CN107823204A - A kind of new application of gemifloxacin - Google Patents
A kind of new application of gemifloxacin Download PDFInfo
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- CN107823204A CN107823204A CN201711029621.2A CN201711029621A CN107823204A CN 107823204 A CN107823204 A CN 107823204A CN 201711029621 A CN201711029621 A CN 201711029621A CN 107823204 A CN107823204 A CN 107823204A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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Abstract
Purposes in the medicine of disease caused by the present invention discloses a kind of compounds for treating bacterium glycuronidase, the compound are gemifloxacin (Gemifloxacin) and its metabolite or the compound pharmaceutically acceptable salt.Above compound may be incorporated for the treatment of cancer, can also alleviate the caused diarrhoea of Irinotecan, gastrointestinal ulceration caused by non-steroid anti-inflammatory drug, or other curative effect of medication and side effect via the metabolism of bacterium glycuronidase are adjusted, and the associated conditions as caused by bacterium glycuronidase.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to gemifloxacin (Gemifloxacin) new application, specifically, lucky
Meter Sha Xing is as bacterium β glucuronic acids enzyme inhibitor and its application.
Background technology
By bacterium GRD beta-glucuronidase, the microorganism in intestines and stomach seizes sugar from the compound of glucuronidation
Base is used for energy supply, cause multi-medicament or its metabolite from non-toxic condition conversion be virulent state, so as to influence medicine
The metabolism of thing and toxic side effect[1,2].The symptom that bacterium GRD beta-glucuronidase influences includes Delayed onset abdomen caused by Irinotecan
Rush down, and gastrointestinal ulceration caused by non-steroid anti-inflammatory drug etc.[3,4]。
Irinotecan (Irinotican, CPT-11), trade name CPT-11 (Camptosar), it is clinically conventional anti-
One of tumor chemotherapeutic drug, its major target class are I type DNA topoisomerases.Since 1996 list, Irinotecan extensively should
For colorectal cancer, lung cancer, the treatment of brain tumor and drug resistance leukaemia and lymph cancer, and it is straight to be listed in treatment metastatic knot
The first-line treatment medicine of intestinal cancer.Clinical practice for many years finds that intestines toxicity is the main dose-limiting side effect of Irinotecan
One of, late-onset diarrhea is shown as, is generally occurred in patient using medicine after 24 hours, principal character includes unpredictable
Property, high incidence and a certain degree of fatal rate.Statistics shows, 88% is up in the patient for receive irinotecan
Ratio there is symptom of diarrhea, there is 3-4 levels severe diarrhea (CTCAE classifications), about 3.5% disease in wherein 20-30% patient
People is dead because of the complication that severe diarrhea triggers[5,6].The patient of a great deal of is because diarrhoea must reduce dosage or even stop
Only medication, effective treatment means are there is no so far.
Although a variety of " second generation Irinotecans " have been developed in recent years, as ONIVYDE (also known as MM-398, PEP02, or
Nal-IRI, Merrimack Pharmaceuticals, Inc.), a kind of irinotecan liposome is formulated capsule in quilt in 2015
U.S. FDA approval listing；PEG-SN38 (SN38, BelrosePharma Inc. of connection polyethylene) is in clinical three phases experiment rank
Section.Although these " new Irinotecans " improve bioavailability and drug effect, diarrhoea is still the dosage for being difficult to overcome
Restricted side effect.
