CN111658633A - Application of biflavone compound in preparation of drugs and/or pharmaceutical compositions for inhibiting human carboxylesterase 2 - Google Patents
Application of biflavone compound in preparation of drugs and/or pharmaceutical compositions for inhibiting human carboxylesterase 2 Download PDFInfo
- Publication number
- CN111658633A CN111658633A CN202010524537.3A CN202010524537A CN111658633A CN 111658633 A CN111658633 A CN 111658633A CN 202010524537 A CN202010524537 A CN 202010524537A CN 111658633 A CN111658633 A CN 111658633A
- Authority
- CN
- China
- Prior art keywords
- biflavone
- compound
- group
- human carboxylesterase
- carboxylesterase
- 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.)
- Granted
Links
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- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
Abstract
The invention provides an application of a biflavone compound in preparing a medicament and/or a medicinal composition for inhibiting the activity of human carboxylesterase 2. The biflavone compound provided by the invention can strongly and specifically inhibit the activity of human carboxylesterase 2 and inhibit IC of the human carboxylesterase 250Can reach nM level; the selectivity of the biflavone compound to target enzyme is high; the local exposure of the biflavone compound in the intestinal tract system is as high as 68.57 mu M which is higher than the inhibition constant of the biflavone compound to the human carboxylesterase 2, which indicates that the in-vivo drug exposure concentration of the biflavone compound can effectively inhibit the human carboxylesterase 2, thereby improving the delayed diarrhea caused by the antitumor drug, and the biflavone compound also has the advantages of easily obtained raw materials, high safety, simple extraction and preparation process, high yield and the like, in order to relieve the delayed diarrhea,the intestinal protection function provides a new medicine source, and the compound has good application prospect in the aspect of preparing medicines and/or medicine compositions for inhibiting the activity of human carboxylesterase 2.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to an application of a biflavone compound in preparation of a medicament and/or a medicinal composition for inhibiting human carboxylesterase 2.
Background
Irinotecan (CPT-11) is widely used for the treatment of various cancers because of its superior anticancer activity. However, irinotecan can cause serious toxic and side effects and mainly shows intestinal toxicity such as lethal diarrhea and the like, so the clinical application of irinotecan is greatly limited. Numerous studies have found that irinotecan causes delayed diarrhea primarily due to its hydrolytic metabolite, SN-38, accumulating in the intestinal tract in excess. Human carboxylesterase 2 is a key target in irinotecan metabolism and can participate in the hydrolysis and metabolism of about 99 percent of irinotecan in human duodenum, jejunum, ileum and kidney tissues. In view of the key role of human carboxylesterase 2 in irinotecan metabolism, more and more research is focused on finding potent inhibitors of human carboxylesterase 2 to alleviate irinotecan-induced late diarrhea and other related diseases.
At present, few medicines capable of relieving irinotecan tardive diarrhea exist, loperamide is commonly used for relieving irinotecan tardive diarrhea, and although loperamide has extremely excellent human carboxylesterase 2 inhibition effect, loperamide hydrochloride can act on opioid receptors, so that toxic and side effects on nervous systems are often caused, and continuous taking is impossible. It would be beneficial if the hydrolysis of irinotecan could be locally reduced to reduce the extent of damage to the body. Therefore, it is especially necessary to develop a safe and effective human carboxylesterase 2 inhibitor for reducing excessive hydrolysis of irinotecan in the intestinal tract by human carboxylesterase 2 to toxic component SN-38.
Researches find that safe and efficient human carboxylesterase 2 inhibitor is searched from medicinal and edible Chinese herbal medicines, and is expected to relieve delayed diarrhea caused by clinical irinotecan. Studies on the inhibition of human carboxylesterase 2 by hundreds of natural components have been carried out. A large number of researches show that the biflavone component plays an important pharmacological role in the aspects of oxidation resistance, anticoagulation, neuroprotection, anti-inflammation, anti-tumor and anti-infection.
