CN100471847C - Eremophilane containing chlorine atom in Heizituowu and its anti-biotic and cell-toxin activity - Google Patents
Eremophilane containing chlorine atom in Heizituowu and its anti-biotic and cell-toxin activity Download PDFInfo
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Abstract
The invention relates to a furan para-eremophilane and the medicine compound. It has obvious activity restraining to growth of oral epithelium cancer cell. It is respected to be used as antitumor medicine. It also could obviously restrain the growth of staphylococcus aureus and B type hemolytic streptococcus.
Description
Technical field
The present invention relates to medical technical field, particularly, the present invention relates to furo eremophilane and a pharmacologically acceptable salt and a pharmaceutical composition that control streptococcus aureus and beta hemolytic streptococcus catch that has that from black purple Farfugium kaemferi, separates to obtain.Growth shows that inhibition is active to this natural product to oral squamous carcinoma cell, can expect as the antitumor drug purposes.This sesquiterpene also obviously suppresses the growth of golden Portugal bacterium and beta hemolytic streptococcus, can expect to be used to prevent and treat furuncle, warts, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, the trachelitis that this two infection causes, and the abscess of muscle, skin, urodeum, central nervous system.
Technical background
Streptococcus aureus (Staphylococcus aureus) is the Gram-positive coccus, the streptococcus aureus (MRSA) in anti-methyl XiLin is the bacterial strain that begins to occur the eighties in 20th century, it is the epiphytotics main pathogeny of microorganism in the hospital and clinically, the main infection that causes the people has furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, mazoitis, urocystitis, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, pharyngitis, trachelitis, pelvic inflammatory disease, and muscle, skin, urodeum, the abscess of central nervous system.So be that HUMAN HEALTH is influenced great pathogenic species.Suis (Streptococcus species) is into catenation, amphimicrobian Gram-positive bacillus.Medically common pathogenic suis major part belongs to β haemolysis type.They are present on people's the mucous membrane of skin, respiratory tract, digestive tube and urodeum, can cause diseases such as skin, respiratory tract and soft tissue infection such as pneumonia, microbemia, endocarditis, meningitis, urinary tract inflammation and sacroiliitis.
In addition, because the selectivity of at present clinical used cytotoxicity antitumor drug is not high, cause Normocellular pernicious killing and wounding limited the general usability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to discovery, screening and the research of this class natural drug.And according to the whole world especially susceptibility of often swell the knurl spectrum of disease and the tumour cell of China, the index of having selected the strain of oral squamous carcinoma cell (KB) human body tumour cell to estimate as cell in vitro cytotoxic activity pharmacology.
It is the little genus of composite family that Farfugium kaemferi belongs to (Ligularia genus), belongs to about 130 kinds entirely, and most kinds originate in the Asia, and only 2 kinds are distributed in Europe, and other has tingia Farfugium kaemferi [Ligularia dentate (A.Gray) Hara] to have cultivation or ease to give birth in Britain.China has 111 kinds, and most of kind concentrates on the southwest.This root that belongs to some kinds contains chemical ingredientss such as liguloxide, Farfugium kaemferi ether alcohol, ligularol, Airy ligularol, ligularone, ligularenolide, and is used as medicine with the name of aster or mountain aster.Disease [S.W.Liu, Chinese Plants will such as mainly treating bronchitis, asthma, pulmonary tuberculosis, spitting of blood, hepatitis.Science Press, 1989, page 4].The content of sesquiterpene is higher in the Farfugium kaemferi platymiscium.People have got multiple new sesquiterpenoids from this platymiscium, wherein much have various biological activitys, and this further seeks new skeleton sesquiterpene and new active target spot to us, and rich basic substance is provided.