Diarrhoea mechanism and the metabolic pathway of Irinotecan have substantial connection.CPT-11 main metabolic place is liver
Dirty, CPT-11 sloughs dipiperidino group generation active metabolite through carboxy-lesterase (carboxylesterase, CES) first
SN-38；Then SN-38 connects under glucuronyl transferase (UDP-glucuronosyl-transferase, UGT) catalysis
Nonactive metabolite SN-38G is further converted into by glycosylation modified[7].SN-38 is the major active metabolite of Irinotecan
Product, the rejection ability to DNA topoisomerases is active compound CPT-11 and more than 100 times of nonactive metabolite SN-38G, right
The tumour cell quickly divided has extremely strong lethality[8].CPT-11 and metabolite part enter blood circulation, its remaining part
Divide and be discharged into enteric cavity with bile.Research finds that the symbiotic bacteria being rich in enteron aisle is using nonactive metabolite SN-38G as energy
One of source, SN-38G glycosyl is sloughed by the beta-glucuronidase (β-glucuronidase, β-GUS) of bacterium to supply
The energy of itself, is reactivated into SN-38, so as to cause enteric cavity toxic compounds SN-38 concentration to be significantly greatly increased, killing
Enterocyte simultaneously causes the irreversible damage of intestinal mucosa, has ultimately resulted in the generation of delayed diarrhoea[3,9].Therefore selectivity
Suppress the activity of bacterium β-GUS enzymes in enteron aisle, can directly reduce SN-38 local concentration and protect intestinal tissue, fundamentally
Prevent and treat late-onset diarrhea.
Bacterium β-GUS enzymes exist with tetramer, and micromolecular compound is incorporated in the catalytic pocket of enzyme, special with bacterial enzyme
By the loop structures that form of one section of 17 amino acid residue there is stronger interaction.Because this section of loop region is people's
Respective regions sequence and structure difference are obvious in homologous protein β-GUS, and the combination of the peculiar loop structures of bacterial enzyme make it that this is
Alternative β-the GUS suppressed in bacterium of row compound, then have no significant effect to the β-GUS of mammal[3].Zoopery knot
Fruit shows that bacterium β-GUS inhibitor inhibitor 2 can reduce the incidence of diarrhoea, extends the time-to-live of animal, further
Demonstrate the security and validity of the target spot.High-throughput screening method based on enzymatic activity is found that a series of β-GUS suppress
Agent[3,10].But the toxicity of the compound due to completely newly developing in itself and pharmaceutical properties are unclear, are used in combination with CPT-11
Later security and drug effect are more difficult to assess, therefore still suffer from larger gap with clinical practice.
The present invention has found that Gemifloxacin is alternative using the method for integrating virtual screening and measuring and suppresses thin
Bacterium glycuronidase.Because Gemifloxacin is a kind of known drug, used in human body, its security and pharmaceutical
Matter is clear and definite, can rapidly enter clinical trial, for alleviating diarrhoea, stomach and intestine caused by non-steroid anti-inflammatory drug caused by Irinotecan
Road ulcer, or other curative effect of medication and side effect via the metabolism of bacterium glycuronidase are adjusted, and by bacterium glucose
Associated conditions caused by aldehydic acid enzyme.
The content of the invention
The present invention has found that Gemifloxacin is alternative using the method for integrating virtual screening and measuring and suppresses thin
Bacterium glycuronidase.Because Gemifloxacin is a kind of known drug, used in human body, its security and pharmaceutical
Matter is clear and definite, can rapidly enter clinical trial, for alleviating diarrhoea caused by Irinotecan, or adjusts other via bacterium glucose
The curative effect of medication of aldehydic acid enzyme metabolism and side effect, and the associated conditions as caused by bacterium glycuronidase.
The present invention provides a kind of compound A and is used in the medicine of disease caused by preparing treatment bacterium glycuronidase
Purposes, the compound A are compound of formula I, the metabolite of compound of formula I or compound of formula I pharmaceutically acceptable salt.
Disease of the present invention is preferably for diarrhoea, gastrointestinal toxicity or other diseases caused by bacterium glycuronidase
Disease.The diarrhoea include but is not limited to be caused by chemotherapeutics；The gastrointestinal toxicity includes but is not limited to nonsteroidal anti-inflammatory
Efficacy-enhancing ingredient rises.
Chemotherapeutics of the present invention includes but is not limited to Irinotecan or the hydroxy-camptothecin of its active metabolite 7- ethyls -10
Alkali, or other medicines using camptothecine compounds and its derivative as principle active component.
Compound of formula I of the present invention and one or more pharmaceutically acceptable carriers composition pharmaceutical composition.
The present invention also provides a kind of purposes of chemotherapeutics and compound A in the drug combination for preparing treatment tumour, institute
It is compound of formula I, the metabolite of compound of formula I or compound of formula I pharmaceutically acceptable salt to state compound A.
Chemotherapeutics of the present invention includes but is not limited to like for Irinotecan or the hydroxyl of its active metabolite 7- ethyls -10
Set alkali, or other medicines using camptothecine compounds and its derivative as principle active component.The compound A and it is a kind of or
A variety of pharmaceutically acceptable carriers form pharmaceutical composition, and the formulation of described pharmaceutical composition is tablet, capsule, particle
Agent, pill or other formulations that can be prepared.The tumour includes colorectal cancer, stomach cancer, liver cancer, breast cancer, brain tumor, drug resistance
One or more in leukaemia, lymph cancer, prostate cancer, lung cancer or carcinoma of urinary bladder.
The present invention is carried out using medicine reorientation as elementary tactics, using computer simulation method to the validity of drug molecule
Prior assessment, and surveyed and lived using biological experimental method, it was found that Gemifloxacin is effective bacterium β-GUS enzyme selectivities
Inhibitor, the horizontal IC of its zymetology50Value is respectively 2.0900 ± 1.2270 μM (Fig. 1)；Its cellular level IC50Value is respectively
0.9157 ± 1.4830 μM (Fig. 2)；To the β-GUS enzymes of mammal source under 100 μM of concentration without obvious effect, indicate
Its good selectivity (Fig. 3)；Growth of the compound to Escherichia coli simultaneously has no significant effect, and shows compound without obvious cell
Toxicity, the activity (Fig. 4) of its β-GUS enzyme can be suppressed in the case where not killing Escherichia coli.
The Gemifloxacin of suitable dosage can be used for selective depression bacterium β-GUS enzymes, so as to influence by bacterium β-
The drug effect of the medicine of GUS enzymes metabolism and side effect, treat the illness triggered by bacterium β-GUS enzymes.Such as Gemifloxacin with
CPT-11 or other camptothecin derivative Drug combinations, available for intestines toxicity is reduced, alleviate diarrhoea side effect, and have can
Antitumous effect can be improved.
Because Gemifloxacin is a kind of known drug, being used in human body, its security and pharmaceutical properties are clear and definite,
Clinical trial can be rapidly entered, for alleviating diarrhoea caused by Irinotecan, or adjusts other via bacterium glycuronidase
The effect of medicine of metabolism and side effect, and other associated conditions as caused by bacterium glycuronidase.
Brief description of the drawings
Fig. 1：Gemifloxacin is on protein level to the IC of bacterium β-GUS enzyme level abilities50Figure.Gemifloxacin
There is good bacterium β-GUS enzyme level effects, its IC on protein level50It is worth for 2.0900 ± 1.2270 μM.
Fig. 2：Gemifloxacin is on a cellular level to the IC of bacterium β-GUS enzyme level abilities50Figure.Gemifloxacin
There is good bacterium β-GUS enzyme level effects, its IC in cellular level50Value is respectively 0.9157 ± 1.4830 μM.
Fig. 3：Gemifloxacin is under 100 μM of concentration to the Bovine taurus β aGUS enzymes of mammal source without bright
Aobvious inhibitory activity.Using the Gemifloxacin of 100 μM of concentration test its Bovine taurus β to mammal source-
GUS enzymatic activitys, find the β-GUS enzymes in compounds for mammalian source without obvious inhibition.
Fig. 4：Cytotoxicity experiments of the Gemifloxacin to bacterium.Wherein black, Dark grey and light grey column difference
Expression is incubated altogether with Escherichia coli respectively using 1%DMSO solution, 100 μM of aspartames and 10 μM of concentration Gemifloxacin
Result.As a result show that growth of the compound to Escherichia coli has no significant effect, show compound without obvious cytotoxicity, can be
Suppress the activity of its β-GUS enzyme in the case of not killing Escherichia coli.
Specific embodiment
Test example
First, Gemifloxacin determines to bacterium glucuronic acid enzyme inhibition activity
1. experimental method
1.1 virtual screenings based on acceptor
Use firstAlbumen preparation module Protein Preparation Wizard couple in software kit
Crystal structure (the PDB of bacterium β-GUS enzymes：3LPF) handled, including amendment bond order, add hydrogen atom and Partial charge.Delete
Except all crystalline water molecules, whole system is optimized based on the OPLS-2005 field of forces, when RMSD values reach Shi You
Change and terminate.UsingModules of Ligprep 2.5 in 9.0 to known drug library of molecules LOPAC and
Microsource Spectrum electronic edition molecule files are pre-processed, including duplicate removal, removal salt ion and inorganic matter, in pH
The possibility ionization state and dynamic isomer of compound, the chiralityization for not determining chiral centre are produced under the conditions of=7.4
Compound produces various energy-poor compound structures that may be chiral, and under default condition, it is different that each molecule at most produces 32 solids
Structure body, finally obtain about 50,000 compound conformations.Docked and given a mark using Glide SP patterns first, retained all
Small molecule binding pattern.In document report, bioactive molecule includes two obvious pharmacophore features substantially：Formed with GLU413
Hydrogen bond, hydrophobic interaction is formed with PHE365.For preceding 10,000 small molecule binding patterns caused by docking, pharmacophore is taken
Feature is selected and forms hydrogen bond with GLU413 as screening conditions, and the binding pattern of hydrophobic interaction is formed with PHE365, most
After select and have purchased part of compounds carry out assay activity measure.
1.2 bacterium glycuronidase zymetologys are horizontal to survey step living
4mg/ml bacterium β-GUS (300,000 × 125pM) are used into 50mM HEPES buffer solutions (pH7.4with
0.017%Triton x-100) be diluted to 1 × 125pM, substrate 4MUG use 50mM HEPES (pH7.4) dissolved dilutions for
312.5μM.Concrete operation step is：1) 20 μ l testing compound is added to 96 orifice plates (blackboard)；2) 40 μ l GUS enzymes are added
(125pM)；3) 40 μ l substrates (4MUG, 312.5 μM) are added；4) it is incubated at room temperature 30 minutes, adds 40 μ l 1M Na2CO3 and terminate
Reaction；5) fluoroscopic examination is carried out on EnVision (Perkin Elmer USA) multi-function microplate reader：Excitation wavelength 335nm,
Launch wavelength 460nm.The orifice plate of compound is wherein not added with as positive control, not enzyme-added orifice plate is as negative control.
1.3 mammal source glycuronidase zymetologys are horizontal to survey step living
Specific steps are replaced by mammal with bacterium glycuronidase zymetology level activity test experiments, wherein enzyme
The Bovine taurus β-GUS enzymes in source, its final concentration of 1nM.
1.4 cellular level GUS enzymatic activity test experiments
Empty plasmid pGex-4T-1 is transformed into E.coli (DH5 α), 37 DEG C, cultivated in LB (100 μM of ampicillins)
Night.Then 1/100 expands culture to OD600 to 0.6,8000rpm centrifugations 5 minutes.With 50mM HEPES (100 μM of ampicillins,
PH 7.4) clean precipitation twice, the OD600 to 1.0 of concentrating and precipitating, this bacterium solution will replace GUS enzymes and be detected for experiment.Reaction exists
37 DEG C of progress 2h, buffer solution use 50mM HEPES (pH7.4), and other experimental procedures test phase with data processing with GUS enzymes
Together.
1.5 bacterial cell toxicity tests
Cytotoxicity experiment is carried out using Escherichia coli bacteria liquid used in GUS cell experiments.From testing compound final concentration
100 μM and 10 μM (1%DMSO) two concentration carry out cytotoxicity experiment.The μ L of testing compound 20 and bacterium are added into 96 orifice plates
Liquid 80 μ L, 1%DMSO as a control group, 37 DEG C of reaction 2h, then add Cell Counting Kit-8 in every hole
(Dojindo, Japan) 10 μ L, mix.Reacted 5 minutes respectively at 37 DEG C, 30 minutes, 60 minutes, then use multi-function microplate reader
(Thermo Scientific, USA) surveys 490nm absorbance.
2. experimental result
Determine Gemifloxacin directed toward bacteria β-GUS and β-GUS enzymes of mammal source on protein level
Activity, and the activity of compound directed toward bacteria β-GUS enzymes on a cellular level, and the cytotoxicity of compound.
Suppress the IC of bacterium β-GUS activity on protein level50Curve is as shown in Figure 1.Gemifloxacin is in albumen water
It is flat that above there is good bacterium β-GUS enzyme level effects, its IC50It is worth for 2.0900 ± 1.2270 μM.
Suppress the IC of bacterium β-GUS enzymes on a cellular level50Curve is as shown in Figure 2.Have on a cellular level well
Bacterium β-GUS enzyme level effects, its IC50Value is respectively 0.9157 ± 1.4830 μM.
Its β-GUS enzymatic activity to mammal source is tested using the Gemifloxacin of 100 μM of concentration, finds the change
Compound is to the β-GUS enzymes of mammal source without obvious inhibition (Fig. 3).
Using 10 μM, the Gemifloxacin of 100 μM of concentration is incubated altogether with Escherichia coli, and the growth to Escherichia coli is without bright
Development rings, and illustrates that the compound without obvious cytotoxicity, can suppress the work of its β-GUS enzyme in the case where not killing Escherichia coli
Property (Fig. 4).
2nd, diarrhea of mouse is tested caused by Gemifloxacin alleviates Irinotecan
CT-26 cell lines are used to build mouse tumor model.The female Balb/cJ mouse 18 of 6-8 weeks are chosen, small
The PBS suspension of cell is subcutaneously injected in mouse back part position.After 10 days or so, the tumour of mouse reaches about 500mm3(tumour
Volume formula π/6 × a2× b is calculated, and wherein a is the short axle of tumour, and b is the major axis of tumour).Then mouse is randomly divided into
Three groups are administered：(1) control group, the intraperitoneal injection distilled water of equal volume is received, and 1%DMSO solution gavage is (altogether
About 100 μ L, twice daily)；(2) CPT-11 administration groups, intraperitoneal injection CPT-11, dosage 50mg/kg, and 1%DMSO are molten
Liquid gavage (about 100 μ L altogether, twice daily)；(3) CPT-11 adds Gemifloxacin drug combination groups, and CPT- is injected intraperitoneally
11, dosage 50mg/kg, and Gemifloxacin solution gavage (about 100 μ L altogether, twice daily), dosage 50mg/
kg.To obtain diarrhea of mouse model, wherein CPT-11 administration groups and drug combination group continuously injects 9 days CPT-11；Joint is used
Medicine group oral Gemifloxacin since CPT-11 injects the previous day, after to CPT-11 injections terminating, it is further continued for being administered orally
Two days, then terminate to be administered.Control group, CPT-11 administration groups, and CPT-11 are observed respectively adds Gemifloxacin drug combinations
The diarrhoea status of group, record the body weight and tumor size of mouse.
Experimental result shows that CPT-11 administration group mouse blood samples Incidence of Diarrhea is 83.33%, and CPT-11 adds
The incidence of Gemifloxacin drug combination groups blood sample diarrhoea is 50%, and drug combination has significantly than single use CPT-11
Improve the effect of Incidence of Diarrhea.In addition, drug combination group Body weight loss situation is brighter than also having with single CPT-11 administration groups
Aobvious improvement (P<0.05).Meanwhile drug combination group and single CPT-11 administration groups nothing in terms of tumor size effect is suppressed
Notable difference.
Claims (10)
1. the purposes that a kind of compound A is used in the medicine of disease caused by preparing treatment bacterium glycuronidase, its feature
It is, the compound A is compound of formula I, the metabolite of compound of formula I or compound of formula I pharmaceutically acceptable salt
2. purposes according to claim 1, it is characterised in that the disease for diarrhoea, gastrointestinal toxicity or other due to thin
Illness caused by bacterium glycuronidase.
3. purposes according to claim 2, it is characterised in that the diarrhoea is caused by chemotherapeutics；The stomach and intestine poison
Property is caused by non-steroid anti-inflammatory drug.
4. purposes according to claim 3, it is characterised in that the chemotherapeutics refers to Irinotecan or its active metabolism
Thing SN38, or other medicines using camptothecine compounds and its derivative as principle active component.
5. purposes according to claim 1, it is characterised in that the compound of formula I and one or more can pharmaceutically connect
The vehicle group received is into pharmaceutical composition.
6. the purposes of chemotherapeutics and compound A in the drug combination for preparing treatment tumour, it is characterised in that the compound
A is compound of formula I, the metabolite of compound of formula I or compound of formula I pharmaceutically acceptable salt.
7. purposes according to claim 6, it is characterised in that the chemotherapeutics is Irinotecan or its active metabolite
SN38, or other medicines using camptothecine compounds and its derivative as principle active component.
8. purposes according to claim 6, it is characterised in that the compound A and one or more are pharmaceutically acceptable
Vehicle group into pharmaceutical composition.
9. purposes according to claim 8, it is characterised in that the formulation of described pharmaceutical composition be tablet, capsule,
Granula, pill or other formulations that can be prepared.
10. purposes according to claim 6, it is characterised in that the tumour includes colorectal cancer, stomach cancer, liver cancer, mammary gland
One or more in cancer, brain tumor, drug resistance leukaemia, lymph cancer, prostate cancer, lung cancer or carcinoma of urinary bladder.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111419843A (en) * | 2020-05-14 | 2020-07-17 | 浙江工业大学 | Application of cyanoimine thiazolidine furan carboxamide compound in preparation of β -glucuronidase inhibitor |
| CN111467361A (en) * | 2020-05-14 | 2020-07-31 | 浙江工业大学 | Application of iridoid glycoside compound in preparation of β -glucuronidase inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014926A (en) * | 2008-05-01 | 2011-04-13 | 宝洁公司 | Methods and kits for the treatment of inflammatory bowel disorder conditions |
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2017
- 2017-10-30 CN CN201711029621.2A patent/CN107823204B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102014926A (en) * | 2008-05-01 | 2011-04-13 | 宝洁公司 | Methods and kits for the treatment of inflammatory bowel disorder conditions |
Non-Patent Citations (1)
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| TUN-CHIEH CHEN ET AL.: "Gemifloxacin inhibits migration and invasion and induces mesenchymal–epithelial transition in human breast adenocarcinoma cells", 《J MOL MED》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111419843A (en) * | 2020-05-14 | 2020-07-17 | 浙江工业大学 | Application of cyanoimine thiazolidine furan carboxamide compound in preparation of β -glucuronidase inhibitor |
| CN111467361A (en) * | 2020-05-14 | 2020-07-31 | 浙江工业大学 | Application of iridoid glycoside compound in preparation of β -glucuronidase inhibitor |
| CN111419843B (en) * | 2020-05-14 | 2021-07-27 | 浙江工业大学 | Application of cyanoimine thiazolidine furan carboxamide compound in preparation of beta-glucuronidase inhibitor |
| CN111467361B (en) * | 2020-05-14 | 2021-10-15 | 浙江工业大学 | Application of iridoid glycoside compound in preparation of beta-glucuronidase inhibitor |
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