CN105753936A - Rakicidins compounds Rakicidin B1 and preparation method thereof - Google Patents
Rakicidins compounds Rakicidin B1 and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of medicine, in particular to Rakicidins compounds Rakicidin B1. Pharmacodynamic tests prove that the Rakicidin B1 can be applied to treatment of diseases such as diarrhea, digestive tract inflammation, oral inflammation, skin acne and the like caused by solid tumors such as stomach cancer, liver cancer, breast cancer, pancreatic cancer, intestinal cancer in a tumor hypoxia condition as well as anaerobic bacteria.
Description
Technical field
The present invention relates to field of medicaments, being specifically related to a kind of Rakicidins compounds RakicidinB1, pharmacodynamics test proves that the RakicidinB1 of the present invention has the purposes that treatment exists the disease such as the solid tumor such as microbial diarrhoea of gastric cancer, hepatocarcinoma, breast carcinoma, cancer of pancreas, intestinal cancer and anaerobism, alimentary canal inflammation, oral inflammation and skin acne of tumor hypoxia state.
Background technology
Grow at top speed in recent years in antitumor drug market, anticarcinogen market global marketing volume 100,000,000,000 dollars in 2014；By 2018, anticarcinogen market was up to 147,000,000,000 dollars, compound growth rate 11.6%, and research and development anticarcinogen will be made a profit huge.Anoxia is one of feature of malignant entity tumor, and anoxia is closely related with the angiogenesis of tumor, Invasion and Metastasis, chemicotherapy opposing and prognosis mala etc..Hypoxic inducing factor-1 (hypoxia-induciblefactor1, HIF-1) is the transcriptional regulatory factor the most key in the regulation and control of anoxia effect.HIF-1 selectivity in solid tumor tissue continues high expressed, and the generation development of downstream key controlling gene and tumor is closely related, as promoted angiogenesis, cell survival, suppression apoptosis of tumor cells, metabolism to reinvent and the adjustment of pH stable state.Just because of the difference of oxygen content in the environment residing for cancer cell under different space-times, the signal path of the promotion tumor growth thus activated is typically not to be induced in the normal tissue, so weary oxygen signal path becomes potential therapy target.Also the emphasis of tumor hypoxia effect regulating medicine research and development is become with the HIF-1 specific small molecule inhibitor being target spot.
RakicidinA and B is because containing 1 rare rare 4-amino-2 in its 15 yuan of cyclic lipopeptide structures, 4-pentadienoic acid monooctyl ester also has Anti-tumor angiogenesis and the [McBrienKD that receives publicity, BerryRL, LoweSEetal.Rakicidins, NewCytotoxicLipopeptidesfromMicromonosporasp.Fermentatio n, IsolationandCharacterization [J] .JAntibiot, 1995,48:1446].Yamazaki (2007) research finds that RakicidinA has the weary oxygen selective Anti-tumor angiogenesis of brilliance, under weary oxygen condition, inhibitor against colon carcinoma cells HCT-8 cytoactive is 17.5 times of [YamazakiY under normal oxygen condition, KunimotoS, IkedaD.RakicidinA:ahypoxia-selectivecytotoxin [J] .BiolPharmBull.2007,30 (2): 261-5.].Apoptosis [the TakeuchiM of marrow chronic leukemia stem cell can be induced under the weary oxygen condition of Takeuchi (2011) reported first RakicidinA, AshiharaE, YamazakiY, etal.RakicidinAeffectivelyinducesapoptosisinhypoxiaadapt edBcr-Ablpositiveleukemiccells [J] .CancerSci.2011,102 (3): 591-6.].The anti-hypoxic tumor cells of this compound and resisting tumour stem cells (CSC) though mechanism of action unclear, but RakicidinA has been thought an anti-hypoxic tumor cells being rich in DEVELOPMENT PROSPECT and anti-CSC medicine by many colleagues.
First inventor seminar reported at home in 2006 and is separated to RakicidinA and B from microbial metabolic products, and the relevant biologic activity of RakicidinB (FW523-3) has been carried out preliminary study (document 1；Jiang Hong, Lin Ru, Cheng Yuanrong. the anti tumor activity in vitro of the brisk rhzomorph BFW523-3 in sea micromonoad source. China's antibiotic magazine, 2008,33 (9): 531；Document 2；XieJJ, ZhouF, LiEM, JiangH, DuZP, LinR, FangDS, XuLY.FW523-3, anovellipopeptidecompound, inducesapoptosisincancercells.MolMedRep.2011,4 (4): 759-63).