Black purple Farfugium kaemferi [Ligularia atroviolacea (Franch.) Hand.-Mazz.] is a per nnial herb.The root meat, majority.Stem is upright, branch not, and high 25-60 centimetre, by close black purple the long pubescence of joint is arranged, mix and give birth to white arachnoid hair at the nearly inflorescence in top place, and base diameter 3-5 millimeter is deposited the encirclement of petiole fiber by withered.The whole tubuloses of Xiao Hua, majority, yellow, long 6-7 millimeter, about 3 millimeters of pipe minister, pappus is faint yellow, and is closely isometric with corolla.Achene is cylindrical, is about 5 millimeters, and is smooth.The flowering fruit bearing stage 8-12 month.Originate in northwestern Yunnan Province.Be born under the fir forest of height above sea level 3000-4000 rice, alpine meadow [SW Liu, Chinese Plants will.Science Press, 1989,77 pages, 41 pages].Yunnan is among the people to be used for clearing heat and detoxicating and treatment flu, cough are used.The inventor is in extraction and chemical constitution study to composite family Farfugium kaemferi platymiscium and composite family Senecio, once found wherein to contain a large amount of eremophilane lactones, find that as contriver in recent years the eremophilane lactone in the Senecio wightii has tumour cell HL-60, A549 and KB strain all have certain cytotoxicity (Zhao Yu etc., Chinese Chemical Letters, 2002,13 the 4th phases of volume, 333-334 page or leaf).In addition, the inventor has reported that also several eremophilane lactones of chicken foot squaw weed also have certain cytotoxicity (Zhao Yu etc., Chinese Chemical Letters,, 3 the 8th phases of volume, 754-757 page or leaf in 2002 to KB tumor cell line and A549 cell strain; Zhao Yu etc., ChineseChemical Letters,, 16 the 3rd phases of volume, 362-364 page or leaf in 2005).But, still rarely report for the chemical constitution study and the bioactivity research of black purple Farfugium kaemferi.The chemical constitution study of black purple Farfugium kaemferi has only one piece of bibliographical information [R Hanai etc. so far, Chemical and genetic study of Ligularia tongolensis, Ligularia cymbulifera and Ligularia atroviolacea in the Hengduan mountainsof China, Bulletin Chemical Society of Japan, 2005,78,1302-1308], the author uses thin-layer chromatography TLC to detect the compound that main component wherein is positive as the Ehrlich reaction, and these compounds are difficult to separate owing to poor stability, so the author adopts liquid chromatography (LC) to combine with NMR (Nuclear Magnetic Resonance) spectrum coupling technology such as (LC-NMR) with mass spectrometry (LC-MS) and liquid chromatography (LC)
1H-
1Two-dimentional spectroscopic technique means such as H COSY and HSQC identify wherein, and three main components are furans eremophilane sesquiterpene: 3 β-angeloyl groups-furo eremophilane-15; 6 α-lactone, 3 β, 6 β-two angeloyl groups-furo eremophilane-15 acid and 3 β-angeloyl groups-6 β-(3-methylbutyryl base) furo eremophilane-15 acid.And so far, do not see that as yet the scientific research personnel gos deep into this plant and the chemistry and the pharmacology activity research of system, therefore select for use this plant to carry out chemical ingredients and relevant pharmacology activity research, it is a kind of more satisfactory selection, not only can fill up historical blank, can also provide true foundation for further studying later on.
Summary of the invention
The purpose of this invention is to provide a kind of chloride furo eremophilane and pharmacologically acceptable salt and antibiotic and cell toxicant anticancer usage that from the black purple Farfugium kaemferi of composite family, obtains.
Another object of the present invention has provided The compounds of this invention is used to prepare prevention and treats the furuncle that is caused by streptococcus aureus and/or beta hemolytic streptococcus, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, trachelitis, and muscle, skin, urodeum, the medicine of the abscess of central nervous system and medicine or the healthcare products purposes relevant with above-mentioned disease; Formula (1) compound is also inhibited to oral squamous carcinoma cell strain (KB) growth, might develop into new control tumour medicine.
Another object of the present invention has provided the pharmaceutical composition that contains chloride furo eremophilane of the present invention.
The present invention prepares a kind of chloride furo eremophilane by extracting from the black purple Farfugium kaemferi of feverfew, concrete structure is as follows:
This compound name is called: 1 α-chloro-6 β-isobutyryl-9-ketone-10 beta-hydroxies-furo eremophilane.
The medicinal material that formula (1) compound is mainly derived among the present invention can be arbitrary position of black purple Farfugium kaemferi Ligulariaatroviblacea (Franch.) Hand.-Mazz., promptly can be its root, stem, leaf, seed, skin, fruit, also can be their mixture.Preferred its underground part.
Characteristics of the present invention are, from black purple Farfugium kaemferi, separate purification formula (1) compound and have important biological, it has very strong inhibition streptococcus aureus and beta hemolytic streptococcus effect, provide and to have expected to be used to prepare to cause or relevant physiological change or treatment of diseases medicine and prevention and health care product with gram-positive bacteria especially streptococcus aureus and beta hemolytic streptococcus, include but not limited to furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, trachelitis, and muscle, skin, urodeum, the abscess of central nervous system.Formula (1) compound is also inhibited to oral squamous carcinoma cell strain (KB) growth, might develop into new control tumour medicine.
Specific embodiments
The inventor obtains this to this plant milk extract by multiple positive and negative phase chromatography means and effectively suppresses streptococcus aureus and beta hemolytic streptococcus activity and have a Cytotoxic active compound, derives the furo eremophilane sesquiterpene of the novel structure that its chemical structure do not report for forefathers again through integration analysis such as infrared, mass spectrum, ultraviolet and NMR (Nuclear Magnetic Resonance) spectrum.The inventor finds that the furo eremophilane sesquiterpene composition of this novel structure has the function that suppresses streptococcus aureus and beta hemolytic streptococcus growth; Can be used to prevent and treat the furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, the trachelitis that cause by streptococcus aureus and beta hemolytic streptococcus, and the abscess and medicine or the healthcare products purposes relevant with above-mentioned symptom or disease of muscle, skin, urodeum, central nervous system; Thereby may develop the anti-infection drug composition.This pharmaceutical composition can be made various formulations with the routine techniques in the pharmacy field, as tablet, granule, capsule, oral liquid, dripping pill, injection, transdermal patch, aerosol etc.Formula (1) compound has important biological, its cytotoxic activity in vitro tests to oral squamous carcinoma cell strain (KB) of downpayment test is found: this furo eremophilane might develop into new control tumour medicine to human body tumour cell growth inhibited (specifically seeing embodiment).
In order to understand essence of the present invention better, at first use the process of formal specification formula (1) compound of embodiment below, embodiment has provided part physics and the chemistry and the Wave Spectrum data of representative compounds.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: the preparation of formula (1) compound: 1 α-chloro-6 β-isobutyryl-9-ketone-10 beta-hydroxies-furo eremophilane
1.1 instrument and reagent
Fusing point is measured with micro-fusing point instrument (production of Beijing Imtech), and temperature is not proofreaied and correct; Optically-active is produced on the automatic polarimeter of Polax-2L type in Japan and is measured; Infrared spectra IR is by Bruker Vector-22 determination of infrared spectroscopy, through the KBr compressing tablet; UV spectrum is measured with Shimadzu UV-240 ultraviolet spectrophotometer; Proton nmr spectra
1H-NMR, carbon-13 nmr spectra
13C-NMR and 2D NMR measure (tetramethylsilane ether TMS is interior mark) by INOVA type NMR spectrometer with superconducting magnet (VARIANINOVA-400MHz); Electrospray ionization mass spectrum ESI-MS is measured by BrukerEsquire 3000+ mass spectrograph, and column chromatography is produced by Haiyang Chemical Plant, Qingdao with silica GF254 (10-40 order) with silica gel (100-200,200-300 and 300-400 order) and thin-layer chromatography; Agents useful for same is analytical pure, and wherein the sherwood oil boiling range is 60-90 ℃; Thin layer preparative chromatography (PTLC) the aluminium foil silica-gel plate of Merck company; Column chromatography adopts the biochemical plastic molding and processing plant of Taizhou, Zhejiang Province city road and bridge tetramethyl product with polymeric amide (14-30 order and 100-200 order); Dextrane gel Sephadex LH-20 adopts Sweden Amersham Pharmacia Biotech AB company product; Reverse phase silica gel RP-18 adopts the Chromatorex product of Japanese Fuji Silysia Chemical company; MCI is a Mitsubishi chemical company product, and thin plate (TLC) detects the ultraviolet lamp with 254nm and 365nm; Developer iodine vapor, 10% sulfuric acid-ethanol and phosphorus molybdenum acid solution.
1.2 plant origin and evaluation
It is domestic to supply extraction to pick up from the Yunnan Lijing August calendar year 2001 with black purple Farfugium kaemferi medicinal material underground part, is accredited as black purple Farfugium kaemferi (Ligularia atroviolacea (Franch.) Hand.-Mazz.) by professor Peng Hua of Kunming plant institute of the Chinese Academy of Sciences.Herbarium (LSP200108-04) is deposited in pharmaceutical college of Zhejiang University Chinese medicine and natural drug research department.
