosis [J] .Phytomedicine, 2006,13(1-2): 43.) but above report all fail to determine which kind of composition plays clear and definite function of resisting osteoporosis.Simultaneously, less to the pharmacological research of monomeric compound 1,8,9-trihydroxy-3-methoxy-benzo[4,5, be mainly anti-hepatotoxicity (Wong SM, Antus S, Gottsegen A, et al.Wedelolactone and coumestan derivatives as newantihepatotoxic and antiphlogistic principles [J].
Arzneimittelforschung, 1988,38(5): 661.) and antitumor action (Lin FM, ChenLR, Lin EH, et al.Compounds from Wedelia chinensis synergisticallysuppress androgen activity and growth in prostate cancer cells [J] .Carcinogenesis, 2007,28(12): 2521.) whether there is function of resisting osteoporosis to it, also there is no bibliographical information.
Our research work tentative confirmation, during 1,8,9-trihydroxy-3-methoxy-benzo[4,5 is tested in vitro, has the effect directly suppressing preosteoclast propagation, and preosteoclast can be suppressed to break up to maturation.This is for being developed as bone resorption inhibitor class osteosporosis resistant medicament or health product provide probability.Based on above-mentioned research work, this patent is proposed.
Summary of the invention
The object of this invention is to provide the novelty teabag of 1,8,9-trihydroxy-3-methoxy-benzo[4,5, namely 1,8,9-trihydroxy-3-methoxy-benzo[4,5 is preparing the application in Prevention and Curation medicine for treating osteoporosis and health product as active component.
We adopt conventional mtt assay, and research 1,8,9-trihydroxy-3-methoxy-benzo[4,5 is to the effect of mice preosteoclast RAW264.7.Experimental result shows, the 1,8,9-trihydroxy-3-methoxy-benzo[4,5 of 1.56-400 μM all can have an impact to the propagation of RAW264.7 cell.The 1,8,9-trihydroxy-3-methoxy-benzo[4,5 effect of 6.25 μMs can suppress the propagation of RAW264.7 cell for 24 hours, and the rate of increase is down to 82.73%, and is time, dose dependent.1,8,9-trihydroxy-3-methoxy-benzo[4,5 prepared by different batches all has the effect suppressing RAW264.7 cell proliferation.
Adopt RANKL test kit, the impact that research 1,8,9-trihydroxy-3-methoxy-benzo[4,5 breaks up preosteoclast.Experimental result shows, differentiation of osteoclast marker enzyme-TRAP activity that 1,5,10 μM of 1,8,9-trihydroxy-3-methoxy-benzo[4,5 all can suppress RANKL to induce in various degree.5 μMs of 1,8,9-trihydroxy-3-methoxy-benzo[4,5s can make RAW264.7 cell TRAP enzymatic activity be down to 64.88%, show that 1,8,9-trihydroxy-3-methoxy-benzo[4,5 can suppress preosteoclast RAW264.7 to break bone differentiation to maturation.
The present invention has the following advantages:
The 1 new activity that present invention finds 1,8,9-trihydroxy-3-methoxy-benzo[4,5, i.e. anti-osteoporosis activity, and activity is comparatively strong, has enriched the scope of application of 1,8,9-trihydroxy-3-methoxy-benzo[4,5;
2 provide probability for the osteoporosis new drug or health product developing high-efficiency low-toxicity.
Detailed description of the invention
Now be described in further details the present invention, embodiment is only limitted to the present invention is described in conjunction with the embodiments, but not limitation of the invention.
Embodiment 1:
Experiment material and reagent: 1,8,9-trihydroxy-3-methoxy-benzo[4,5 extracts preparation by this laboratory from Herba Ecliptae, HPLC purity >=98%, batches 20111026.
The cell strain adopted is mice preosteoclast RAW264.7, purchased from American Type Culture Collection committee of Chinese Academy of Sciences cell bank (Shanghai), DMEM(Gibco with containing 10% hyclone (Hangzhou Ilex purpurea Hassk.[I.chinensis Sims)) cultivate, 0.05% trypsin Solarbio) had digestive transfer culture.Cell is placed in 37 DEG C, 5%CO 2, cultivate in the incubator of saturated humidity.Agents useful for same: MTT, RANK Ligand from mouse(RANKL), Tartrate resistant acid phosphatase test kit (TRAP kit) is sigma product, estradiol (E 2) purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Instrument: CO2 gas incubator (HEAL FORCE), superclean bench (HEALFORCE), microplate reader (sunrise, TECAN), inverted microscope (Olymbus).
