CN103463023A - Application of Lycojaponicumin B in helicobacter pylori resistant medicine - Google Patents
Application of Lycojaponicumin B in helicobacter pylori resistant medicine Download PDFInfo
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- CN103463023A CN103463023A CN2013104355732A CN201310435573A CN103463023A CN 103463023 A CN103463023 A CN 103463023A CN 2013104355732 A CN2013104355732 A CN 2013104355732A CN 201310435573 A CN201310435573 A CN 201310435573A CN 103463023 A CN103463023 A CN 103463023A
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- lycojaponicumin
- helicobacter pylori
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- 229930185194 lycojaponicumin Natural products 0.000 title claims abstract description 26
- 229940037467 helicobacter pylori Drugs 0.000 title claims abstract description 22
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- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 208000007882 Gastritis Diseases 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 7
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- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229960000723 ampicillin Drugs 0.000 description 6
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 6
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- 241000927897 Lycopodium japonicum Species 0.000 description 2
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- 206010017758 gastric cancer Diseases 0.000 description 2
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- 229940126409 proton pump inhibitor Drugs 0.000 description 2
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
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- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
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- 229920002472 Starch Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
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- 108010046334 Urease Proteins 0.000 description 1
- 241001661641 Verrucosa Species 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
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- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
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- 230000002183 duodenal effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002575 gastroscopy Methods 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000004206 stomach function Effects 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003245 working effect Effects 0.000 description 1
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- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
In-vitro activity experiments show that Lycojaponicumin B has strong helicobacter pylori (Hp) resistant activity. The Lycojaponicumin B can be applied to treatment of diseases, such as acute and chronic gastritis and gastric and duodenal ulcer, and preparation of medicines for treating the acute and chronic gastritis and the gastric and duodenal ulcer. The application of the Lycojaponicumin B in preparation of the Hp resistant medicine is disclosed for the first time. The skeleton type of the Lycojaponicumin B belongs to a brand-new skeleton type, and the inhibiting activity of the Lycojaponicumin B on the Hp is unexpectedly strong, so that no possibility for providing any inspiration by other compounds exists. The Lycojaponicumin B has predominant substantial characteristics and obviously has a remarkable progress in prevention and treatment of Hp infection.
Description
Technical field
The invention belongs to biological pharmacy technical field, relate in particular to the application of Lycojaponicumin B in preparing Anti-helicobacter pylori drugs.
Background technology
Helicobacter pylori (Helicobacter pylori, Hp) is a kind of Gram-negative spiral bacteria.Studies show that, helicobacter pylori is the main pathogenesis of acute and chronic gastritis and Stomach duodenum ulcer, and may be relevant with the morbidity of gastric cancer stomach function regulating mucosa-associated lymphoid tissue (MALT) malignant lymphoma.Recently, World Health Organization (WHO) is classified as I class carcinogen by Hp, and it plays a leading role in the gastric cancer development.The scheme that at present popular treatment Hp infects is to take the triple therapy that proton pump inhibitor (PPI) adds two kinds of antibiotic (clarithromycin, amoxicillin, tetracycline, metronidazole etc. select two kinds) simultaneously.The main factor that affects triple therapy is considered to the drug resistance of Hp to antibacterial; Another serious problems are that proton pump inhibitor can bring out dyspepsia, and a large amount of antibacterial cause the serious destruction of flora in digestive tract.Therefore, find the active kind new medicine thing of efficient, safe anti-Hp and become an important and urgent task.
The compound L ycojaponicumin B the present invention relates to is one and within 2012, delivers (Wang, X. J. et al., 2012. Lycojaponicumins A-C, Three Alkaloids with an Unprecedented Skeleton from Lycopodium japonicum. Organic Letters 14 (10), 2614-2617.) New skeleton compound, this compound has brand-new framework types, purposes for the Lycojaponicumin B the present invention relates in preparation treatment Anti-helicobacter pylori drugs belongs to open first, because framework types belongs to brand-new framework types, and it suppresses active unexpectedly strong for helicobacter pylori, there do not is the possibility that is provided any enlightenment by other compounds, possesses outstanding substantive distinguishing features, control for helicobacter pylori infections simultaneously obviously has significant progress.
Summary of the invention
The objective of the invention is to study the application of Lycojaponicumin B in Anti-helicobacter pylori drugs.
Described compound L ycojaponicumin B structure is as shown in formula I:
The experiment in vitro of Lycojaponicumin B shows, Lycojaponicumin B has very strong anti Helicobacter pylori activity, and paper disk method shows that its antibacterial circle diameter is 29 mm (ATCC43504).Show that with agar dilution it can suppress the growth of 5 random clinical strains (Hp001, Hp003, Hp004, Hp018 and Hp036) and 1 reference culture (ATCC43504) fully, minimal inhibitory concentration (MIC) is 1.0 μ g/ml.Make positive control with ampicillin, its Cmin (MIC) that 6 strain test bacterium are suppressed fully is 0.5 μ g/ml.
This result of study shows, the energy force rate ampicillin of the inhibition helicobacter pylori activity of Lycojaponicumin B is strong, explanation for the diseases such as the closely-related acute and chronic gastritis of helicobacter pylori, duodenal ulcer, Lycojaponicumin B is the compound of a great exploitation potential for its.It can be directly used in the treatment of corresponding disease and the preparation of related drugs.
The purposes of the Lycojaponicumin B the present invention relates in preparation treatment Anti-helicobacter pylori drugs belongs to open first, because framework types belongs to brand-new framework types, and it suppresses active unexpectedly strong for helicobacter pylori, there do not is the possibility that is provided any enlightenment by other compounds, possess outstanding substantive distinguishing features, the control for helicobacter pylori infections simultaneously obviously has significant progress.
The specific embodiment
The preparation method of compound L ycojaponicumin B involved in the present invention is referring to document (Wang, X. J. et al., 2012. Lycojaponicumins A-C, Three Alkaloids with an Unprecedented Skeleton from Lycopodium japonicum. Organic Letters 14 (10), 2614-2617.).
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to any restriction of specific embodiment, but be limited by claim.
Embodiment 1: the preparation of compound L ycojaponicumin B tablet involved in the present invention:
Get 20 and digest compound Lycojaponicumin B, add conventional adjuvant 180 grams that prepare tablet, mix, conventional tablet machine is made 1000.
Embodiment 2: the preparation of compound L ycojaponicumin B capsule involved in the present invention:
Get 20 and digest compound Lycojaponicumin B, add the conventional adjuvant for preparing capsule as starch 180 grams, mix, encapsulatedly make 1000.
Further illustrate its pharmaceutically active below by pharmacodynamic experiment.
The pharmacological evaluation of Lycojaponicumin B
1) strains tested
Helicobacter pylori (Helicobacter pylori, Hp) reference culture ATCC 43504 is purchased from U.S.'s strain and preserves center (American Type Culture Collection, ATCC).15 strain Hp clinical strains are picked up from Jiangsu Prov. People's Hospital Gastroenterology dept., clinical laboratory of Jiangsu TCM Hospital and Nanjing Children's Hospital Dndoscope Laboratory and are accepted gastroscopic patient; In continuous gastroscopy to the patient of peptic ulcer, duodenal bulbar inflammation or gastritis verrucosa, first through the RUT experiment, be defined as the Hp positive, get again antral gastric mucosa 1-2 piece, after chopping, be inoculated in containing 8% horse serum, trimethoprim (trimethropin, TMP) in the Columbia selectivity agar culture medium of 1.25 g/L, polymyxin (polymyxin) B2500 U/L, vancomycin (vancomycin) 10 mg/L, in 37 ° of C (5% O under micro-oxygen environment
2, 10% CO
2with 85% N
2) cultivate 72 hours.Collect antibacterial, through the smear Gram’s staining, after oxidase, catalase and urease are accredited as the positive, the pure culture of going down to posterity, obtained strains is as experimental strain.
2) strain culturing
We adopt micro-aerobic bag (purchased from Shanghai Medical Univ) to carry out the strain culturing of HP, and it can produce the needed micro-aerobic environment of Hp by chemical reaction.
3) biological activity determination
Adopt paper disk method (Microbiological paper method) to measure the inhibitory action of compound to helicobacter pylori, measure the minimum inhibitory concentration (minimal inhibitory concentration, MIC) of test sample with agar dilution.
I. paper disk method experiment
(A) prepare culture medium by the Columbia culture medium for preparing after high pressure steam sterilization, be cooled to 50-60 ℃, add 8% horse serum or Sheep Blood, mix in the culture dish that is poured into sterilizing, every ware 7-10 ml, culture medium thickness is 1.5 mm (sterile workings).
(B) switching experimental bacteria (be coated with bacterium) with microscale sampler get diluted 10
8cFU/ml (1OD
660=10
8cFU/ml) bacteria suspension 0.1 ml of Hp spreads upon suitable culture dish surface equably.Be inverted in the 37oC drying baker and take out after 15 min, purpose makes the agar surface drying, standby.
(C) pasting the sample scraps of paper gets 6 μ l testing samples (mass concentration 2 mg/ml) with microscale sampler and injects on the round filter paper of sterilizing.With the aseptic nipper tweezer containing the scraps of paper of sample and the blank scraps of paper of contrast, by sterile working respectively the scraps of paper be close to containing the bacterio-agar surface, paste at a certain distance a piece of paper sheet.Every kind of bacterium is cooked 3 wares, and acquired results is asked its meansigma methods.
(D) cultivate each plate is placed in to micro-aerobic bag, sealing, open gas generator, then be placed in the 37oC incubator and cultivate 72h.
(E) after surveying antibacterial circle diameter taking-up flat board, measure respectively each scraps of paper size of antibacterial circle diameter on every side.With reference to the result of matched group, can draw the result of testing sample sensitive experiment.Triplicate.
II. agar dilution is measured MIC
(A) at first the preparation of medicine flat board becomes dimethyl sulfoxide for compound (DMSO) solution preparation of test the mother solution of 0.5 mg/ml, then, with the sterilized water dilution, finally is made into 10.0,8.0,6.0,4.5,4.0,3.5,3.0,2.5,2.0,1.5,1.0,0.5, with the concentration series of 0.25 μ g/ml, the concentration of DMSO in medium is less than 1%.The test compounds solution that 1 ml is prepared separately adds 1 ml in the 9 ml Colombia culture medium of 50 ° of C and is incubated in the horse serum of 50 ° of C and fully mixes with being incubated, and casts in culture dish cooling.
(B) switching experimental bacteria (be coated with bacterium) with microscale sampler draw diluted 1 * 10
8bacteria suspension 0.1 ml of CFU/ml Hp spreads upon the culture dish surface equably, is inverted in the 37oC drying baker and takes out after 15 min, and purpose makes the agar surface drying, standby.
(C) determine that MIC (contains culture dish to be measured: 85% N at micro-aerobic bag
2, 10% CO
2with 5% O
2) in, be incubated 37
oc cultivates 72 hours, observes the Hp growing state, with blank group contrast, take and there is no the sample of bacteria growing least concentration fully as minimum inhibitory concentration (minimal inhibitory concentration, MIC) value.Positive control is ampicillin (Ampicillin).
3, the pharmacological results of Lycojaponicumin B
Experiment in vitro shows, Lycojaponicumin B has very strong anti Helicobacter pylori activity, and paper disk method shows that its antibacterial circle diameter is 29 mm (ATCC43504).Show that with agar dilution it can suppress the growth of 5 random clinical strains (Hp001, Hp003, Hp004, Hp018 and Hp036) and 1 reference culture (ATCC43504) fully, minimal inhibitory concentration (MIC) is 1.0 μ g/ml.Make positive control with ampicillin, its Cmin (MIC) that 6 strain test bacterium are suppressed fully is 0.5 μ g/ml.
Conclusion: the ability that Lycojaponicumin B suppresses the helicobacter pylori activity only than a little less than ampicillin some, explanation for the diseases such as the closely-related acute and chronic gastritis of helicobacter pylori, duodenal ulcer, Lycojaponicumin B is the compound of a great exploitation potential for its.It can be directly used in the treatment of corresponding disease and the preparation of related drugs.
Claims (1)
1.Lycojaponicumin the application of B in Anti-helicobacter pylori drugs, described compound L ycojaponicumin B structure as
formula Ishown in:
formula I.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310435573.2A CN103463023B (en) | 2013-09-23 | 2013-09-23 | Application of Lycojaponicumin B in helicobacter pylori resistant medicine |
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|---|---|---|---|
| CN201310435573.2A CN103463023B (en) | 2013-09-23 | 2013-09-23 | Application of Lycojaponicumin B in helicobacter pylori resistant medicine |
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| CN103463023A true CN103463023A (en) | 2013-12-25 |
| CN103463023B CN103463023B (en) | 2015-07-08 |
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ID=49788221
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|---|---|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059043A (en) * | 2011-10-24 | 2013-04-24 | 中国医学科学院药物研究所 | Clavatine A-C and preparation method as well as pharmaceutical composition and application thereof |
-
2013
- 2013-09-23 CN CN201310435573.2A patent/CN103463023B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059043A (en) * | 2011-10-24 | 2013-04-24 | 中国医学科学院药物研究所 | Clavatine A-C and preparation method as well as pharmaceutical composition and application thereof |
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