CN105753936B - A kind of Rakicidins class compound R akicidin B1 and preparation method thereof - Google Patents
A kind of Rakicidins class compound R akicidin B1 and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to field of medicaments, more particularly to a kind of Rakicidins class compound R akicidin B1, pharmacodynamics test proves Rakicidin B1 of the invention, and with treatment, there are the purposes of the diseases such as the solid tumor of tumor hypoxia state diarrhea as caused by gastric cancer, liver cancer, breast cancer, cancer of pancreas, intestinal cancer and anaerobic bacteria, alimentary canal inflammation, oral inflammation and skin acne.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of Rakicidins class compound R akicidin B1, pharmacodynamics
Test proves Rakicidin B1 of the invention, and with treatment, there are the solid tumor of tumor hypoxia state such as gastric cancer, liver cancer, mammary gland
The purposes of the diseases such as diarrhea caused by cancer, cancer of pancreas, intestinal cancer and anaerobic bacteria, alimentary canal inflammation, oral inflammation and skin acne.
Background technique
Anti-tumor drug market is grown at top speed in recent years, 100,000,000,000 dollars of anticarcinogen market global marketing volume in 2014；It arrives
2018, anticarcinogen market was up to 147,000,000,000 dollars, and compound growth rate 11.6%, research and development anticarcinogen will make a profit huge.Anoxic
It is one of the feature of malignant entity tumor, anoxic and angiogenesis, invasion transfer, chemicotherapy resistance and the prognosis mala of tumour etc.
It is closely related.Hypoxic inducing factor-1 (hypoxia-inducible factor 1, HIF-1) be anoxic effect regulation in the most
The crucial transcriptional regulatory factor.HIF-1 selectively continues high expression in solid tumor tissue, downstream key controlling gene with
The occurrence and development of tumour are closely related, such as promote angiogenesis, cell survival, inhibit apoptosis of tumor cells, metabolism remodeling and
The adjusting of pH stable state.Just because of the difference of oxygen content in environment locating for cancer cell under different space-times, the rush thus activated
Signal path into tumour growth will not usually be induced in the normal tissue, so weary oxygen signal access becomes potential treatment
Target spot.Also become the emphasis of tumor hypoxia effect regulating medicine research and development using HIF-1 as the specific small molecule inhibitor of target spot.
Rakicidin A and B is because contain 1 rare rare 4- amino -2,4- pentadiene in its 15 yuan of cyclic lipopeptide structures
Misery ester simultaneously has Anti-tumor angiogenesis and [McBrien K D, Berry R L, Lowe S the E et that attracts attention
al.Rakicidins,New Cytotoxic Lipopeptides from Micromonospora sp.Fermentation,
Isolation and Characterization[J].J Antibiot,1995,48:1446].Yamazaki (2007) research
It was found that Rakicidin A has brilliant weary oxygen selective Anti-tumor angiogenesis, inhibitor against colon carcinoma cells HCT-8 is thin under hypoxic condition
Cytoactive is 17.5 times of [Yamazaki Y, Kunimoto S, Ikeda D.Rakicidin A:a under normoxic condition
hypoxia-selective cytotoxin[J].Biol Pharm Bull.2007,30(2):261-5.]。Takeuchi
(2011) apoptosis [Takeuchi that can induce marrow chronic leukemia stem cell under Rakicidin A hypoxic condition is reported for the first time
M,Ashihara E,Yamazaki Y,et al.Rakicidin A effectively induces apoptosis in
hypoxia adapted Bcr-Abl positive leukemic cells[J].Cancer Sci.2011,102(3):
591-6.].The anti-hypoxic tumor cells of the compound and resisting tumour stem cells (CSC) though mechanism of action it is unclear,
Rakicidin A is considered the anti-hypoxic tumor cells and anti-CSC drug for being rich in development prospect by many colleagues.
In 2006, report was separated to Rakicidin A from microbial metabolic products first at home for inventor seminar
And B, and Primary Study (document 1 has been carried out to the related biological activity of Rakicidin B (FW523-3)；Jiang Hong, Lin Ru, journey
The anti tumor activity in vitro China antibiotic magazine of the brisk rhzomorph B FW523-3 in first honor sea micromonoad source,
2008,33(9):531；Document 2；Xie JJ,Zhou F,Li EM,Jiang H,Du ZP,Lin R,Fang DS,Xu
LY.FW523-3,a novel lipopeptide compound,induces apoptosis in cancer cells.Mol
Med Rep.2011,4 (4): 759-63).
