CN112315964B - Application of cyclopentyl phenanthridine benzene compound in preparation of TLN1 protein inhibitor - Google Patents
Application of cyclopentyl phenanthridine benzene compound in preparation of TLN1 protein inhibitor Download PDFInfo
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- -1 cyclopentyl phenanthridine benzene compound Chemical class 0.000 title claims abstract description 23
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- 101000598025 Homo sapiens Talin-1 Proteins 0.000 title abstract description 35
- 229940121649 protein inhibitor Drugs 0.000 title abstract description 11
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- PBDDHCCPRLJKRP-UHFFFAOYSA-N 1-cyclopentylphenanthrene Chemical class C1CCCC1C1=CC=CC2=C1C=CC1=CC=CC=C21 PBDDHCCPRLJKRP-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
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- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
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- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to application of a cyclopentylphenanthrene compound in preparation of a TLN1 protein inhibitor. The application of the cyclopentyl phenanthridine benzene compound in preparing the TLN1 protein inhibitor is provided, wherein the cyclopentyl phenanthridine benzene compound has the structure shown in the general formula I:in the general formula I, Q 1 And Q 2 Each independently selected from hydrogen, halogen, linear or branched alkyl, cycloalkyl, trihaloalkyl, alkoxy, - (CO) R 1 and-S (O) 2 )R 2 Any one of them; wherein R is 1 And R is 2 Each independently selected from C 1 ‑C 2 Linear alkyl or amino; q (Q) 3 Any one selected from hydrogen, halogen, cycloalkyl, trihaloalkyl and alkoxy. The invention provides application of cyclopentyl phenanthridine benzene compounds in preparing TLN1 protein inhibitors for the first time, and in-vitro animal experiments prove that the compounds can effectively reverse diseases mediated by TLN1SOST protein abnormality. Provides effective treatment methods and novel therapeutic drugs for clinically treating diseases mediated by SOST protein abnormality.
Description
Technical Field
The invention belongs to the field of medicines, relates to novel medical application of a cyclopentylphenanthrene compound, and in particular relates to application of the cyclopentylphenanthrene compound in preparation of a TLN1 protein inhibitor.
Background
Hardened TLN1 (also known as Talin-1) protein was found to be widely present in the cytoplasm 30 years ago and has an important role in cytoskeletal tissue, extracellular matrix adhesion. Talin-1 plays a key regulatory role in a range of physiological processes related to integrin-mediated cell adhesion, such as cell deformation, growth, differentiation, migration, etc. Talin-1 has the capability of combining integrin and actin, can be used as a linker molecule to connect a cytoskeleton with an extracellular matrix, and can activate the integrin, so that the capability of combining ligand is converted from a low affinity state to a high affinity state, and further, the signal is transmitted from the inside of a cell to the outside of the cell.
Recent researches of the inventor find that TLN1 shows high expression in tumor tissues of breast cancer patients, and invasion and metastasis of breast cancer can be remarkably enhanced by regulating FAK-YAP/TAZ channels after TLN1 is combined with integrin beta 1. The inventors also demonstrated in experiments that after knockdown of TLN1 in breast cancer cells, invasion and metastasis of breast cancer cells was significantly reduced. TLN1 is thus a potential drug target for the treatment of invasive metastases of breast cancer.
There are no reports in the prior art about the use of cyclopentylphenanthrene compounds as TLN1 protein inhibitors.
Disclosure of Invention
In view of the problems existing in the prior art, the invention aims to provide application of cyclopentyl phenanthridine benzene compounds in preparing TLN1 protein inhibitors. The cyclopentyl phenanthridine benzene compound provided by the invention is a small molecule inhibitor of TLN1 protein, can antagonize the function of the TLN1 protein, and in vivo animal experiment results prove that the compound can effectively reverse the metastasis of diseases (such as breast cancer) mediated by TLN1 protein abnormality.
In order to achieve the above purpose, the present invention adopts the following technical scheme.
The application of the cyclopentyl phenanthridine benzene compound in preparing the TLN1 protein inhibitor is characterized in that the chemical structural general formula I of the cyclopentyl phenanthridine benzene compound is as follows:
wherein Q is 1 And Q 2 Each independently selected from hydrogen, halogen, linear or branched alkyl, cycloalkyl, trihaloalkyl, alkoxy, - (CO) R 1 and-S (O) 2 )R 2 Any one of them; wherein R is 1 And R is 2 Each independently selected from C 1 -C 2 Linear alkyl or amino; q (Q) 3 Any one selected from hydrogen, halogen, cycloalkyl, trihaloalkyl and alkoxy.