Both at home and abroad about the rarely seen above-mentioned antitumor cell of report of the activity of RakicidinA, B and resisting tumour stem cells activity, other biological activity has no report.We find that Rakicidins compounds has anti-clinic and causes a disease anaerobe clostridium difficile etc., anti-vancomycin-resistant enterococcus isoreactivity first, are worth research and development further.
The C. difficile infection of anaerobism is the primary cause of disease of antibiotic-associated diarrhea in hospital, it is the recommendation medicine being currently used for C. difficile infection treatment that metronidazole, vancomycin, phenanthrene reach mycin, but the relapse rate that C. difficile infection is after metronidazole or vancomycin treatment is all significantly high, in the urgent need to new medicine.Phenanthrene reaches the novel macrolide antibiotic that mycin is a kind of Orally-administrable, within 2012, gets permission for treating C. difficile infection at US and European.Vancomycin-resistant enterococcus and Pseudomonas aeruginosa and Acinetobacter bauamnnii have become operation and wound infection, pneumonia, endocarditis, meningitis, blood source are infected and the Main Pathogenic Bacteria of amputation, and the health and lives of the mankind in serious threat.Enterococcus (enterococcus faecalis and enterococcus faecalis) is widely distributed in nature, normal perch people, the intestinal of animal and female genitourinary system, is one of the normal flora of the mankind.In recent years, due to the extensive use of antibacterials, make script just beta-lactam class, Aminoglycosides be had inherent drug-fast Enterococci resistance and be expanded further, gradually formed multi-drug resistant bacteria.In China, the incidence rate that vancomycin-resistant enterococcus (VRE) infects is in ascendant trend, one of VRE important pathogen becoming hospital infection year by year.In aerobic gram positive coccus, enterococcus is to be only second to staphylococcic important Nosocomial Infection Pathogens, can cause urinary tract infection, abdominal cavity infection, pelvic inflammatory disease and endocarditis, may result in sepsis time serious, and case fatality rate reaches 21.0%～27.5%.Therefore the clinical medicine developing anti-VRE has certain prospect.
Summary of the invention
The invention discloses a Rakicidins compounds, called after RakicidinB1, structural formula is as follows:
The compound R akicidinB1 of the present invention is obtained by fermentable, and it has the pathogenic anaerobe of anti-hypoxic tumor cells clinic active, anti-and anti-vancomycin-resistant enterococcus activity.
The invention discloses a micromonospora bacterial strain, be called for short: its preserving number at China Committee for Culture Collection of Microorganisms's common micro-organisms center of FIM02-523, Classification And Nomenclature: Micromonosporasp.FIM02-523. is: CGMCCNo.12132.Preservation address: Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3.Preservation day: on February 18th, 2016.Obtain from the marine clay of Putian, Fujian Province.
Micromonospora strain FIM02-523 can prepare RakicidinB1 by fermentable.Preparation method is as follows:
The micromonospora bacterial strain FIM02-523 that deposit number is CGMCCNo.12132 is fermented, fermentation liquid is centrifuged, obtain mycelia slag, mycelia slag soak with ethanol obtains soak with ethanol liquid, soak with ethanol liquid carries out HP20 macroporous resin adsorption column chromatography, 60%-80% ethanol water gradient elution, obtain eluent 1, eluent 1 carries out NM200 resin absorption column chromatography, 55%-80% ethanol water gradient elution obtains eluent 2, after eluent dilute with water, it is extracted with ethyl acetate, concentration obtains crude product methanol and dissolves, carry out the anti-phase C18 column chromatography of middle pressure, 60-90% acetonitrile water gradient elution, fraction collection, liquid is collected with HPLC detection, obtain.
Pharmacodynamic experiment proves, the compound R akicidinB1 of the present invention has anti-hypoxic tumor disease, anaerobe resistant relevant disease, anti-vancomycin-resistant enterococcus isoreactivity.
Its pharmaceutically acceptable salt of the compound of the present invention has same pharmacological effect with compound.
Present invention also offers a kind of pharmaceutical composition, wherein contain the compounds of this invention and pharmaceutically acceptable carrier.Described pharmaceutical composition can be dosage form conventional on the galenic pharmacy such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when the compounds of this invention is used for treating, people's dosage range is 1mg～5000mg/ days.Also dependent on difference and the disease severity of dosage form, using dosage exceeds this scope.
Biological activity test and the result of the compounds of this invention RakicidinB1 are presented herein below:
One, anti-tumor activity test
Respectively RakicidinB1 sample is dissolved in DMSO and makes solubility reach 1mg/ml, then dilution makes final concentration of 0.75ug/ml, 0.5ug/ml, 0.25ug/ml, 0.125ug/ml, 0.1ug/ml, 0.05ug/ml, 0.005ug/ml, 0.0025ug/ml respectively.
Nostoc commune Vanch: take and be in the people colon-cancer cell HCT-8 of Exponential growth stage, esophageal cancer cell ECA109 plants in 96 orifice plates that (cell concentration is 10 respectively5Individual/ml, 100ul/ hole), to cultivate 24hr and make it adherent, add 100ul/ pore area medicine fresh culture, each concentration sets 3 multiple holes, and sets blank control wells (only adding culture medium) as negative control, sets 3 multiple holes equally.Continue to be cultured to 72hr, terminate cultivating.
Weary oxygen is cultivated: (cell concentration is 10 in 96 orifice plates to take people's colon-cancer cell HCT-8 kind of being in Exponential growth stage5Individual/ml, 100ul/ hole), weary oxygen is ventilated 30 minutes, close gas valve, put into incubator 37 DEG C, cultivate 24hr and make it adherent, add 100ul/ pore area medicine fresh culture, each concentration sets 3 multiple holes, and sets blank control wells (only adding culture medium) as negative control, sets 3 multiple holes equally.Weary oxygen is ventilated 30 minutes, closes gas valve, puts into incubator 37 DEG C, continues to be cultured to 72hr, terminates cultivating.
SRB detects: terminating cultured cells, every hole adds 10%TCA50ul, 4 DEG C of fixing 1hr of condition.With distilled water flushing 5 times, after naturally drying, every hole adds 4mg/mlSRB solution 50ul, and dye under room temperature 30min, abandons supernatant, with 1% acetic acid flushing 5 times to remove the dyestuff of non-specific binding.Every hole adds 150ul10mMTris solution, shakes 5 minutes, and under 540 wavelength, microplate reader surveys OD value, and calculates suppression ratio.By the conversion to suppression ratio, SPSS computed in software is used to go out IC50 value.Result is in Table 1.
The hypoxic tumor cells toxicity of table 1RakicidinB1
The above results show the compounds of this invention RakicidinB1 have potent antitumor activity particularly anti-hypoxic tumor cells activity, and to weary oxygen cultured tumor cells HCT-8 activity more normal oxygen strong 15 times.
Two, the anti-anaerobe active testing that causes a disease
Compound R akicidinB1 is dissolved into 0.64mg/ml in DMSO.Its test concentrations is: 128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml.Test remaining solution and will be positioned over-20 DEG C.Antibiotic feldamycin and metronidazole are as reference compound.The preparation of 2 × solution: maximum concentration is 256 μ g/ml, and then dilutes through the twice of 10 times in 96 deep-well plates, obtains 2 required × solution.With work station subpackage 100 μ l to 96 hole circle base plate.12nd row are negative controls, the only culture medium containing same volume.
The preparation of bacterial inoculum: 1 day (aerobic bacteria) or 2-3 days (anaerobe) [culture medium: aerobic bacteria on corresponding growth flat board in advance, CAMHB (cationadjustedMueller-Hintonmedium, pungent culture medium of the Miller of ion-select electrode；Anaerobe, Brucellabrothsupplementedwithhemin (5g/mL), VitaminK1 (1g/mL), andlysedhorseblood (5%v/v)] inoculation.Bacterial concentration is transferred to about 1-2 × 10 by experimental day6CFU/ml, then shifts (96 orifice plates added with compound prepared in [0056]) in 100 μ l to 96-hole circle base plates.
MIC measures: for aerobic bacteria, 96-hole circle base plate derived above is positioned over 37 DEG C, 85% humidity, cultivates 20 hours under atmospheric condition；For anaerobe, 96-hole circle base plate derived above is positioned over 37 DEG C, under 85% damp condition, cultivates 46-48 hour under anaerobic condition.The concentration point that bacterial growth is completely or significantly suppressed will be defined as the MIC of this compound.Result is in Table 2
Table 2.RakicidinB1 antibacterial activity
* Quality Control bacterium
Anti-bacteria test result shows that RakicidinB1 has the clinical anaerobe activity of causing a disease such as anti-clostridium difficile, clostridium difficile fastbacteria, peptostreptococcus, propionibacterium acnes, and it is suitable that activity and phenanthrene reach mycin；RakicidinB1 also has the activity of anti-vancomycin-resistant enterococcus, and activity is better than phenanthrene and reaches mycin, is its 8 times.
Detailed description of the invention
Embodiment 1
The preparation of RakicidinB1
Step one: the fermentation culture conditions reference literature (Jiang Hong of micromonospora bacterial strain FIM02-523, Lin Ru, Zheng Wei, Deng. the separation discriminating of the lipopeptide compound FW523 that ocean Micromonospora chalcea FIM02-523 produces and biologic activity [J]. China's antibiotic magazine, 2006,31 (5): 267-270).
Step 2: by the FIM02-523 fermentation liquid of step one gained by after the centrifugal 15min of 4500rpm, obtain mycelia slag, the mycelia slag obtained overnight is soaked 2 times with absolute methanol or the ethanol of 2 times of volumes, containing spirituous mycelia slag again to be merged by supernatant after the centrifugal 15min of 4500rpm, fermented extracted liquid will be obtained.
Step 3: HP20 macroporous resin adsorption column chromatography (blade diameter length ratio is 1:5～1:10, fills column volume 1.5-2.5L): the fermented extracted liquid (40-60L) of employing is with the alcohol concentration of 50%-55%, and flow velocity is that 40ml/min carries out upper prop absorption；After absorption completely, carry out gradient elution with the ethanol of concentration 60%-80%, detect eluent 1 with HPLC, merge the same composition (30L) containing RakicidinB1.
Step 4: step 3 eluent carries out NM200 resin absorption column chromatography (blade diameter length ratio is 1:2～1:10, fill column volume 1-2L): by the step 3 eluent alcohol concentration with 50%-55%, flow velocity is 40ml/min, carries out upper prop absorption；After absorption completely, carry out gradient elution with the ethanol of concentration 55%-80%, detect eluent 2 with HPLC, merge the same composition (25L) containing RakicidinB1.
Step 5: step 4 eluent 2, after monoploid hydrops dilutes, with equal-volume extraction into ethyl acetate 2 times, concentrating under reduced pressure, obtains crude product.
Step 6: crude product step 5 obtained, dissolves with methanol, carries out the anti-phase C18 column chromatography of middle pressure (blade diameter length ratio 1:3～1:10), flow velocity 30ml/min, with concentration for 60%-90% acetonitrile-water gradient, fraction collection, collect liquid with HPLC detection, merge same composition.
Described micromonospora FIM02-523 hid and China Committee for Culture Collection of Microorganisms's common micro-organisms center in January, 2016, and deposit number is CGMCCNo.12132.
Compound R akicidinB1: white amorphous powder.It is dissolved in chloroform, methanol, DMSO, water insoluble.High resolution mass spectrum (HR-ESI-MS) shows its molecular ion peak [M+H]+be 621.1175, infers that its molecular formula is C33H56N4O7, degree of unsaturation is 8.13CNMR and DEPT135 shows that this molecule contains 33 carbon signals, including 5 quaternary carbon (δC172.6,172.4,169.2,167.6,165.9), 4 double key carbons [comprise a sp2Mesomethylene carbon, two sp2Methine carbon (δC138.4,118.8)], 6 sp3Methine carbon [comprises two even oxygen carbon atom (δC78.0,72.4)], 13 sp3Mesomethylene carbon and 5 methine carbon atom (δC36.5,19.1,15.4,13.2,11.2)。1HNMR shows that this compound has 4 double bond proton [δH6.87 (1H, d, J=15.0Hz), 6.16 (1H, d, J=15.0Hz), 5.44 (1H, s), 5.32 (1H, s)], 5 exchangeable protons [δH8.88 (1H, s), 8.05 (1H, d, J=9.9Hz), 7.31 (1H, s), 7.28 (1H, s), 5.66 (1H, d, J=6.0Hz)], 5 methyl proton [δH2.95 (3H, s), 1.05 (3H, d, J=7.0Hz), 0.93 (3H, d, J=6.9Hz), 0.83 (3H, t, J=7.0Hz), 0.81 (3H, d, J=6.7Hz)].All of Hydrogen Proton passes through hsqc spectrum1H–13C is relevant to be pointed out.1H–1The coupling constant of HCOSY Correlated Spectroscopy and proton shows that this compound contains 4 independent spin coupling systems: NH-2 C-2 C-3 OH-3, C-9 C-10, C-31 C-14 C-15 C-16 (C-32) C-17 C-18 and C-26 C-27 C-28 (C-33) C-29 C-30.In conjunction with1H–1HCOSY and HMBC is it can be seen that H-2 and C-1/C-5 is correlated with, and H-3 and C-4 is correlated with, and OH-3 and C-2/C-3 is correlated with, and Ha-6 and C-5/C-7 is correlated with, H3-7 is relevant to C-6/C-8, and H-9 and C-8/C-11 is correlated with, and H-10 and C-8/C-11 is correlated with, and Hb-12 and C-10/C-11 is correlated with, and H-15 and C-1 is correlated with, H3-30 is relevant to C-28/C-29, H3-31 is relevant to C-13/C-14/C-15, H3-32 is relevant to C-15/C-16/C-17, and H3-33 is relevant to C-27/C-28/C-29, and the chemical shift of hydrogen and carbon is listed in the table below:
