CN112939909A - Nano-docetaxel condensation compound and preparation method and application thereof - Google Patents
Nano-docetaxel condensation compound and preparation method and application thereof Download PDFInfo
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Abstract
The present invention discloses a nano-doxylamine condensation compound, its preparation method and application, and is characterized by that it is collected from west sand island coast of south China seaLemnaliaIs separated from secondary metabolite produced by coral soft, and the preparation method comprises the following steps: extracting lyophilized soft coral with acetone, extracting with diethyl ether and water, mixing diethyl ether extractive solutions, and concentrating to obtain extract; separating the crude extract with normal phase silica gel chromatography, gradient eluting with petroleum ether-ethyl acetate solution as mobile phase, collecting fraction, separating with reversed phase medium pressure column chromatography, eluting with methanol-water solution as mobile phase, separating with normal phase silica gel chromatography, gradient eluting with petroleum ether-ethyl acetate solution as eluent, collecting fraction, separating with reversed phase semi-preparative high performance liquid chromatography to obtain compound 1 and compound 2Has effects in resisting Bacillus subtilis and Staphylococcus aureus, and also has antiinflammatory activity.
Description
Technical Field
The invention relates to a nano-doxane sesquiterpene condensate, in particular to a nano-doxane sesquiterpene condensate collected from XishaLemnaliaA nano-doxylamine condensation compound extracted from coral, a preparation method and application thereof.
Background
Marine soft coral has a beautiful appearance and is very attractive to predators, so that these organisms must possess an effective self-protection method for survival, which promotes the production of characteristic metabolites. Therefore, the soft coral is a rich source for finding terpenoids with various structures and potential therapeutic application values. In recent years, the potential bioactive chemical composition of many marine soft corals has been studied, from tropical to polar oceans, such as taiwan and south sea waters.
LemnaliaBelonging to the genus of coral (Lemnaliasp.) belonging to the phylum coelenterates (Coelenterata), the subclasses octodecahydrozoa (Octocorallia), the order galliformes (Alcyonacea), the family phellandra (Nephtheidae), belonging to the lower primary marine organisms, there are more than 30 species, of which only about 15 chemical components have been studied.LemnaliaMarine soft coral of the genus provides a number of new terpenoids with different chemical structures, including sesquiterpenes, norsesquiterpenes, diterpenes, diterpene glycosides and steroids. Sesquiterpenes are the most prominent metabolites in coral softgels and are often considered as chemical taxonomic markers for coral softgels. They can be classified according to their chemical structure of the carbon skeleton, such as the nardosinane type (naldoxane type), the neolemnane type, the ylangane type and other types of sesquiterpenes.
In the process of exploring marine bioactive secondary metabolites, soft coral is collected in the sea area (7 m depth) of Xisha Islands by a hydropneumoniae diving technologyLemnaliasp. The chemical composition of the acetone extract was studied and 2 new natdosinoids A (1) and B (2) were obtained as the condensates of the sesquiterpenes of the naldoxane type. At present, no report exists on the 2 structures and the functional activities thereof.
Disclosure of Invention
The invention aims to solve the technical problem of providing a nano-doxycycline condensation compound with antibacterial and anti-inflammatory activities, a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows: sodium containerDocetaxel condensate collected from deep coast of Xisha Taoism island of south China seaLemnaliaIs separated from secondary metabolite produced by genus coral (number XSSC 201915) and has the following chemical structure general formula:
the preparation method of the nano-doxylamine condensate comprises the following steps:
(1) obtaining a crude extract: cutting frozen soft coral into blocks, freeze-drying, ultrasonically extracting with acetone until colorless, recovering acetone under reduced pressure until dry, repeatedly extracting with mixed solution of water and diethyl ether with equal volume for several times, mixing diethyl ether extractive solutions, and concentrating under reduced pressure to obtain crude extract;
(2) separating the crude extract obtained in the step (1) by using normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with a volume ratio of (50: 1) - (1: 1) as a mobile phase, collecting eluates tube by tube, arranging the eluates from small to large according to the polarity of fractions, and combining to obtain 5 components;
(3) performing reversed-phase medium-pressure column chromatographic separation on the 3 rd component obtained in the step (2), eluting by using a methanol-water solution with the methanol content of 40-100 wt% as a mobile phase, collecting eluates tube by tube, arranging the eluates from large to small according to the polarity of fractions, and combining to obtain 8 components;
(4) separating the 5 th component obtained in the step (3) by using normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with volume ratio of (10: 1) - (1: 1) as eluent, collecting the eluent tube by tube, arranging the eluents from small to large according to the polarity of the fractions, and combining to obtain 9 components;
(5) and (3) separating the 5 th component obtained in the step (4) by using reverse phase semi-preparative high performance liquid chromatography to obtain a compound 1 and a compound 2.