A pharmaceutical composition with TLN1 protein inhibitory activity comprises the cyclopentylphenanthrene compound and derivatives thereof, pharmaceutically acceptable salts, hydrates or solvates thereof and pharmaceutically acceptable carriers.
The cyclopentylphenanthrene compound and the derivative thereof, pharmaceutically acceptable salts, hydrates, solvates and pharmaceutically acceptable carriers thereof or the pharmaceutical composition are applied to the preparation of medicaments for treating diseases mediated by TLN1 protein abnormality.
Further, diseases mediated by abnormalities of the TLN1 protein include malignant tumors and metastasis of malignant tumors.
Further, the malignant tumor mainly comprises breast cancer, lung cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal cancer, osteosarcoma, renal cancer, cervical cancer, bladder cancer, head and neck cancer, multiple myeloma, brain tumor, prostate cancer, melanoma, gastric cancer, liver cancer, glioma, oral cancer, soft tissue sarcoma, leukemia and lymphoma.
Further, the medicament is in any pharmaceutically acceptable dosage form.
Further, the drug is in any pharmaceutically acceptable dose.
A method of treating a disease mediated by an abnormality of a TLN1 protein, comprising malignancy and metastasis of malignancy; the method comprises administering a therapeutically effective amount of a compound of formula I, or a salt or other form of a pharmaceutically acceptable derivative thereof.
The TLN1 protein-mediated diseases refer to related diseases caused by significant disturbance of TLN1 expression levels, and more specifically, diseases such as malignant tumors and metastasis of malignant tumors.
The preparation of the TLN1 protein inhibitor comprises the step of combining the compound shown in the formula I or the pharmaceutically acceptable salt and solvate thereof with pharmaceutically common auxiliary materials or carriers to prepare a pharmaceutical composition with TLN1 protein inhibition activity. The pharmaceutical composition can be prepared into tablet, granule, capsule, oral liquid, injection, aerosol, etc.; controlled or sustained release dosage forms or nano-formulations known in the modern pharmaceutical community may also be employed. These choices as to the manner and method of formulation are believed to be well within the skill of those in the art and are not repeated herein.
The terms used in the present invention should have the following general meanings.
The term "halogen" means a halogen substituent, referring to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).
The term "straight or branched alkyl" refers to a straight or branched alkyl group.
The term "C 1 -C 2 The straight-chain or branched-chain alkyl group refers to a direct-chain alkyl group or a branched-chain alkyl group, and the number of carbon atoms in the substituent group is 1-2, including methyl and ethyl.
The term "trihaloalkyl" refers to a straight or branched chain alkyl group substituted with 3 halo substituents.
The term "cycloalkyl" refers to non-aromatic cycloalkanes including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "alkoxy" refers to a chemical group after the alkyl group is attached to an oxygen atom, typical examples include, but are not limited to, methoxy (-OCH) 3 ) Ethoxy (-OC) 2 H 5 )。
The term "amino" refers to-NH 2 A group.
Compared with the prior art, the invention has the following beneficial effects.
The invention provides application of cyclopentyl phenanthridine benzene compounds in preparing TLN1 protein inhibitors for the first time, and in-vitro animal experiments prove that the compounds can effectively reverse diseases mediated by TLN1 protein abnormality. Provides effective treatment methods and novel therapeutic drugs for clinically treating diseases mediated by TLN1 protein abnormality.
Drawings
FIG. 1 is a representation of the detection of binding of compound C67399 to the TLN1 protein using a molecular docking technique, wherein the yellow club model is C67399 small molecule, the cyan cartoon protein is integrin beta 1, and the green cartoon protein is the F3 domain of the TLN1 protein.
FIG. 2 is an illustration of the inhibition of the ability of MDA-MB-231 to migrate in triple negative breast cancer cells following treatment with compound C67399, wherein the left panel is a DMSO solvent treated control group, the right panel is a C67399 small molecule treated group, and the right panel is a statistical plot of the number of migrating cells.
Fig. 3 is an in vivo animal experiment of compound C67399 for treating breast cancer, wherein the blue curve is tumor volume data of DMSO solvent treated control group, the red curve is tumor volume data of C67399 small molecule treated group, and the administration time is 21 days.
Fig. 4 is statistical data of reversal of breast cancer lung metastasis after treatment with C67399, statistical value is number of nodes of breast cancer lung metastasis, left bar graph is DMSO solvent control group, right bar graph is number of lung metastasis nodes of C67399 small molecule treatment group.