Domestic and international active report rarely seen above-mentioned antitumor cell and resisting tumour stem cells in relation to RakicidinA, B
Activity, other biological activity have not been reported.We have found that Rakicidins class compound has anti-clinical pathogenic anaerobism for the first time
Bacterium clostridium difficile etc., anti-vancomycin-resistant enterococcus isoreactivity are worth further research and development.
The clostridium difficile infection of anaerobism is the primary cause of disease of antibiotic-associated diarrhea in hospital, metronidazole, vancomycin,
Phenanthrene is up to the recommendation drug that mycin is currently used for clostridium difficile infection treatment, but clostridium difficile infection is in metronidazole or vancomycin
Recurrence rate after treating is very high, and there is an urgent need to new therapeutic agents.Phenanthrene reaches the Novel macrocyclic that mycin is a kind of Orally-administrable
Lactone antibiotic is approved in US and European for treating clostridium difficile infection for 2012.Vancomycin-resistant enterococcus and
Pseudomonas aeruginosa and Acinetobacter bauamnnii have become operation and wound infection, pneumonia, endocarditis, meningitis, the infection of blood source
With the main pathogenic bacteria of amputation, the health and lives of the mankind are seriously threatened.Enterococcus (enterococcus faecium and enterococcus faecalis) is extensive
Be distributed in nature, normal perch people, animal enteron aisle and female genitourinary system, be one of normal flora of the mankind.In recent years
Come, due to the extensive use of antibacterials, makes that just there is inherent anti-medicine to beta-lactam class, Aminoglycosides originally
The Enterococci resistance further expansion of property, has gradually formed multi-drug resistant bacteria.In China, vancomycin-resistant enterococcus (VRE)
For the incidence of infection in trend is risen year by year, VRE has become one of important pathogen of nosocomial infection.In aerobic Grain-positive ball
In bacterium, enterococcus is to be only second to staphylococcic important Nosocomial Infection Pathogens, can cause urethral infection, abdominal cavity infection, basin
Chamber is scorching and endocarditis, can lead to pyemia when serious, and case fatality rate is up to 21.0%~27.5%.Therefore the clinic of anti-VRE is developed
Drug has certain prospect.
Summary of the invention
The invention discloses a Rakicidins class compounds, are named as Rakicidin B1, structural formula is as follows:
The compound of the present invention RakicidinB1 is obtained by microbial fermentation, active with anti-hypoxic tumor cells,
Anti- clinical pathogenic anaerobic bacteria and anti-vancomycin-resistant enterococcus activity.
The invention discloses a micromonospora bacterial strains, referred to as: FIM02-523, classification naming: Micromonospora
Sp.FIM02-523. its deposit number in China Committee for Culture Collection of Microorganisms's common micro-organisms center are as follows: CGMCC
No.12132.Preservation address: Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3.Preservation day: on 2 18th, 2016.From Fujian Province
It is obtained in the marine clay of Putian.
RakicidinB1 can be prepared by microbial fermentation in micromonospora strain FIM02-523.Preparation method is such as
Under:
The micromonospora bacterial strain FIM02-523 that deposit number is CGMCC No.12132 is fermented, fermentation liquid centrifugation,
Mycelia slag is obtained, mycelia slag is impregnated to obtain ethyl alcohol soak with ethyl alcohol, and ethyl alcohol soak carries out HP20 macroporous resin adsorption column layer
Analysis, 60%-80% ethanol water gradient elution obtain eluent 1, and eluent 1 carries out NM200 resin absorbing column chromatography, 55%-
80% ethanol water gradient elution obtains eluent 2, after eluent is diluted with water, is extracted with ethyl acetate, and concentration obtains crude product and uses
Methanol dissolves, and pressure reverse phase C18 column chromatography, 60-90% acetonitrile water gradient elution, fraction collection are detected with HPLC and collected in progress
Liquid to get.
Pharmacodynamic experiment proves that the compound of the present invention RakicidinB1 has anti-hypoxic tumor disease, anaerobe resistant phase
Related disorders, anti-vancomycin-resistant enterococcus isoreactivity.
Its pharmaceutically acceptable salt of the compound of the present invention and compound have same pharmacological effect.