1.3 extract and separate
Get black purple Farfugium kaemferi Ligularia atroviblacea (Franch.) the Hand.-Mazz. underground part of 5.0 kilograms of exsiccant and be ground into powder, add 50 liter of 95% alcohol immersion.At room temperature soak each 7 days 3 times.Ethanol extract merges, and decompression and solvent recovery disperses with 3 literss of water to the dried 462 gram medicinal extract that obtain, and uses 60-90o sherwood oil, vinyl acetic monomer, n-butanol extraction more successively.Reclaim under reduced pressure ethyl acetate extraction liquid obtains 89.0 gram medicinal extract.This medicinal extract restrains 100-200 order silica gel column chromatographies, chloroform-methanol (50:0-0:1) gradient elution with 800.Thin-layer chromatography detects and merges same stream part, the part medicinal extract that contains formula (1) compound continues with dextrane gel Sephadex LH-20 column chromatography purification (methanol-eluted fractions) through preparation thin layer (60-90o sherwood oil-vinyl acetic monomer 4:1) again, finally obtains 45 milligrams of formulas (1) compound.
1.4 structure is identified
Formula (1) compound is colourless needle crystal, and ESI-MS provides its molecular ion peak [M+H]+for m/z 369, and in the ESI-MS spectrum, [M+H]
+The intensity of quasi-molecular ions is [M+2+H]
+3 times of the intensity of quasi-molecular ions can be inferred in view of the above and contain the chlorine atom in the compound, in conjunction with carbon-13 nmr spectra
13It is C that C-NMR and DEPT spectrum are released its molecular formula
19H
25ClO
5The IR spectrum shows in the molecule to have hydroxyl (3500cm
-1), ester group (1705cm
-1) and α-Fu Nan ketone (1680,1560cm
-1).Maximum absorption peak 285nm also showed the existence of α-Fu Nan ketone during wherein UV spectrum UV composed.Proton nmr spectra
1H-NMR composes the bimodal methyl proton signal that shows two features, and (δ 1.28, and 3H is bimodal, J=7.2Hz, H-3 '; 1.30,3H, bimodal, J=7.2Hz, H-4 ') and a methine protons signal (δ 2.73,1H, two quartets, J=7.2,7.2Hz, H-2 '), in conjunction with carbon-13 nmr spectra
13C-NMR composes an existing stack features signal [δ 176.5 (s), 34.1 (d), 18.6 (q) and 19.5 (q)] and shows in formula (1) compound and have the isobutyryl structure fragment.Remove the isobutyryl structure fragment,
1H-NMR and
13C-NMR shows that also this compound belongs to the structural unit that has α-Fu Nan ketone in eremophilane compounds and the molecule.This compound is removed the hydrogen spectrum of isobutyryl structure fragment and 1 α that carbon spectrum and Cheng Dongliang etc. assign to from the composite family wood groundsel, the wave spectrum feature of the blue type sesquiterpene of the refined sill of 10 beta-dihydroxyies-6 β-angeloyl groups-9-ketone-furans is very with [Cheng Dongliang etc., wood groundsel The Chemical Constituents; SCI; 1992; 13; 781-783]; only difference appears at the slightly δ 3.94 of High-Field in the difference of 6 bit substituents and the proton signal of 1 hydrogen of formula (1) compound, and molecular ion peak speculating type (1) compound that provides in the mass spectrum of combined type (1) compound is the blue type sesquiterpene of the refined sill of furans that 1 chlorine atom replaces again.Formula (1) compound proton nmr spectra
1Do not have 10 hydrogen signals among the H-NMR, know that 10 hydroxyl replaces change.Above-mentioned inference has also been verified in the HMBC experiment.From the HMBC spectrum, can clearly find out H-15 and C-3, C-5; Have long-range relevant between H-1 and C-3, C-9, C-5 and H-6 and the C-1 '.14-CH
3Chemical shift compare [F Bohlmann etc. with similar compound, Newsesquiterpenes and acetylenes from Athanasia and Pentzia species, Phytochemistry, 1978,17,1595-1599] show that 14 methyl and 10 hydroxyls have 1, two Van der Waals effects of 3-at low, therefore can infer that 10 hydroxyls replace the position at β, promptly the A of formula (1) compound, B two rings condense for cis.
1In the H-NMR spectrum, the coupling constant maximum value of H-1 and H-2 is 3Hz, shows H-1 on the e key, knows that by conformational analysis 1 chlorine atom is in the α position again.In the HMBC spectrum, there are correlation effect in H-6 (δ 7.06s) and C-1 ' (δ 176.5), so isobutyryl is connected in 6 simultaneously.In addition, find H-1 and 10-OH in NOESY spectrum, between H-14 and H-1 and H-6 α and the H-4 α NOE effect is arranged, the above-mentioned ring to cis about A, B two of these information supports condenses and the deduction of each substituting group relative configuration.Above-mentioned deduction is finally proved conclusively (shown in the See Figure) by the experiment of X-ray single crystal diffraction.X-ray result has provided the absolute configuration of this compound.According to above inference, the structure of formula (1) compound finally is decided to be 1 α-chloro-6 β-isobutyryl-9-ketone-10 beta-hydroxies-furo eremophilane [1 α-Chloro-6 β-isobutyroxy-9-oxo-10 β-hydroxy-furanoeremophilane].The eremophilane compounds of isolating chloride atom has only two pieces of documents that report [Y Yaoita etc. are arranged so far from natural product, Structures of six neweremophilenolides from the rhizomes of Petasites japonicus Maxim, Chemicaland Pharmaceutical Bulletin, 1994,42,1944-1947; HC Cheng etc.; A novelchlorinated norsesquiterpenoid and two related new metabolites from the softcoral Paralemnalia thyrsoides; Tetrahedron Letters; 2005; 46; 7711-7714]; Cheng Dongliang etc. are once with 1 α; the blue type sesquiterpene of the refined sill of 10 beta epoxides-6 β-angeloyl groups-9-ketone-furans oxidation cracking in dilute hydrochloric acid solution obtains the blue type sesquiterpene of the refined sill of 1 α-chloro-10 beta-hydroxies-6 β-angeloyl groups-9-ketone-furans [Cheng Dongliang, high building up the Army; Niu Jinkui; field Xuan, the absolute configuration of the blue type sesquiterpene of the refined sill of two furans of circular dichroism spectrum research, SCI; 1993; 14,363-365], and studied the absolute configuration of this compound by circular dichroism spectrum.
The steric configuration that the single crystal diffraction result of formula (1) compound provides
1 α-chloro-6 β-isobutyryl-9-ketone-10 beta-hydroxies-furo eremophilane [1 α-Chloro-6 β-isobutyroxy-9-oxo-10 β-hydroxy-furanoeremophilane]: colourless needle; C
19H
25ClO
5Fusing point: 107-108 ℃;
:+0.90 ° of (methyl alcohol; C 0.20); UV spectrum UV maximum absorption wavelength λ
Max(chloroform CHCl
3): 221,285nm; IR
(cm
-1): 3500,1705,1680,1560; Electrospray ionization mass spectrum ESI-MS m/z:369[M+H]
+Proton nmr spectra
1H-NMR (deuterochloroform, 400MHz) δ 1.05 (3H, unimodal, H-14), 1.14 (3H, bimodal, J=7.6Hz, H-15), 1.28 (3H, bimodal, J=7.2Hz, H-3 '), 1.30 (3H, bimodal, J=7.2Hz, H-4 '), 1.44 (1H, bimodal, J=13.6Hz, H-3a), (1.05 1H, multiplet, H-4 α), 1.76 (1H, double doublets, J=14.0,2.0Hz, H-2a), 2.47 (1H, triplet, J=14Hz, H-3b), 2.59 (1H, triplet, J=14.0Hz, H-2b), 2.73 (1H, two quartets, J=7.2,7.2Hz, H-2 '), 3.94 (1H, wide unimodal, H-1 β), 4.01 (1H, wide unimodal, 10-OH), 7.06 (1H, unimodal, H-6 α), 7.50 (1H, unimodal, H-12); Carbon-13 nmr spectra
13C-NMR (CDCl3,100MHz) δ 8.5 (q, C-13), 15.9 (q, C-15), 16.0 (q, C-14), (18.6 q, C-3 '), 19.5 (q, C-4 '), 23.3 (t, C-3), 24.3 (t, C-2), 31.9 (d, C-4), 34.1 (d, C-2 '), 50.1 (s, C-5), 62.0 (d, C-1), 68.2 (d, C-6), 80.5 (s, C-10), 121.8 (s, C-11), 139.6 (s, C-7), 145.9 (s, C-8), 147.4 (d, C-12), 176.5 (s, C-1 '), 186.3 (s, C-9).
Formula (1) compounds represented
1H-
1H COSY, HMBC, NOESY are correlated with, and synoptic diagram (represent by thick lines
1H-
1H COSY)
Embodiment 2: formula (1) compound suppresses the gram-positive bacteria ability and detects
2.1 principle:
Adopt the antibacterial activity in vitro of " cup-plate method " research trial medicine, be to utilize the trial drug that is added in the cup of Oxford to be diffused into inoculation to have in the substratum of test organisms, thereby suppress the growth of bacterium, the antibiotic work that comes the confirmed test medicine by the diameter that detects the inhibition zone that around the cup of Oxford, forms.
2.2 detect bacterium:
Streptococcus aureus 26003-23 is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Beta hemolytic streptococcus 32210 is available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
2.3 trial drug:
The DMSO:DMSO solvent control;
Norfloxicin: 1.25mg/ml;
Formula (1) compound: 5.0mg/ml; Sample dissolves with DMSO.
2.4 method and step:
2.4.1, the preparation of M-H agar, M-H meat soup and test organisms liquid.
2.4.2, the preparation of two dish:
(1), M-H agar bottom: get sterilization M-H agar liquid naturally cooling and solidify.
(2), M-H agar bacterium layer: get bacterium liquid 150 μ l and 30mlM-H agar mixing.Get about 5ml and contain bacterium liquid agar, evenly spread out cloth in plate with M-H agar bottom.
2.4.3, treat culture medium solidifying after, in each plate, evenly put the upright test soup Oxford cup of filling it up with.
2.4.4, put 37 ℃ and cultivated 24 hours.
2.4.5, use the vernier caliper measurement antibacterial circle diameter.
Table 2 formula (1) compound is to the antibacterial circle diameter (mm) of standard pathogenic bacterium
2.5 experiment conclusion:
By adopting the antibacterial activity in vitro of " micro-dilution method " research formula (1) compound to streptococcus aureus and beta hemolytic streptococcus.The result shows: formula (1) compound has better antibacterial activity to streptococcus aureus and beta hemolytic streptococcus.Illustrate that it is that potential suppresses the gram-positive bacteria active substance, has further exploitation and is worth.
Formula of the present invention (1) compound can combine with spoke material or carrier pharmaceutically commonly used, prepares the medicine and pharmaceutical composition or the healthcare products that have prevention and treat the infection that is caused by streptococcus aureus and beta hemolytic streptococcus.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Formula of the present invention (1) compound can also infect the medicine of associated conditions and bulk drug thereof such as cephalosporin, Macrolide and sulfamido such as husky magnitude types of drugs with the similar gram-positive bacteria of the streptococcus aureus that has now gone on the market, beta hemolytic streptococcus inhibitor and/or other treatment and unite use, prepare and have the treatment gram-positive bacteria and infect active composition of associated conditions effect or compound preparation, can expect that becoming the treatment gram-positive bacteria infects disease medicine or healthcare products.Above-mentioned various kinds of drug composition or healthcare products can adopt drug forms such as tablet, capsule, injection, aerosol, suppository, film, pill, comprise the conventional preparation of pharmaceutics general knowledge that employing has now been generally acknowledged and various slowly-releasings, controlled release form or the nanometer formulation that gets.
Embodiment 3: formula (1) compound is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, the dimethyl sulfoxide solution of the formula that will newly join (1) compound joins in each hole with concentration gradient respectively, make hole Chinese style (1) compound ultimate density be respectively 100 μ g/mL, 33.3 μ g/mL, 11.1 μ g/mL and 3.7 μ g/mL.After 72 hours, the phosphate buffered saline buffer that adds 10 μ L MTT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole, with brilliant this Jia Za (formazan) of the MTT of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Its Chinese style (1) compound is to KB cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of formula (1) compound
50For: 7.55 * 10
-5M; The positive control cis-platinum is to the IC of KB cell
50Be 5.07 * 10
-6M.
Experiment conclusion: the KB cell is cytotoxicity effective tool and the evaluation index of test compounds to tumour cell.This experiment shows that this chloride atom furo eremophilane compound K B cell has stronger cytotoxicity, might develop into the new medicine with antitumor action.
