CN115737628B - Application of bergenin sulfonate derivative in resisting drug-resistant bacteria activity - Google Patents
Application of bergenin sulfonate derivative in resisting drug-resistant bacteria activity Download PDFInfo
- Publication number
- CN115737628B CN115737628B CN202211545776.2A CN202211545776A CN115737628B CN 115737628 B CN115737628 B CN 115737628B CN 202211545776 A CN202211545776 A CN 202211545776A CN 115737628 B CN115737628 B CN 115737628B
- Authority
- CN
- China
- Prior art keywords
- bergenin
- resistant bacteria
- drug
- sulfonate derivative
- activity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 bergenin sulfonate derivative Chemical class 0.000 title claims abstract description 70
- XULPLJSODQQHPH-UHFFFAOYSA-N Bergenin Natural products OCC1OC2C(OC(=O)c3cc(O)c(CO)c(O)c23)C(O)C1O XULPLJSODQQHPH-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 230000000694 effects Effects 0.000 title claims abstract description 26
- 229940079593 drug Drugs 0.000 title claims abstract description 22
- 241000894006 Bacteria Species 0.000 title claims abstract description 17
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 claims 1
- 235000009754 Vitis X bourquina Nutrition 0.000 claims 1
- 235000012333 Vitis X labruscana Nutrition 0.000 claims 1
- 240000006365 Vitis vinifera Species 0.000 claims 1
- 235000014787 Vitis vinifera Nutrition 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- 206010006187 Breast cancer Diseases 0.000 abstract description 5
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 5
- 206010009944 Colon cancer Diseases 0.000 abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 5
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 5
- 201000007270 liver cancer Diseases 0.000 abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 abstract description 5
- 201000005202 lung cancer Diseases 0.000 abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 abstract description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 4
- 208000032839 leukemia Diseases 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 241001454768 Mentzelia nuda Species 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- YWJXCIXBAKGUKZ-HJJNZUOJSA-N Bergenin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]2C3=C(O)C(OC)=C(O)C=C3C(=O)O[C@@H]21 YWJXCIXBAKGUKZ-HJJNZUOJSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 229960004316 cisplatin Drugs 0.000 description 6
- 230000036512 infertility Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 150000003871 sulfonates Chemical class 0.000 description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 3
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000000719 anti-leukaemic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- 241001092371 Bergenia Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000941 anti-staphylcoccal effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
-
- 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
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of bergenin sulfonate derivative in the aspect of drug-resistant bacteria resistance, belonging to the field of pharmaceutical chemistry. The bergenin sulfonate derivative has the structure ofWherein R is 1 Is C1-C4 alkyl or arylsulfonyl, R 2 Is hydrogen, C1-C4 alkane, benzyl or substituted benzyl. Preliminary biological activity tests show that the compounds can effectively inhibit leukemia, lung cancer, liver cancer, breast cancer, colon cancer cell lines and the like, have better anti-tumor and drug-resistant bacteria activity, and provide good mother nucleus structural units for the research of anti-tumor and drug-resistant bacteria lead compounds.
Description
The invention is a divisional application, and the original patent name is: bergenin sulfonate derivative and application thereof, as per the original application number: 2022101653599, date of filing: 2022, 2 and 23.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to application of bergenin sulfonate derivatives in the aspect of drug-resistant bacteria resistance.
Background
Bergenia is a very important natural medicine and has long been used as an antitussive in China. Bergenin becomes an important pharmaceutical lead compound based on its specific structure and remarkable biological activity. The bergenin is used as a raw material to obtain a plurality of compounds with remarkable biological activity through structural modification, for example, 11-site aryl ester bergenin derivatives have tyrosinase inhibition effect, 11-site fatty ester bergenin derivatives have antioxidant, anti-inflammatory and anti-anesthetic effects, and 11-site nitrogen heterocyclic group substituted bergenin derivatives have anti-leukemia activity.
In recent years, the regioselective esterification reaction plays an important role in the development of new drugs, and has become a research hotspot. The development of a synthesis method for synthesizing the selective esterified bergenin compound has important significance for synthesizing the bergenin compound and developing new medicines.