The elution gradient volume ratio of the petroleum ether-ethyl acetate solution in the step (2) is 50: 1. 20: 1. 10: 1. 5: 1. 2: 1 and 1: 1.
the elution gradient of the methanol-water solution in the step (3) is that the methanol volume content is 40%, 50%, 60%, 70%, 80%, 90% and 100% in sequence.
The elution gradient volume ratio of the petroleum ether-ethyl acetate solution in the step (4) is 10: 1. 5: 1. 2: 1 and 1: 1.
the mobile phase of the reversed-phase semi-preparative high performance liquid chromatography in the step (6) is a methanol-water solution with the mass concentration of 95%, and the flow rate is 2 mL/min.
The application of the nano-docetaxel condensation compound 1 and the condensation compound 2 in preparing the bacillus subtilis inhibitor.
The application of the nano-doxycycline condensation compound 2 in the preparation of staphylococcus aureus inhibitor.
The use of the above described naldoxane condensate 2 for in vitro anti-inflammatory activity.
Compared with the prior art, the invention has the advantages that: the present invention relates to a nano-doxylamine condensate, its preparation method and application, including two nano-doxylamine condensates, and its preparation method is that the nano-doxylamine condensate is prepared by using the nano-doxylamine condensate obtained from south sea Xisha islandLemnaliaFreeze-drying coral, ultrasonic extracting with acetone for 6 times to colorless, recovering acetone under reduced pressure to dryness, extracting with water and ether in the same volume, mixing extractive solutions, concentrating under reduced pressure to obtain crude extract, separating and purifying the crude extract by reduced pressure silica gel column chromatography, medium pressure column chromatography and reversed phase semi-preparative high performance liquid chromatography to obtain compounds 1 and 2, wherein the compounds 1 and 2 have effects of resisting Bacillus subtilis and Staphylococcus aureus, and provide a new lead compound for developing new antibacterial drugs. In addition, compound 2 also had a moderate inhibitory effect on LPS-induced macrophage NO production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Compound 1 of the present invention;
FIG. 2 is a NMR spectrum of Compound 2 of the present invention;
FIG. 3 is a NMR carbon spectrum of Compound 1 of the present invention;
FIG. 4 is a NMR carbon spectrum of Compound 2 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Example 1
FromLemnalia2 new naddosinoids A (1) and B (2) of the condensates of sesquiterpenes of the naldosaline type isolated from the genus coral, the compounds having the formula:
example 2
The preparation method of the nano-docetaxel condensation compound comprises the following steps:
1. obtaining a crude extract: cutting frozen soft coral into blocks, freeze-drying, ultrasonically extracting with acetone until colorless, recovering acetone under reduced pressure until dry, repeatedly extracting with mixed solution of water and diethyl ether with equal volume for several times, mixing diethyl ether extractive solutions, and concentrating under reduced pressure to obtain crude extract;
2. separation and purification of compounds
(1) Separating the crude extract by normal phase silica gel chromatography (200-: 1. 20: 1. 10: 1. 5: 1. 2: 1 and 1: 1;
(2) performing reversed-phase medium-pressure column chromatographic separation on the fraction 3 obtained in the step (1), eluting by using a methanol-water solution with the methanol content of 40 wt% to 100 wt% as a mobile phase, collecting eluates tube by tube, arranging the eluates according to the polarity of the fractions from large to small, and collecting and combining the eluates in sequence to obtain 8 components, wherein the elution gradient of the methanol-water solution is 40%, 50%, 60%, 70%, 80%, 90% and 100% in sequence;
(3) separating the 5 th component (Fr.3.5) obtained in the step (2) by normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with volume ratio of (10: 1) - (1: 1) as eluent, collecting the eluent tube by tube, and arranging the eluent according to fraction polarity from small to large to obtain 9 components (Fr.3.5.1-Fr.3.5.9), wherein the elution gradient volume ratio of the petroleum ether-ethyl acetate solution is 10: 1. 5: 1. 2: 1 and 1: 1;
(4) subjecting the 5 th fraction (Fr.3.5.5) obtained in step (3) to reverse phase semi-preparative high performance liquid chromatography (95% methanol-water solution, flow rate 2 mL/min, isocratic 50 min) to obtain compound 1 (9.8 mg) and compound 2 (28.0 mg), which have the following chemical structural formulas:
example 3
Structural identification and nuclear magnetic signal assignment of compounds:
nardosinoid a (compound 1): a colorless oily solid; [ alpha ] to]25 D=-42 (c0.1, MeOH); accurate molecular weight M/z 493.3293 [ M + Na ] provided by positive ion high resolution mass spectrometry (HRESIMS) excimer ion peak]+(calculated value is C)30H46O4Na, 493.3294) giving the compound the formula C30H46O4With 8 unsaturations. Of the compound1H and13the C NMR data are shown in FIG. 1 and FIG. 3, Table 1.
