CN118161495A - Application of quinoxaline derivative in preparing wound healing promoting medicine - Google Patents
Application of quinoxaline derivative in preparing wound healing promoting medicine Download PDFInfo
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- CN118161495A CN118161495A CN202410306820.7A CN202410306820A CN118161495A CN 118161495 A CN118161495 A CN 118161495A CN 202410306820 A CN202410306820 A CN 202410306820A CN 118161495 A CN118161495 A CN 118161495A
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- 210000002950 fibroblast Anatomy 0.000 abstract description 29
- ZQXMPDVGBWOTBY-UHFFFAOYSA-N N-[4-(6-chloroquinoxalin-2-yl)phenyl]acetamide Chemical compound C=1(C=CC(=CC=1)NC(=O)C)C1=NC2=C(N=C1)C=C(Cl)C=C2 ZQXMPDVGBWOTBY-UHFFFAOYSA-N 0.000 abstract description 26
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- 238000002474 experimental method Methods 0.000 description 12
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Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to application of quinoxaline derivatives in preparing medicaments for promoting wound healing, and discovers that the quinoxaline derivatives CA77.1 show remarkable migration and invasion activity on human foreskin fibroblast HFF-1 after acting for 24-48 hours at a concentration lower than 2 mu M, which indicates that the CA77.1 can rapidly improve the movement capability of the cells; meanwhile, the quinoxaline derivative CA77.1 has no drug toxicity trend to human foreskin fibroblast HFF-1 and mouse embryo fibroblast L-929 at the concentration of 100 mu m/L, and has very high safety; therefore, the quinoxaline derivative provided by the invention can realize the effect of promoting wound healing safely and without toxic or side effects in a larger dosage range, and has obvious effect of reducing chronic wound healing time especially for diabetics with poor wound healing capacity.
Description
Technical Field
The invention belongs to the technical field of medicines and preparations, and particularly relates to application of quinoxaline derivatives in preparation of medicines for promoting wound healing.
Background
The skin is used as the largest organ of human body, plays a vital role in protecting human organs and tissues, preventing infection, maintaining water and electrolyte balance, regulating body temperature and the like, and also maintains the stability of the environment in the human body. The skin is quite fragile, and is inevitably wounded in daily life. Skin wounds can not only cause pain to the patient and affect the patient's health, but also affect the patient's mental and mental health. Wound healing is an extremely complex and dynamic process, and how to effectively promote wound healing and prevent infection is an important subject in the field of wound repair. Wound self-repair and tissue regeneration are complex cellular processes involving interactions between GFs, chemokines, cytokines, and other signaling molecules. The wound healing process is continuous and interdigitated and can be roughly divided into 4 phases: the proliferation stage is the most critical stage, and mainly consists of keratinocytes, vascular endothelial cells and fibroblasts, so that the angiogenesis in the stage is extremely difficult for healing of chronic wounds, such as the process of revascularization in wounds of diabetics is very slow, the surface area of blood vessels, branch connection numbers, total blood vessel length and total branch numbers in wounds are obviously reduced, angiogenesis can effectively support wound closure, and vascular lesions are one of causes of difficult healing of chronic wounds.
At present, the treatment of wounds and wound surfaces mainly comprises treatment means such as laser, treatment auxiliary materials, negative pressure treatment, skin transplantation and the like, the clinical application is limited, and the effect is not ideal especially for chronic wounds. Therefore, development of new drugs for accelerating wound healing, especially chronic wound healing for diabetics and the like, is a highly-needed problem. Based on the fact that the development difficulty of new drugs for promoting wound healing is high, the wound healing activity is still low, and cytotoxicity is difficult to control, the development of new applications by adopting known drugs is a rapid and effective drug development way.
Disclosure of Invention
Aiming at the prior art problems, the invention provides application of quinoxaline derivatives in preparing medicaments for promoting wound healing, and the quinoxaline derivatives can remarkably improve migration and invasion capacities of cells and can be used for promoting wound healing of diabetics or non-diabetics.
In a first aspect, the invention provides application of quinoxaline derivatives in preparing medicaments for promoting wound healing, wherein the quinoxaline derivatives comprise the following molecular structural formula:
Preferably, the quinoxaline derivative is N- (4- (6-chloroquinoxalin-2-yl) phenyl) acetamide (CA 77.1), and the molecular structural formula is:
further, the medicament comprises promoting wound healing of diabetics.
Further, the medicament comprises promoting wound healing in non-diabetic patients.
In a second aspect, the invention also provides a medicament for promoting wound healing, which comprises the quinoxaline derivative, geometric isomer thereof or pharmaceutically acceptable salt thereof and/or solvate thereof and/or hydrate thereof.
Further, the medicament also comprises pharmaceutically acceptable auxiliary materials.
Further, the dosage forms of the medicament comprise suspension, granules, capsules, powder, tablets, emulsion, solution, dripping pills, injection, aerosol, gel, patch, drops or liniment, and other non-enumerated indications are also applicable in the scope of the above dosage forms.
Further, the medicament comprises promoting wound healing of diabetics.
The pharmaceutical indications include wounds, wounds of diabetics or wounds of non-diabetics, but are not limited to the above listed indications, and other non-listed indications within the above indicated range are equally applicable;
Further, wounds of the non-diabetic patients include burns, scalds, ulcers, dermatitis, childbirth, but are not limited to the above-listed indications, and other non-listed indications within the above-listed indications are equally applicable.
Compared with the prior art, the invention has the following beneficial effects:
According to the invention, new application of the quinoxaline derivative is developed, and the quinoxaline derivative is found to be capable of promoting migration and invasion of cells, especially, the quinoxaline derivative has remarkable migration and invasion effects on human foreskin fibroblast HFF-1, wherein the compound CA77.1 has remarkable activity on migration and invasion of human foreskin fibroblast HFF-1 at a concentration lower than 2 mu M, so that the quinoxaline derivative can be found to remarkably improve the migration capacity and invasion penetration capacity of human foreskin fibroblast HFF-1 at a very low concentration; meanwhile, the quinoxaline derivative CA77.1 has no drug toxicity trend to human foreskin fibroblast HFF-1 and mouse embryo fibroblast L-929 at the concentration of 100 mu m/L, and has very high safety; therefore, the quinoxaline derivative provided by the invention can quickly improve the movement capability of cells within a large dosage range, realize the effect of promoting wound healing, and accelerate the wound healing, especially for diabetics with poor wound healing capability, can further reduce the chronic wound healing time, and can be widely applied to promoting the wound healing of trauma, burns, scalds, ulcers, dermatitis, chronic wounds and childbirth.
Drawings
FIG. 1 is an in vitro toxicity test of quinoxaline derivative CA77.1 of the present invention on human foreskin fibroblast HFF-1.
FIG. 2 is an in vitro toxicity test of quinoxaline derivative CA77.1 of the present invention on mouse embryonic fibroblast L-929.
FIG. 3 is a graph showing migration of quinoxaline derivative CA77.1 of the present invention to human foreskin fibroblast HFF-1.
FIG. 4 is a statistical data of the quinoxaline derivative CA77.1 of the present invention on human foreskin fibroblast HFF-1 migration.
FIG. 5 is an invasiveness graph of quinoxaline derivative CA77.1 of the present invention to human foreskin fibroblast HFF-1.
FIG. 6 is a data statistical result of the invasion of the quinoxaline derivative CA77.1 of the present invention to human foreskin fibroblast HFF-1.
Detailed Description
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
The present invention will be further described in detail with reference to the following embodiments, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the description is only illustrative and is not intended to limit the scope of the invention. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the present invention.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
The specific example of the invention adopts N- (4- (6-chloroquinoxalin-2-yl) phenyl) acetamide (CA 77.1) for experiments, and the molecular structural formula is as follows:
example 1CCK8 cytotoxicity assay
(1) The experimental object: human foreskin fibroblast HFF-1, mouse embryo fibroblast L-929;
(2) Experimental drugs: compound CA77.1, solvent DMSO (dimethyl sulfoxide);
(3) The experimental method comprises the following steps:
the first pm plating: collecting logarithmic phase cells, regulating cell suspension concentration, adding 90uL,5000 human foreskin fibroblast HFF-1 and 8000 mouse embryo fibroblast L-929 into each hole;
Dosing the next morning: adding 10 mu L of medicine with concentration gradient into each hole, arranging 3 compound holes for each medicine concentration, placing into 5% CO 2, and incubating in a 37 ℃ incubator;
plate collection after 48h of dosing: firstly, carrying out visual observation under an inverted microscope, then adding 10uLCCK solution into each hole, and after incubation for 1h at 37 ℃, stopping the reaction;
OD value detection: detecting the light absorption value of each hole at the wavelength of 450nm of the enzyme label instrument, and calculating the relative survival rate or the drug inhibition rate of the cells according to formulas (1) and (2);
drug inhibition%1-relative survival%
In the experiment, a cell-free culture medium is used as a blank control group, a DMSO solution with the same dilution ratio as that of the compound CA77.1 is added into each hole to be used as a negative control group, and the compound CA77.1 is used as a compound experiment group.
The effect of compound CA77.1 on the growth activities of human foreskin fibroblast HFF-1 and mouse embryo fibroblast L-929 was tested according to the above-described experimental method (CCK 8 toxicity test, 48 h), and the results obtained by calculation are shown in FIG. 1 and FIG. 2, and the compound CA77.1 does not have a drug toxicity trend to human foreskin fibroblast HFF-1 and mouse embryo fibroblast L-929 under the concentration of 100 μm/L, and IC 50 could not be detected.
Example 2 cell migration Capacity experiment (cell scratch experiment)
(1) The experimental object: human foreskin fibroblast HFF-1;
(2) Experimental drugs: compound CA77.1, solvent DMSO (dimethyl sulfoxide);
(3) The experimental method comprises the following steps:
Before plating, a marker pen thin head is used for uniformly drawing a transverse line behind a 6-hole plate, a straight ruler is used for comparison, a hole is traversed approximately every 0.5-1 cm, three lines are generally drawn, the line is sequentially named as a line, b and c, the line is traversed to the center, two other lines are drawn at equal intervals on two sides of the line b, six-hole plates are plated, 2mL of complete culture medium containing 10% FBS (fetal bovine serum) is added into each hole, 2X 10 6 cells are respectively arranged in 2 multiple holes, the culture is carried out for about 24 hours, the cell number is preferably equal to or greater than 90% after overnight, the cover of the hole plate is properly adjusted, the old culture medium is sucked off the next day, a straight ruler vertical b line frame is arranged on the hole plate, a 200uL gun head is used for tightly clinging to the straight ruler, cell scratch lines are manufactured, similarly, two parallel lines are respectively drawn on two sides of the line at equal intervals, line 2 and line 3 are respectively named as line 1, cell culture medium is washed 3 times by sterile 1X (phosphate buffer solution diluted to 1 time), the cell is removed, the cell culture medium containing 10% FBS (fetal serum) is completely dissolved at a temperature of 5 mu.77 ℃, and the cell culture medium is completely dissolved at a concentration of 5 mu.0 ℃ after the cell culture medium is completely dissolved, and the cell culture medium is completely dissolved at a temperature of 5 mu.5M, and is added.
The migration ability test is carried out according to the above test method, and the obtained results are shown in fig. 3 and fig. 4, and the test results show that, compared with the Control group (DMSO solution), the low concentration (1 μm, 2 μm) of the compound CA77.1 can significantly improve the movement and migration ability of human fibroblast HFF-1 after 24 hours of action, and promote the healing of scratch wound, wherein P <0.001 is shown, and the significant difference exists between the Control group without drug addition and the drug addition group (concentration 1 μm/L and 2 μm/L).
Example 3 cell migration Capacity experiment (cell invasion Transwell experiment)
(1) The experimental object: human foreskin fibroblast HFF-1;
(2) Experimental drugs: compound CA77.1, solvent DMSO (dimethyl sulfoxide);
(3) The experimental method comprises the following steps:
Preparing a cell suspension: digesting cells, centrifuging after stopping digestion, discarding culture solution, washing with PBS (phosphate buffer solution) for 1 time, re-suspending in serum-free culture medium, and adjusting cell density to proper concentration (the plate density of human foreskin fibroblast HFF-1 is 1×10 5/200 μL);
Inoculating cells: each cell is provided with a negative Control group Control (DMSO with the same dilution ratio as that of the compound CA77.1 is added), a dosing group (the working concentration of the compound CA77.1 of human foreskin fibroblast HFF-1 is 0.1 mu M and 0.2 mu M), 3 compound holes are respectively arranged in each group, a proper amount of cell suspension is taken according to the cell density, a proper amount of 10% BSA is added to make the final percentage of the cell suspension be 0.1%, then the compound CA77.1 is added, and finally DMEM is used for supplementing, so that the total volume of each hole is 200 mu L, after uniform mixing, the mixture is gently and uniformly added into a Transwell upper chamber, 800 mu L of culture medium containing 20% FBS is generally added into a 24-hole plate lower chamber immediately, and plates are harvested after 48 hours of dosing;
Cell staining: taking out Transwell chamber, discarding culture solution in the well, gently wiping off non-migrated cells in the upper chamber with cotton bud, placing into clean 24-well plate, washing 1 time with 1 XPBS, fixing with methanol for 30min, sucking methanol, air drying the chamber in fume hood, dyeing for 20min with 0.1% crystal violet, sucking off recovered crystal violet, washing 1 time with PBS, sucking PBS, and air drying in fume hood.
And (3) result statistics: the cells were observed under 5X microscope, photographed, counted and statistically plotted, and the results are shown in fig. 5 and 6, wherein compound CA77.1 can significantly promote migration and invasion capacity of human foreskin fibroblasts HFF-1 at low concentrations of 0.1 μm and 0.2 μm, with P <0.001 indicating that there is a significant difference between the non-dosed control and dosing groups (concentrations of 0.1 μm/L and 0.2 μm/L), indicating that compound CA77.1 can promote wound healing, enhance wound healing capacity, and accelerate wound healing rate.
It should be noted that, in the present specification, specific features, structures, materials, or characteristics may be arbitrarily combined, and in order to simplify the description, all possible combinations of the features in the foregoing embodiments are not described, and those skilled in the art may combine and combine the features of the different embodiments and the different embodiments described in the present specification without contradiction.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (9)
1. The application of the quinoxaline derivative in preparing a wound healing promoting drug is characterized in that the molecular structural formula of the quinoxaline derivative comprises:
2. The application of the quinoxaline derivative according to claim 1 in preparing a wound healing promoting drug, wherein the quinoxaline derivative has a molecular structural formula:
3. The use of quinoxaline derivatives according to claim 1 for the preparation of a medicament for promoting wound healing, wherein said medicament comprises promoting wound healing in diabetic patients.
4. The use of quinoxaline derivatives according to claim 1 for the preparation of a medicament for promoting wound healing, wherein said medicament comprises promoting wound healing in non-diabetic patients.
5. A medicament for promoting wound healing, characterized in that the medicament comprises a quinoxaline derivative according to any one of claims 1 to 4, a geometric isomer thereof or a pharmaceutically acceptable salt thereof and/or a solvate thereof and/or a hydrate thereof.
6. The wound-healing-promoting medicament of claim 5, further comprising a pharmaceutically acceptable adjuvant.
7. The wound-healing-promoting agent according to claim 5, wherein the dosage form of the agent comprises a suspension, a granule, a capsule, a powder, a tablet, an emulsion, a solution, a drop pill, an injection, an aerosol, a gel, a patch, a drop, or a liniment.
8. The wound healing promoting medicament of claim 5, wherein the pharmaceutical indication comprises a diabetic wound or a non-diabetic wound.
9. The wound healing promoting medicament of claim 8, wherein the non-diabetic patient's wound comprises a burn, a scald, an ulcer, a dermatitis, a labor.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202410306820.7A CN118161495A (en) | 2024-03-18 | 2024-03-18 | Application of quinoxaline derivative in preparing wound healing promoting medicine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202410306820.7A CN118161495A (en) | 2024-03-18 | 2024-03-18 | Application of quinoxaline derivative in preparing wound healing promoting medicine |
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