The present invention also provides a kind of pharmaceutical compositions, wherein containing the compounds of this invention and pharmaceutically acceptable load
Body.Described pharmaceutical composition can be conventional tablet or capsule, sustained-release tablet or capsule, Dospan or capsule, oral solution, note
Penetrate dosage form conventional on the galenic pharmacies such as agent.
Generally, the compounds of this invention is for when treating, people to be 1mg~5000mg/ days with dosage range.It can also be according to agent
The difference and disease severity of type, dosage exceed the range.
Here is the biological activity test and result of the compounds of this invention RakicidinB1:
One, anti-tumor activity is tested
Rakicidin B1 sample, which is dissolved in DMSO, respectively makes solubility reach 1mg/ml, then is diluted respectively so that eventually
Concentration be 0.75ug/ml, 0.5ug/ml, 0.25ug/ml, 0.125ug/ml, 0.1ug/ml, 0.05ug/ml, 0.005ug/ml,
0.0025ug/ml。
Nostoc commune Vanch: people's colon-cancer cell HCT-8, esophageal cancer cell ECA109 in Exponential growth stage is taken to plant respectively
(cell concentration 10 in 96 orifice plates5The hole a/ml, 100ul/), r keeps its adherent for 24 hours for culture, adds 100ul/ pore area medicine fresh cultured
Base, each concentration set 3 multiple holes, and set blank control wells (only plus culture medium) as negative control, equally set 3 multiple holes.After
Continuous culture terminates culture to 72hr.
Weary oxygen culture: (the cell concentration 10 in 96 orifice plates of people's colon-cancer cell HCT-8 kind in Exponential growth stage is taken5
The hole a/ml, 100ul/), weary oxygen is ventilated 30 minutes, and gas valve is closed, and is put into 37 DEG C of incubator, and r keeps its adherent for 24 hours for culture,
Add 100ul/ pore area medicine fresh culture, each concentration sets 3 multiple holes, and sets blank control wells (only plus culture medium) as yin
Property control, equally set 3 multiple holes.Weary oxygen is ventilated 30 minutes, is closed gas valve, is put into 37 DEG C of incubator, continues culture extremely
72hr terminates culture.
SRB detection: will terminate the cell of culture, and every hole adds 10%TCA 50ul, the fixed 1hr of 4 DEG C of conditions.It is rushed with distilled water
It washes 5 times, 4mg/ml SRB solution 50ul is added in every hole after natural drying, dyes 30min at room temperature, abandons supernatant, is rushed with 1% acetic acid
Wash 5 times dyestuffs to remove non-specific binding.150ul 10mM Tris solution is added in every hole, shakes 5 minutes, in 540 wavelength
Lower microplate reader surveys OD value, and calculates inhibiting rate.By the conversion to inhibiting rate, IC50 value is calculated using SPSS software.As a result
It is shown in Table 1.
The hypoxic tumor cells toxicity of 1 RakicidinB1 of table
The above results show that there is the compounds of this invention Rakicidin B1 potent antitumor activity especially to resist weary oxygen swollen
Oncocyte activity, and to the 15 times strong of the more normal oxygen of tumour cell HCT-8 activity of weary oxygen culture.
Two, resist pathogenic anaerobic bacteria active testing
Compound R akicidinB1 is dissolved into 0.64mg/ml in DMSO.Its test concentrations are as follows: 128,64,32,16,8,
4,2,1,0.5,0.25,0.125 μ g/ml.To be placed in by testing remaining solution by -20 DEG C.Antibiotic feldamycin and metronidazole are made
For reference compound.The preparation of 2 × solution: maximum concentration is 256 μ g/ml, and the two of 10 times are and then passed through in 96 deep-well plates
It dilutes again, obtains 2 required × solution.100 μ l to 96 hole round bottom plates are dispensed with work station.12nd column are negative controls, are contained only
The culture medium of same volume.
The preparation of bacterial inoculum: 1 day (aerobic bacteria) or [culture on accordingly growth plate in 2-3 days (anaerobic bacteria) in advance
Base: aerobic bacteria, CAMHB (cation adjusted Mueller-Hinton medium, the Miller of ion-select electrode pungent culture
Base；Anaerobic bacteria, Brucella broth supplemented with hemin (5g/mL), Vitamin K1 (1g/mL), and
Lysed horse blood (5%v/v)] inoculation.Bacterial concentration is transferred to about 1-2 × 10 by experimental day6Then CFU/ml turns
(96 orifice plates added with compound prepared in [0056]) are moved in 100 hole μ l to 96- round bottom plates.
