CN112716954A - New medicinal application of nitidine chloride - Google Patents
New medicinal application of nitidine chloride Download PDFInfo
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- CN112716954A CN112716954A CN202110142735.8A CN202110142735A CN112716954A CN 112716954 A CN112716954 A CN 112716954A CN 202110142735 A CN202110142735 A CN 202110142735A CN 112716954 A CN112716954 A CN 112716954A
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- multiple myeloma
- cells
- pharmaceutically acceptable
- nitidine chloride
- prodrug
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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
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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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
Abstract
The invention discloses a new application of nitidine chloride in medicaments, and relates to an application of a compound shown in a formula (I), pharmaceutically acceptable salt thereof or a prodrug thereof in preparation of medicaments for preventing and/or treating multiple myeloma, which is shown in the formula (I). The test results of the invention prove that: nitidine chloride has inhibitory effect on multiple myeloma cells, and can promote apoptosis. The nitidine chloride can be used as a new medicine for resisting multiple myeloma.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a new application of nitidine chloride.
Background
Currently, Multiple Myeloma (MM) is a hematological malignancy, characterized primarily by clonal proliferation of myeloid plasma cells with most of the concomitant overproduction of immunoglobulin M proteins. With the elucidation of the biological mechanism of MM and the clinical application of targeted drugs, MM treatment has been greatly advanced, but most of the available drugs are prone to toxic and side effects and drug resistance, and MM remains an incurable malignant tumor.
The effective component of nitiduM chloride (Zanthox yluM nitiduM (Ro xb.) DC) in the traditional Chinese medicine achieves the anti-tumor effect mainly through inhibiting the activity of topoisomerase, blocking the cell cycle, inducing the apoptosis of tumor cells, reversing the multidrug resistance of the tumor cells and other action mechanisms. As a new application method of the traditional Chinese medicine, the nitidine chloride has great development and application values of the antitumor effect, the structure-activity relationship and the structure optimization of a nitidine chloride system are proposed in the future, and a target compound or a candidate drug molecule is provided for researching and developing a new drug; at the same time, new drugs are developed by synthesizing and building up libraries of compounds of natural active substance analogues. The action effect and mechanism of nitidine chloride in multiple myeloma cells have not been studied.
Disclosure of Invention
Therefore, the invention provides a new medicinal application of nitidine chloride.
In order to achieve the above purpose, the invention provides the following technical scheme:
the embodiment of the invention provides an application of a compound shown as a formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof in preparing a medicament for preventing and/or treating multiple myeloma,
in one embodiment of the invention, the multiple myeloma cell is a multiple myeloma cell U266/8266.
In one embodiment of the invention, the compound, its pharmaceutically acceptable salt or prodrug thereof is used for preparing a product for preventing and/or treating multiple myeloma cells; a product that inhibits multiple myeloma cell activity; and
a product for promoting apoptosis of multiple myeloma cells.
In one embodiment of the present invention, the compound, its pharmaceutically acceptable salt or prodrug thereof comprises an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable pharmaceutical carriers.
In one embodiment of the invention, diluents, excipients, binders, wetting agents, absorption enhancers, surfactants, lubricants.
In one embodiment of the present invention, the pharmaceutical composition is in the form of tablet, capsule, oral liquid, injection, powder, paste or external liquid.
In the present invention, the term "prodrug" refers to a compound that is a drug precursor that, when administered, undergoes chemical transformation in vivo, either by metabolic or chemical processes (e.g., exposure to physiological pH or by enzymatic activity), releasing the active drug. . The "prodrug" of the present invention may also include metabolic precursors of the compounds of the present invention, which may not be active when administered to a subject, but may be converted in vivo to a compound of formula (I) of the present invention or a salt and/or solvate thereof. Prodrugs can also be naturally occurring or chemically synthesized compounds.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of a compound of formula (I) or a stereoisomer thereof, or a prodrug thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. Or by mixing a compound represented by the formula (I), or a stereoisomer thereof, or a prodrug thereof with a certain amount of an acid or a base as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
In the present invention, the term "prodrug" refers to a compound that is a drug precursor that, when administered, undergoes chemical transformation in vivo, either by metabolic or chemical processes (e.g., exposure to physiological pH or by enzymatic activity), releasing the active drug. The "prodrug" of the present invention may also include metabolic precursors of the compounds of the present invention, which may not be active when administered to a subject, but may be converted in vivo to a compound of formula (I) of the present invention or a salt and/or solvate thereof. Prodrugs can also be naturally occurring or chemically synthesized compounds.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of a compound of formula (I) or a stereoisomer thereof, or a prodrug thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. Or by mixing a compound represented by the formula (I), or a stereoisomer thereof, or a prodrug thereof with a certain amount of an acid or a base as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
In the present invention, the pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, such as: diluents, excipients such as water, etc., fillers such as starch, sucrose, etc.; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; humectants such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and bentonite; lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, and the like. Other adjuvants such as flavoring agent, sweetener, etc. can also be added into the composition.
