CN116003489A - Preparation of Atramycin C and application of Atramycin C in drug research and development - Google Patents
Preparation of Atramycin C and application of Atramycin C in drug research and development Download PDFInfo
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- CN116003489A CN116003489A CN202111271606.5A CN202111271606A CN116003489A CN 116003489 A CN116003489 A CN 116003489A CN 202111271606 A CN202111271606 A CN 202111271606A CN 116003489 A CN116003489 A CN 116003489A
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- 238000012827 research and development Methods 0.000 title abstract description 6
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- 238000002474 experimental method Methods 0.000 description 4
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- SHZGCJCMOBCMKK-PQMKYFCFSA-N alpha-D-rhamnose Chemical compound C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 2
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- XRAVYESZTUBEBU-UHFFFAOYSA-N cyclohexane;propan-2-ol Chemical compound CC(C)O.C1CCCCC1 XRAVYESZTUBEBU-UHFFFAOYSA-N 0.000 description 2
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 238000000238 one-dimensional nuclear magnetic resonance spectroscopy Methods 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention relates to a chemical structure, a preparation method and application of a novel compound of Atramycin C in the research and development of antibacterial novel drugs. The invention discloses a novel compound discovered by the applicant from secondary metabolites of marine actinomycetes sp.strain KCB-032, pharmacological activity research shows that the compound has good growth inhibition effect on 2 bacteria, and the chemical structure, the preparation method and the antibacterial activity of the Atramycin C are disclosed for the first time, so that the compound has the potential of being developed into a novel antibacterial drug.
Description
Technical Field
The invention relates to a structure determination and preparation method of Atramycin C and a prospect in the development of new antibacterial drugs.
Background
In the 21 st century, with the rapid development of science and technology, antibacterial drugs for preventing and treating bacterial infection are increasing clinically, so that drug-resistant strains are also increasing synchronously, and bacteria are continuously upgraded and intensified for antibacterial drugs and are widely spread in pathogenic microorganisms. In addition, the unreasonable use and abuse of antibacterial drugs presents a series of adverse drug reactions as well as the challenges of anti-bacterial infection treatment. Therefore, the development of novel and efficient antibacterial drugs is quickened, and the method has very important clinical significance for solving the problem of drug-free availability caused by drug resistance.
Antibacterial agents are generally derived from fermentation products of microorganisms such as bacteria, actinomycetes and fungi, chemical semisynthetic compounds, and structurally identical or similar compounds that are synthesized entirely by chemical reactions. Innovative drug research and development experience shows that searching an active lead from a natural product to create a new drug is one of the most effective ways, and the unique chemical structure complexity and biological activity diversity of the natural product lay a successful probability of discovering the active lead from the natural product to create the new drug. Marine actinomycetes are important drug source microorganisms, and actinomycetes living in the ocean have great potential in searching novel lead compounds from the marine actinomycetes and further developing antibacterial agents because of the obvious differences between the physiological and biochemical characteristics, the molecular biological characteristics such as 16S rRNA and the like of the marine actinomycetes and the terrestrial actinomycetes, so that the structure types of secondary metabolites of the marine actinomycetes are more novel and the biological activities of the marine actinomycetes are more obvious.
The invention relates to an atlamycin C which is a novel compound and is a novel compound separated from secondary metabolites of marine active actinomycetes sp.strain KCB-032 by the applicant. Pharmacological activity experiments show that the Atramycin C has better growth inhibition effect on 2 bacteria, so that the novel compound Atramycin C has the potential of developing into novel antibacterial drugs. The chemical structure, the preparation method and the antibacterial activity research of the Atramycin C are disclosed for the first time, so that the Atramycin C has outstanding substantive characteristics.
Disclosure of Invention
The invention provides a chemical structure determination method and a preparation method of a novel compound of Atramycin C and application of the novel compound in the research and development of antibacterial novel drugs.