Detailed Description
The present invention will now be described in more detail with reference to the following examples and figures, which are given by way of illustration and not limitation, and the following non-limiting examples are set forth to provide a more thorough understanding of the present invention, and are intended to be illustrative of, but not limiting of, the present invention. The terms described herein, such as malignant bone metastases, are scientific terms commonly used in the art of professional science and do not limit the scope of the invention in any way.
The cyclopentyl phenanthridine benzene compound provided by the invention specifically represents a compound C67399, and the chemical structural formula is as follows:
example 1 the binding of compound C67399 to TLN1 protein was predicted using molecular docking techniques.
Molecular docking techniques (molecular docking) are common computational techniques for predicting binding of small molecule compounds to target proteins. Compound C67399 was converted to PDBQT file using the autonomously developing molecular docking tool FIPSDock, the crystal structure of TLN1 protein was pre-treated to remove metal ions and water molecules, hydrogenated and charged, and converted to PDBQT format (PDB number: 3 VIF). Subsequent docking using the FIPSDock tool, compound C67399 showed a good binding to the TLN1 protein and antagonized the binding of TLN1 to integrin, as shown in FIG. 1, with an affinity binding affinity of-10.17 kcal/mol for the binding of compound C67399 to the TLN1 protein.
Example 2 in vitro experiments in which compound C67399 killed migrating breast cancer cells.
The effect of the compound C67399 on killing the migration type breast cancer cells is verified by using an in vitro cell model, and the cell line used in the experiment is a triple negative breast cancer cell line MDA-MB-231. The control group was treated with solvent DMSO, and the dosing group was treated with C67399 compound at a concentration of 2.0 μm for 24 hours. The results show that the migration type breast cancer cells of the group to which the compound C67399 is administered are obviously inhibited, and the number of the migration type breast cancer cells is obviously reduced after the drug treatment, as shown in figure 2. The small molecule compound C67399 was shown to be effective in killing migrating malignant tumor cells.
Example 3 animal experiments in which compound C67399 was used to treat breast cancer and breast cancer lung metastases.
The effect of compound C67399 in treating breast cancer was verified using an in vivo animal model. First, the MDA-MB-231 tumor cells (2×10) were planted in the underarm fat pad of BALB/C nude mice (4-6 weeks old) 6 ). The control group was subjected to intragastric administration with a DMSO solution, and the administration group was subjected to intragastric administration with a DMSO solution of Compound C67399 at a dose of 1.75mg/kg. Dosing was performed for 3 weeks and tumor volume data was counted. The results showed that the tumor volume increase was significantly inhibited in the group to which compound C67399 was administered as compared to the control group, as shown in fig. 3. In this in vivo animal experiment, the therapeutic effect of compound C67399 in reversing breast cancer metastasis to the lung was simultaneously observed and counted. After 3 weeks of administration, the number of nodes for lung metastasis of breast cancer was counted. The results showed that the number of nodes of breast cancer lung metastasis was significantly reduced in the group to which compound C67399 was administered as compared to the DMSO solution control group, as shown in fig. 4, indicating that small molecule compound C67399 could effectively reverse metastasis and invasion of malignant tumor to distant tissues and organs.
Claims (3)
1. Cyclopentyl phenanthridine benzene compound or medicine thereofThe application of the salt which is acceptable in the science to prepare the medicine for treating the triple negative breast cancer and the lung metastasis of the triple negative breast cancer is characterized in that the chemical structure of the cyclopentenophenanthrene compound is as follows:。
2. the use of claim 1, wherein the medicament is in any pharmaceutically acceptable dosage form.
3. The use of claim 1, wherein the medicament is in any pharmaceutically acceptable dose.
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| CN202011417825.5A CN112315964B (en) | 2020-12-07 | 2020-12-07 | Application of cyclopentyl phenanthridine benzene compound in preparation of TLN1 protein inhibitor |
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Non-Patent Citations (2)
| Title |
|---|
| Binding blockade between TLN1 and integrin β1 represses triple-negative breast cancer;Yixiao Zhang等;《eLife》;第11卷;e68481：1-21 * |
| Discovery and Synthesis of Amino Acids Modified Deoxycholic Acid Derivatives and in Vitro Antiproliferative Evaluation;Chunhui Zhao等;《Chem. Pharm. Bull.》;第65卷(第3期);276-283 * |
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