CN103120697B - Squamatic acid is preparing the application in antitumor drug - Google Patents
Squamatic acid is preparing the application in antitumor drug Download PDFInfo
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- CN103120697B CN103120697B CN201110369116.9A CN201110369116A CN103120697B CN 103120697 B CN103120697 B CN 103120697B CN 201110369116 A CN201110369116 A CN 201110369116A CN 103120697 B CN103120697 B CN 103120697B
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Abstract
The invention belongs to chemical field and field of medicaments, relate to squamatic acid and preparing the application in antitumor drug.The invention provides squamatic acid and preparing the application in antitumor drug, especially suppress the propagation of hepatoma carcinoma cell.Squamatic acid belongs to natural product, and toxic and side effects is little, bioavailability is high, stable in properties, has Clinical practice and is worth.Micromolecular compound of the present invention is developed as new antitumor drug or its auxiliary element, and tumor killing effect is obvious, environmental protection, provides a kind of new approach and means by for treatment and healing tumor.
Description
Technical field
The invention belongs to chemical field and field of medicaments, relate to squamatic acid and preparing the application in antitumor drug.
Background technology
Squamatic acid, is also called the acid of scale clothing.Molecular weight 390.35, molecular formula C19H18O9.Its structural formula is as follows:
As far back as nineteen forty-four, Shibata etc. just report have extracted squamatic acid (Didymic acid, a new kind of lichensubstance.Shibata, Shoji.Imperial Univ., Tokyo, Acta Phytochimica (1944), 14.9-38.).1975, Elix etc. successfully synthesized squamatic acid (compound 9, Synthesis of p-β-orcinol depsides.Australian Journal of Chemistry (1975), 28 (5), 1113-24).
Domestic, 2002, Jiang Bei etc. are separated and obtain 10 compositions from Guan Zhiyi section ground Tea plant Thamnolia vermicularis (Ach.) Asa-hina (Thamnoliavermicularis) acetone extract, and by Spectrum Analysis and with the method such as known product contrast, finally determine that the 2nd compound is wherein squamatic acid (squamatic acid namely in literary composition, Thamnolia vermicularis (Ach.) Asa-hina chemical constitution study, (2002), 24 (4), 525-530).
Sartorelli etc. think, squamatic acid may be that lichens can resist gamma-ray reason preferably, because it can as electron acceptor (Effects of gamma radiation of lichen acids.Sartorelli, C.MichiganTechnol Univ., Houghton, MI, USA.Avail.Dep.NTIS.Report (1972), (COO-2085-5), 41pp.From:Nucl.Sci.Abstr.1973,27 (6), 12294).
Lawrey thinks that squamatic acid may affect sperm and produce (Adaptive significance of O-methylatedlichendepsides and depsidones.Lichenologist (1977), 9 (2), 137-42).
Sankawa thinks that squamatic acid can have influence on biosynthesis (Depside as potent inhibitor ofprostaglandin biosynthesis:a new active site model for fatty acid cyclooxygenase.Prostaglandins (1982) of prostaglandin, 24 (1), 21-34.).
2009, Zain etc. report that squamatic acid may affect secondary metabolite and fatty acid generation (the Effect of olive oil on secondary metabolite and fattyacid profiles of Penicillium expansum of such as penicillium expansum, Aspergillus flavus, parasitic aspergillosis, Aspergillus ochraceus etc., Aspergillus flavus, A.parasiticus and A.ochraceus.Australian Journal of Basic and Applied Sciences (2009), 3 (4), 4274-4280.).
Squamatic acid molecule is little, and bioavailability is high, stable in properties, has Clinical practice and is worth.Along with people's going deep into this type of alkaloidal chemistry and biology research, its molecular mechanism of action will be progressively clear and definite, and this will promote modifying for chemical structure and the structure activity study of this compounds further, and contribute to the medical value improving this compounds.
Summary of the invention
The object of this invention is to provide the new medicinal usage of squamatic acid.
The invention provides squamatic acid and prepare the application in antitumor drug.Described antitumor drug can be medicines resistant to liver cancer, Antilung gland cancer medicine or anti-leukemia medicine, etc.This antitumor drug can be injection or tablet.