Nardosinoid B (compound 2): a colorless oily solid; [ alpha ] to]25 D=-66 (c0.1, MeOH); accurate molecular weight M/z 493.3286 [ M + Na ] provided by positive ion high resolution mass spectrometry (HRESIMS) excimer ion peak]+(calculated value is C)30H46O4Na, 493.3294) giving the compound the formula C30H46O4With 8 unsaturations. Of the compound1H and13the C NMR data are shown in FIG. 2 and FIG. 4, Table 1.
TABLE 1 of Compounds 1 and 21H NMR and13C NMR (1H 600 MHz, 13 C 150 MHz, CDCl3)
a Overlapped signals。
example 4
Detection of antibacterial activity of compounds nardosinoids A (1) and B (2) and application thereof
1. Experimental sample
Preparing a solution of a sample to be detected: the test samples were monomeric compounds of the compounds 1 and 2 isolated and purified in the above example 1, and appropriate amounts of the samples were precisely weighed and prepared into 1.28 mg/mL solutions in DMSO, respectively. The indicator bacteria used in the experiment are bacillus subtilis, and gentamicin is a positive control.
2. Experimental methods
Compounds 1 and 2 were tested for in vitro antibacterial activity using medium microdilution in 96-well microplates. The designated glycerol stock culture strains are respectively absorbed by 10 mu L of the glycerol stock culture strains and put into a broth culture medium, and the glycerol stock culture strains are activated by shaking culture. 100 mu L of MH culture medium containing 2,3, 5-triphenyltetrazolium chloride (TTC) developer is added into each well of a sterile 96-well microplate, 10 mu L of the compound and 90 mu L of MH culture medium containing TTC are added into the first row of wells, the mixture is sequentially diluted, the final concentration of the corresponding test compound is 256, 125, 64, 32, 16, 8, 4, 2, 1 and 0.5 mu g/mL, 50mL of MH culture medium is added into 10 mu L of seed liquid, the mixture is fully mixed, 100 mu L of bacterial liquid is added into each well, the culture is carried out in an incubator at 37 ℃, and the color is observed after 18h and 36 h.
3. Results of the experiment
TABLE 2 antibacterial Activity screening results for Compounds 1 and 2
As can be seen from Table 2, compounds 1 and 2 had moderate inhibitory effects against Bacillus subtilis with a Minimum Inhibitory Concentration (MIC) of 4-8. mu.g/mL, whereas compound 2 also had inhibitory effects against Staphylococcus aureus with a Minimum Inhibitory Concentration (MIC) of 16. mu.g/mL.
Example 5
The anti-inflammatory activity of the compounds nardosinoid A (1) and B (2) is detected and applied.
1. Experimental sample
Preparing a solution of a sample to be detected: the test samples were pure compounds 1 and 2 obtained by separation and purification in example 2, and an appropriate amount of the sample was precisely weighed and prepared into 50. mu.L of 20 mM stock solution in DMSO. The positive drug used in this experiment was hydrocortisone.
2. Experimental methods
Taking RAW264.7 cell line 1X 104cells/well (peritoneal macrophages 1X 105 cells/well) are placed in a 96-well culture plate to be pre-pasted into a monolayer, an alone hole (without LPS stimulation and without adding a compound to be detected), a control hole (100 ng/mL of LPS final concentration and without adding a compound to be detected) and a detection hole (100 ng/mL of LPS final concentration and 10 mu mol/mL of each compound to be detected) are arranged, the culture is carried out at 37 ℃ and 5% CO2 for 24 h, and supernatant is collected.
The NO concentration is detected by a Griess method, 100 mu L of culture supernatant is added with an equal volume of Griess reagent (1% of sulfamilamide, 0.1% of N- (1-naphthyl) -ethylene diamine, 2% of phosphoric acid) to react for 10 min at room temperature, an absorbance value of each hole is measured by an enzyme-linked immunosorbent assay at 540 nm, and the NO concentration is calculated by a sodium nitrite standard curve.
3. Results of the experiment
TABLE 3 screening results for anti-inflammatory Activity of Compounds 1 and 2
As can be seen from Table 3, Compound 2 has a moderate inhibitory effect on LPS-induced macrophage NO production, and its IC50The concentration was 13.09. mu.M.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also realize that changes, modifications, additions and substitutions can be made without departing from the true spirit and scope of the invention.
Claims (9)
1. A nano-doxylamine condensate characterized by being prepared fromLemnaliaIs obtained by separating secondary metabolites produced by coral soft, and the chemical structure general formula is as follows:
。
2. a method of preparing a nano-docetaxel condensate according to claim 1, comprising the steps of:
(1) obtaining a crude extract: cutting frozen soft coral into blocks, freeze-drying, ultrasonically extracting with acetone until colorless, recovering acetone under reduced pressure until dry, repeatedly extracting with mixed solution of water and diethyl ether with equal volume for several times, mixing diethyl ether extractive solutions, and concentrating under reduced pressure to obtain crude extract;
(2) separating the crude extract obtained in the step (1) by using normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with a volume ratio of (50: 1) - (1: 1) as a mobile phase, collecting eluates tube by tube, arranging the eluates from small to large according to the polarity of fractions, and combining to obtain 5 components;
(3) performing reversed-phase medium-pressure column chromatographic separation on the 3 rd component obtained in the step (2), eluting by using a methanol-water solution with the methanol content of 40-100 wt% as a mobile phase, collecting eluates tube by tube, arranging the eluates from large to small according to the polarity of fractions, and combining to obtain 8 components;
(4) separating the 5 th component obtained in the step (3) by using normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with volume ratio of (10: 1) - (1: 1) as eluent, collecting the eluent tube by tube, arranging the eluents from small to large according to the polarity of the fractions, and combining to obtain 9 components;
(5) and (3) separating the 5 th component obtained in the step (4) by using reverse phase semi-preparative high performance liquid chromatography to obtain a compound 1 and a compound 2.
3. The method of preparing a nano-docetaxel condensate as set forth in claim 1, wherein: the elution gradient volume ratio of the petroleum ether-ethyl acetate solution in the step (2) is 50: 1. 20: 1. 10: 1. 5: 1. 2: 1 and 1: 1.
4. the method of preparing a nano-docetaxel condensate as set forth in claim 1, wherein: the elution gradient of the methanol-water solution in the step (3) is that the methanol volume content is 40%, 50%, 60%, 70%, 80%, 90% and 100% in sequence.
5. The method of preparing a nano-docetaxel condensate as set forth in claim 1, wherein: the elution gradient volume ratio of the petroleum ether-ethyl acetate solution in the step (4) is 10: 1. 5: 1. 2: 1 and 1: 1.
6. the method of preparing a nano-docetaxel condensate as set forth in claim 1, wherein: the mobile phase of the reversed-phase semi-preparative high performance liquid chromatography in the step (6) is a methanol-water solution with the mass concentration of 95%, and the flow rate is 2 mL/min.
7. Use 1 of a sodium docetaxel condensate 1 and condensate 2 as defined in claim 1 for preparing a bacillus subtilis inhibitor.
8. Use of a naldoxane condensate 2 as claimed in claim 1 for the preparation of a staphylococcus aureus inhibitor.
9. Use of a naldoxane condensate 2 as claimed in claim 1 for in vitro anti-inflammatory activity.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102134225A (en) * | 2011-01-17 | 2011-07-27 | 广州中医药大学 | Tricyclic diterpene lactone and preparation method and application thereof |
| CN102731242A (en) * | 2011-04-12 | 2012-10-17 | 中国科学院上海药物研究所 | Diterpenoid compounds lobophytumins C or D and their application in preparing medicaments |
| CN111362849A (en) * | 2020-03-23 | 2020-07-03 | 子辰海洋医药科技(上海)有限公司 | Mixed-element terpenoid and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102134225A (en) * | 2011-01-17 | 2011-07-27 | 广州中医药大学 | Tricyclic diterpene lactone and preparation method and application thereof |
| CN102731242A (en) * | 2011-04-12 | 2012-10-17 | 中国科学院上海药物研究所 | Diterpenoid compounds lobophytumins C or D and their application in preparing medicaments |
| CN111362849A (en) * | 2020-03-23 | 2020-07-03 | 子辰海洋医药科技(上海)有限公司 | Mixed-element terpenoid and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
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| MAGIE MELANIE KAPOJOS ET AL.: "Three New Nardosinane Type Sesquiterpenes from an Indonesian Soft Coral Nephthea sp.", 《CHEM. PHARM. BULL.》 * |
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