MIC measurement: for aerobic bacteria, being placed in 37 DEG C for the hole 96- round bottom plate derived above, 85% humidity, big gas bar
It is cultivated 20 hours under part；For anaerobic bacteria, the hole 96- round bottom plate derived above is placed in 37 DEG C, under 85% damp condition, is detested
It is cultivated 46-48 hours under the conditions of oxygen.The concentration point that bacterial growth is completely or significantly inhibited will be defined as the compound
MIC.It the results are shown in Table 2
Table 2.RakicidinB1 antibacterial activity
* Quality Control bacterium
Anti-bacteria test result show RakicidinB1 have anti-clostridium difficile, clostridium difficile drug-fast bacteria, peptostreptococcus,
The clinical pathogenic anaerobic bacteria activity such as propionibacterium acnes, activity are suitable up to mycin with phenanthrene；RakicidinB1 also have resist it is resistance to through the ages
The enterococcal activity of mycin, activity are better than phenanthrene up to mycin, are its 8 times.
Specific embodiment
Embodiment 1
The preparation of RakicidinB1
Step 1: (Jiang Hong, Lin Ru, Zheng Wei wait to the fermentation culture conditions reference literature of micromonospora bacterial strain FIM02-523
In the separation identification and biological activity [J] of the lipopeptide compound FW523 that ocean Micromonospora chalcea FIM02-523 is generated
State's antibiotic magazine, 2006,31 (5): 267-270).
Step 2: after the resulting FIM02-523 fermentation liquid of step 1 is centrifuged 15min by 4500rpm, mycelia is obtained
Slag overnight impregnates the anhydrous methanol or ethyl alcohol of 2 times of volumes of the mycelia slag of acquisition 2 times, will contain spirituous mycelia slag again
Supernatant is merged after being centrifuged 15min with 4500rpm, obtains fermentation extracting solution.
Step 3: (diameter height compares for 1:5~1:10, packed column volume 1.5-2.5L) HP20 macroporous resin adsorption column chromatography: adopting
For fermentation extracting solution (40-60L) with the alcohol concentration of 50%-55%, flow velocity is that 40ml/min carries out upper prop absorption；It has adsorbed
Quan Hou, carries out gradient elution with the alcohol of concentration 60%-80%, detects eluent 1 with HPLC, merges and contain Rakicidin B1
Same composition (30L).
Step 4: step 3 eluent carries out NM200 resin absorbing column chromatography, and (diameter height compares for 1:2~1:10, packed column volume
1-2L): by step 3 eluent with the alcohol concentration of 50%-55%, flow velocity 40ml/min carries out upper prop absorption；It has adsorbed
Quan Hou, carries out gradient elution with the alcohol of concentration 55%-80%, detects eluent 2 with HPLC, merges and contain Rakicidin B1
Same composition (25L).
Step 5: step 4 eluent 2 is extracted 2 times after the dilution of monoploid ponding with isometric ethyl acetate, decompression
Concentration, obtains crude product.
Step 6: the crude product that step 5 is obtained is dissolved with methanol, presses reverse phase C18 column to chromatograph (diameter height ratio 1:3 in progress
~1:10), flow velocity 30ml/min, with concentration for 60%-90% acetonitrile-water gradient, fraction collection is detected with HPLC and is collected
Liquid merges same composition.
The micromonospora FIM02-523 hides general with China Committee for Culture Collection of Microorganisms in January, 2016
Logical microorganism center, deposit number are CGMCC No.12132.