CN109045015A discloses an application of ginkgetin compound in preparing weight-reducing medicines and/or weight-reducing medicine compositions. The ginkgo flavone compounds can strongly inhibit the activity of pancreatic lipase. Particularly, the isoginkgetin suggests that the in-vivo drug exposure concentration of the components can effectively inhibit pancreatic lipase, so as to improve the digestion and absorption of lipid in organisms, and the isoginkgetin also has the advantages of easily available raw materials, high safety, simple extraction and preparation process, high yield and the like, provides a new drug source for the prevention and treatment of obesity, and has good application prospect in the aspect of preparing weight-reducing drugs.
CN101991567A discloses the application of three biflavone monomer components extracted from folium Ginkgo in preparing alpha-glucosidase inhibitor drugs. Pharmacological experiments prove that the three biflavone compounds all have the activity of inhibiting alpha-glucosidase, the invention discloses new application of Ginkgetin, Isoginkgetin and 7-demethylginkgetin in preparing alpha-glucosidase inhibitor drugs, and also discloses new preparation methods of the three biflavone compounds.
Although the biflavone has more effects and efficacies reported at present, the inhibition effect of the biflavone compound on human carboxylesterase 2 is not reported, and the biflavone compound is not reported to relieve the delayed diarrhea caused by irinotecan. Meanwhile, in view of the serious neurotoxicity of loperamide currently approved, if a safe and effective human carboxylesterase 2 inhibitor derived from nature can be developed, the loperamide is very significant as an irinotecan attenuated drug.
Disclosure of Invention
Aiming at the current research situation and the current demand in the prior art, the invention aims to provide the application of biflavonoid compounds in preparing the drugs and/or the pharmaceutical compositions for inhibiting the human carboxylesterase 2, provides a new strategy for improving the delayed diarrhea caused by antitumor drugs, and has wide application prospect and great market value.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides the use of a biflavone compound in the manufacture of a medicament and/or pharmaceutical composition for inhibiting human carboxylesterase 2.
In the present invention, the half inhibitory concentration IC of said biflavone compound to human carboxylesterase 250Can reach nM level; the inhibitor has high selectivity on target enzyme; the topical exposure of biflavone compounds is high up to 68.57. mu.M, which is higher than its inhibition constant for human carboxylesterase 2. The biflavone compound provided by the invention can reduce the accumulation of a toxic product SN-38 of an anti-tumor medicament in intestinal tracts by strongly inhibiting human carboxylesterase 2, thereby improving the delayed diarrhea caused by the anti-tumor medicament.
In the present invention, the structure of the biflavone compound is shown as formula I, formula II and/or formula III:
wherein R is1-R16Any one of which is independently selected from hydrogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy or
R is substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy.
Preferably, the substituents of the alkyl group and the alkoxy group are independently any one of a halogen atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a mercapto group, a sulfonyl group, an acyl group, a carboxyl group, or an ester group.
Preferably, the halogen atom is any one of F, Cl, Br or I.
In the present invention, the substituted or unsubstituted C1-C5 alkyl group is any one of a substituted or unsubstituted C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, or a C5 alkyl group; the C1-C5 alkyl group is a straight or branched alkyl group having 1 to 5 carbon atoms, preferably methyl.
Preferably, the substituted or unsubstituted C1-C5 alkoxy group is any one of a substituted or unsubstituted C1 alkoxy group, a C2 alkoxy group, a C3 alkoxy group, a C4 alkoxy group or a C5 alkoxy group; the C1-C5 alkoxy group is a linear or branched alkoxy group having 1 to 5 carbon atoms, preferably a methoxy group.
Preferably, the
Is a linear acyl group or a branched acyl group, preferably an acetyl group.