The invention provides a kind of method suppressing tumor cell in vitro to be bred, squamatic acid is added in the culture fluid of tumor cell.Described tumor cell can be hepatoma carcinoma cell, blood cell, lung adenocarcinoma cell or pancreatic cancer cell.The hepatoma carcinoma cell adopted in one embodiment of the present of invention is HGC.Generally speaking, the final concentration adding squamatic acid is 0.3-100 μM.Such as, 0.3-1 μM, 0.3-0.55 μM, 0.3-5 μM, 0.3-10 μM, 0.3-20 μM, 0.3-40 μM, 0.3-55 μM, 1-5 μM, 1-10 μM, 1-20 μM, 1-40 μM, 1-55 μM, etc.
Present invention also offers a kind of antitumor drug, the active component of described antitumor drug is squamatic acid.Described tumor can be hepatocarcinoma, leukemia, adenocarcinoma of lung or cancer of pancreas.
Micromolecular compound of the present invention can adopt the preparation method of various routine to prepare.Such as, the method for artificial chemistry synthesis is adopted.
Squamatic acid of the present invention purchased from purchased from
shanghai Pharmaceutical Inst., Chinese Academy of Sciences.
Utilize micromolecular compound of the present invention, by various conventional screening assays, can filter out, with squamatic acid, interactional material occur, as receptor, inhibitor or antagonist etc.
The present invention and inhibitor, antagonist etc., when carrying out using (administration) on treating, can provide different effects.Usually, but these materials are formulated in nontoxic, inertia with in pharmaceutically acceptable aqueous carrier medium, wherein pH is about 5-8 usually, and preferably pH is about 6-8, although pH value can with being formulated the character of material and disease to be treated and changing to some extent.The pharmaceutical composition prepared can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
For squamatic acid of the present invention, can by itself and suitable pharmaceutically acceptable carrier coupling.This kind of pharmaceutical composition contains the compound and pharmaceutically acceptable carrier or excipient for the treatment of effective dose.This kind of carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should match with administering mode.Squamatic acid of the present invention can be made into injection form, such as, be prepared by conventional method with normal saline or the aqueous solution containing glucose and other adjuvant.The pharmaceutical composition of such as Tablet and Capsula and so on, is prepared by conventional method.Pharmaceutical composition such as injection, solution, Tablet and Capsula should aseptically manufacture.The dosage of active component is treatment effective dose, such as every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, squamatic acid of the present invention also can use together with other treatment agent.
When squamatic acid of the present invention is used as medicine, the squamatic acid for the treatment of effective dose can be applied to mammal, wherein this treatment effective dose is usually at least about 10 micrograms/kg body weight, and be in most of the cases no more than about 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
The invention provides squamatic acid and prepare the application in antitumor drug.Squamatic acid is natural product, can the propagation of obvious inhibition tumor cell.Micromolecular compound of the present invention is developed as new antitumor drug or its auxiliary element, and tumor killing effect is obvious, environmental protection, provides a kind of new approach and means by for treatment and healing tumor.
Detailed description of the invention
Experimental technique:
1. cell recovery
1) from liquid nitrogen container, take out cryopreservation tube, directly drop in 37 DEG C of warm water, and shake makes it melt as early as possible frequently.
2) from 37 DEG C of water-baths, take out cryopreservation tube, with suction pipe sucking-off cell suspension, inject centrifuge tube and add more than 10 times culture fluid, low-speed centrifugal after mixing, abandons supernatant, then repeats to wash once with culture fluid.
3), after suitably diluting with culture fluid, inoculated and cultured bottle, be placed on 37 DEG C of incubator quiescent culture, next day changes culture fluid, continues to cultivate.Go down to posterity when being cultured to finite concentration.HGC and HepG2 cell culture, containing in the DMEM high glucose medium of 10% hyclone, contains 100U/ml penicillin and 100 μ g/ml streptomycins in culture medium.
2. passage is cultivated
Every day observation of cell growth situation, when cell grow in culture bottle about 90% converge time go down to posterity, about went down to posterity once every 2-4 days.One bottle goes down to posterity into three bottles, or a 25cm
2go down to posterity in a 75cm
2culture bottle in.Method:
1) with 1 × phosphate buffer washed cell once.
2) add the digestion of 2-3ml trypsinization liquid, be placed in 37 DEG C of incubator numbers minute.Pat Tissue Culture Flask with hands, make cell separation.
3) trypsinization is stopped with the suitable culture medium of the Gibico hyclone containing 10-15%.Cell is sub-packed in new culture bottle, continues to cultivate.
3. cell cryopreservation
1) get the cell tryptase protease digestion being cultured to exponential phase, to be collected in centrifuge tube and to count, centrifugal.
2) reject trypsin and old culture fluid, add the frozen culture fluid (containing 10%DMSO, 40%DMEM and 50%Gibico hyclone) configured, in cryopreserving liquid, the ultimate density of cell is 0.5-1 × 10
7/ ml.Blowing and beating gently with suction pipe makes cell even, and be then distributed in aseptic cryopreservation tube, often pipe adds 1-1.5ml.
3) cryopreservation tube is put into freezing storing box and put-80 DEG C of quick-freezings, move in liquid nitrogen container after 5 hours and preserve.
4. medicine prepares:
Squamatic acid is dissolved in DMSO (dimethyl sulfoxide), and the mother solution being mixed with 100mM or 50mM is for subsequent use.
Embodiment MTS method measures squamatic acid to the growth inhibited effect of hepatoma carcinoma cell
HGC cell (purchased from Chinese Academy of Sciences's cell bank) 3 × 10
3/ hole is seeded to 96 orifice plates, cultivate within 24 hours, make it adherent after add squamatic acid (purchased from
shanghai Pharmaceutical Inst., Chinese Academy of Sciences), if 6 Concentraton gradient, each concentration establishes 3 multiple holes.Cell at 37 DEG C, 5%CO
2cultivate after 72 hours under condition, outwell culture fluid, measure cell survival rate with MTS test kit (Promega company).
Method of testing is: cell serum-free medium is washed one time, adds the MTS chromophoric solution (add 2ml solution 1 and 100 μ l solution 2 in 10ml serum-free medium, fully mix) prepared in advance according to the amount of 100 μ l/well.Do not have the hole of cell to be set to this bottom outlet by one, the bias light in order to calibration solution absorbs.Cell is put into cell culture incubator and continues cultivation 2 ~ 4 hours, then absorbance value (reference wavelength 630-700nm is read by microplate reader, measure wavelength 490nm), calculate cell survival rate, to measure the numerical value of hole absorbance value/control wells absorbance value as cell survival rate.According to cell survival rate, calculate squamatic acid to the IC50 value of HGC cell.
IC50 refers to the concentration of a suppressed half inhibitor.Here the concentration that HGC cell quantity is a half squamatic acid of contrast is.The calculating of IC50 generally needs the dosage effect of mensuration more than 5, then obtains function calculating by curve fitting and obtain.
Result: the IC50 value of squamatic acid to HGC cell is 35.14 μMs.
With said method test HepG2 cell (purchased from Chinese Academy of Sciences's cell bank), the IC50 value of result squamatic acid to HepG2 cell is 0.31 μM.
Claims (5)
1. squamatic acid is preparing the application in antitumor drug, and described tumor is formed by external HepG2 cell proliferation.
2. the method suppressing tumor cell in vitro to be bred, is characterized in that, is added by squamatic acid in the culture fluid of tumor cell, and described tumor cell is hepatoma carcinoma cell.
3. method as claimed in claim 2, it is characterized in that, described tumor cell is HepG2 cell.
4. method as claimed in claim 2, it is characterized in that, the final concentration adding squamatic acid is 0.3-100 μM.
5. method as claimed in claim 2, it is characterized in that, the final concentration adding squamatic acid is 0.3-40 μM.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110369116.9A CN103120697B (en) | 2011-11-18 | 2011-11-18 | Squamatic acid is preparing the application in antitumor drug |
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| CN201110369116.9A CN103120697B (en) | 2011-11-18 | 2011-11-18 | Squamatic acid is preparing the application in antitumor drug |
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| CN103120697A CN103120697A (en) | 2013-05-29 |
| CN103120697B true CN103120697B (en) | 2015-10-07 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010056413A2 (en) * | 2008-11-14 | 2010-05-20 | Parkinson's Institute | COMPOSITIONS AND METHODS FOR THE TREATMENT OF ALTERED α-SYNUCLEIN FUNCTION |
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- 2011-11-18 CN CN201110369116.9A patent/CN103120697B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010056413A2 (en) * | 2008-11-14 | 2010-05-20 | Parkinson's Institute | COMPOSITIONS AND METHODS FOR THE TREATMENT OF ALTERED α-SYNUCLEIN FUNCTION |
Non-Patent Citations (2)
| Title |
|---|
| Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro;Sigurdis Haraldsdottir等;《 Planta Medica》;20041231;第70卷(第11期);第1098-1110页 * |
| 雪茶化学成分研究;姜北;《云南植物研究》;20021231;第24卷(第4期);第525-530页 * |
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