CN118121578B - Compound EH-P008V and application thereof in preparation of wound healing promoting drugs - Google Patents
Compound EH-P008V and application thereof in preparation of wound healing promoting drugs Download PDFInfo
- Publication number
- CN118121578B CN118121578B CN202410544232.7A CN202410544232A CN118121578B CN 118121578 B CN118121578 B CN 118121578B CN 202410544232 A CN202410544232 A CN 202410544232A CN 118121578 B CN118121578 B CN 118121578B
- Authority
- CN
- China
- Prior art keywords
- compound
- medicament
- wound healing
- promoting
- diabetes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 230000029663 wound healing Effects 0.000 title claims abstract description 25
- 230000001737 promoting effect Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229940079593 drug Drugs 0.000 title description 11
- 208000027418 Wounds and injury Diseases 0.000 claims description 25
- 206010052428 Wound Diseases 0.000 claims description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims description 17
- -1 N- (naphthalene-2-yl) -4-oxo-3, 4-dihydronaphthalene-2-carboxamide Chemical group 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 208000002249 Diabetes Complications Diseases 0.000 claims description 5
- 239000006196 drop Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000018380 Chemical injury Diseases 0.000 claims description 2
- 206010012655 Diabetic complications Diseases 0.000 claims description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 208000004104 gestational diabetes Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000013270 controlled release Methods 0.000 claims 1
- 239000003595 mist Substances 0.000 claims 1
- 210000002950 fibroblast Anatomy 0.000 abstract description 33
- 210000004027 cell Anatomy 0.000 abstract description 32
- 230000005012 migration Effects 0.000 abstract description 12
- 238000013508 migration Methods 0.000 abstract description 12
- 238000002474 experimental method Methods 0.000 abstract description 11
- 210000003953 foreskin Anatomy 0.000 abstract description 11
- 210000001161 mammalian embryo Anatomy 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 abstract description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 abstract description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 8
- 230000035876 healing Effects 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- NIOAVQYSSKOCQP-UHFFFAOYSA-N 4-hydroxynaphthalene-2-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC(O)=C21 NIOAVQYSSKOCQP-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000008960 Diabetic foot Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003517 fume Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 208000001034 Frostbite Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000003897 fog Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000006453 vascular barrier function Effects 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a compound EH-P008V and application thereof in preparing a medicine for promoting wound healing, and belongs to the technical field of pharmacy. The invention successfully synthesizes a small molecular compound EH-P008V by reacting a compound II with 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and compounds I, N-diisopropylethylamine at room temperature, and verifies through a cell scratch experiment and a Transwell experiment that the EH-P008V can promote migration of human foreskin fibroblasts HFF-1 and mouse embryo fibroblasts 3T3, thereby further proving that the invention can promote wound healing process. Meanwhile, the cost is lower, and the clinical application value is higher.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a small molecular compound EH-P008V and application thereof in preparing a medicine for promoting wound healing.
Background
Wound healing refers to the healing process of the body after the body is subjected to the action of external force and the tissues such as skin are separated or damaged, and comprises the complex combination of regeneration of various tissues and granulation tissue proliferation and scar tissue formation, and the synergistic effect of various processes is shown. The skin of a diabetic patient is easier to damage and difficult to heal due to the influence of hyperglycemia and diabetes related complications, researches show that 34% of diabetic patients are subject to skin ulcers on lower limbs, and by taking diabetic foot ulcers (diabetic foot ulcers, DFUs) as an example, if the diabetic patients are infected by microorganisms, large-area open necrosis is easily caused, amputation and even death of the patients are finally caused, the angiogenesis process in wounds of the diabetic patients is very slow, the vascular surface area, branch connection number, total vascular length and total branch number in the wound surface are obviously reduced, angiogenesis can effectively support wound closure, vascular lesions are one of causes of difficult healing of wounds of the diabetic patients, the diabetic wounds are common complications of diabetes, and have the characteristics of complex pathogenesis, easy infection and difficult healing of wounds, the formation of the diabetic wounds is closely related to various factors, firstly, the long-term hyperglycemia level can cause local vascular injury of the diabetic patients, poor blood circulation, and insufficient oxygen and nutrient supply are caused, so that the healing of the wounds is influenced; second, nerve damage can lead to pain and diminished sensation in the wound by diabetics, making them unable to discover and treat the wound in time, increasing the risk of infection, and in addition, impaired immune system function makes diabetics more susceptible to infection, making the wound difficult to heal. The wound healing process caused by diabetes is more complex, the self-conditioned environment is more unfavorable, and the possibility of infection is greatly increased by long-term exposure to the external environment compared with normal wound healing. Meanwhile, the vascular barrier caused by chronic continuous inflammatory environment and hyperglycemia greatly delays the healing of wounds. Therefore, searching for drugs effective in treating wounds that are difficult to heal is a highly desirable problem.
At present, some growth factors or miRNAs are reported to promote wound healing, but have great side effects on human bodies and high cost, so the growth factors or miRNAs are not used for clinical treatment. The small molecular compound is always the main body of a clinical disease treatment drug, is easy to administer, quick in response, low in cost and easy to operate and store, is used for wound healing treatment, and is not reported at present. For this reason, there is a strong need to design a small molecule compound for wound healing.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a compound EH-P008V and application thereof in preparing a medicine for promoting wound healing.
In order to achieve the above purpose, the technical solution of the present invention is as follows:
The invention provides application of a compound EH-P008V in preparing a medicine for promoting wound healing, wherein the compound EH-P008V is N- (naphthalene-2-yl) -4-oxo-3, 4-dihydronaphthalene-2-carboxamide, and the structural formula is shown as follows:
。
preferably, the medicament further comprises an EH-P008V geometric isomer or a pharmaceutically acceptable salt thereof and/or a solvate thereof and/or a hydrate thereof.
Preferably, the medicament is a medicament for promoting diabetic wound healing.
Further preferably, the diabetes is at least one of type 1 diabetes, type 2 diabetes, gestational diabetes, special diabetes, and diabetic complications.
Preferably, the administration route of the drug is sublingual oral, injection, inhalation administration, intravenous administration, application.
Preferably, the medicament further comprises pharmaceutically acceptable excipients, excipients or carriers.
Preferably, the dosage form of the medicine is suspension, granule, capsule, powder, tablet, patch, emulsion, gel, solution, drop pill, injection, aerosol, powder fog, drop, lotion, controlled release preparation or compound prescription.
Preferably, the wound comprises a difficult-to-heal wound caused by physical injury, chemical injury, microbial infection, bacterial infection of the skin.
In particular, the wounds include cuts, lacerations, punctures, bruises, burns, scalds, frostbites, ulcers, dermatitis, chronic wounds, childbirth, diabetic wounds, surgical incisions.
The invention also provides application of the compound EH-P008V in preparing medicaments for promoting migration of human foreskin fibroblasts HFF-1.
Specifically, the compound EH-P008V is N- (naphthalene-2-yl) -4-oxo-3, 4-dihydronaphthalene-2-carboxamide, and the structural formula is shown as follows:
。
the invention also provides application of the compound EH-P008V in preparing medicaments for promoting 3T3 migration of mouse embryo fibroblasts.
Specifically, the compound EH-P008V is N- (naphthalene-2-yl) -4-oxo-3, 4-dihydronaphthalene-2-carboxamide, and the structural formula is shown as follows:
。
Compared with the prior art, the invention has the following beneficial effects:
The invention successfully synthesizes a small molecular compound EH-P008V by reacting acid with 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, naphthylamine and N, N-diisopropylethylamine at room temperature, and verifies through cell scratch experiments and Transwell experiments that the EH-P008V can promote migration of human foreskin fibroblasts HFF-1 and mouse embryo fibroblasts 3T3, thereby further proving that the invention can promote the healing process of wounds. Meanwhile, the toxicity is small, the cost is low, and the clinical application value is high.
Drawings
In order to more clearly illustrate the technical solutions of the present invention, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram of the molecular structure of the compound EH-P008V according to the present invention.
FIG. 2 is a 1 H NMR spectrum of compound EH-P008V synthesized in example 1.
FIG. 3 is a graph showing the results of cytotoxicity test on compound EH-P008V: a is EH-P008V and is toxicity experiment result of mouse embryo fibroblast 3T 3; b is the toxicity test result of EH-P008V human fibroblast HFF-1.
FIG. 4 is a graph of the effect of compound EH-P008V on the migration capacity of human fibroblasts HFF-1 at 0h and 20h of administration on cell scarification.
FIG. 5 is a bar graph of a statistical analysis of the ability of compound EH-P008V to migrate to human fibroblasts HFF-1.
FIG. 6 is a graph of a cell scratch assay of compound EH-P008V at 0h, 20h administration for the effect of 3T3 migration capacity of mouse embryonic fibroblasts.
FIG. 7 is a bar graph of a statistical analysis of the ability of compound EH-P008V to migrate to mouse embryonic fibroblasts 3T 3.
FIG. 8 is a graph of a Transwell experiment showing the effect of varying concentrations of compound EH-P008V on the migration capacity of human fibroblasts HFF-1.
FIG. 9 is a bar graph of a statistical analysis of the ability of different concentrations of compound EH-P008V to migrate to human fibroblasts HFF-1.
FIG. 10 is a graph of a Transwell experiment showing the effect of varying concentrations of compound EH-P008V on the 3T3 migration capacity of mouse embryonic fibroblasts.
FIG. 11 is a bar graph of statistical analysis of the ability of different concentrations of compound EH-P008V to migrate to mouse embryonic fibroblasts 3T 3.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
Example 1: synthesis of Compound EH-P008V
1. The reaction formula of the compound EH-P008V is shown below:
；
wherein, the compound I is naphthylamine and the compound II is 4-hydroxy-2-naphthoic acid.
2. The synthetic steps of the compound EH-P008V specifically comprise:
4-hydroxy-2-naphthoic acid (fw: 188, 100 mg,0.53 mmol) was taken in 10mL Dimethylformamide (DMF), 144 mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 0.8 mmol naphthylamine (83 mg,1.1 eq), 0.1 mL of N, N-Diisopropylethylamine (DIPEA) were added to react at room temperature 6 h, washed, dried over anhydrous sodium sulfate, filtered and concentrated, and column chromatography (petroleum ether: ethyl acetate=15:1) gave the product 10 mg as shown in FIG. 1, namely N- (naphthalen-2-yl) -4-oxo-3, 4-dihydronaphthalen-2-carboxamide designated EH-P008V (C 21H15O2 N, molecular weight: 313.1) in a yield of 6.1%.
1H NMR (600 MHz,Chloroform-d) δ 8.35-8.23 (m,2H), 7.93-7.75 (m,5H), 7.65 (dd,J=8.7, 2.2 Hz, 1H), 7.55 (dt,J=6.0, 2.4 Hz,2H), 7.48 (t,J=7.2 Hz,1H), 7.45-7.38 (m,1H), 7.30 (s,1H), 7.17 (s,2H). The nuclear magnetic hydrogen spectrum is shown in figure 2.
Example 2: test Compound EH-P008V for Effect on cytotoxicity on cell growth (CCK 8 method)
Test object: human foreskin fibroblast HFF-1; mouse embryonic fibroblasts 3T3.
Test sample: compound EH-P008V synthesized in example 1, compound solvent DMSO.
The testing steps specifically comprise:
1. the first pm plating: log phase cells were collected, cell suspension concentration was adjusted, and 90 μl of cell suspension was added to each well. 6000 human foreskin fibroblasts HFF-1, 7000 mouse embryonic fibroblasts 3T3.
2. Dosing the next morning: a10. Mu.L concentration gradient of drug was added to each well, 3 multiplex wells were placed for each drug concentration, and incubated in a 5% CO 2, 37℃incubator.
3. And (3) collecting a plate after adding the medicine 48 h: visual observation under an inverted microscope was performed first, followed by addition of 10. Mu.L of CCK8 solution per well, incubation at 37℃ (human foreskin fibroblast HFF-1 incubation 2h, mouse embryonic fibroblast 3T3 incubation 1 h) and termination of the reaction after incubation.
4. OD value detection: the absorbance of each well was measured at the microplate reader wavelength 450 nm and the relative cell viability or drug inhibition was calculated.
Culture medium without fibroblasts was set as a blank control group, DMSO solution with the same dilution ratio as that of compound EH-P008V was added per well as a negative control group, and compound EH-P008V was added as an experimental group.
The calculation formula of this embodiment is as follows:
；
drug inhibition = 1-relative survival.
Analysis of results: as can be seen from FIG. 3, the IC 50 of the compound EH-P008V was 105.2. Mu.M and 71.31. Mu.M, respectively, to the cells 3T3 and HFF-1, which were less toxic.
Example 3: analysis of the Effect of Compound EH-P008V on cell migration ability (cell scratch test)
The experimental object: human foreskin fibroblast HFF-1; mouse embryonic fibroblasts 3T3.
Experimental samples: compound EH-P008V synthesized in example 1, compound solvent DMSO.
The experimental method specifically comprises the following steps:
1. The thin head of a marker is arranged behind a 6-hole plate before the plate is paved, transverse lines are uniformly marked by comparing with a ruler, about every 0.5-1 cm line crosses a through hole, three lines are generally marked in sequence, namely a line, a line b and a line c, wherein the line b crosses the center, and the other two lines are marked on two sides of the line b at equal intervals.
2. Six well plates were plated, 2 mL complete medium containing 10% fbs was added to each well, 2×10 6 cells were placed in 2 duplicate wells each, and approximately 24 h were cultured. The cell number is preferably regulated so that the cells can be covered with the wall over night by more than 90%.
3. The next day the lid of the well plate was opened, the old medium was sucked off, the ruler was placed on the well plate perpendicular to the b-wire frame, the cell score line was made by moving up and down evenly with a 200 μl gun head against the ruler, and two more parallel lines were drawn at equal intervals on both sides of the line, designated line 1, line 2 and line 3, respectively, from left to right.
4. Cells were rinsed 3 times with sterile 1 XPBS, after removal of the scraped cells, complete medium containing 20% FBS was added, compound EH-P008V (working concentration 5. Mu.M) was added, and incubated in a 5% CO 2 incubator at 37 ℃. Taking samples according to the dosage of 0 and 20h for photographing.
In this example, DMSO was added to each cell at the same dilution ratio as EH-P008V as a control group.
Analysis of results: as can be seen from fig. 4-7, compound EH-P008V significantly promotes migration of human HFF-1 cells or mouse 3T3 cells after 20 h, and accelerates filling and repair of cells on the surface of the wound by promoting migration of HFF-1 cells or 3T3 cells, thereby promoting the healing process of the wound. The experimental results were of significant statistical significance (P < 0.0001).
Example 4: analysis of the Effect of Compound EH-P008V on cell migration ability (Transwell experiment)
The experimental object: human foreskin fibroblast HFF-1; mouse embryonic fibroblasts 3T3.
Experimental samples: compound EH-P008V synthesized in example 1, compound solvent DMSO.
The experimental method specifically comprises the following steps:
1. Preparing a cell suspension: cells were digested, centrifuged after termination of digestion, and the culture broth was discarded, washed 1 time with PBS, resuspended in serum-free medium, and the cell density was adjusted to a suitable concentration (the plate density of mouse embryonic fibroblasts 3T3 was 8.8X10 4/200. Mu.L; the plate density of human foreskin fibroblasts HFF-1 was 7X 10 4/200. Mu.L).
2. Inoculating cells: each cell was set with a negative control group (DMSO at the same dilution ratio as compound EH-p008v_5 was added), the dosing groups (working concentrations of compound EH-P008V were set to 1,2, 5 μm respectively), 3 wells each, an appropriate amount of cell suspension was taken according to the cell density, an appropriate amount of 10% BSA was added to make the final percentage 0.1%, compound EH-P008V was added, and finally, DMEM was used to make the total volume of each well 200 μl, and after mixing, the mixture was gently and uniformly added to the Transwell upper chamber. Immediately in the 24 hole plate chamber under the general adding 800 u L containing 20% FBS medium, dosing 24h about harvest plate.
3. Cell staining: taking out the Transwell chamber, discarding the culture solution in the hole, lightly wiping off the cells which do not migrate in the upper chamber by using a cotton swab, placing the cells into a clean 24-hole plate, washing the cells for 1 time by using 1XPBS, fixing the cells with methanol for 30min, sucking the methanol, and placing the cells into a fume hood for air drying; then, the recovered crystal violet was stained with 0.1% crystal violet 20 min, blotted off, washed 1 pass with PBS, blotted off, and air dried in a fume hood.
4. And (3) result statistics: cells were observed under 5X microscope, randomly five fields under 10X microscope, photographed, counted and statistically plotted.
Analysis of results: as can be seen from FIGS. 8-11, the compound EH-P008V at 1. Mu.M, 2. Mu.M, and 5. Mu.M significantly promoted migration of human foreskin fibroblast HFF-1 or mouse embryonic fibroblast 3T3 compared to the control group, indicating that the compound EH-P008V promotes wound healing.
In conclusion, the invention synthesizes the small molecular compound EH-P008V through the reaction of naphthylamine and 4-hydroxy-2-naphthoic acid, has lower toxicity, and uses cell scratch experiments and Transwell experiments to verify that the small molecular compound EH-P008V can promote the migration of human foreskin fibroblast HFF-1 and mouse embryo fibroblast 3T3, further promote the healing of diabetic wounds, provides a new thought for the research and development of diabetes medicines, and fills the blank of the small molecular compound in the field of wound healing.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (8)
1. The application of the compound EH-P008V in preparing a medicine for promoting wound healing is characterized in that the compound EH-P008V is N- (naphthalene-2-yl) -4-oxo-3, 4-dihydronaphthalene-2-carboxamide, and the structural formula is shown as follows:
。
2. the use of compound EH-P008V for the manufacture of a medicament for promoting wound healing according to claim 1, wherein the medicament further comprises a pharmaceutically acceptable salt.
3. Use of compound EH-P008V according to claim 1 or 2 for the preparation of a medicament for promoting wound healing, wherein the medicament is a medicament for promoting diabetic wound healing.
4. The use of compound EH-P008V for preparing a wound healing promoting medicament according to claim 3, wherein the diabetes is at least one of type 1 diabetes, type 2 diabetes, gestational diabetes, special diabetes and diabetic complications.
5. Use of compound EH-P008V according to claim 1 or 2 for the preparation of a medicament for promoting wound healing, wherein the route of administration of the medicament is sublingual, injectable, inhalable, smeared.
6. Use of compound EH-P008V according to claim 1 or 2 for the manufacture of a medicament for promoting wound healing, wherein the medicament further comprises pharmaceutically acceptable excipients.
7. The use of compound EH-P008V according to claim 1 or 2 for the preparation of a medicament for promoting wound healing, wherein the medicament is in the form of a suspension, granule, capsule, powder, tablet, emulsion, gel, solution, drop, injection, aerosol, powder mist, drop, lotion, controlled release formulation or a compound formulation.
8. Use of compound EH-P008V according to claim 1 or 2 for the preparation of a medicament for promoting wound healing, wherein the wound comprises a physical injury, a chemical injury, a microbial infection of the skin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410544232.7A CN118121578B (en) | 2024-05-06 | 2024-05-06 | Compound EH-P008V and application thereof in preparation of wound healing promoting drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410544232.7A CN118121578B (en) | 2024-05-06 | 2024-05-06 | Compound EH-P008V and application thereof in preparation of wound healing promoting drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN118121578A CN118121578A (en) | 2024-06-04 |
| CN118121578B true CN118121578B (en) | 2024-08-16 |
Family
ID=91233950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410544232.7A Active CN118121578B (en) | 2024-05-06 | 2024-05-06 | Compound EH-P008V and application thereof in preparation of wound healing promoting drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118121578B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101287483A (en) * | 2003-08-07 | 2008-10-15 | 希尔洛有限公司 | Pharmaceutical compositions and methods for accelerating wound healing |
| CN108495659A (en) * | 2015-11-02 | 2018-09-04 | 韦里格拉福特公司 | Composition and method for wound healing |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2002120366A (en) * | 2002-08-01 | 2005-02-27 | БиоДием Лимитед (AU) | NEW IMIDAZOLIA DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS ON THEIR BASIS |
| KR20090056584A (en) * | 2007-11-30 | 2009-06-03 | (주)아모레퍼시픽 | Pharmaceutical composition for controlling the function of sphingosylphosphorylcholine |
| WO2014089546A1 (en) * | 2012-12-09 | 2014-06-12 | The Scripps Research Institute | Targeted covalent probes and inhibitors of proteins containing redox-sensitive cysteines |
| EP3829299A4 (en) * | 2018-07-31 | 2022-04-13 | Microbion Corporation | Bismuth-thiol compositions and methods for treating wounds |
| CN117899072A (en) * | 2023-12-22 | 2024-04-19 | 广州市朝利良生物科技有限公司 | Application of sodium ion channel inhibitor in preparation of medicine for promoting wound healing |
-
2024
- 2024-05-06 CN CN202410544232.7A patent/CN118121578B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101287483A (en) * | 2003-08-07 | 2008-10-15 | 希尔洛有限公司 | Pharmaceutical compositions and methods for accelerating wound healing |
| CN108495659A (en) * | 2015-11-02 | 2018-09-04 | 韦里格拉福特公司 | Composition and method for wound healing |
Also Published As
| Publication number | Publication date |
|---|---|
| CN118121578A (en) | 2024-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108586575B (en) | Polypeptide and application of polypeptide in skin repair function | |
| CN113087665B (en) | Compound and pharmaceutical composition for promoting cell movement, and preparation and application thereof | |
| US20240287014A1 (en) | Biflavone compound against i-type herpes simplex virus, and preparation method therefor and use thereof | |
| CN117357521A (en) | Application of azaindole compounds in preparation of wound healing promoting drugs | |
| CN117257808B (en) | Application of rutaecarpine in preparation of product for promoting wound healing | |
| CN117899072A (en) | Application of sodium ion channel inhibitor in preparation of medicine for promoting wound healing | |
| CN118121578B (en) | Compound EH-P008V and application thereof in preparation of wound healing promoting drugs | |
| CN118121595B (en) | Application of compound EH-P005J in preparation of wound healing promoting drugs | |
| CN118121594B (en) | Application of EH-P006N in preparation of medicine for promoting wound healing | |
| CN115850381A (en) | Synthetic polypeptide and application thereof in promoting skin healing | |
| CN115737661A (en) | Application of baicalin in preparation of medicine for inhibiting retinal neovascularization | |
| CN115192573A (en) | Application of demethyleneberberine hydrochloride in preparation of medicine for treating pulmonary fibrosis | |
| CN118340765B (en) | Application of benzamide compound in preparation of wound healing promoting medicine | |
| CN118271276B (en) | Naphthalenone derivative for promoting wound healing as well as preparation method and application thereof | |
| CN113004253A (en) | Di- (benzimidazole) -1,2, 3-triazole derivative, preparation method thereof and application thereof in inflammatory skin diseases | |
| CN114380680B (en) | Flavonoid compound and application thereof | |
| CN118161487A (en) | Application of benzisoxazole derivative in preparing wound healing promoting medicine | |
| CN104224796A (en) | Application of oleanane triterpene ester derivative in preparation for anti-neurodegeneration medicine | |
| CN118304286B (en) | Application of sinapine thiocyanate in preparation of medicine for treating retinal neovascular related diseases | |
| CN118178407A (en) | Application of pan DUB enzyme inhibitor in preparation of wound healing promoting medicine | |
| CN110974826B (en) | Application of ouabain or 12-epi-ouabain in preparation of medicine for treating leukemia | |
| CN118178418A (en) | Application of GPR119 agonist in preparation of wound healing promoting drugs | |
| CN118161474A (en) | Application of N-benzamide compound in preparation of wound healing promoting medicine | |
| CN118161503A (en) | Application of small molecular compound BTZ043 in preparation of wound healing promoting medicine | |
| CN106890182A (en) | A kind of combination of oral medication of vascular endothelial growth factor receptor inhibitors hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |