CN117567438A - Preparation method and application of novel alkaloid aplysingoniopora A - Google Patents

Preparation method and application of novel alkaloid aplysingoniopora A Download PDF

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Publication number
CN117567438A
CN117567438A CN202311516086.9A CN202311516086A CN117567438A CN 117567438 A CN117567438 A CN 117567438A CN 202311516086 A CN202311516086 A CN 202311516086A CN 117567438 A CN117567438 A CN 117567438A
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aplysingoniopora
alkaloid
novel
compound
preparation
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刘芳
冯广福
陈成琼
周立喜
陈耀
吴家栋
幸继联
朱锐
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Guangdong Leizhou Rare Marine Life National Nature Reserve Administration
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Guangdong Leizhou Rare Marine Life National Nature Reserve Administration
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a preparation method and application of a novel alkaloid compound aplysinogoniopora A. The alkaloid compound aplysinogoporaA is a novel compound, has good inhibition effect on DLD-1 and HT-29 of colorectal cancer, and improves the application scenes of the aplysinogoporaA in the fields of immunity improvement and bacteriostasis through intensive research. The invention provides an alternative compound for developing new ocean medicaments and provides medicinal value in the field of disease treatment.

Description

Preparation method and application of novel alkaloid aplysingoniopora A
[ field of technology ]
The invention relates to the technical field of marine biological medicines, in particular to a preparation method of novel alkaloid aplysingoniopora A and application of the novel alkaloid aplysingoniopora A in multiple fields.
[ background Art ]
Due to the characteristic of ocean habitat variability, corals produce chemical defense systems built from various secondary metabolites in extreme environments. The potential pharmaceutical value of these small molecule compounds is also gaining increasing attention to chemists and pharmacologists, and has been a hotspot for research on marine natural products for many years. Malignant tumors are a serious class of diseases that threaten human life and health. According to the estimated worldwide health organization in 2020, the incidence rate of Chinese malignant tumor is 23.7% of the incidence rate of global malignant tumor, and the death rate of Chinese malignant tumor is 30.2% of the death rate of residents in China. Because the existing clinical medicines for treating cancers such as alkylating agents, antibiotics, plant medicines, antimetabolites and hormone medicines all have the defects of drug resistance, multi-drug resistance, time dependence of drug effect, obvious toxic and side effects and the like, scientists are promoted to search for antitumor medicines with novel structures.
The subject group separates a new alkaloid aplysingoniopora A from the northern bay columnar coral hydra, and the alkaloid has an anti-tumor effect, can be used as a new anti-tumor drug, researches the immune effect and other functions of the alkaloid, and provides a new possibility for the application of the new alkaloid aplysingoniopora A.
[ invention ]
The invention aims to provide a novel alkaloid compound, a preparation method thereof and application of the alkaloid compound in preparation of a pharmaceutical composition, the application of the compound is researched, the application field of the compound is improved, the application of the novel compound is accelerated, and a novel direction is provided for the pharmaceutical field.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a novel alkaloid aplysingoniopora A, which has the chemical structural formula as follows:
the invention also comprises the application of the novel alkaloid aplysingoniopora A in preparing anticancer related medicaments.
Further, the cell of the colon cancer is DLD-1 and/or HT-29.
The invention also comprises application of the novel alkaloid aplysingoniopora A in preparation of related medicaments and/or foods for improving immunity.
The invention also comprises application of the novel alkaloid aplysingoniopora A in preparation of a bacteriostatic agent.
Further, the bacteria that the bacteriostat can inhibit are Escherichia coli (Escherichia coli), staphylococcus aureus (Staphylococcus aureus), bacillus subtilis (Bacillus subtilis), saccharomyces cerevisiae (Saccharomyces cerevisiae) and/or salmonella enterica subspecies swine cholera serotype (Salmonella enterica subsp.
The invention also comprises a preparation method of the novel alkaloid aplysingoniopora A, which comprises the following steps:
(1) Taking a columnar coral hydra sample, breaking the wall, crushing, and extracting with ethanol to obtain a crude extract;
(2) Separating the obtained crude extract of the sample by decompression normal phase silica gel column chromatography, carrying out gradient elution by using chloroform-methanol solution, collecting the eluate, decompressing, concentrating and drying, and merging the components to obtain 7 component extracts Fr.A 1-Fr.A7;
(3) Separating the obtained component extractum Fr.A5 by medium-pressure normal phase silica gel column chromatography, sequentially carrying out gradient elution by using chloroform-methanol solution, collecting the eluate, concentrating and drying under reduced pressure, and combining the components to obtain 5 component extractum Fr.A5-1-Fr.A5-5.
(4) Separating the obtained component extract Fr.A5-4 by pretreated ODS column chromatography, sequentially performing gradient elution with methanol-water solution, collecting eluate, performing TLC detection, developing color, concentrating the developed eluting part under reduced pressure to dry to obtain concentrate component Fr.A5-4-4 for use;
(5) And (3) separating the component extract Fr.A5-4-4 obtained in the step (4) through semi-preparative high performance liquid phase to obtain the novel alkaloid aplysingoniopora A.
The invention has the following beneficial effects:
1. the alkaloid compound 1 (aplysingoniopora A) is a novel compound, has an inhibiting effect on tumor cells, and can be used as a lead compound for preparing anti-tumor drugs to treat malignant tumors. The intensive studies on this compound have found that: the drug also has good inhibition effect on DLD-1 and HT-29 of colorectal cancer, in addition, a novel compound (aplysingoniopora A) is found to have better antibacterial effect and immunity improving effect, the deep research of the effect improves the application scene of the compound (aplysingoniopora A), provides an alternative compound for developing a novel anti-tumor drug, and has important significance for developing Chinese ocean drug resources.
[ description of the drawings ]
FIG. 1 is a structural formula of compound aplysingoniopora A;
[ detailed description ] of the invention
All of the features disclosed in this specification, or all of the steps in a method or process disclosed, may be combined in any combination, except for mutually exclusive features and/or steps.
Any feature disclosed in this specification (including any accompanying claims, abstract) may be provided with respect to each feature disclosed herein, unless otherwise indicated, as an example of a generic series of equivalent or similar features.
Example 1:
(1) The preparation and verification of the alkaloid compound aplysingoniopora A are carried out.
Taking 100g of a columnar coral Goniopora columna hydroid sample, breaking the wall, crushing, extracting with 95% ethanol for 3 times, soaking for 3 days each time, wherein the consumption of 95% ethanol is 3-5 times of that of the sample, filtering the extracting solution, merging the filtrates, and concentrating under reduced pressure to obtain 20g of ethanol crude extract.
Separating the crude extract by vacuum normal phase silica gel column chromatography, wherein the column volume is veffectively=120cm 3 Sequentially using chloroform-methanol solution with the volume ratio of 9: 1. 8: 2. 7: 3. 1: 1. 3: 7. 2:8 and 0:10 gradient elution, collecting the eluate, concentrating under reduced pressure, drying, TLC checking, and combining the components to obtain 7 component extractum Fr.A1-Fr.A7.
Separating the component extract Fr.A5 (1.2 g) by medium pressure normal phase silica gel column chromatography, column volume Veffective=40cm 3 Sequentially using chloroform-methanol with the volume ratio of 8: 2. 7: 3. 1: gradient elution 1, flow rate = 15min/mL. Collecting the eluate, concentrating under reduced pressure, drying, performing TLC inspection, and combining the components to obtain 5 component extractum Fr.A5-1 to Fr.A5-5.
Separating the component extract Fr.A5-4 (128 mg) by chromatography with pretreated ODS column, column volume Veffective=10cm 3 Sequentially using methanol-water volume ratio of 1: 9. 3: 7. 1: 1. 7: 3. 9:1 and 10:0 gradient elution to obtain a plurality of elution parts, TLC inspection and color development, and concentrating the developed elution parts under reduced pressure until the elution parts are dry to obtain a concentrate component Fr.A5-4-4 (35 mg) for later use;
the component extract fr.a5-4-4 was prepared by semi-preparative high performance liquid separation using COSMOSIL C18 semi-preparative chromatography column (250 mm x 10mm,5 μm, shanghai Qin Zhen biotechnology ltd) under the preparation conditions of chromatographic methanol/pure water volume ratio = 21:79 isocratic elution separation preparation, flow rate = 3min/mL, retention time t R =16 to 17min. Compound (4 mg) was obtained.
(2) Structural resolution of Compound aplysingoniopora A
The chemical structure, physicochemical property and spectrum data of the compound aplysingoniopora A are determined by nuclear magnetic resonance detection analysis: aplysingoniopora A: yellow powder; 1 H NMR(500MHz,DMSO-d 6 ,Jin Hz)δ H :7.55(H-4,s),7.49(H-1,d,J＝8.4Hz),7.27(H-6,s),7.16(H-2,d,J＝8.5Hz),4.25(H-11,t,J＝6.2Hz),3.72(H 2 -9,m),3.94(H-13,m),3.69(H 2 -14,d),2.03(H-12a,m),1.91(H-12b,m)。 13 C NMR(125MHz,DMSO-d 6 )δ C :177.0(C-16),173.9(C-10),161.4(C-15),139.0(C-5),127.4(C-8),126.2(C-6),123.2(C-2),120.8(C-1),115.3(C-4),116.1(C-3),109.7(C-7),54.6(C-13),53.3(C-11),49.3(C-14),39.7(C-12),33.9(C-9)；HR-ESI-MS:m/z 406.0515[M+H] - 。
(3) Test of Compound aplysingoniopora A for tumor cell growth inhibition Activity
The isolated compound: aplysingoniopora A, see FIG. 1 for structural formula. For this reason, the inhibitory effect of the compound on colorectal cancer cells was studied, specifically: three colorectal cancer cells DLD-1, HT-29 and SW480PDC were inoculated into 96-well plates at a density of 3000 cells per well, respectively, and the inhibitory effect of the compounds on proliferation of colorectal cancer cells DLD-1, HT-29 and SW480PDC cells was measured by the Sulfonyl Rhodamine B (SRB) method at different concentrations of the compounds; cisplatin was used as a positive control. All colorectal cancer cells DLD-1, HT-29 were cultured with RPMI-1640 medium; l15 medium for SW480PDC was maintained at 37℃and CO 2 The cells after the third generation culture were used in the experimental study of the present invention by culturing in an incubator with saturated humidity. Tumor cells were seeded in 96-well plates and aplysingoniopora A at different concentrations were added 24h after adherence. After the medicine is treated for 72 hours, SRB is used for staining, an absorption luminosity value at 515nm is measured by an enzyme-labeling instrument, the survival rate of tumor cells is detected, and the IC for inhibiting the proliferation of the tumor cells is calculated by aplysingoniopora A 50 Values.
The results obtained are shown in Table 1:
table 1 inhibition of various colorectal cancer cells by alkaloid aplysingoniopora A (IC 50 ：μM)
As can be seen from the experimental results in Table 1, when IC 50 When the value is less than 5, the inhibition ratio of corresponding cells is effective, aplysingoniopora A has inhibition effect on colorectal cancer cells DLD-1 and HT-29, but has no inhibition effect on colorectal cancer cells SW480PDC, compared with positive control cisplatin, aplysingoniopora A has more obvious inhibition effect on colorectal cancer cells DLD-1 and HT-29, and has no obvious inhibition effect on colorectal cancer cells SW480 PDC.
Example 2:
a compound: aplysingoniopora A, the following are specific examples:
mice of comparable body weight were randomly divided into 9 groups: normal control, compound high and low dose, model and levamisole groups; each group of 10.
The preparation method of the high and low dose groups comprises the following steps: compounds were dissolved in DMSO (cell grade) to formulate low dose groups respectively: 1mg/kg; and a high dose group of 10mg/kg; 0.01ml/g cyclophosphamide solution; levamisole solution 30mg/kg.
Normal control group is injected with 10 ml/(kg.d) of physiological saline by abdominal cavity for 3 days; the compound high and low dose groups, model group and levamisole group were injected intraperitoneally with equal volumes of cyclophosphamide for 3 consecutive days. Starting on the 4 th day, normal control group and model group are respectively infused with normal saline with equal volume of stomach for 4 days; the compound high and low dose groups continued for 4 days. Day 8 Indian ink was injected intravenously via the tail of the mice 0.1ml/10g at 1 (t) 1 ) And 5 (t) 2 ) After min, 20 μl of the mixture was collected via orbital veins and added with 2ml of Na at 0.1% by mass 2 CO 3 In the solution, absorbance value is measured at 680nm of a 722 spectrophotometer, after blood collection, mice are killed by cervical removal, livers and spleens are weighed, and clearance index (K) and phagocytosis index (alpha) are calculated according to the following formula.
K＝(logA 1 -logA 5 )/(t 2 -t 1 )＝log(A 1 /A 5 )/4
α=body weight/(liver weight+spleen weight) ×k 1/3
Effects on cell proliferation:
taking mice, removing neck, killing, soaking in 75% ethanol solution for 5min, aseptically taking spleen, washing with Hanks solution, shearing on 100 mesh wire mesh, lightly grinding with sterilized glass injection core, washing, filtering, centrifuging, and centrifuging with Tris-NH 4 Cl destroys red blood cells, and after ice bath standing and centrifugation, the cells are washed 2 times with RPMI1640 culture solution to prepare 1X 10 6 Spleen lymphocyte suspension per ml. The cell suspension was added to a 96-well plate at 180. Mu.l/well, 20. Mu.l of the corresponding solution was added to each well, and 20. Mu.l of ConA (5. Mu.g/ml) was added separately to add onlyWells with 20 μl RPMI1640 medium without cells served as blank control, wells with 20 μl RPMI1640 medium served as negative control, wells with 20 μl ConA (5 μg/ml) served as positive control. Placing each group of cells into CO 2 After 3d incubation in incubator, 20. Mu.l MTT (5 mg/ml) was added, the culture was continued, the supernatant was centrifuged off, 180. Mu.l DMSO was added to each well, and the mixture was mixed by shaking, and the A value was measured at 570nm in an ELISA. The results obtained are shown in tables 2 to 3, and are specifically as follows:
TABLE 2 clearance index and phagocytosis index of mice of each group
Note that: aa, P <0.01 compared to normal control; and b, comparing P <0.05 with the model group.
Both the carbon clearance index and phagocytic index were significantly reduced in the model group compared to the normal control group; both the levamisole group and the compound high dose group significantly improved the clearance index and phagocytic index of immunosuppressive mice compared to the model group, but the difference in phagocytic index was not significant.
TABLE 3 proliferation levels of spleen lymphocytes from groups of mice
Note that: aa: P <0.01 compared to the negative control group; comparing with ConA group, b is P <0.05; bb P <0.01.
As shown in Table 3, compared with the negative control group, 5 mug/ml ConA can obviously induce proliferation of T lymphocytes of mice, the compound can obviously improve the proliferation capacity of the T lymphocytes of the mice, and the improvement effect is most obvious when the final concentration of the compound is 10 mg/kg. The compound has good effect of improving the immunity of mice.
Example 3:
a compound: aplysingoniopora A, the following are specific:
4 holes are drilled on a cultured test bacteria culture medium plate, and 1ml of each compound with different concentrations (1 mg/kg, 3mg/kg and 5 mg/kg) is injected into the holes; the blank group was filled with distilled water, left to stand for 3min, placed in an incubator at 37 ℃ overnight, and the diameter of the inhibition zone was measured and recorded the next day. Wherein the test bacteria are: the results obtained by averaging Escherichia coli (Escherichia coli), staphylococcus aureus (Staphylococcus aureus), bacillus subtilis (Bacillus subtilis), saccharomyces cerevisiae (Saccharomyces cerevisiae) and Salmonella enterica subspecies cholera serotype (Salmonella enterica subsp. Enterica serovar Choleraesuis) are shown in Table 4:
TABLE 4 bacteriostatic effects of different alkaloids on different test bacteria
As can be seen from Table 4, the compounds have inhibitory effects on Escherichia coli, staphylococcus aureus, bacillus subtilis, yeast and Salmonella, and the inhibitory effects are Staphylococcus aureus > Escherichia coli > Yeast > Bacillus subtilis > Salmonella.
In conclusion, the compound aplysingoniopora A has obvious inhibition effect on colorectal cancer cells DLD-1 and HT-29, has good promotion effect on mouse immunity, and has good inhibition effect on escherichia coli, staphylococcus aureus, bacillus subtilis, saccharomycetes and salmonella.
The above examples merely represent a few embodiments of the present invention, which are described in more detail and are not to be construed as limiting the scope of the present invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.

Claims (7)

1. Novel alkaloid aplysingoniopora A is characterized by having the following chemical structural formula:
2. the use of the novel alkaloid aplysingoniopora A according to claim 1 for the preparation of an anticancer related medicament.
3. The use according to claim 1, wherein the cells of the colon carcinoma are DLD-1 and/or HT-29.
4. Use of a novel alkaloid aplysingoniopora A according to claim 1 for the preparation of an immunity enhancing related medicament and/or food.
5. The use of a novel alkaloid aplysingoniopora A according to claim 1 for the preparation of a bacteriostatic agent.
6. The use according to claim 5, wherein the bacteria inhibited by the bacteriostatic agent are Escherichia coli (Escherichia coli), staphylococcus aureus (Staphylococcus aureus), bacillus subtilis (Bacillus subtilis), saccharomyces cerevisiae (Saccharomyces cerevisiae) and/or salmonella enterica subspecies swine cholera serotype (Salmonella enterica subsp.
7. The method for preparing the novel alkaloid aplysingoniopora A according to claim 1, which comprises the following steps:
(1) Taking a columnar coral hydra sample, breaking the wall, crushing, and extracting with ethanol to obtain a crude extract;
(2) Separating the obtained crude extract of the sample by decompression normal phase silica gel column chromatography, carrying out gradient elution by using chloroform-methanol solution, collecting the eluate, decompressing, concentrating and drying, and merging the components to obtain 7 component extracts Fr.A 1-Fr.A7;
(3) Separating the obtained component extractum Fr.A5 by medium-pressure normal phase silica gel column chromatography, sequentially carrying out gradient elution by using chloroform-methanol solution, collecting the eluate, concentrating and drying under reduced pressure, and combining the components to obtain 5 component extractum Fr.A5-1-Fr.A5-5.
(4) Separating the obtained component extract Fr.A5-4 by pretreated ODS column chromatography, sequentially performing gradient elution with methanol-water solution, collecting eluate, performing TLC detection, developing color, concentrating the developed eluting part under reduced pressure to dry to obtain concentrate component Fr.A5-4-4 for use;
(5) And (3) separating the component extract Fr.A5-4-4 obtained in the step (4) through semi-preparative high performance liquid phase to obtain the novel alkaloid aplysingoniopora A.
CN202311516086.9A 2023-11-14 2023-11-14 Preparation method and application of novel alkaloid aplysingoniopora A Pending CN117567438A (en)

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