In particular, R1-R16Examples of any of the groups include, but are not limited to, the following: H. CH (CH)2F、CH2Cl、CH2Br、CH2I、CF3、CCl3、CBr3、CI3、C2F5、CF3CH2CHOH、CCl3CH2CHSH、CF3(CF2)2CHNH2、CCl3CH2CH2、CH3、C2H5、CH3CH2CH2、(CH3)2CH、CH3(CH2)2CH2、FC2H4O、ClC2H4O、BrC2H4O、IC2H4O、FCH2CH2CH2O、ClCH2CH2CH2O、BrCH2CH2CH2O、ICH2CH2CH2O、HOCH2(CH2)2CH2O、HSCH2(CH2)2CH2O、H2NCH2(CH2)2CH2O、ICH2(CH2)2CH2O、CH3O、C2H5O、CH3CH2CH2O、CH3(CH2)2CH2O、
Any one of them.
In the present invention, the biflavone compound includes any one or a combination of at least two of ginkgo biflavone, 4 '-acetoxy ginkgo biflavone, 5' -methoxy ginkgo biflavone, sciadopitysin, isoginkgo biflavone, amentoflavone, hinokiflavone or ester derivatives thereof.
In the present invention, the biflavone compound includes any one or a combination of at least two of ginkgetin, sciadopitysin, amentoflavone, and hinokiflavone.
In the present invention, the biflavonoid compound further includes derivatives of ginkgetin, isoginkgetin, amentoflavone, hinokiflavone or chamaejasmine, and the derivatives are any one of esterified, oxidized, alkoxylated, acyloxidized or alkylated derivatives of the above biflavonoids. Such as 4' -acetoxy ginkgetin, an acyloxyderivative of ginkgetin; such as 5' -methoxy biflavone, which is an alkoxylated derivative of biflavone.
In the invention, by early-stage large-scale screening, nine potent inhibitors of carboxylesterase 2 are found: seven of the compounds are biflavone compounds and derivatives thereof, namely ginkgo biflavone, sciadopitysin, isoginkgetin, amentoflavone, 5 '-methoxy ginkgo biflavone and 4' -acetoxy ginkgo biflavone, the general formula of the ginkgo biflavone compound is shown in formula I, and the names and structures of some specific compounds are shown in the following table 1; the other two biflavone compounds are hinokiflavone and chamaejasmine respectively, wherein the hinokiflavone has a structure shown in formula II-1, and the chamaejasmine has a structure shown in formula III-1.
TABLE 1
| Name of biflavone Compound | R1 | R2 | R3 | R4 | R5 |
| Ginkgo biflavone | CH3 | CH3 | H | H | H |
| Ginkgo biflavone | CH3 | H | H | H | H |
| Chinese Pinus Densiflora biflavone | CH3 | CH3 | CH3 | H | H |
| Isoflavone of ginkgo biloba | CH3 | H | CH3 | H | H |
| Amentoflavone | H | H | H | H | H |
| 5' -methoxy biflavone of ginkgo | CH3 | H | H | H | OCH3 |
| 4' -acetoxy ginkgetin | CH3 | CH3 | CH3CO | H | H |
The biflavone compound can reduce the accumulation of SN-38 in intestinal tracts by strongly inhibiting human carboxylesterase 2 and relieve the delayed diarrhea caused by irinotecan, and has strong inhibitory activity, namely the half Inhibition Constants (IC) of ginkgetin, ginkgo biflavone, sciadopitysin, kumquatflavone, isoginone, amentoflavone, hinokiflavone, chamaejasmine, 5 '-methoxy ginkgo biflavone and 4' -acetoxy ginkgo biflavone to human carboxylesterase 2 mediated Fluorescein Diacetate (FD)50) 26.26nM, 53.91nM, 46.51nM, 36.60nM, 117.10nM, 37.81nM, 87.54nM, 143.90nM, 35.76nM, respectively; the biflavone compound has high selectivity to target enzyme, and the in vitro activity determination finds that the compound inhibits IC of human carboxylesterase 150With IC inhibiting human carboxylesterase 250Ratio 800-; the biflavone compound has high local exposure, and the local exposure in intestinal tract can reach 68.57 μ M, which is higher than the inhibition constant (K) of human carboxylesterase 2i＝0.082μM)。
In the invention, the biflavone compound is obtained by taking gymnospermum as a raw material and simply extracting.