Experimental technique:
Mtt assay detects 1,8,9-trihydroxy-3-methoxy-benzo[4,5 to the impact of RAW264.7 cell survival rate: RAW264.7 cell is inoculated into 96 orifice plates with the concentration in 10000, every hole, every hole 100 μ L, overnight incubation.1,8,9-trihydroxy-3-methoxy-benzo[4,5 1.2mg adds 48 μ L DMSO, is mixed with mother solution; With estradiol (E 2) be positive control medicine, 1.2mg E 2add 55 μ L dehydrated alcohol, be mixed with mother solution.Face in order to culture medium dilution mother solution, be mixed with desired concn, every hole adds 100 μ L, and negative control hole adds equivalent culture medium.After cultivating 24h, 48h and 72h, every hole adds MTT(5mgmL -1) 20 μ L, after reaction 4h, carefully get rid of culture fluid, every hole adds 150 μ L DMSO, concussion 10min fully dissolves, microplate reader, at 492nm wavelength detecting absorbance, calculates cell survival rate, calculates cell survival rate formula: survival rate (PR%)=(A experimental group-A blank group)/(A negative control group-A blank group) × 100%.
Result shows, and the propagation of 1,8,9-trihydroxy-3-methoxy-benzo[4,5 to RAW264.7 cell of 1.56-400 μM is inhibited, and is time, dose dependent.The 1,8,9-trihydroxy-3-methoxy-benzo[4,5 effect 24h of 6.25 μMs can suppress the propagation of RAW264.7 cell, and the rate of increase is down to 82.73%, with the effect of positive control drug estradiol suitable (table 1).
Table 1. estradiol and 1,8,9-trihydroxy-3-methoxy-benzo[4,5 are on the impact of RAW264.7 cell proliferation
Note: compare with negative control group 1)p < 0.05, 2)p < 0.01, 3)p < 0.001
Embodiment 2:
1,8,9-trihydroxy-3-methoxy-benzo[4,5 batch is 20130123,96 orifice plate every hole inoculating cell numerical digit 15000, and experiment agents useful for same, method step and date processing are with embodiment 1.
Table 2. estradiol and 1,8,9-trihydroxy-3-methoxy-benzo[4,5 are on the impact of RAW264.7 cell proliferation
Note: compare with negative control group 1)p < 0.05, 2)p < 0.01, 3)p < 0.001
TRAP test kit detects the RAW264.7 cell TRAP enzyme activity of RANKL induction: 1,8,9-trihydroxy-3-methoxy-benzo[4,5 batch is 20111026.RAW264.7 cell is inoculated into 96 orifice plates with 8000, every hole, every hole 50 μ L, overnight incubation.The every hole of RANKL matched group adds RANKL and the 100 μ L serum-free mediums of 50 μ L serum-free medium preparations, and the every hole of 1,8,9-trihydroxy-3-methoxy-benzo[4,5 experimental group adds with the RANKL50 μ L of serum-free medium preparation and 1,8,9-trihydroxy-3-methoxy-benzo[4,5 100 μ L, E 2the every hole of experimental group adds with RANKL50 μ L and E of serum-free medium preparation 2the final concentration of 100 μ L, RANKL is 30ngmL -1, after cultivating 6d, TRAP test kit qualitative, quantitative dyes, and with RANKL induction group positive stained cells rate for 100%, calculates 1,8,9-trihydroxy-3-methoxy-benzo[4,5 experimental group and E 2experimental group positive stained cells rate.Calculate positive stained cells rate formula: positive rate (PR%)=A experimental group/A RANKL induction group × 100%
Tartrate resistant acid phosphatase TRAP is one of marker enzyme of differentiation of osteoclast maturation, it is active directly related with the bone resorption of osteoclast, from table 3, the TRAP vigor that the 1,8,9-trihydroxy-3-methoxy-benzo[4,5 of 5 μMs and 10 μMs obviously inhibits RANKL to induce, illustrates that 1,8,9-trihydroxy-3-methoxy-benzo[4,5 can suppress bone resorption function by suppressing differentiation of osteoclast maturation.
Table 3. estradiol and 1,8,9-trihydroxy-3-methoxy-benzo[4,5 are on the impact of RAW264.7 cell Tartrate resistant acid phosphatase (TRAP) enzyme activity that RANKL induces
Note: compare with RANKL group 1)p < 0.05, 2)p < 0.01, 3)p < 0.001
Above-mentioned experiment shows, 1,8,9-trihydroxy-3-methoxy-benzo[4,5 can suppress osteoclast proliferation and Tartrate resistant acid phosphatase activity, having anti-osteoporosis activity, therefore, can be used for preventing and treating osteoporotic medicine and health product by suppressing bone resorption.

