CN115804764B - Application of secoisolariciresinol diglucoside compound in preparation of medicine with respiratory syncytial virus resisting effect - Google Patents
Application of secoisolariciresinol diglucoside compound in preparation of medicine with respiratory syncytial virus resisting effect Download PDFInfo
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- CN115804764B CN115804764B CN202211594044.2A CN202211594044A CN115804764B CN 115804764 B CN115804764 B CN 115804764B CN 202211594044 A CN202211594044 A CN 202211594044A CN 115804764 B CN115804764 B CN 115804764B
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- -1 secoisolariciresinol diglucoside compound Chemical class 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 241000725643 Respiratory syncytial virus Species 0.000 title claims abstract description 24
- SBVBJPHMDABKJV-UHFFFAOYSA-N secoisolariciresinol diglycoside Natural products C1=C(O)C(OC)=CC(CC(COC2C(C(O)C(O)C(CO)O2)O)C(COC2C(C(O)C(O)C(CO)O2)O)CC=2C=C(OC)C(O)=CC=2)=C1 SBVBJPHMDABKJV-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 10
- PLGZOIJJUOHZJA-UHFFFAOYSA-N 2-butanoyl-4-[(3-butanoyl-2,6-dihydroxy-4-methoxy-5-methylphenyl)methyl]-3,5-dihydroxy-6,6-dimethylcyclohexa-2,4-dien-1-one Chemical compound CC1(C)C(=O)C(C(=O)CCC)=C(O)C(CC=2C(=C(C(=O)CCC)C(OC)=C(C)C=2O)O)=C1O PLGZOIJJUOHZJA-UHFFFAOYSA-N 0.000 claims abstract description 68
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of natural pharmaceutical chemistry, and particularly discloses application of a smoothie type phloroglucinol compound in preparation of a medicament with an anti-respiratory syncytial virus effect. The above-mentioned secoisolariciresinol diglucoside compound is selected from one or more of secoisolariciresinol diglucoside BB (aspidin BB), secoisolariciresinol diglucoside PB (aspidin PB), secoisolariciresinol diglucoside BB (desaspidin BB) and secoisolariciresinol diglucoside PB (desaspidin PB). The invention discovers that the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB have excellent effect of resisting respiratory syncytial virus for the first time; therefore, the active ingredient of the compound has important application value in preparing medicaments with the effect of resisting respiratory syncytial virus.
Description
Technical Field
The invention relates to the technical field of natural pharmaceutical chemistry, in particular to application of a smoothie phloroglucinol compound in preparation of a medicament with an anti-respiratory syncytial virus effect.
Background
Respiratory syncytial virus (Respiratory Syncytial Virus, RSV) is a single-stranded negative-strand, non-segmented RNA virus of the genus pneumovirus of the family paramyxoviridae, is the most common respiratory infectious virus other than influenza virus, and is also the main pathogen causing respiratory diseases in infants, the elderly and immunocompromised persons. RSV infection can cause severe bronchitis, pneumonia and exacerbation of chronic obstructive pulmonary disease, and in severe cases respiratory failure and even death, and it does not produce sustained immunity after infection, which can lead to life-long or repeated infection in the host. Thus, RSV infection has been listed as a global public health problem. However, there is no specific drug for treating RSV infection in clinic at present, and the commonly used antiviral drugs are mainly ribavirin and palivizumab. Among them, ribavirin (ribavirin) is a broad-spectrum antiviral drug currently acknowledged to have a certain curative effect on RSV, but it has higher toxicity to host cells, and its clinical curative effect remains controversial, and the american society of pediatrics only recommends high-risk infants for hospitalization; palivizumab (neutralizing antibody of RSV-F protein) can be clinically used for treating high-risk infants such as premature infants and bronchial dysplasia, and treating serious diseases of the lower respiratory tract caused by RSV infection, but the palivizumab has the defects of poor long-term effect, long service period, high cost and the like, and cannot be widely popularized and used. Thus, there remains a need to continually find and develop drugs with anti-respiratory syncytial virus effects.
Natural products have abundant and diverse chemical structures and good biological activities, and the searching and finding of active ingredients from traditional Chinese medicines and natural plants is an important way for finding lead substances or developing new medicines. And the Chinese herbal medicine has long history of treating infectious diseases, definite curative effect and unique advantages of broad-spectrum effect and small side effect. Therefore, the method for searching and developing the medicine with the effect of resisting the respiratory syncytial virus from the Chinese herbal medicines has good prospect.
Aspidin BB, low aspidin BB and low aspidin PB are known compounds isolated from Dryopteris platyphylla in the earlier stage of the subject group: as in document 1 (Chen NH, zhang YB, huang XJ, et al Drychammones A-C: three meroterpenoids from Dryopteris championii [ J ]. Journal of Organic Chemistry,2016,81 (19): 9443-9448), only the antibacterial activity thereof has been reported; it was not found to have an anti-respiratory syncytial virus effect until the completion of the present invention.
Heretofore, chinese patents CN 103102255A and CN105061179A disclose a method for separating and purifying phloroglucinol compounds including aspidin BB from dryopteris fragrans, and document 2 (Zuo Li, wang Hongqing, chen Reyun. Study of chemical composition of dryopteris fragrans [ J ]. Chinese herbal medicine, 2005,36 (2): 177-179) discloses a method for separating aspidin BB from dryopteris fragrans and physicochemical data identified by the same; in addition, chinese patent CN 103191086A discloses application of aspidin BB in preparing antitumor drugs, which has obvious inhibition effect on various tumor cells such as human breast cancer MCF-7, ovarian cancer HO-8910, prostate cancer PC-3, colon cancer HCT-8 and the like; document 3 (Sun Y, mu FS, li CY, et al, aspidin BB, a phloroglucinol derivative, induces cell cycle arrest and apoptosis in human ovarian HO-8910cells, chemico-Biological Interactions,2013,204,88-97) also discloses the antitumor effect of aspidin BB; in addition, chinese patents CN 111269105 A,CN 107837247A and CN105061179a, and literature 4 (Gao C, guo N, li N, et al invest of antibacterial activity of aspidin BB against Propionibacterium acids, arches of Dermatological Research,2016, 308:79-86.) and literature 5 (Li N, gao C, peng X, et al aspidin BB, a phloroglucinol derivative, exerts its antibacterial activity against Staphylococcus aureus by inducing the generation of reactive oxygen species, research in Microbiology,2014, 165:263-272) both disclose antimicrobial activity of aspidin BB or analogs thereof.
Although chinese patent CN 101502501a discloses that the use of compositions including aspidin BB may be involved in the treatment of viral infectious diseases, all that is mainly involved in the description are fungi, without any mention of viruses; it is not mentioned yet that it has an anti-respiratory syncytial virus effect. It is known in the art that the kinds of viruses are various, and even if one drug has an antiviral effect, it is difficult for those skilled in the art to predict whether it has an anti-respiratory syncytial virus effect without explicitly disclosing that it has an anti-respiratory syncytial virus effect. This is why there are numerous antiviral drugs at present, but only ribavirin and palivizumab have a therapeutic effect on respiratory syncytial virus.
In summary, the prior art does not disclose that aspidin BB, aspidin PB, low aspidin BB, low aspidin PB and the like have an anti-respiratory syncytial virus effect, but discloses that they have antibacterial, antitumor and other effects. Thus, based on the above prior art, it is not expected that such a secomalin-like phloroglucinol compound has an anti-RSV virus effect.
Disclosure of Invention
In order to overcome at least one technical problem existing in the prior art, the invention firstly provides application of a smoothie phloroglucinol compound in preparation of a medicament with an anti-respiratory syncytial virus effect.
The technical problems to be solved by the invention are realized by the following technical scheme:
the invention firstly provides application of a secoisolariciresinol diglucoside compound in preparation of a medicament with an anti-respiratory syncytial virus effect, wherein the secoisolariciresinol diglucoside compound is selected from any one or more than one of secoisolariciresinol diglucoside BB, secoisolariciresinol diglucoside PB, low secoisolariciresinol diglucoside BB and low secoisolariciresinol diglucoside PB.
The inventors have surprisingly found in the study that aspidin BB, aspidin PB, low aspidin BB and low aspidin PB have excellent anti-respiratory syncytial virus effect; therefore, the active ingredient of the compound has important application value in preparing medicaments with the effect of resisting respiratory syncytial virus.
The structural formulas of the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB are as follows:
preferably, the secoisolariciresinol diglucoside compound is selected from the group consisting of secoisolariciresinol diglucoside BB and secoisolariciresinol diglucoside BB.
Preferably, the mass ratio of the aspidin BB to the low aspidin BB is 1-3:1.
More preferably, the mass ratio of the aspidin BB to the low aspidin BB is 2-3:1.
The inventors have surprisingly found in further studies that after the aspidin BB and the low aspidin BB are combined, the anti-respiratory syncytial virus effect is significantly higher than that of the aspidin BB or the low aspidin BB alone, and the anti-respiratory syncytial virus effect is very excellent; the effect of the anti-respiratory syncytial virus is obviously higher than that of ribavirin. In particular, when the aspartyl BB and the low aspartyl BB are combined according to the mass ratio of 2-3:1, the effect of resisting respiratory syncytial virus is obviously higher than that of ribavirin. This is probably due to the synergistic effect of both aspidin BB and low aspidin BB when combined.
Furthermore, the inventors have surprisingly found that either aspirine BB or low aspirine BB, in combination with other compounds, or in combination with any two of the other compounds, does not have a significant increase in anti-respiratory syncytial virus effect compared to the compound prior to combination and does not produce a synergistic anti-respiratory syncytial virus effect.
Preferably, the medicament contains a therapeutically effective amount of a phloroglucinol compound of the secoisolariciresinol diglucoside type and a pharmaceutically acceptable carrier.
Preferably, the medicament is prepared into powder, pills, tablets, capsules, oral liquid, aerosol or injection.
The invention also provides a medicine with the effect of resisting respiratory syncytial virus, and the active ingredients of the medicine comprise any one or more than one of the following components of the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB.
Preferably, the active ingredients of the medicine with the effect of resisting respiratory syncytial virus comprise aspidin BB and low aspidin BB.
Further preferably, the mass ratio of the aspidin BB to the low aspidin BB is 1-3:1.
Preferably, the dosage form of the medicament is powder, pill, tablet, capsule, aerosol or injection.
The beneficial effects are that: the invention discovers that the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB have excellent effect of resisting respiratory syncytial virus for the first time; therefore, the active ingredient of the compound has important application value in preparing medicaments with the effect of resisting respiratory syncytial virus. Further researches of the inventor show that the combination of the aspart BB and the low aspart BB has a synergistic effect of resisting respiratory syncytial virus, and the combination of the aspart BB and the low aspart BB has a more excellent effect of resisting respiratory syncytial virus, and the effect of resisting respiratory syncytial virus is close to or even higher than that of ribavirin.
Detailed Description
The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way.
EXAMPLE 1 Studies of anti-RSV Activity of Mirabilin-type phloroglucinol Compounds
The anti-RSV activity of the phloroglucinol compound is tested by adopting a plaque reduction experiment method, and the specific method is as follows: (1) HEp-2 cells were seeded into 24-well cell culture plates (1 mL for each well, cell density 2X 10) 5 cell/mL) followed by 37℃at 5% CO 2 Culturing in an incubator until a cell monolayer grows; (2) 100 mu L of 100PFU/mL respiratory syncytial virus suspension and 100 mu L of medicines with different concentrations are added into each hole, and a cell control group and a virus control group are simultaneously arranged; placed at 37 ℃ and 5% CO 2 Culturing in an incubator for 2 hours. Every 15min, the virus is gently swayed in a crisscross manner, so that the virus is uniformly and fully adsorbed and penetrates into cells; (3) After virus is adsorbed for 2 hours, absorbing and discarding virus liquid, washing for 2 times by using PBS, adding 0.5mL of agarose gel covering liquid into each hole, adding 0.5mL of medicine with corresponding concentration after the covering liquid is solidified, and adding an equal volume of maintenance liquid into a cell control group and a virus control group; (4) Placing a 24-hole plate into a cell culture box for culturing for 4-5 d, adding 10% formaldehyde for fixing overnight, discarding agarose gel, staining with 1% crystal violet for 30min, lightly flushing the 24-hole culture plate with tap water, airing and counting the number of plaques. Calculating the plaque inhibition rate of the sample, and further calculating the half inhibition concentration IC 50 The method comprises the steps of carrying out a first treatment on the surface of the Plaque inhibition ratio = [ (plaque number of virosome-plaque number of pharmacosome)/plaque number of virosome]×100％。
By adopting the method, the anti-respiratory syncytial virus activity of the following experimental group medicaments is tested; the test results are shown in Table 1.
Experiment group 1: aspidin BB;
experiment group 2: aspidin PB;
experiment group 3: low aspidin BB;
experiment group 4: low aspidin PB;
experimental group 5: a combination of the aspidin BB and the aspidin PB according to a mass ratio of 1:1;
experiment group 6: a combination of aspidin BB and low aspidin PB in a mass ratio of 1:1;
experiment group 7: a combination of the aspidin PB and the low aspidin BB in a mass ratio of 1:1;
experiment group 8: a combination of the aspidin PB and the low aspidin PB in a mass ratio of 1:1;
experiment group 9: a combination of low-content aspidin BB and low-content aspidin PB in a mass ratio of 1:1;
experimental group 10: a combination of the aspidin BB and the low aspidin BB in a mass ratio of 1:1;
experiment group 11: a combination of the aspidin BB and the low aspidin BB in a mass ratio of 2:1;
experiment group 12: a combination of aspidin BB and low aspidin BB in a mass ratio of 3:1.
Experiment group 13: ribavirin.
TABLE 1 results of test of anti-RSV Activity of secoisolariciresinol diglucoside compounds
As can be seen from the test results of the anti-RSV activity of the experimental groups 1 to 4 in Table 1, the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB all have strong anti-respiratory syncytial virus effect; wherein, the aspidin BB shows the optimal anti-respiratory syncytial virus effect, and the anti-respiratory syncytial virus effect is equivalent to that of ribavirin, and is obviously higher than that of aspidin BB and is greatly higher than that of aspidin PB and low aspidin PB.
From the test results of the anti-RSV activity in the experimental groups 5 to 12, it can be seen that: after the experimental groups 10-12 use the aspidin BB and the low aspidin BB, the effect of resisting respiratory syncytial virus is obviously higher than that of single aspidin BB or low aspidin BB, and the effect of resisting respiratory syncytial virus is very excellent; the effect of the anti-respiratory syncytial virus is obviously higher than that of ribavirin. In particular, when the aspartyl BB and the low aspartyl BB are combined according to the mass ratio of 2-3:1, the effect of resisting respiratory syncytial virus is obviously higher than that of ribavirin. In experimental groups 5 to 9, after the combination of the aspartyl BB or the low aspartyl BB with other compounds, or after the combination of the aspartyl PB and the low aspartyl PB, the effect of resisting respiratory syncytial virus cannot be significantly improved compared with the compound before the combination, and is also significantly smaller than the combination of the aspartyl BB and the low aspartyl BB. This illustrates: only after the aspirine BB and the low aspirine BB are combined, compared with the compound before the combination, the anti-respiratory syncytial virus effect can be obviously improved, the antiviral effect can be higher than that of the compound even more obviously than that of the ribavirin, and the synergistic anti-respiratory syncytial virus effect can be generated; however, either aspirine BB or low aspirine BB, in combination with other compounds, or any combination of both, does not provide a significant increase in anti-respiratory syncytial virus effect as compared to the compound prior to combination, and does not provide a synergistic anti-respiratory syncytial virus effect.
Example 2 preparation of tablets
Taking 1g of each of the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB, respectively mixing with 27g of microcrystalline cellulose and 2g of magnesium stearate, and preparing the mixture into tablets with the weight of 300 mg/tablet by a single-punch tablet press.
Example 3 preparation of tablets
Mixing 0.5g of each of aspidin BB and low aspidin BB with 27g of microcrystalline cellulose and 2g of magnesium stearate, and making into tablet with weight of 300 mg/tablet by a single punch tablet press.
Example 4 preparation of capsules
Taking 1g of each of the aspidin BB, the aspidin PB, the low aspidin BB and the low aspidin PB, respectively mixing with 27g of lactose and 2g of magnesium stearate, and filling into capsules every 300 mg.
Example 5 preparation of capsules
Mixing 0.5g of each of aspidin BB and low aspidin BB with 27g of lactose and 2g of magnesium stearate, and making into capsule by filling every 300 mg.
Claims (5)
1. The application of the secoisolariciresinol diglucoside compound in preparing a medicament with the effect of resisting respiratory syncytial virus is characterized in that the secoisolariciresinol diglucoside compound is selected from any one or more than one of secoisolariciresinol diglucoside BB and secoisolariciresinol diglucoside BB.
2. The use of a phloroglucinol compound of the type of claim 1 in the manufacture of a medicament having an anti-respiratory syncytial virus effect, wherein the phloroglucinol compound of the type of phloroglucinol is selected from the group consisting of a combination of aspirine BB and low aspirine BB.
3. The use of a phloroglucinol compound in accordance with claim 2 for the manufacture of a medicament having an anti-respiratory syncytial virus effect, characterized in that the mass ratio of aspidin BB to low aspidin BB is 1-3:1.
4. The use of a phloroglucinol compound of the type of claim 1 in the manufacture of a medicament for use against respiratory syncytial virus, wherein the medicament comprises a therapeutically effective amount of the phloroglucinol compound of the type of bregmatocyst and a pharmaceutically acceptable carrier.
5. The use of a phloroglucinol compound in accordance with claim 1 for the manufacture of a medicament having an anti-respiratory syncytial virus effect, wherein the medicament is formulated as a powder, pill, tablet, capsule, oral liquid, aerosol or injection.
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| CN101502501A (en) * | 2009-03-03 | 2009-08-12 | 广东药学院 | Anti-infective medicament composition and application |
| CN103191086A (en) * | 2012-01-05 | 2013-07-10 | 东北林业大学 | Application of aspidin BB in dryopteris fragrans in preparing antitumor medicines |
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| CN101502501A (en) * | 2009-03-03 | 2009-08-12 | 广东药学院 | Anti-infective medicament composition and application |
| CN103191086A (en) * | 2012-01-05 | 2013-07-10 | 东北林业大学 | Application of aspidin BB in dryopteris fragrans in preparing antitumor medicines |
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