Claims (10)
1. the compound of structural formula (I) or its pharmaceutically acceptable salt:
2. the preparation method of the compound of claim 1, including: the micromonospora bacterial strain FIM02-523 that deposit number is CGMCCNo.12132 is fermented, fermentation liquid is centrifuged, obtain mycelia slag, mycelia slag soak with ethanol obtains soak with ethanol liquid, soak with ethanol liquid carries out HP20 macroporous resin adsorption column chromatography, 60%-80% ethanol water gradient elution, obtain eluent 1, eluent 1 carries out NM200 resin absorption column chromatography, 55%-80% ethanol water gradient elution obtains eluent 2, after eluent dilute with water, it is extracted with ethyl acetate, concentration obtains crude product methanol and dissolves, carry out the anti-phase C18 column chromatography of middle pressure, 60-90% acetonitrile water gradient elution, fraction collection, liquid is collected with HPLC detection, obtain.
3. a pharmaceutical composition, wherein contains the compound of claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
4. the compound of claim 1 or its pharmaceutically acceptable salt are for preparing the purposes of the medicine for the treatment of hypoxic tumor disease.
5. the purposes of claim 4, wherein hypoxic tumor disease is gastric cancer, hepatocarcinoma, breast carcinoma, cancer of pancreas or intestinal cancer.
6. the compound of claim 1 or its pharmaceutically acceptable salt are for preparing the purposes of the medicine for the treatment of anaerobe relevant disease.
7. the purposes of claim 6, wherein anaerobe relevant disease is the diarrhoea, enteritis, alimentary canal inflammation, oral disease or the skin acne that are caused by clostridium difficile, clostridium difficile fastbacteria, peptostreptococcus or propionibacterium acnes.
8. the compound of claim 1 or its pharmaceutically acceptable salt are for preparing the purposes of the medicine of anti-vancomycin-resistant enterococcus.
9. a micromonospora bacterial strain, its preserving number at China Committee for Culture Collection of Microorganisms's common micro-organisms center is: CGMCCNo.12132.
10. the micromonospora bacterial strain of claim 9 is for preparing the purposes of the compound of claim 1.
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| PCT/CN2016/104337 WO2017166812A1 (en) | 2016-03-28 | 2016-11-02 | Rakicidin compounds and applications thereof in treating diseases caused by pathogenic anaerobes |
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| WO2017166812A1 (en) * | 2016-03-28 | 2017-10-05 | 福建省微生物研究所 | Rakicidin compounds and applications thereof in treating diseases caused by pathogenic anaerobes |
| CN108300672A (en) * | 2017-11-24 | 2018-07-20 | 福建省微生物研究所 | A kind of the sea micromonoad strain and its application of fermentation production Rakicidin B1 |
| CN108329280A (en) * | 2018-03-27 | 2018-07-27 | 福建省微生物研究所 | A kind of natural Rakicidins classes compound R akicidin I and its extracting method |
| CN108586380A (en) * | 2018-03-27 | 2018-09-28 | 福建省微生物研究所 | A kind of natural Rakicidins classes compound R akicidin H and its extracting method |
| CN108969519A (en) * | 2017-06-02 | 2018-12-11 | 天津尚德药缘科技股份有限公司 | Purposes of the big cyclic lipopeptide compound in the preparation of target on cancer stem cell drugs |
| CN110437314A (en) * | 2019-08-12 | 2019-11-12 | 福建省微生物研究所 | A kind of natural Rakicidins class compound R akicidin B1-1 and its fermentation extraction method |
| CN110698537A (en) * | 2019-08-12 | 2020-01-17 | 福建省微生物研究所 | Natural Rakicidins compound Rakicidin B1-2 and fermentation extraction method thereof |
| CN116023648A (en) * | 2022-12-26 | 2023-04-28 | 福建省微生物研究所 | Polyethylene glycol-RakicidinB 1 derivative and preparation method and application thereof |
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