CN112939909B - 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 invention discloses a nano-doxycycline condensation compound, a preparation method and application thereofIs characterized by being collected from west sand islands 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 by normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution as a mobile phase, collecting components for performing reverse phase medium pressure column chromatography, performing elution by using methanol-water solution as a mobile phase, collecting components for performing gradient elution by using petroleum ether-ethyl acetate solution as an eluent, and collecting components for performing separation by using reverse phase semi-preparative high performance liquid chromatography to obtain a compound 1 and a compound 2.
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.) belongs to the phylum coelenterates (Coelenterata), subclasses octonares (Octocorallia), coracoides (Alcyonacea), cerariaceae (Nephtheidae) and belongs to the lower class of the original marine organisms, and the species of the animals belong to more than 30 kinds, wherein only about 15 kinds of chemical components are studied.LemnaliaGenus marine soft coral provides many new terpenoids with different chemical structures, including sesquiterpenes, norsesquiterpenes, diterpenes, diterpene glycosides and steroids. The sesquiterpenoids are softThe most significant metabolites in coral are often considered chemical taxonomic markers of this genus of soft coral. 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: a nano-doxylamine condensate collected from deep coast of Xisha Taoism island in 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 volume content of methanol 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 soft coral, ultrasonic extracting with acetoneTaking 6 times until colorless, recovering acetone under reduced pressure until dry, then repeatedly extracting with water and ether with the same volume, combining the extracts, 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 the functions 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 nano-docetaxel type sesquiterpene condensates A (1) and B (2) extracted and separated from coral saxifraga, the compound structural formula is shown as follows:
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 (200-300 meshes), carrying out gradient elution by using a petroleum ether-ethyl acetate solution with a volume ratio of (50:1) - (1:1) as a mobile phase, sequentially collecting and merging 5 components Fr.1-Fr.5 according to the monitoring of a thin layer plate and the arrangement of fraction polarities from small to large, wherein the elution gradient volume ratio of the petroleum ether-ethyl acetate solution is 50: 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 2mL/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 attribution of the compound:
nardosinoid a (compound 1): a colorless oily solid; [ alpha ] of]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 peaks]+(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) color developing agent is added into each hole of a sterile 96-hole microplate, 10 mu L of the compound and 90 mu L of MH culture medium containing TTC are added into the first row of holes and are 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 respectively added into each hole, the mixture is cultured 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 isolated and purified in example 2, and an appropriate amount of the samples 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 (8)
1. The nano-docetaxel condensation compound is characterized by being separated from secondary metabolites generated by Lemnalia genus coral, and the chemical structural formula of the nano-docetaxel condensation compound is shown as follows:
2. the 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 normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with a volume ratio of (50:1) to (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 normal phase silica gel chromatography, performing gradient elution by using petroleum ether-ethyl acetate solution with the volume ratio of (10:1) to (1:1) as eluent, collecting the eluent tube by tube, arranging the eluents from small to large according to the polarity of 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, wherein a mobile phase is a methanol-water solution with the mass concentration of 95%, and the flow rate is 2mL/min, so that a compound 1 and a compound 2 are obtained.
3. A method of preparing a nano-doxylamine condensate as claimed in claim 2 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. a method of preparing a nano-doxylamine condensate as claimed in claim 2 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. A method of preparing a nano-doxylamine condensate as claimed in claim 2 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. use of the naldoxane condensate 1 and condensate 2 of claim 1 in the preparation of a bacillus subtilis inhibitor.
7. Use of a naldoxane condensate 2 as claimed in claim 1 for the preparation of a staphylococcus aureus inhibitor.
8. Use of a naldoxane condensate 2 as claimed in claim 1 for the preparation of an in vitro anti-inflammatory medicament.
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