Claims (2)

1. the application of 1,8,9-trihydroxy-3-methoxy-benzo[4,5 in preparation prevention or treatment osteoporosis agents or health product.
2. apply according to described in claim 1, it is characterized in that: 1,8,9-trihydroxy-3-methoxy-benzo[4,5 has obvious inhibitory action to preosteoclast propagation, and the Tartrate resistant acid phosphatase of osteoclast can be suppressed active; By suppressing propagation and the differentiation of osteoclast, reduce the loss of sclerotin, therefore, it has anti-osteoporosis activity, can be used for medicine or the health product of preparing protect against osteoporosis.
CN201310410289.XA 2013-09-10 2013-09-10 Application of wedelolactone in preparation of medicaments or healthcare products for treating osteoporosis Pending CN104415031A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105748546A (en) * 2015-05-14 2016-07-13 大连医科大学 Application of Herba Ecliptae extract to preparation of anti-osteoporosis multi-target medicines or healthcare products
CN106176782A (en) * 2016-07-06 2016-12-07 天津中医药大学 Herba Ecliptae chemical composition is as the purposes of phytoestrogen
CN106728679A (en) * 2016-12-30 2017-05-31 福建中医药大学 A kind of molecule Chinese medicine sustained release tablets for anti-bone loss and preparation method thereof
WO2024169680A1 (en) * 2023-02-15 2024-08-22 上海萨美细胞技术有限公司 Drug for treating osteoporosis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101259124A (en) * 2007-11-21 2008-09-10 上海交通大学医学院 Pharmaceutical use of wedelolactone and its derivative

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101259124A (en) * 2007-11-21 2008-09-10 上海交通大学医学院 Pharmaceutical use of wedelolactone and its derivative

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHIRWAIKAR ANNIE ET AL: "Activity of Wedelia calendulacea Less. in post-menopausal osteoporosis. Shirwaikar Annie et al. Phytomedicine 13 (2006) 43–48", 《PHYTOMEDICINE》 *
YAN ZHANG ET AL: "Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action", 《ASIAN JOURNAL OF TRADITIONAL MEDICINES》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105748546A (en) * 2015-05-14 2016-07-13 大连医科大学 Application of Herba Ecliptae extract to preparation of anti-osteoporosis multi-target medicines or healthcare products
CN106176782A (en) * 2016-07-06 2016-12-07 天津中医药大学 Herba Ecliptae chemical composition is as the purposes of phytoestrogen
CN106728679A (en) * 2016-12-30 2017-05-31 福建中医药大学 A kind of molecule Chinese medicine sustained release tablets for anti-bone loss and preparation method thereof
WO2024169680A1 (en) * 2023-02-15 2024-08-22 上海萨美细胞技术有限公司 Drug for treating osteoporosis

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Application publication date: 20150318