In the invention, the dosage form of the medicine or the pharmaceutical composition comprises any one of enteric-coated solvent, tablet, powder, suspension, injection, spray, solution, enema, emulsion, membrane, suppository, capsule, electuary, dripping pill or granule or the combination of at least two of the above.
In the present invention, the drug or the pharmaceutical composition further comprises a pharmacologically acceptable excipient.
In the present invention, the excipient includes any one of a carrier, a solvent, an emulsifier, a dispersant, a wetting agent, a binder, a stabilizer, or a colorant, or a combination of at least two thereof.
In the present invention, the biflavone compound can be administered alone or in combination with an excipient to form a suitable dosage form, and it is generally preferred to add an appropriate amount of excipient to perform the combination administration.
In the present invention, when the dosage form of the drug is a tablet, an excipient such as pharmaceutical starch or microcrystalline cellulose; when the medicament is a capsule, the medicament can be prepared into a hard capsule or a soft capsule, and the biflavone compound and the excipient can be prepared into powder or granules to be filled into the capsule; in addition, a flavoring agent can be added to adjust the taste and mouthfeel, and the flavoring agent can be lactose or sucrose; when the pharmaceutical formulation is an emulsion, an emulsifier may be appropriately added to adjust the solubility and the degree of emulsification, and administration may be carried out.
In the present invention, the administration route of the drug or the pharmaceutical composition includes any one of oral administration, sublingual administration or suppository, and preferably oral administration.
In the present invention, the preferred mode of administration is oral administration, generally in the form of tablets or capsules. In addition, when the tablet or the capsule is orally taken, the tablet or the capsule can be prepared into a controlled release preparation or a sustained release preparation, and a proper dosage of controlled release auxiliary materials or sustained release auxiliary materials is selected according to the required drug effect and action time.
In the present invention, the biflavone compound represented by formula I can be used in an amount ranging from 50 to 600mg/kg/d, for example, 50mg/kg/d, 100mg/kg/d, 200mg/kg/d, 300mg/kg/d, 400mg/kg/d, 500mg/kg/d, 600 mg/kg/d.
When the dosage range of the ginkgo biflavone is 50-600mg/kg/d, the ginkgo biflavone can directly target human carboxylesterase 2 after being orally taken, so that the ginkgo biflavone has high local exposure, and the local exposure of the ginkgo biflavone in the intestinal tract can reach 68.57 mu M and is far higher than the inhibition constant (K) of the ginkgo biflavone in the human carboxylesterase 2i0.082 mu M), which indicates that the in-vivo drug exposure concentration of the components can effectively inhibit human carboxylesterase 2, thereby achieving the effect of reducing the accumulation of toxic product SN-38 of the antitumor drug in intestinal tracts, and further improving the delayed diarrhea caused by the antitumor drug.
In a second aspect, the present invention provides an irinotecan-attenuated drug characterized in that it comprises a biflavone compound as a human carboxylesterase 2 inhibitor.
In the invention, as mentioned above, the biflavone compound can effectively relieve the accumulation of the hydrolysate SN-38 of irinotecan in the intestinal tract and further relieve the intestinal toxicity of the irinotecan by strongly inhibiting the human carboxylesterase 2.
Compared with the prior art, the invention has the following beneficial effects: the invention provides a biflavone compound, which can reduce the accumulation of a toxic product SN-38 of an anti-tumor medicament in intestinal tracts by strongly inhibiting human carboxylesterase 2, thereby improving the delayed diarrhea caused by the anti-tumor medicament.