The compound for developing the novel antibacterial drug is a novel compound, named as Atramycin C, and the molecular formula of the compound is C 25 H 24 O 9 The chemical structural formula is as follows:
the preparation method of the Atramycin C provided by the invention comprises the following steps: the active actinomycetes sp.strain KCB-032 isolated from the submarine sediment was streaked on a solid medium, cultured at 28℃for 3 days until spores were grown, then inoculated on a liquid medium, and shake-cultured at 28℃for 10 days to obtain a fermented product. Filtering the fermented product to obtain fermentation liquor and mycelium, adsorbing the fermentation liquor by using macroporous adsorption resin column, eluting and concentrating under reduced pressure; crushing mycelium by ultrasonic, extracting with ethyl acetate, and concentrating under reduced pressure; combining the reduced pressure concentrates, extracting with organic solvent, and concentrating under reduced pressure to obtain total extract. The total extract is subjected to silica gel column chromatography, dichloromethane-methanol gradient elution, and 15 eluting components are obtained by means of thin layer chromatography detection. Subjecting the eluted fraction 1 to ODS reversed-phase column chromatography, collecting 40% methanol-water eluted fraction, and concentrating the eluate to obtain mixture 1. The mixture is eluted by utilizing isopropanol-cyclohexane through HPLC of chiral packing, and 30:70 eluting parts are collected, concentrated and recrystallized to obtain the Atramycin C monomer compound with the purity of more than 98 percent.
The culture medium used in the process is one of a semi-seawater ISP2 culture medium and a pure seawater ISP2 culture medium, and is preferably the semi-seawater ISP2 culture medium.
The macroporous adsorption resin column used in the process is eluted into organic alcohol, which is one of methanol and ethanol, and methanol is preferably used as an eluting solvent through repeated experiments.
The macroporous adsorption resin column involved in the process is weak-polarity or nonpolar macroporous adsorption resin, and is preferably XAD-16 weak-polarity type.
The extractant involved in the process is one of chloroform, ethyl acetate and n-butanol, and preferably ethyl acetate is used as the extractant.
The recrystallization solvent involved in the process is one or more solvents selected from methanol, ethanol, acetone, ethyl acetate, chloroform, dichloromethane and the like, and methanol is preferred as the recrystallization solvent.
The chiral separation packing involved in the process may be Chiralpak AS-H, chiralpak AD-H, chiralpak OD-H and (R, R) WHELK 01, preferably (R, R) WHELK 01, AS separation packing.
The invention also provides an antibacterial experimental method, an antibacterial experimental result and an application prospect in research and development of new medicines of the Atramycin C.
The novel compound Atramycin C related to the invention is disclosed for the first time in chemical structure, preparation method and antibacterial activity research, does not have the possibility of giving any hint through other compounds, has outstanding substantive characteristics, and is expected to be used for developing a novel antibacterial drug.
Drawings
FIG. 1 Nuclear magnetic resonance Hydrogen Spectrum of novel Compound Atramycin C
FIG. 2 Nuclear magnetic resonance carbon Spectrum of novel Compound Atramycin C
FIG. 3 DEPT-135 map of novel compound Atramycin C
FIG. 4, hydrogen-Hydrogen correlation Profile of novel compound Atramycin C
FIG. 5 HSQC pattern of novel Compound Atramycin C
FIG. 6 HMBC Pattern of novel Compound Atramycin C
FIG. 7 NOESY map of novel compound Atramycin C
FIG. 8 high resolution Mass Spectrometry of novel Compound Atramycin C
FIG. 9 HPLC of a rhamnose structural fragment after hydrolysis of the novel compound Atramycin C [ (a) chromatogram of L-rhamnose Standard derivative, (b) chromatogram of D-rhamnose Standard derivative, chromatogram of actetophenone A hydrolysate ]
FIG. 10 LC/MS of the rhamnose structural fragment after hydrolysis of the novel compound Atramycin C [ (a) LC-MS of L-rhamnose Standard derivative, (b) LC-MS of D-rhamnose Standard derivative, LC-MS of actetrofenone A hydrolysate ]
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the spirit of the invention.
EXAMPLE 1 preparation of novel compound Atramycin C
Inoculating Streptomyces sp.strain KCB-032 onto ISP2 semi-seawater solid culture medium, culturing at 28deg.C for 3 days, and collecting 1cm 2 The lawn was inoculated into ISP2 semi-seawater ISP2 liquid medium, and the fermented product was harvested after shaking culture for 10 days at 28℃and 180 rpm. Filtering the fermented product to obtain fermentation liquor and mycelium, adsorbing the fermentation liquor by XAD-16 macroporous adsorption resin column, eluting with deionized water and methanol, and concentrating under reduced pressure; crushing mycelium by ultrasonic wave, extracting with ethyl acetate, concentrating the extract under reduced pressure; mixing the above concentrates, and concentrating under reduced pressure to obtain total extract. The total extract was subjected to silica gel column chromatography, dichloromethane-methanol gradient elution (100:0, 99:1, 98:2, 95:5, 90:10, 80:20, volume ratio), and the eluate was separated into 15 components by thin layer chromatography. Subjecting the eluted fraction 1 to ODS reversed-phase column chromatography, collecting 40% (volume ratio) methanol-water eluted fraction, and concentrating the eluate under reduced pressure to obtain 1 mixture. The mixture is eluted by HPLC of chiral packing and isopropanol-cyclohexane, 30:70 (volume ratio) elution part is collected, concentrated and recrystallized by methanol to obtain Atr with purity reaching more than 98 percentamycin C monomer compounds.
EXAMPLE 2 Structure determination of novel Compound Atramycin C
(1) Instrument and materials
Jasco P-1020 digital polarimeter, agilent TOF/6500 high resolution mass spectrometer, shimadzu UV-2401 visible-ultraviolet spectrophotometer, bruker AVANCE IIITM nuclear magnetic resonance spectrometer.
(2) Chemical structure identification
Atlamycin C: yellow powder (methanol), which is easily dissolved in methanol, dimethyl sulfoxide and acetone, [ alpha ]] 25 D +37.1(CH 3 COCH 3 ,c 0.06)；UV(CH 3 CN)λ max (logε)191(4.3),225(4.2),265(4.3)nm；HR-ESIMS[M-H] － M/z 467.1342 (calculated 467.1348), see FIG. 8; the 1D and 2D NMR data are shown in Table-1 and in the accompanying figures-1 to 7.
TABLE-1 NMR data for novel compound, atramycin C 1 H NMR 600MHz， 13 C NMR 150MHz)
The planar structure of the Atramycin C and the absolute configuration of C-3 in the structure are determined to be S, and the configuration of rhamnose is determined to be alpha-L according to the physicochemical parameters, the spectrum data (figures-1 to 8) of the compounds and the LC/MS and HPLC (figures-9 and 10) of the hydrolyzed rhamnose structural fragment, and the chemical structure of the novel compound is determined to be shown in the following figure.
EXAMPLE 3 antibacterial Activity of novel compound Atramycin C
Screening the novel compound of Atramycin C for gram-positive bacterial activity (4 strains, respectively bacillus subtilis CMCC63501 and staphylococcus aureus CMCC 26003, and bacillus cereus 32210 and nocardia found from clinical isolation) by using penicillin and nystatin as positive controls and adopting a microplate biological experiment method, and finding that the novel compound of Atramycin C has a good inhibition effect on the growth of 2 bacteria, and the MIC value of the novel compound of Atramycin C is shown in the following table-2 (-representing that the activity is not shown) at the concentration of 64 mu g/mL.
Table-2, results of study on antibacterial Activity of novel Compound Atramycin C
Claims (9)
1. The chemical structure of the novel compounds is shown in the following figure:
2. a process for the preparation of novel compounds as claimed in claim 1, characterized in that: scribing and inoculating Streptomyces sp.strain KCB-032 on a solid culture medium, culturing at 28deg.C for 3 days until spores grow, inoculating to a liquid culture medium, and shake culturing at 28deg.C and 180 rpm for 10 days to obtain fermented product; adsorbing the fermentation liquor by macroporous adsorption resin column chromatography, eluting, concentrating under reduced pressure, performing ultrasonic crushing, extracting with organic solvent, concentrating under reduced pressure, and mixing the concentrates to obtain total extract; subjecting the total extract to silica gel column chromatography, gradient eluting, and separating into 15 components according to thin layer chromatography detection; performing ODS reversed phase column chromatography on the eluting component, collecting 40% of eluting part of the eluting solvent, and concentrating the eluting part to obtain a mixture; the mixture is separated by chiral packing HPLC and recrystallized to obtain the novel compound of claim 1 with purity of more than 98%.
3. A process for the preparation of novel compounds according to claim 2, characterized in that: the culture medium used in the process is one of a semi-seawater ISP2 culture medium and a pure seawater ISP2 culture medium, and is preferably the semi-seawater ISP2 culture medium.
4. A process for the preparation of novel compounds according to claim 2, characterized in that: the eluting solvent is organic alcohol, which is one of methanol and ethanol, preferably methanol.
5. A process for the preparation of novel compounds according to claim 2, characterized in that: the macroporous adsorption resin column involved in the process is weak-polarity or nonpolar macroporous adsorption resin, and weak polarity is preferred.
6. A process for the preparation of novel compounds according to claim 2, characterized in that: the organic solvent used as the mycelium extraction step after ultrasonic crushing in the process is one of chloroform, ethyl acetate and n-butanol, and is preferably ethyl acetate.
7. A process for the preparation of novel compounds according to claim 2, characterized in that: the recrystallization in the process adopts an organic solvent for recrystallization, wherein the organic solvent is one or more solvents of methanol, ethanol, acetone, ethyl acetate and the like, and methanol is preferred.
8. A process for the preparation of novel compounds according to claim 2, characterized in that: chiral fillers involved in the separation of the novel compounds are one or more of Chiralpak AS-H, chiralpak AD-H, chiralcel OD-H and (R, R) WHELK 01, preferably (R, R) WHELK 01 AS separating fillers.
9. Use of the novel compounds according to claim 1 for the preparation of therapeutic antibacterial pharmaceutical formulations.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601607A (en) * | 2016-03-10 | 2016-05-25 | 广东省微生物研究所 | Compound acaromycin A and preparation method thereof and application of compound in preparation of antitumor drug |
| CN108084126A (en) * | 2016-11-21 | 2018-05-29 | 山东国际生物科技园发展有限公司 | compound Furamycins I and II and its preparation method and application |
| CN111454869A (en) * | 2020-06-22 | 2020-07-28 | 滨州医学院 | Marine streptomyces and application thereof |
| CN112679516A (en) * | 2019-10-18 | 2021-04-20 | 烟台蓝创生物技术有限公司 | Preparation and application of Actinoxocine and isomer thereof |
| CN112759569A (en) * | 2019-11-06 | 2021-05-07 | 烟台蓝创生物技术有限公司 | Preparation and application of Actinephthoran A and Actinephthoran B |
-
2021
- 2021-10-29 CN CN202111271606.5A patent/CN116003489A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601607A (en) * | 2016-03-10 | 2016-05-25 | 广东省微生物研究所 | Compound acaromycin A and preparation method thereof and application of compound in preparation of antitumor drug |
| CN108084126A (en) * | 2016-11-21 | 2018-05-29 | 山东国际生物科技园发展有限公司 | compound Furamycins I and II and its preparation method and application |
| CN112679516A (en) * | 2019-10-18 | 2021-04-20 | 烟台蓝创生物技术有限公司 | Preparation and application of Actinoxocine and isomer thereof |
| CN112759569A (en) * | 2019-11-06 | 2021-05-07 | 烟台蓝创生物技术有限公司 | Preparation and application of Actinephthoran A and Actinephthoran B |
| CN111454869A (en) * | 2020-06-22 | 2020-07-28 | 滨州医学院 | Marine streptomyces and application thereof |
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Application publication date: 20230425 |