Claims (9)
1. the not fragrant sesquiterpene of furo Airy or its pharmacologically acceptable salt that have following structure:
This compound name is called: 1 α-chloro-6 β-isobutyryl-9-ketone-10 beta-hydroxies-furo eremophilane.
2 are used to prepare the purposes of the medicine of related symptoms that prevention or treatment streptococcus aureus and/or beta hemolytic streptococcus infect or disease according to the not fragrant sesquiterpene of the described furo Airy of claim 1 or its pharmacologically acceptable salt.
3 purposes according to claim 2, wherein the related symptoms of infection of staphylococcus aureus or disease are meant furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, mazoitis, urocystitis, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, pharyngitis, trachelitis, pelvic inflammatory disease, and muscle, skin, urodeum, central nervous system abscess; Related inflammation was meant skin, respiratory tract and soft tissue infection such as pneumonia, microbemia, endocarditis, meningitis, urinary tract inflammation and arthritis disease due to beta hemolytic streptococcus infected.
4 one kinds are used to prevent or treat streptococcus aureus and/or the related symptoms of beta hemolysis domestic animal streptococcal infection or the pharmaceutical composition of disease, it contains the described not fragrant sesquiterpene of furo Airy or its pharmacologically acceptable salt of claim 1 for the treatment of significant quantity as the smelting of activeconstituents, or the mixture of the not fragrant sesquiterpene of this furo Airy and its one or more pharmaceutical salts compositions, and pharmaceutically acceptable carrier.
5 pharmaceutical compositions according to claim 4, its effect be prevention and treatment streptococcus aureus/or beta hemolytic streptococcus infect furuncle, warts, toxicity epidermis decomposition, pneumonia, osteomyelitis, acute myocarditis, endocarditis, meningitis, mazoitis, urocystitis, pelvic inflammatory disease, urinary tract inflammation, prostatitis, microbemia, toxic shock syndrome, poradenolymphitis, sacroiliitis, pharyngitis, the trachelitis cause, and the abscess of muscle, skin, urodeum, central nervous system.
6 are used to prepare the purposes of antitumor cell cytotoxic drug according to the not fragrant sesquiterpene of the described furo Airy of claim 1 or its acceptable salts.
7 one kinds of pharmaceutical compositions that are used to prevent or treat tumor disease, it contains as the not fragrant sesquiterpene of the described furo Airy of the claim 1 of the treatment significant quantity of activeconstituents or its pharmacologically acceptable salt, or the mixture of the not fragrant hemiterpene of this furo Airy and its one or more pharmacologically acceptable salts compositions, and pharmaceutically acceptable carrier.
8 pharmaceutical compositions according to claim 7, it is the prevention of cell toxicant class and treats various tumor disease medicines.
9 pharmaceutical compositions according to claim 5 and/or 8, its dosage form are tablet, granule, capsule, oral liquid, lotion, suppository, liniment, injection, transdermal patch, aerosol or controlled release or slow release formulation or nanometer formulation.
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| CN100471847C true CN100471847C (en) | 2009-03-25 |
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| CN101759675B (en) * | 2008-12-25 | 2011-08-31 | 中国科学院兰州化学物理研究所 | Method for preparing active sesquiterpenes with functions of cancer resistance and bacterium inhibition from ligularia fischeri |
| CN104606184B (en) * | 2015-01-23 | 2017-06-27 | 西安交通大学 | The inflammatory applications and its extracting method of the not fragrant lactone of 7 (11) alkene 12,8 of 6 hydroxyl Airies in Radix Ligulariae Dentatae |
| CN105001188B (en) * | 2015-07-13 | 2017-03-01 | 电子科技大学 | A kind of eremophilane type sesquiterpene dimers and its preparation method and application |
| CN110013473B (en) * | 2018-01-10 | 2022-03-29 | 石河子大学 | Application of bisabolane sesquiterpene compound in preparation of anticomplement medicines |
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Non-Patent Citations (2)
| Title |
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| 芫花根的酚类成分及其免疫调节活性. 石枫等.徐州师范大学学报（自然科学版），第22卷第4期. 2004 |
| 芫花根的酚类成分及其免疫调节活性. 石枫等.徐州师范大学学报（自然科学版），第22卷第4期. 2004 * |
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