The literature reports about bergenin 11-position structural modification, most of the bergenin is carboxylic ester derivative, the bergenin sulfonate derivative is very few, and the research on the anti-tumor activity of the bergenin sulfonate derivative is also very few at present, so the method has great significance for the synthesis of the bergenin sulfonate derivative, the research on anti-tumor, antibacterial and the like.
Disclosure of Invention
In order to overcome the defects in the prior art, enrich the variety of bergenin derivatives and the application thereof in medicine, a bergenin sulfonate derivative and the application thereof are provided.
In order to achieve the above purpose, the invention provides a bergenin sulfonate derivative, which has the following structural general formula:
wherein R is 1 Is C1-C4 alkylsulfonyl or arylsulfonyl, R 2 Is hydrogen, C1-C4 alkane, benzyl or substituted benzyl.
Further preferred is R 1 Is benzenesulfonyl, 4-methylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-trifluoromethoxybenzenesulfonyl, 4-nitrobenzenesulfonyl, thiazolesulfonyl, naphthalenesulfonyl, methanesulfonyl, ethylsulfonyl, propylsulfonyl or cyclopropylsulfonyl; r is R 2 Is benzyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-fluorobenzyl, hydrogen, methyl, ethyl, propyl or butyl.
Further, in the above technical scheme, the bergenin sulfonate derivative is prepared by the following two methods:
the synthesis method has the advantages of short synthesis route, high product yield, simple post-treatment and low cost, and is very suitable for industrialization.
The invention also provides application of the bergenin sulfonate derivative in an anti-tumor medicament. The bergenin sulfonate derivative has the following structural general formula:
wherein R is 1 Is C1-C4 alkylsulfonyl or arylsulfonyl, R 2 Is hydrogen, C1-C4 alkane, benzyl or substituted benzyl.
Further, in the above technical solution, the R 1 Is benzenesulfonyl, 4-methylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-trifluoromethoxybenzenesulfonyl, 4-nitrobenzenesulfonyl, thiazolesulfonyl, naphthalenesulfonyl, methanesulfonyl, ethylsulfonyl, propylsulfonyl or cyclopropylsulfonyl.
Further, in the above technical solution, the R 2 Is benzyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-fluorobenzyl, hydrogen, methyl, ethyl, propyl or butyl.
Further, in the above technical scheme, the antitumor activity is leukemia, lung cancer, liver cancer, breast cancer and colon cancer resistance.
The invention also provides application of the bergenin sulfonate derivative in preparing medicines for resisting drug-resistant bacteria. The bergenin sulfonate derivative has the following structural general formula:
further, in the above technical solution, the R 1 Is benzenesulfonyl, 4-methylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-fluorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-trifluoromethoxybenzenesulfonyl, 4-nitrobenzenesulfonyl, thiazolesulfonyl, naphthalenesulfonyl, methanesulfonyl, ethylsulfonyl, propylsulfonyl or cyclopropylsulfonyl.
Further, in the above technical solution, the R 2 Is benzyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-fluorobenzyl, hydrogen, methyl, ethyl, propyl or butyl.
Further, in the above technical scheme, the drug-resistant bacteria are staphylococcus aureus, escherichia coli or salmonella.
Advantageous effects of the invention
According to the invention, from commercialized bergenin, bergenin sulfonate derivatives can be obtained through two simple continuous reactions. The method has the advantages of good regioselectivity, low cost, mild reaction conditions and simple purification of intermediates and final target products in the whole process.
Wherein, the bergenin in the first step can be directly subjected to the next reaction after being subjected to alkane protection and post-treatment; and secondly, reacting the reaction product of the first step with sulfonyl chloride to obtain a corresponding sulfonate compound, and recrystallizing the product to obtain a pure product.
The invention improves the acylation reaction condition, has milder reaction condition, better 11-acylation selectivity, high product yield, simple post-treatment and easy operation, can reuse the solvent and is beneficial to mass production popularization. The invention enriches the application of bergenin sulfonate derivatives in resisting tumor and drug-resistant bacteria, and is hopeful to develop bergenin sulfonate derivatives into lead compounds of anti-tumor and drug-resistant bacteria drugs.