The pharmaceutical compositions of the present invention are administered to a patient in need of such treatment by oral, nasal inhalation, rectal or parenteral administration. For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc., liquid preparations such as aqueous or oil suspension, or other liquid preparations such as syrup, elixir, etc.; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field. For example, the active ingredient may be combined with one or more carriers and then formulated into the desired dosage form.
The invention has the following advantages:
the test results of the invention prove that: nitidine chloride has inhibitory effect on multiple myeloma cells, and can promote apoptosis. The nitidine chloride can be used as a new medicine for resisting multiple myeloma.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It should be apparent that the drawings in the following description are merely exemplary, and that other embodiments can be derived from the drawings provided by those of ordinary skill in the art without inventive effort.
FIG. 1 is a bar graph of activity change of CCK8 in U266 cells treated with nitidine chloride, 24h IC50About 4. mu. mol/L, 48h IC50About 2.5 micromoles/L;
FIG. 2 is a bar graph of the change in viability of cells 8266 treated with nitidine chloride measured by CCK8 according to an embodiment of the present invention, 24h IC50About 4. mu. mol/L, 48h IC50About 2.5 micromoles/L;
FIG. 3 is a bar graph of activity change of CCK8 after nitidine chloride treatment of SP2/0 cells, 24h IC, provided by an embodiment of the present invention50About 4. mu. mol/L, 48h IC50About 2.5 micromoles/L;
FIG. 4 is a diagram of the change of apoptosis of Annexin V-FITC/PI cells after nitidine chloride treatment of U266 cells according to the embodiment of the invention;
FIG. 5 is a graph of the change of apoptosis of Annexin V-FITC/PI cells after 8266 cells are treated by nitidine chloride according to the embodiment of the invention;
FIG. 6 is a graph of the change of apoptosis of Annexin V-FITC/PI cells after nitidine chloride treatment of SP2/0 cells according to the embodiment of the invention.
Detailed Description
The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The embodiment of the invention provides a compound nitidine chloride for resisting multiple myeloma, which has a chemical formula shown as a formula (I):
the compound shown in the chemical formula (I) of the embodiment of the invention is used for oral administration, and the oral dosage is 0.5mg/kg body weight;
in this example, nitidine chloride was purchased from a leaf organism of shanghai origin.
Example 2, method of CCK8 to demonstrate the effect of nitidine chloride on cell viability of multiple myeloma cells
In this example, multiple myeloma cells U266/8266/SP2/0 were obtained from Shanghai cell Bank, Chinese academy of sciences. CCK8 was purchased from shanghai bluewood chemical.
Using U266 cells in logarithmic growth phase, collecting U266 cells for cell counting, plating to make the number of U266 cells in each well of 96-well plate be 5000, using different concentrations (1-10 μ M) of nitidine chloride to treat multiple myeloma cells U26624 h and 48h, adding 20 μ l CCK8 reagent in each well of cells, incubating for 2-4h, detecting absorbance (OD ═ 450) by enzyme labeling instrument (Biotek, epoch2), calculating cell activity formula as: cell viability (%) ═ 100 (experimental OD/control OD).
Nitidine chloride can resist the cell viability of U266 of multiple myeloma cells and can promote the apoptosis of multiple myeloma cells in a concentration-dependent manner.
Cells were tested for viability by treating 8266 and SP2/0 cells, respectively, as described for U266 cells in CCK 8.
As shown in fig. 1-3, the method using CCK8 is a bar graph demonstrating the viability change of nitidine chloride on the cell viability of multiple myeloma cells U266/8266/SP2/0, respectively.
Example 3 inhibition of multiple myeloma cell growth by nitidine chloride
Respectively adopting U266 cells in a logarithmic growth phase, collecting the cells, counting the cells, plating to ensure that the number of the cells in each well of a 6-well plate is 40 ten thousand, treating the multiple myeloma cells U26624 h by using nitidine chloride with different concentrations (2, 4, 6, 8 and 10 mu M), collecting the cells, washing the cells for 2 times by using PBS, detecting by using a Bebo biological kit (BB-4101), adding 400 mu l of Annexin V-FITC binding reagent, adding 5 mu l of Annexin V-FITC, keeping out of the sun for 15min, adding 10 mu l of PI, staining for 5min, and detecting the apoptosis by flow: the flow cytometer is an AINSNOVO CYTE with the excitation wavelength of 488, a 1 channel and a 3 channel are selected for detection, after Annexin V-FITC/PI double staining, the apoptosis condition is detected by the flow cytometer, and the apoptosis is detected by the flow cytometer: the research result shows that the nitidine chloride has an inhibiting effect on multiple myeloma cells and can promote apoptosis of the multiple myeloma cells.
The inhibitory effect of nitidine chloride on multiple myeloma cells was determined according to the method for treating U266 cells, treatment 8266 and SP2/0 cells, respectively.
As shown in fig. 4 to 6, the present inventors found that nitidine chloride can resist the growth of multiple myeloma cells and promote the apoptosis thereof.
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (6)
1. The application of the compound shown in the formula (I), the pharmaceutically acceptable salt thereof or the prodrug thereof in preparing the medicines for preventing and/or treating multiple myeloma,
2. the use according to claim 1,
the multiple myeloma cell is a multiple myeloma cell U266/8266.
3. The use according to claim 1,
the compound, the pharmaceutically acceptable salt thereof or the prodrug thereof can be used for preparing products for preventing and/or treating multiple myeloma cells; a product that inhibits multiple myeloma cell activity; and
a product for promoting apoptosis of multiple myeloma cells.
4. The use according to claim 1,
the compound, the pharmaceutically acceptable salt thereof or the prodrug thereof, wherein the compound, the pharmaceutically acceptable salt thereof or the prodrug thereof contains one or more pharmaceutically acceptable drug carriers.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical carrier comprises:
diluent, excipient, adhesive, wetting agent, absorption enhancer, surfactant and lubricant.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of a tablet, a capsule, an oral liquid, an injection, a powder, a paste, or a liquid for external use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110142735.8A CN112716954B (en) | 2021-02-02 | 2021-02-02 | New medicinal application of nitidine chloride |
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| CN202110142735.8A CN112716954B (en) | 2021-02-02 | 2021-02-02 | New medicinal application of nitidine chloride |
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| CN112716954A true CN112716954A (en) | 2021-04-30 |
| CN112716954B CN112716954B (en) | 2022-03-15 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113786406A (en) * | 2021-08-12 | 2021-12-14 | 遵义医科大学珠海校区 | Application of nitidine chloride in preparation of urease inhibitor |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1012153A1 (en) * | 1997-09-03 | 2000-06-28 | Guilford Pharmaceuticals Inc. | Parp inhibitors, pharmaceutical compositions comprising same, and methods of using same |
| CN101564393A (en) * | 2008-04-25 | 2009-10-28 | 中国科学院化学研究所 | Novel application of nitidine |
| WO2014011540A1 (en) * | 2012-07-09 | 2014-01-16 | Emory University | Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto |
| CN109715171A (en) * | 2016-08-19 | 2019-05-03 | 蓝鸟生物公司 | Genome editor's enhancer |
| WO2020008262A2 (en) * | 2018-07-03 | 2020-01-09 | Menri Group Ltd | Uses for calcium channel modulators |
| CN111494382A (en) * | 2020-05-28 | 2020-08-07 | 吉林大学 | Novel application of nitidine chloride |
-
2021
- 2021-02-02 CN CN202110142735.8A patent/CN112716954B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1012153A1 (en) * | 1997-09-03 | 2000-06-28 | Guilford Pharmaceuticals Inc. | Parp inhibitors, pharmaceutical compositions comprising same, and methods of using same |
| CN101564393A (en) * | 2008-04-25 | 2009-10-28 | 中国科学院化学研究所 | Novel application of nitidine |
| WO2014011540A1 (en) * | 2012-07-09 | 2014-01-16 | Emory University | Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto |
| CN109715171A (en) * | 2016-08-19 | 2019-05-03 | 蓝鸟生物公司 | Genome editor's enhancer |
| WO2020008262A2 (en) * | 2018-07-03 | 2020-01-09 | Menri Group Ltd | Uses for calcium channel modulators |
| CN111494382A (en) * | 2020-05-28 | 2020-08-07 | 吉林大学 | Novel application of nitidine chloride |
Non-Patent Citations (3)
| Title |
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| XIAO-GUANG YANG等: ""Nitidine chloride induces S phase cell cycle arrest and mitochondriadependent dependent apoptosis in HaCaT cells and ameliorates skin lesions in psoriasis-like mouse models"", 《EUROPEAN JOURNAL OF PHARMACOLOGY》 * |
| 李强、夏晓晖主编: ""两面针碱"", 《新编常用中药有效成分手册》 * |
| 杨彦忠等: ""靶向STAT3信号通路抗肿瘤治疗策略的研究进展"", 《中国肿瘤生物治疗杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113786406A (en) * | 2021-08-12 | 2021-12-14 | 遵义医科大学珠海校区 | Application of nitidine chloride in preparation of urease inhibitor |
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| CN112716954B (en) | 2022-03-15 |
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