The application of the biflavone compound provided by the invention has the following advantages:
1. the raw materials are cheap and easy to obtain: the biflavone compound provided by the invention is obtained by extracting cheap gymnosperm serving as a raw material, and has the advantages of simple and feasible process and high yield.
2. The inhibition activity is strong: the biflavone compound provided by the invention has half inhibition concentration IC of human carboxylesterase 2 in human tissue microsomes50Can reach nM level.
3. High selectivity for the target enzyme: in vitro activity determination finds that the biflavone compound provided by the invention inhibits IC of human carboxylesterase 150With IC inhibiting human carboxylesterase 250The ratio is 800-3000.
4. High local exposure: the application dosage range of the biflavone compound provided by the invention is 50-600mg/kg/d, and the biflavone compound can directly target human carboxylesterase 2 after being orally taken, so that the local exposure of the biflavone compound is very high, the local exposure of the biflavone compound in an intestinal tract system can reach 68.57 mu M, and is far higher than the inhibition constant (K) of the biflavone compound to the human carboxylesterase 2i＝0.082μM)。
5. High safety: the ginkgo biflavone powder is used for carrying out acute toxicity test and long-term toxicity test on mice, and the result shows that the ginkgo biflavone medicine has no toxic reaction and can be used for a long time.
Drawings
FIG. 1A is a graph showing the inhibition of ginkgetin on the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxylesterase 2(hCE 2);
FIG. 1B is a graph showing the inhibition of bilobalide on the hydrolysis of human carboxylesterase 2(hCE2) mediated Fluorescein Diacetate (FD);
FIG. 1C is a graph showing the inhibition of sciadopitysin on the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxyesterase 2(hCE 2);
FIG. 1D is a graph showing the inhibition of isoginkgetin against the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxylesterase 2(hCE 2);
FIG. 1E is a graph showing the inhibition of amentoflavone on the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxyesterase 2(hCE 2);
FIG. 1F is a graph showing the inhibition of hinokiflavone on the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxylesterase 2(hCE 2);
FIG. 1G is a graph showing the inhibition of the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxylesterase 2(hCE2) by chamaejasmine;
FIG. 1H is a graph showing the inhibition of 5' -methoxy-bilobanone by hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxyesterase 2(hCE 2);
FIG. 1I is a graph showing the inhibition curves of 4' -acetoxy ginkgetin against the hydrolysis of Fluorescein Diacetate (FD) mediated by human carboxylesterase 2(hCE 2).
FIG. 2A is a graph showing the inhibition of ginkgetin on the human carboxylesterase 2(hCE2) mediated hydrolysis of irinotecan (CPT-11);
FIG. 2B is a graph showing the inhibition of ginkgolide to human carboxylesterase 2(hCE2) -mediated hydrolysis of irinotecan (CPT-11);
FIG. 2C is a graph showing the inhibition of sciadopitysin on the carboxylesterase 2(hCE2) -mediated hydrolysis of irinotecan (CPT-11);
FIG. 2D is a graph showing the inhibition of the hydrolysis of irinotecan (CPT-11) mediated by human carboxylesterase 2(hCE2) by using isoginkgetin;
FIG. 2E is a graph showing the inhibition of amentoflavone on the carboxylesterase 2(hCE2) -mediated hydrolysis of irinotecan (CPT-11);
FIG. 2F is a graph showing the inhibition of hinokiflavone on the human carboxylesterase 2(hCE2) mediated hydrolysis of irinotecan (CPT-11);
FIG. 2G is a graph showing the inhibition of the hydrolysis of irinotecan (CPT-11) mediated by human carboxylesterase 2(hCE2) by chamaejasmine;
FIG. 2H is a graph showing the inhibition of 5' -methoxy bilobanone on the human carboxylesterase 2(hCE2) mediated hydrolysis of irinotecan (CPT-11);
FIG. 2I is a graph showing the inhibition of the hydrolysis of irinotecan (CPT-11) mediated by human carboxylesterase 2(hCE2) by 4' -acetoxyginkgetin.
FIG. 3 shows the body weight and time variation of each group of mice tested in the delayed-type experimental study of ginkgo biflavone for irinotecan alleviation.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
Quantitative evaluation of human carboxylesterase 2 inhibitory potency of biflavone compounds
In this embodiment, the adopted equipment and its model are: detection was performed by a Molecular Devices ID3 microplate reader (shanghai damimai biotechnology limited) liquid chromatography system (Shimadzu, Kyoto, Japan) and a fluorescence detector (Shimadzu, Kyoto, Japan).
In this example, the IC inhibition of human carboxylesterase 2 by ginkgetin diacetate (FD) and irinotecan (CPT-11) were measured with human liver microsome incubation system as probe substrates for human carboxylesterase 2, and ginkgetin, isoginkgetin, amentoflavone, hinokiflavone, chamaejasmine, 5 '-methoxybilobflavone and 4' -acetoxy ginkgetin50The specific test method is as follows:
a. human liver microsomes were added to 200. mu.l of 0.1M phosphate buffer solution containing pH 7.4 to a final concentration of 2. mu.g/mL, inhibitors were added to a final concentration of 0.1. mu.M-100. mu.M at different concentrations, and the mixture was subjected to pre-incubation at 37 ℃ for 10min with shaking to obtain a series of pre-incubation solutions.
b. Adding pre-incubation liquid and substrate FD (final concentration of 5 μ M) into 96-well plate, initiating reaction, and continuously detecting metabolism hydrolysate fluorescein of FD for 30min (excitation wavelength of 480nm and emission wavelength of 525nm) with multifunctional microplate reader
c. The concentration of inhibitor is plotted on the abscissa and the residual enzyme activity is plotted on the ordinate, and the IC is calculated using software50The value is obtained.
Wherein the calculation formula of the residual enzyme activity is as follows:
the residual enzyme activity (F0-F1)/F0X 100%
F0The fluorescence intensity value measured in the absence of inhibitor in the pre-incubation fluid, F1The fluorescence intensity values measured when the inhibitors were added to the pre-incubation solution at each concentration.
The inhibition curves of nine biflavonoids of this example on the hydrolysis of human carboxylesterase 2(hCE2) mediated Fluorescein Diacetate (FD) are shown in fig. 1; the inhibition curves of nine biflavone compounds on the hydrolysis reaction of irinotecan (CPT-11) mediated by human carboxylesterase 2(hCE2) are shown in FIG. 2. In this embodiment, IC is calculated by plotting inhibition curves50The inhibition parameter IC of biflavone compound to human carboxylesterase 250Table 2, table of values.
TABLE 2 inhibition parameters of biflavone Compounds on human carboxylesterase 2
As can be seen from Table 1, the biflavone compound has strong inhibitory activity, and the human carboxylesterase inhibitor provided by the invention has half inhibitory concentration IC of human carboxylesterase 2 in human tissue microsomes50Can reach nM level. Wherein the measured ginkgetin, sciadopitysin, isoflavone, chamaemelon, chamaejasmine, 5 '-methoxy ginkgetin and 4' -acetoxy ginkgetin are used as probe substrate of human carboxylesterase 2Half Inhibition Constant (IC) of enzyme 250) 26.26nM, 53.91nM, 46.51nM, 36.60nM, 117.10nM, 37.81nM, 87.54nM, 143.90nM and 35.76nM, respectively, and the inhibitory effect was more significant in terms of FD. In particular to the IC of the ginkgetin50The value can reach 26.26nM, and the effect is very outstanding.
Example 2
This example prepares a Ginkgo biflavone tablet
Accurately weighing 50g of ginkgo biflavone monomer (the purity is more than 98.5 percent) and adding 250g of medicinal starch, fully mixing the two to prepare 1000 tablets, wherein each tablet is 0.3 g and contains 50mg of ginkgo biflavone.
Example 3
This example prepares sciadopitysin capsules
Accurately weighing 50g of sciadopitysin monomer (the purity is more than 98.5%), adding 250g of medicinal starch, mixing the two materials, granulating with a 20-mesh sieve, drying at 60 deg.C, subpackaging and filling into hollow capsules, and subpackaging into 1000 capsules, each capsule weighing 0.3 g, and containing sciadopitysin 50 mg.
Example 4
This example prepares 4' -acetoxy ginkgetin enteric capsules
50g of 4' -acetoxy ginkgetin monomer (purity is more than 98.5%) is accurately weighed, 285.7g of microcrystalline cellulose and 114.3g of lactose are added, the mixture is uniformly mixed, granulated by a 20-mesh sieve and dried under reduced pressure. Adding 0.15% micropowder silica gel, mixing, and encapsulating into enteric capsule shell, wherein each capsule has a weight of 0.45 g and contains 50mg of 4' -acetoxy ginkgetin.
Example 5
Test of Ginkgo biflavone for alleviating mice diarrhea caused by irinotecan
30 Balb/c mice were selected and randomly divided into 5 groups: a normal control group, an irinotecan diarrhea model group + loperamide group, a ginkgetin group and a ginkgetin + irinotecan diarrhea model group, wherein each group comprises 6 mice. Seven days were administered as in table 3 below.
TABLE 3 mice seven day regimen
The mice were weighed daily, the diarrhea status of each group of mice was observed, the mice were sacrificed on day 8, and intestinal tissue was sampled and examined by staining tissue sections. Taking 3cm of ileum, 1cm of cecum and 3cm of colon tissue from the position 5cm away from ileocecal valve to the position 7-9 cm above anus, and fixing with 10% formaldehyde for observation by using a light microscope. Observing the change of the intestinal mucosa tissue structure of each group of mice by conventional HE staining; according to the Chiu intestinal mucosal injury scoring method [ Arch Surg 1970; 101:478-83], grading the degree of damage to the intestinal mucosa: level 1: normal intestinal mucosal villi; and 2, stage: the subepithelial space is enlarged, usually at the top of the intestinal villi, with epithelial congestion; and 3, level: subepithelial space dilation with moderate detachment of the epithelial layer from the intestinal mucosal lamina propria; 4, level: the large epithelium on the side surface of the intestinal mucosa is separated, and the top of most intestinal villi becomes smooth; and 5, stage: intestinal villi become smooth, capillaries dilate, and the cell composition of the intestinal mucosa lamina propria is increased; and 6, level: the lamina propria of the intestinal mucosa digests and disintegrates, bleeds and ulcerations occur.
The results of the degree of injury of mouse cecal mucosa are shown in Table 4 (wherein the degree of injury is graded as n (%), n represents the number of mice, and (%) represents the percentage of mice classified by the degree of injury), and the results of the change in body weight of mice are shown in FIG. 3.
TABLE 4 mouse cecal intestinal mucosa damage degree grading n (%)
As is apparent from fig. 3, when the degree of intestinal mucosa injury was evaluated, the ginkgo biflavone + irinotecan diarrhea model group showed a significant decrease in the degree of diarrhea compared to the irinotecan diarrhea model group and the irinotecan diarrhea model group + loperamide group. As is apparent from Table 4, the degree of damage to the intestinal mucosa was graded lower and slightly less in the ginkgetin group than in the diarrhea model group and the loperamide + irinotecan diarrhea model group.
The experimental results prove that the ginkgetin not only can reduce the degrees of irinotecan-induced tardive diarrhea and intestinal mucosa injury of mice, but also can better inhibit the occurrence of diarrhea. Therefore, the ginkgetin has certain prevention effect on irinotecan-induced late diarrhea in mice.
In conclusion, the biflavone compound can inhibit the hydrolysis and metabolism of irinotecan in the intestinal tract by inhibiting human carboxylesterase 2, reduce the accumulation of SN-38 in the intestinal tract and further prevent and treat the delayed diarrhea and related diseases caused by irinotecan.
The applicant states that the application of the biflavone compound of the present invention in the preparation of irinotecan attenuated drug is illustrated by the above examples, but the present invention is not limited to the above examples, i.e., it is not meant to imply that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. An application of biflavone compound in preparing medicine and/or pharmaceutical composition for inhibiting human carboxylesterase 2 inhibitor is provided.
2. Use according to claim 1, wherein the biflavonoid compound has the structure according to formula I, formula II and/or formula III:
wherein R is1-R16Any one of which is independently selected from hydrogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy or
R is substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted C1-C5 alkoxy.
3. The use according to claim 2, wherein the substituents of the alkyl group and the alkoxy group are independently any one of a halogen atom, a cyano group, a hydroxyl group, an amino group, a nitro group, a mercapto group, a sulfonyl group, an acyl group, a carboxyl group, or an ester group.
4. The use of any one of claims 1 to 3, wherein the biflavone compound comprises any one or a combination of at least two of ginkgetin, 4 '"-acetoxyginkgetin, ginkgetin, 5' -methoxyginkgetin, sciadopitysin, isoginkgetin, amentoflavone, hinokiflavone or ester derivatives thereof.
5. The use according to any one of claims 1 to 4, wherein the medicament or the pharmaceutical composition is in a dosage form selected from one or a combination of at least two of enteric agents, tablets, powders, suspensions, injections, sprays, solutions, enemas, emulsions, films, suppositories, capsules, granules, dripping pills or granules.
6. Use according to any one of claims 1 to 5, wherein the medicament or pharmaceutical composition further comprises a pharmacologically acceptable excipient.
7. The use according to claim 6, wherein the excipient comprises any one or a combination of at least two of a carrier, a solvent, an emulsifier, a dispersant, a wetting agent, a binder, a stabilizer or a colorant.
8. Use according to any of claims 1 to 7, wherein the route of administration of the medicament or pharmaceutical composition comprises any of oral administration, sublingual administration or suppository, preferably oral administration.
9. The use according to any one of claims 1 to 8, wherein the biflavone compound of formula I is administered in an amount ranging from 50 to 600 mg/kg/d.
10. An irinotecan-attenuated drug comprising a biflavone compound as a human carboxylesterase 2 inhibitor.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115850295A (en) * | 2022-12-01 | 2023-03-28 | 河南中医药大学 | Preparation method and application of diketone compound dysosma versipellis biflavone A-E |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106728145A (en) * | 2016-12-17 | 2017-05-31 | 郑州郑先医药科技有限公司 | It is a kind of to treat Chinese and western medicinal composition of acute diarrhea and preparation method thereof |
| CN106822133A (en) * | 2016-12-17 | 2017-06-13 | 郑州郑先医药科技有限公司 | A kind of Western medicine compound for treating acute diarrhea |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106728145A (en) * | 2016-12-17 | 2017-05-31 | 郑州郑先医药科技有限公司 | It is a kind of to treat Chinese and western medicinal composition of acute diarrhea and preparation method thereof |
| CN106822133A (en) * | 2016-12-17 | 2017-06-13 | 郑州郑先医药科技有限公司 | A kind of Western medicine compound for treating acute diarrhea |
Non-Patent Citations (1)
| Title |
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| PAUL COULERIE 等: "Biflavonoids of Dacrydium balansae with Potent Inhibitory Activity on Dengue 2 NS5 Polymerase" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850295A (en) * | 2022-12-01 | 2023-03-28 | 河南中医药大学 | Preparation method and application of diketone compound dysosma versipellis biflavone A-E |
| CN115850295B (en) * | 2022-12-01 | 2024-01-26 | 河南中医药大学 | Preparation method and application of diketone compound dysosma versipellis biflavone A-E |
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