Detailed Description
The features and advantages of the present invention will become more apparent and clear from the following detailed description of the invention. The invention is further described below by means of specific examples. These examples do not limit the scope of the invention in any way.
EXAMPLE 1 preparation of 8, 10-dimethoxy bergenin sulfonate derivative
(1) 2mmol bergenin was weighed into a 100mL round bottom flask, 25mL of N, N-dimethylformamide was added, 6mmol of potassium carbonate was added, then 4.5mmol of methyl iodide was added, and the reaction was stirred at room temperature for 12 hours. Adding 6N hydrochloric acid into the reaction system to quench the reaction, extracting with ethyl acetate, washing with water, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 0.67g of 8, 10-dimethoxy bergenin, wherein the yield is 98%.
(2) 1mmol of 8, 10-dimethoxy bergenin is weighed into a 50mL round bottom flask, 25mL of dichloromethane is added, 3mmol of triethylamine is added, then 1mmol of substituted sulfonyl chloride is added, and the reaction is stirred at room temperature for 5 hours. Adding water into the reaction system for quenching reaction, extracting with ethyl acetate, washing with water, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 8, 10-dimethoxy-11-sulfonate bergenin, wherein the yield is 95-99%.
8, 10-dimethoxy-11- (4-bromo) sulfonic acid ester bergenin (1-8)
1 H-NMR(400MHz,CDCl 3 )：δ7.80(2H,d,J＝8.8Hz)，7.69(2H,d,J＝8.8Hz),7.43(1H,s)，4.72(1H,d,J＝10Hz)，4.45(1H,d,J＝9.2Hz)，4.38-4.34(1H,m)，4.07(1H,t,J＝10Hz)，3.99-3.97(1H,m)，3.96-3.95(4H,m)，3.91(3H,s)，3.79(3H,s)，3.77-3.75(1H,m)，3.65(1H,d,J＝8Hz).
13 C-NMR(100MHz,CDCl 3 )：δ163.86(C＝O),154.04(C),151.47(C),149.15(C),134.72(CH),132.83(CH),129.60(C),125.47(C),118.70(C),109.97(CH),79.57(CH),77.36(CH),74.96(CH),72.23(CH),69.85(CH),69.20(CH 2 ),61.88(O-CH 3 ),61.27(O-CH 3 ),56.41(O-CH 3 ).
8, 10-dimethoxy-11- (4-fluoro) sulfonic acid ester bergenin (1-11)
1 H-NMR(400MHz,CDCl 3 )：δ7.98-7.94(2H,m)，7.41(1H,s)，7.26-7.20(2H,m)，4.73(1H,d,J＝10.4Hz)，4.45(1H,d,J＝10.8Hz)，4.38-4.33(1H,m)，4.07(1H,t,J＝10Hz)，3.99(1H,d,J＝8.8Hz)，3.94-3.93(4H,m)，3.90(3H,s)，3.88-3.84(1H,m)，3.77(4H,s)，3.65(1H,d,J＝8.8Hz).
13 C-NMR(100MHz,CDCl 3 )：δ167.28(C),164.72(C),164.14(C),153.98(C),151.43(C),149.15(C),131.76(C),131.72(C),131.06(CH),130.96(CH),125.60(C),118.67(C),116.97(CH),116.74(CH),109.95(CH),79.66(CH),77.68(CH),74.82(CH),72.20(CH),69.93(CH),69.17(CH 2 ),61.86(O-CH 3 ),61.25(O-CH 3 ),56.40(O-CH 3 ).
Example 2 preparation of 8, 10-dibenzyloxycbergine sulfonate derivative
(1) 2mmol bergenin was weighed into a 100mL round bottom flask, 25mL of N, N-dimethylformamide was added, 6mmol of potassium carbonate was added, then 4.2mmol of benzyl bromide was added, and the reaction was stirred at room temperature for 12 hours. Adding 6N hydrochloric acid into the reaction system to quench the reaction, extracting with ethyl acetate, washing with water, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 1.008g of 8, 10-dibenzyloxycbergenin with a yield of 99%.
(2) 1mmol of 8, 10-dibenzyloxycbergenin was weighed into a 50mL round bottom flask, 25mL of methylene chloride was added, 3mmol of triethylamine was added, then 1mmol of substituted sulfonyl chloride was added, and the reaction was stirred at room temperature for 5 hours. Adding water into the reaction system for quenching reaction, extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 8, 10-dibenzyloxy-11-sulfonate bergenin with a yield of 95-99%.
8, 10-dibenzyloxy-11-ethyl sulfonate bergenin (2-2)
1 H-NMR(400MHz,CDCl 3 )：δ7.54-7.26(11H,m)，5.13(2H,s)，5.05(2H,s)，4.60(1H,d,J＝8Hz)，4.45(1H,d,J＝12Hz)，4.23(1H,d,J＝4Hz)，4.13-4.09(1H,m)，3.92(3H,s)，3.74(1H,s)，3.64(1H,s),3.00-2.98(3H,m)，1.26(3H,s).
13 C-NMR(100MHz,CDCl 3 )：δ164.23(C＝O)，153.00(C),150.40(C)，149.51(C),13 7.79(C)，136.04(C),118.76(C)，111.82(CH),79.70(CH)，77.99(CH)，75.94(CH 2 )，74.52(CH)，72.40(CH),71.17(Ph-CH 2 )，69.47(CH),67.83(Ph-CH 2 )，61.38(O-CH 3 )，44.75(CH 2 )，8.17(CH 3 ).
8, 10-dibenzyloxy-11-cyclopropylsulfonate bergenin (2-4)
1 H-NMR(400MHz,CDCl 3 )：δ7.57(1H,s)，7.45-7.26(10H,m)，5.18(2H,d,J＝20Hz)，5.07(2H,d,J＝16Hz)，4.58-4.44(2H,m)，4.22(1H,d,J＝8Hz)，4.14-4.09(1H,m)，3.98-3.95(4H,m)，3.76(1H,d,J＝16Hz)，3.598(1H,d,J＝12Hz)，3.39-3.30(2H,m)，2.40(1H,d,J＝4Hz)，1.66(4H,s).
13 C-NMR(100MHz,CDCl 3 )：δ160.20(C＝O)，153.08(C)，150.58(C)，149.63(C),137.91(C)，136.02(C)，118.08(C),111.91(CH)，110.12(C),79.61(CH)，78.02(CH)，76.01(CH 2 )，74.71(CH)，72.54(CH)，71.21(Ph-CH 2 )，69.36(CH)，67.85(Ph-CH 2 )，61.42(O-CH 3 ),27.48(CH)，5.95(O-CH 2 ).
(3) 1mmol of 8, 10-dibenzyl-11-sulfonyl bergenin was weighed into a 50mL round bottom flask, 10mL of methanol was added, 0.1mmol Pd/C was added, and the reaction was stirred at room temperature under a hydrogen atmosphere for 6 hours. Filtering, evaporating the solvent under reduced pressure to obtain 11-sulfonate bergenin with a yield of 94-99%.
8, 10-dihydroxy-11- (4-fluoro) benzenesulfonate bergenin (3-11)
1H-NMR(400MHz,CD 3 OD)：δ8.02-8.01(m,2H),7.34(2H,t,J＝8.4Hz),7.08(1H,s),4.94(1H,d,J＝10.4Hz),4.56(1H,d,J＝11.2Hz),4.31(1H,dd,J＝10.8Hz,11.2Hz),3.92(4H,s),3.84(1H,t,J＝6Hz),3.79(1H,t,J＝8Hz),3.40(1H,t,J＝12.8Hz).
13 C-NMR(100MHz,CD 3 OD)：δ165.59(C),152.44(C),149.29(C),142.28(C),132.19(C),132.09(C),119.47(C),117.92(CH),117.69(CH),116.79(C),111.19(CH),81.01(CH),79.69(CH),75.27(CH),74.24(CH),71.08(CH),70.71(CH 2 ),60.94(CH 3 ).