Compound R akicidin B1: white amorphous powder.It is dissolved in chloroform, methanol, DMSO, it is not soluble in water.High-resolution
Mass spectrum (HR-ESI-MS) shows its molecular ion peak [M+H]+for 621.1175, infers that its molecular formula is C33H56N4O7, unsaturated
Degree is 8.13CNMR and DEPT135 shows that the molecule contains 33 carbon signals, including 5 quaternary carbon (δC 172.6,172.4,
169.2,167.6,165.9), 4 double key carbons [include a sp2Mesomethylene carbon, two sp2Methine carbon (δC 138.4,
118.8)], 6 sp3Methine carbon [includes two company oxygen carbon atom (δC78.0,72.4)], 13 sp3Mesomethylene carbon and 5
Methine carbon atom (δC 36.5,19.1,15.4,13.2,11.2)。1HNMR shows that the compound has 4 double bond proton [δH 6.87
(1H, d, J=15.0Hz), 6.16 (1H, d, J=15.0Hz), 5.44 (1H, s), 5.32 (1H, s)], 5 exchangeable protons [δH
8.88 (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 Hydrogen Protons pass through hsqc spectrum1H–13C correlation is pointed out.1H–1H COSY
The coupling constant of Correlated Spectroscopy and proton shows that the 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–1For H COSY and HMBC it is found that H-2 is related to C-1/C-5, H-3 is related to C-4, and OH-3 is related to C-2/C-3,
Ha-6 is related to C-5/C-7, H3- 7 is related to C-6/C-8, and H-9 is related to C-8/C-11, and H-10 is related to C-8/C-11, Hb-
12 is related to C-10/C-11, and H-15 is related to C-1, H3- 30 is related to C-28/C-29, H3- 31 with C-13/C-14/C-15 phase
It closes, H3- 32 and Hs related to C-15/C-16/C-173- 33 is related to C-27/C-28/C-29, the chemical shift column of hydrogen and carbon
In following table:
Claims (7)
1. the compound of structure formula (I):
2. the preparation method of the compound of claim 1, comprising: the micromonospora bacterium for being CGMCC No.12132 by deposit number
Strain (Micromonospora sp.) FIM02-523 ferments, and fermentation liquid centrifugation obtains mycelia slag, and mycelia slag is soaked with ethyl alcohol
Bubble obtains ethyl alcohol soak, and ethyl alcohol soak carries out HP20 macroporous resin adsorption column chromatography, and 60%-80% ethanol water gradient is washed
It is de-, eluent 1 is obtained, eluent 1 carries out NM200 resin absorbing column chromatography, and 55%-80% ethanol water gradient elution is eluted
Liquid 2 is extracted with ethyl acetate after eluent 2 is diluted with water, and concentration obtains crude product and dissolved with methanol, and reverse phase C18 column is pressed in progress
Chromatography, 60-90% acetonitrile water gradient elution, fraction collection, with HPLC detection collection liquid to get.
3. the purposes that the compound of claim 1 is used to prepare the drug for the treatment of hypoxic tumor disease.
4. the purposes of claim 3, wherein hypoxic tumor disease is gastric cancer, liver cancer, breast cancer, cancer of pancreas or intestinal cancer.
5. the purposes that the compound of claim 1 is used to prepare the drug for the treatment of anaerobic bacteria related disease.
6. the purposes of claim 5, wherein anaerobic bacteria related disease is by clostridium difficile, peptostreptococcus or propionibacterium acnes
Caused diarrhea, alimentary canal inflammation, mouth disease or skin acne.
7. the purposes that the compound of claim 1 is used to prepare the drug of anti-vancomycin-resistant enterococcus.
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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 |
| 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 |
| CN108300672B (en) * | 2017-11-24 | 2019-02-15 | 福建省微生物研究所 | A kind of fermentation produces the sea micromonoad strain and its application of Rakicidin B1 |
| CN108586380B (en) * | 2018-03-27 | 2021-08-31 | 福建省微生物研究所 | Natural Rakicidins compound Rakicidin H and extraction method thereof |
| CN108329280B (en) * | 2018-03-27 | 2021-08-31 | 福建省微生物研究所 | Natural Rakicidins compound Rakicidin I and extraction method thereof |
| CN110698537B (en) * | 2019-08-12 | 2023-05-12 | 福建省微生物研究所 | Natural Rakicidins compound Rakicidin B1-2 and fermentation extraction method thereof |
| CN110437314B (en) * | 2019-08-12 | 2021-03-26 | 福建省微生物研究所 | Natural Rakicidins compound Rakicidin B1-1 and fermentation extraction method thereof |
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| FW523;JIAN-JUN XIE等;《MOLECULAR MEDICINE REPORTS》;20110430;第4卷(第4期);第759-763页 * |
| 海洋青铜小单孢菌FIM 02-523产生的脂肽类化合物FW523的分离鉴别和生物学活性;江红等;《中国抗生素杂志》;20060531;第31卷(第5期);第268页第2.1-2.2小节，270页左栏第1段 * |
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