CN116211856A - Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma - Google Patents
Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma Download PDFInfo
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- CN116211856A CN116211856A CN202310379653.4A CN202310379653A CN116211856A CN 116211856 A CN116211856 A CN 116211856A CN 202310379653 A CN202310379653 A CN 202310379653A CN 116211856 A CN116211856 A CN 116211856A
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- hesperadin
- medicine
- molecular compound
- small molecular
- uveal melanoma
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- GLDSKRNGVVYJAB-DQSJHHFOSA-N hesperadin Chemical compound C12=CC(NS(=O)(=O)CC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 GLDSKRNGVVYJAB-DQSJHHFOSA-N 0.000 title claims abstract description 32
- 201000005969 Uveal melanoma Diseases 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000002347 injection Methods 0.000 claims abstract description 5
- 239000007924 injection Substances 0.000 claims abstract description 5
- 239000002775 capsule Substances 0.000 claims abstract description 3
- 239000002552 dosage form Substances 0.000 claims abstract description 3
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 239000008187 granular material Substances 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 3
- 239000006187 pill Substances 0.000 claims abstract description 3
- 239000000843 powder Substances 0.000 claims abstract description 3
- 239000000725 suspension Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims abstract description 3
- 150000003384 small molecules Chemical class 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims 1
- 238000002474 experimental method Methods 0.000 abstract description 9
- 210000001508 eye Anatomy 0.000 abstract description 9
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000006907 apoptotic process Effects 0.000 description 6
- 238000011580 nude mouse model Methods 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 5
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- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 4
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- 206010028980 Neoplasm Diseases 0.000 description 2
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 2
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
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- 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
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- 230000004668 G2/M phase Effects 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
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Images
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
- A61K31/33—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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 an application of a small molecular compound Hesperadin in preparing a medicament for treating uveal melanoma, wherein the small molecular compound Hesperadin has a structural formula of
The medicine further comprises effective dose of small molecular compound Hesperadin and pharmaceutically acceptable carrier or excipient, and the dosage forms comprise tablets, capsules, granules, pills, powder, ointment, suspension, oral liquid or injection. According to the invention, cell experiments prove that the Hesperadin can obviously inhibit the growth of grape membrane melanoma cells, and the drug action effect is increased along with the increase of the concentration; animal experiments prove that the medicine can obviously inhibit proliferation of the uveal melanoma cells in eyes, provides a new potential therapeutic medicine for clinical treatment of the uveal melanoma,the medicine has the advantages of improving the treatment effectiveness, simultaneously striving for protecting eyes and vision, and having wide application prospect.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to application of a small molecular compound Hesperadin in preparation of a medicine for treating uveal melanoma.
Background
Uveal Melanoma (UM) is a special type of malignant melanoma that originates in the uveal lining of the eye, the most common primary intraocular malignancy in adults. UM can not only lead to patient's vision loss, the eyeball is not protected, serious person threatens patient's life, UM is extremely easy to take place blood circulation transfer, 95% transfer kitchen is liver, usually die within 1 year after transfer, even carry out eyeball excision before not having clear transfer kitchen, its 5 year mortality still is 17% -53%, traditional chemotherapy, immunotherapy, MAPK passageway targeting treatment effect are not good.
The small molecular compound Hesperadin is an inhibitor of Aurora Kinase B, and has a molecular formula of C 29 H 32 N 4 O 3 S, molecular weight 516.65, the molecular structure is shown in figure 1, has anti-tumor activity in various solid tumor and leukemia clinical experiments, and is considered as a promising anti-tumor drug. However, there is no report on application of Hesperadin in UM so far, and the curative effect and action mechanism of the Hesperadin on UM are yet to be studied.
Disclosure of Invention
Aiming at the defects existing in the prior art, the main purpose of the invention is to provide the application of the small molecular compound Hesperadin in preparing the medicine for treating the uveal melanoma, provide a new therapeutic medicine for the clinical treatment of the uveal melanoma, improve the treatment effectiveness and strive for protecting eyes and vision.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an application of a small molecular compound Hesperadin in preparing a medicament for treating uveal melanoma, wherein the small molecular compound Hesperadin has a structural formula of
Preferably, the medicament comprises an effective dose of a small molecular compound Hesperadin and a pharmaceutically acceptable carrier or excipient, and the dosage form comprises tablets, capsules, granules, pills, powder, ointment, suspension, oral liquid or injection.
Preferably, the medicament has the small molecule compound Hesperadin as the only active ingredient and is used at a dosage of 0.1-100mM.
More preferably, the small molecule compound Hesperadin is used at a dose of 10mM.
The Hesperadin is regarded as a promising antitumor drug as an Aurora Kinase B inhibitor, and on the basis, the invention proves that the Hesperadin can obviously inhibit the growth of grape membrane melanoma cells through a cell experiment, and the drug action effect is increased along with the increase of the concentration; animal experiments prove that the Hesperadin can obviously inhibit proliferation of grape membranous melanoma cells in eyes, provides a new potential therapeutic drug for clinical treatment of grape membranous melanoma, improves treatment effectiveness, simultaneously strives for protecting eyes and vision, and has wide application prospect.
Drawings
Other features, objects and advantages of the present invention will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:
FIG. 1 is a molecular structural formula of Hesperadin.
FIG. 2 is the results of a half-lethal-test of uveal melanoma cells in examples.
Fig. 3 is a verification result of inhibiting proliferation and promoting apoptosis of uveal melanoma cells by Hesperadin in the examples.
Figure 4 is a graph showing the proliferation of Hesperadin significantly inhibiting uveal melanoma cells in the eye in the examples.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention.
Example 1IC50 assay
Experimental materials: hesperadin was purchased from MCE (china) and CCK8 kit was purchased from eastern kernel chemistry (china).
The experimental steps are as follows: 4 uveal melanoma cells (92.1, MEL290, OMM2.3, XMP 46) were inoculated into 96-well plates, 4000 cells per well, 100. Mu.L of culture medium, 10 concentration gradients were established, 100. Mu.L of Hesperadin,37℃and 5% CO were added 2 After 72h incubation, 20. Mu.L of CCK8 reagent was added and incubated at room temperature for 4h, and the IC50, i.e., half-lethal dose, was calculated from the experimental results obtained by the on-machine test, and the results are shown in FIG. 2.
Proved by the cell experiment, the heperadin can obviously inhibit the growth of the uveal melanoma cells, and the effect of the medicament is increased along with the increase of the concentration.
Example 2 cell cycle and apoptosis detection
Experimental materials: RNase A, propidium Iodide (PI) and FITC Annexin V apoptosis kits were purchased from BD (USA).
The experimental steps are as follows: 3 strains of uveal melanoma cells (92.1, MEL290, OMM 2.3) were inoculated into 6-well plates, respectively, and after 24h treatment with DMSO and half-lethal concentration of Hesperadin, the cells were collected.
Cell cycle: after fixing cells with 70% ethanol, the cell cycle distribution was examined and counted by flow cytometry after staining with 300. Mu.g/mL RNase A and 10. Mu.g/mL PI for half an hour.
Apoptosis: after washing the cell pellet 2 times with cold PBS, the cell pellet was resuspended to 1X 10 with kit-matched buffer 6 Per mL of cell suspension, 100 μl of cell suspension was taken, 5 μl of Annexin V-FITC and 10 μl PI were added, and after incubation for 15min at room temperature, 400 μl of buffer was added, and the apoptosis was detected and counted by flow cytometry, the results are shown in fig. 3.
The cell experiment proves that the Hesperadin can block the cell cycle of the uveal cell melanoma in the G2/M phase and can induce the apoptosis of the uveal cell melanoma.
Example 3 in situ Ocular Oncology experiments in nude mice
Experimental materials: female nude mice of 8 weeks old were purchased from Shanghai national institute of family planning science.
The experimental steps are as follows: preparation of 92.1 cell suspensions in log phase at a density of 1X 10 8 Per mL, 2.5 μl of cell suspension was injected into the suprachoroidal space of each nude mouse, 2.5 μl of 10mM hepadin was injected into the eyes of the experimental group nude mice after one week, the control group was injected with an equal volume of DMSO, 1 drug and DMSO were injected every other week for 4 total injections, the nude mice were sacrificed 1 week after the 4 th injection, the eyeballs of the nude mice were collected and HE staining was sectioned, and the results are shown in fig. 4.
Proved by animal experiments, the Hesperadin can obviously inhibit proliferation of uveal melanoma cells in eyes, and provides a new potential therapeutic drug for clinical treatment of the uveal melanoma.
The foregoing is illustrative of a preferred embodiment of the present invention, but the present invention should not be limited to the disclosure of this embodiment. So that equivalents and modifications will fall within the scope of the invention, all within the spirit and scope of the invention as disclosed.
Claims (5)
1. Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma, wherein the structural formula of the small molecular compound Hesperadin is as follows
2. The use according to claim 1, wherein the medicament comprises an effective dose of the small molecule compound Hesperadin and a pharmaceutically acceptable carrier or excipient.
3. The use according to claim 2, wherein the pharmaceutical dosage form comprises a tablet, capsule, granule, pill, powder, paste, suspension, oral liquid or injection.
4. The use according to claim 1, wherein the medicament comprises the small molecule compound Hesperadin as the sole active ingredient at a dose of 0.1-100mM.
5. The use according to claim 4, wherein the small molecule compound Hesperadin is used at a dose of 10mM.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310379653.4A CN116211856B (en) | 2023-04-11 | 2023-04-11 | Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310379653.4A CN116211856B (en) | 2023-04-11 | 2023-04-11 | Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma |
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| Publication Number | Publication Date |
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| CN116211856A true CN116211856A (en) | 2023-06-06 |
| CN116211856B CN116211856B (en) | 2024-03-26 |
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| CN202310379653.4A Active CN116211856B (en) | 2023-04-11 | 2023-04-11 | Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017200826A1 (en) * | 2016-05-16 | 2017-11-23 | Albert Einstein College Of Medicine, Inc. | Assays and compounds for treatment of cancer |
| CN109985239A (en) * | 2017-12-29 | 2019-07-09 | 广州威溶特医药科技有限公司 | Aurora kinase inhibitors and Alphavirus are in the application for preparing anti-tumor drug |
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- 2023-04-11 CN CN202310379653.4A patent/CN116211856B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017200826A1 (en) * | 2016-05-16 | 2017-11-23 | Albert Einstein College Of Medicine, Inc. | Assays and compounds for treatment of cancer |
| CN109985239A (en) * | 2017-12-29 | 2019-07-09 | 广州威溶特医药科技有限公司 | Aurora kinase inhibitors and Alphavirus are in the application for preparing anti-tumor drug |
Non-Patent Citations (1)
| Title |
|---|
| 冷莹 等: "Aurora 激酶抑制剂研究进展", 药学与临床研究, vol. 20, no. 3, 30 June 2012 (2012-06-30), pages 211 - 217 * |
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| CN116211856B (en) | 2024-03-26 |
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