Example 3 biological Activity test of bergenin sulfonyl derivatives
The test of anti-tumor activity of the bergenin sulfonate compound obtained by the invention shows that the bergenin sulfonate compound has better effects on leukemia, lung cancer, liver cancer, breast cancer, colon cancer cell lines and staphylococcus aureus. The result shows that the bergenin sulfonate has better effect than bergenin, and is expected to be prepared into an antitumor drug with strong activity.
Specific procedure for antitumor Activity test: single cell suspension is prepared by using culture solution containing 10% fetal bovine serum, 3000-15000 cells are inoculated into a 96-well plate, the volume of each well is 100 μl, and the cells are inoculated and cultured 12-24 hours in advance. Cisplatin was used as a positive compound for each experiment. The compound was dissolved in DMSO and rescreened at concentrations of 40. Mu.M, 8. Mu.M, 1.6. Mu.M, 0.32. Mu.M, 0.064. Mu.M, 200. Mu.l final volume per well, 3 rescreens per treatment. After culturing at 37 ℃ for 48 hours, removing culture solution in the wells of the adherent cells, and adding 20 mu l of MTS solution and 100 mu l of culture solution into each well; suspension cells discard 100. Mu.l culture supernatant, add 20. Mu.l MTS solution per well; 3 blank wells (a mixture of 20. Mu.l MTS solution and 100. Mu.l culture medium) were prepared, and incubation was continued for 2-4 hours to allow the reaction to proceed sufficiently, and then the light absorption value was measured. Selecting 492nm wavelength, reading light absorption value of each hole by a multifunctional enzyme-labeled instrument, recording the result, drawing a cell growth curve by using the concentration as abscissa and the cell survival rate as ordinate after data processing, and calculating the compound IC by using a two-point method 50 Values.
The anti-tumor experimental statistics result of bergenin and its sulfonate derivatives show that the anti-tumor effect of bergenin and its sulfonate derivatives are compared as shown in the following table:
from the above table, it can be seen that there is a certain difference in the corresponding optimal structure for different antitumor activities, specifically:
comparison of anti-leukemia Activity: cisplatin >1-5>1-4>1-7>1-8> bergenin, wherein the activity against leukemia is strongest at 1-5.
Comparison of anti-lung cancer Activity: 1-11>1-8>1-5> cisplatin > bergenin, wherein the lung cancer resistance activity is strongest with 1-11.
Comparison of anti-liver cancer Activity: 1-11>1-8>1-4>1-7>1-5> cisplatin > bergenin, wherein 1-11 of the bergenin has the strongest anti-liver cancer activity.
Comparison of anti-breast cancer activity: 1-8>1-5>1-7>1-4> cisplatin > bergenin, wherein 1-8 of the bergenin has the strongest anti-breast cancer activity.
Comparison of anti-colon cancer Activity: 1-8>1-5>1-4>1-3> cisplatin > bergenin, wherein the activity against colon cancer is strongest at 1-8.
The chemical structures of the compounds 1-8 and 1-11 in the invention are as follows:
example 4
Bergenin and sulfonate derivatives thereof are tested for the activity against drug-resistant bacteria by the following specific procedures: the paper is used for sucking the tested medicines and respectively placing the tested medicines in culture mediums of escherichia coli, staphylococcus aureus and salmonella drug-resistant bacteria, and placing the culture mediums in a 35 ℃ incubator for culturing for 16-18 hours. And measuring the size of the antibacterial ring to judge whether the antibacterial activity exists.
Bergenin and sulfonate derivatives thereof have the activity of resisting drug-resistant bacteria, and experimental statistical results are shown in the following table:
| names of Compounds | Diameter (cm) of staphylococcus aureus antibacterial ring |
| Bergenin | No bacteriostasis ring |
| 1-5 | No bacteriostasis ring |
| 1-7 | No bacteriostasis ring |
| 1-8 | No bacteriostasis ring |
| 2-5 | No bacteriostasis ring |
| 1-6 | Sterility within 1.02 |
| 2-8 | Sterility within 0.75 range |
| 2-12 | Sterility within 0.75 range |
| 3-6 | Sterility within 0.79 |
| 3-7 | Sterility in the range of 0.81 |
| 3-8 | Sterility in the range of 0.80 |
From the table above, it can be seen that: comparison of anti-Staphylococcus aureus Activity: 1-6>3-7>3-8>3-6>2-8, 2-12> bergenin, wherein the activity against staphylococcus aureus is strongest at 1-6. According to the results, the preparation of the medicine with the activity of resisting drug-resistant bacteria is expected.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (1)
1. The application of bergenin sulfonate derivative in preparing medicament with drug-resistant bacteria activity is characterized in that: the bergenin sulfonate derivative has the following structural general formula:
wherein R is 1 ＝4-MeOC 6 H 4 SO 2 ，R 2 ＝Me；R 1 ＝4-BrC 6 H 4 SO 2 ，R 2 ＝Bn；R 1 ＝4-MeOC 6 H 4 SO 2 ，R 2 ＝H；R 1 ＝4-ClC 6 H 4 SO 2 ，R 2 ＝H；R 1 ＝4-BrC 6 H 4 SO 2 ，R 2 ＝H；
The drug-resistant bacteria are golden yellow grape ball drug-resistant bacteria.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211545776.2A CN115737628B (en) | 2022-02-23 | 2022-02-23 | Application of bergenin sulfonate derivative in resisting drug-resistant bacteria activity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210165359.9A CN114456189B (en) | 2022-02-23 | 2022-02-23 | Bergenin sulfonate derivative and application thereof |
| CN202211545776.2A CN115737628B (en) | 2022-02-23 | 2022-02-23 | Application of bergenin sulfonate derivative in resisting drug-resistant bacteria activity |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210165359.9A Division CN114456189B (en) | 2022-02-23 | 2022-02-23 | Bergenin sulfonate derivative and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115737628A CN115737628A (en) | 2023-03-07 |
| CN115737628B true CN115737628B (en) | 2024-04-12 |
Family
ID=81414878
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210165359.9A Active CN114456189B (en) | 2022-02-23 | 2022-02-23 | Bergenin sulfonate derivative and application thereof |
| CN202211545776.2A Active CN115737628B (en) | 2022-02-23 | 2022-02-23 | Application of bergenin sulfonate derivative in resisting drug-resistant bacteria activity |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210165359.9A Active CN114456189B (en) | 2022-02-23 | 2022-02-23 | Bergenin sulfonate derivative and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN114456189B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105851076A (en) * | 2016-04-29 | 2016-08-17 | 山东胜伟园林科技有限公司 | Biopesticide containing Bacillus sphaericus and used for preventing and treating soybean diseases and pests |
| CN106963676A (en) * | 2017-03-24 | 2017-07-21 | 福建师范大学 | A kind of kiss-me bactericidal composition and preparation method thereof |
| CN108314689A (en) * | 2018-05-03 | 2018-07-24 | 安阳工学院 | 4,11- diacyl bergenin derivative synthetic methods |
| CN110870862A (en) * | 2019-12-06 | 2020-03-10 | 中国农业大学 | Application of bergenin in preparing medicine for treating in vivo Klebsiella pneumoniae infection |
| CN114716450A (en) * | 2022-05-12 | 2022-07-08 | 中国药科大学 | Bergenin derivative and preparation method and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812068A (en) * | 2010-03-22 | 2010-08-25 | 云南大学 | Bergenin derivative and preparation method thereof |
| US20150238473A1 (en) * | 2012-09-27 | 2015-08-27 | University Of Rochester | Methods and compositions for treating infection |
| WO2014071198A1 (en) * | 2012-11-01 | 2014-05-08 | The University Of Chicago | Antibiotic methods and compositions for bacteria infections |
| CN106432259B (en) * | 2016-07-28 | 2018-12-04 | 广州科技职业技术学院 | A kind of Bergenin analog derivative and its synthetic method and application |
| CN106632379B (en) * | 2016-12-31 | 2019-06-04 | 西安泰科迈医药科技股份有限公司 | A kind of Bergenin azepine cinnamate derivative compound and its synthetic method having anti-tumor activity |
-
2022
- 2022-02-23 CN CN202210165359.9A patent/CN114456189B/en active Active
- 2022-02-23 CN CN202211545776.2A patent/CN115737628B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105851076A (en) * | 2016-04-29 | 2016-08-17 | 山东胜伟园林科技有限公司 | Biopesticide containing Bacillus sphaericus and used for preventing and treating soybean diseases and pests |
| CN106963676A (en) * | 2017-03-24 | 2017-07-21 | 福建师范大学 | A kind of kiss-me bactericidal composition and preparation method thereof |
| CN108314689A (en) * | 2018-05-03 | 2018-07-24 | 安阳工学院 | 4,11- diacyl bergenin derivative synthetic methods |
| CN110870862A (en) * | 2019-12-06 | 2020-03-10 | 中国农业大学 | Application of bergenin in preparing medicine for treating in vivo Klebsiella pneumoniae infection |
| CN114716450A (en) * | 2022-05-12 | 2022-07-08 | 中国药科大学 | Bergenin derivative and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| Novel heterocyclic analogues of bergenin as anti-mitotic agents: Design, synthesis, biological evaluation and molecular docking study;Rao, BV et al.;《JOURNAL OF MOLECULAR STRUCTURE》;20230515;第1280卷;摘要 * |
| 小叶云实的化学成分及抗菌活性研究;陈屏等;《中国中药杂志》;20121231;第37卷(第14期);2105-2107 * |
| 岩白菜素咪唑衍生物的合成;刘娜娜等;《云南大学学报( 自然科学版)》;20171231;第39卷(第2期);278-282 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114456189A (en) | 2022-05-10 |
| CN114456189B (en) | 2023-03-31 |
| CN115737628A (en) | 2023-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11377457B2 (en) | 3,3,3',3'-tetramethyl-1,1'-spirobiindane-based monophosphine ligand, intermediates thereof, preparation method and use of the same | |
| CN108117507B (en) | Synthesis method and application of azaspiro cyclohexadienone | |
| CN108409746B (en) | Chiral oxo spiro indole compound containing pyrrole or indolocarbazacycloalkane structure, racemate thereof and preparation method | |
| CN114591194B (en) | Para-functional arylamine compound and synthesis method thereof | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN115737628B (en) | Application of bergenin sulfonate derivative in resisting drug-resistant bacteria activity | |
| CN110684024B (en) | Synthetic method of moxifloxacin degradation impurities | |
| CN113173857B (en) | Cannabidiol derivative and preparation method and application thereof | |
| CN112661764B (en) | Tetrahydrofuran indole compound and preparation method and application thereof | |
| CN112778303A (en) | Preparation method of CDK4/6 kinase inhibitor SHR6390 | |
| CN115043826B (en) | Sinomenine furazan derivatives, and preparation method and application thereof | |
| CN114436918B (en) | Cyclobut-1-enamine compound, preparation method thereof and application thereof in medicines | |
| CN112645863B (en) | Dipyrromethene-1-ketone compound and preparation method thereof | |
| CN113511986B (en) | Preparation method of aryl acetonitrile derivative | |
| CN110294758B (en) | 2-substituted 5, 6-dihydropyrazolo [5, 1-alpha ] isoquinoline, derivatives and synthesis method thereof | |
| CN108218847B (en) | Aryloxy phenoxy alkanoic acid derivative and medical application thereof | |
| CN109053513B (en) | Substituted naphthol compound and application thereof in antitumor drugs | |
| CN111004145A (en) | Chiral optical amide substituted α -diamino acid derivative and preparation method and application thereof | |
| JPH01254771A (en) | Novel thiorhodamine and novel production thereof | |
| CN113200902B (en) | Polysubstituted pyrrole derivative and preparation method thereof | |
| CN112250639B (en) | Heterocyclic substituted arylamine compound and preparation method and application thereof | |
| CN113956232B (en) | Quinoline-bisindole compound and preparation method and application thereof | |
| CN109320554B (en) | Novel method for synthesizing practical acetaminoacrylate compound | |
| CN112574133B (en) | Synthesis method of 1, 3-diaryl substituted tetrazolone inner salt | |
| CN111138361B (en) | Substituted phenoxy-2-azabicyclo [3.2.1] octane compounds and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |