CN103463023B - 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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- CN103463023B CN103463023B CN201310435573.2A CN201310435573A CN103463023B CN 103463023 B CN103463023 B CN 103463023B CN 201310435573 A CN201310435573 A CN 201310435573A CN 103463023 B CN103463023 B CN 103463023B
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- lycojaponicumin
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- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 10
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- 241000894006 Bacteria Species 0.000 description 11
- 238000012360 testing method Methods 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 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
- 238000000034 method Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
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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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- 229920002472 Starch Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 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
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- 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
- -1 compound dimethyl sulfoxide Chemical class 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
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- 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
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- 210000004877 mucosa Anatomy 0.000 description 1
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- 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
- 230000001717 pathogenic effect Effects 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
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- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004206 stomach function Effects 0.000 description 1
- 230000001629 suppression 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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, particularly relate to Lycojaponicumin B and preparing the application in Anti-helicobacter pylori drugs.
Background technology
Helicobacter pylori (Helicobacter pylori, Hp) is a kind of Gram-negative spiral bacteria.Research display, helicobacter pylori is the primary pathogenic event of acute and chronic gastritis and taste-blindness rate, and may fall ill relevant with gastric cancer stomach function regulating mucosa-associated lymphoid tissue (MALT) malignant lymphoma.Recently, Hp is classified as I class carcinogen by World Health Organization (WHO), and it plays a leading role in stomach cancer development.Simultaneously the scheme that popular at present treatment Hp infects takes the triple therapy that proton pump inhibitor (PPI) adds two kinds of antibiotic (clarithromycin, amoxicillin, tetracycline, metronidazole etc. select two kinds).The main factor affecting 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 then causes 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 that the present invention relates to is one and delivers (Wang in 2012, X.J.etal., 2012.Lycojaponicumins A-C, Three Alkaloids with an UnprecedentedSkeleton from Lycopodium japonicum.Organic Letters 14 (10), New skeleton compound 2614-2617.), this compound has brand-new framework types, the purposes of the Lycojaponicumin B that the present invention relates in preparation treatment Anti-helicobacter pylori drugs is belonged to first public, because framework types belongs to brand-new framework types, and it is unexpectedly strong for helicobacter pylori inhibit activities, there is not the possibility being provided any enlightenment by other compounds, possesses outstanding substantive distinguishing features, control simultaneously for helicobacter pylori infections obviously has significant progress.
Summary of the invention
The object of the invention is the application of research 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 it is 29mm (ATCC43504) that paper disk method shows its antibacterial circle diameter.With agar dilution display, it can suppress the growth of 5 random clinical strains (Hp001, Hp003, Hp004, Hp018 and Hp036) and 1 reference culture (ATCC43504) completely, and minimal inhibitory concentration (MIC) is 1.0 μ g/ml.Make positive control with ampicillin, its Cmin (MIC) suppressed completely 6 strain test bacterium is 0.5 μ g/ml.
This result of study shows, the energy force rate ampicillin of the suppression helicobacter pylori activity of Lycojaponicumin B is strong, illustrate 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 that the present invention relates in preparation treatment Anti-helicobacter pylori drugs belongs to first public, because framework types belongs to brand-new framework types, and it is unexpectedly strong for helicobacter pylori inhibit activities, there is not the possibility being provided any enlightenment by other compounds, possess outstanding substantive distinguishing features, the control simultaneously for helicobacter pylori infections obviously has significant progress.
Detailed description of the invention
The preparation method of compound L ycojaponicumin B involved in the present invention is see document (Wang, X.J.et al., 2012.Lycojaponicumins A-C, Three Alkaloids with an Unprecedented Skeleton from Lycopodiumjaponicum.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 by 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 g of compound Lycojaponicumin B, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
Embodiment 2: the preparation of compound L ycojaponicumin B capsule involved in the present invention:
Get 20 g of compound Lycojaponicumin B, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Its pharmaceutically active is further illustrated 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 Culture Collection (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; To the patient of peptic ulcer, duodenal bulbar inflammation or gastritis verrucosa in continuous gastroscopy, first be defined as Hp positive through RUT experiment, get antral gastric mucosa 1-2 block again, be inoculated in containing 8% horse serum, trimethoprim (trimethropin after chopping, in the Columbia selectivity agar culture medium of TMP) 1.25g/L, polymyxin (polymyxin) B2500U/L, vancomycin (vancomycin) 10mg/L, in 37 DEG C of (5%O under micro-oxygen environment
2, 10%CO
2and 85%N
2) cultivate 72 hours.Collect antibacterial, through smear Gram’s staining, after oxidase, catalase and urease are accredited as the positive, 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 produces the micro-aerobic environment required for Hp by chemical reaction.
3) biological activity determination
Paper disk method (Microbiological paper method) is adopted to measure the inhibitory action of compound to helicobacter pylori, the minimum inhibitory concentration (minimal inhibitoryconcentration, MIC) of test sample is measured with agar dilution.
I. paper disk method experiment
(A) culture medium is prepared by the Columbia culture medium for preparing after high pressure steam sterilization, be cooled to 50-60 DEG C, add 8% horse serum or Sheep Blood, mixing is poured in the culture dish of sterilizing, every ware 7-10ml, culture medium thickness is 1.5mm (sterile working).
(B) experimental bacteria of transferring (being coated with bacterium) gets diluted 10 with microscale sampler
8cFU/ml (1OD
660=10
8cFU/ml) the bacteria suspension 0.1ml of Hp spreads upon suitable culture dish surface equably.Be inverted in
take out after 15min in drying baker, object makes agar surface dry, for subsequent use.
(C) paste sample scraps of paper microscale sampler to get 6 μ l testing samples (mass concentration 2mg/ml) and inject on the round filter paper of sterilizing.With 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 bacterio-agar surface, paste a piece of paper sheet at a certain distance.Often kind of bacterium is cooked 3 wares, and acquired results asks its meansigma methods.
(D) each plate is placed in micro-aerobic bag by cultivation, and sealing, opens gas generator, then be placed in
72h is cultivated in incubator.
(E), after surveying antibacterial circle diameter taking-up flat board, the size of antibacterial circle diameter around each scraps of paper is measured respectively.With reference to the result of matched group, the result of testing sample sensitive experiment can be drawn.In triplicate.
II. agar dilution measures MIC
(A) first compound dimethyl sulfoxide (DMSO) solution preparation of test is become the mother solution of 0.5mg/ml by the preparation of Drug plates, then with sterilized water dilution, is finally made into 10.0,8.0,6.0,4.5,4.0,3.5,3.0,2.5,2.0,1.5,1.0, the concentration series of 0.5 and 0.25 μ g/ml, DMSO concentration is in media as well less than 1%.The test compounds solution prepared by 1ml separately adds in the 9ml Columbia medium of 50 DEG C the horse serum that 1ml is incubated in 50 DEG C and fully mixes with being incubated, and casts in culture dish to cool.
(B) experimental bacteria of transferring (being coated with bacterium) draws diluted 1 × 10 with microscale sampler
8the bacteria suspension 0.1ml of CFU/ml Hp spreads upon culture dish surface equably, is inverted in
take out after 15min in drying baker, object makes agar surface dry, for subsequent use.
(C) determine that test dish (contains: 85%N at micro-aerobic bag by MIC
2, 10%CO
2and 5%O
2) in, be incubated 37 DEG C and cultivate 72 hours, observe Hp growing state, contrast with blank group, there is no the sample least concentration of bacteria growing completely for 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 it is 29mm (ATCC43504) that paper disk method shows its antibacterial circle diameter.With agar dilution display, it can suppress the growth of 5 random clinical strains (Hp001, Hp003, Hp004, Hp018 and Hp036) and 1 reference culture (ATCC43504) completely, and minimal inhibitory concentration (MIC) is 1.0 μ g/ml.Make positive control with ampicillin, its Cmin (MIC) suppressed completely 6 strain test bacterium is 0.5 μ g/ml.
Conclusion: Lycojaponicumin B suppresses the ability of helicobacter pylori activity only more weak than ampicillin, illustrate 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 B is preparing the application 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 |
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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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|---|---|---|---|
| CN201310435573.2A CN103463023B (en) | 2013-09-23 | 2013-09-23 | Application of Lycojaponicumin B in helicobacter pylori resistant medicine |
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| CN103463023B true CN103463023B (en) | 2015-07-08 |
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