CN108309982B - Use of 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives - Google Patents
Use of 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives Download PDFInfo
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Abstract
The invention belongs to the field of biological medicine, and particularly relates to 3-substituted 5H- [1,2,4]]Triazine [5,6-b ]]Use of indole derivatives. The present invention provides 3-substituted 5H- [1,2, 4%]Triazine [5,6-b ]]Use of indole derivatives, in particular 5H- [1,2,4] substituted in position 3]Triazine [5,6-b ]]The indole derivatives, the salts or the hydrates thereof, or the pharmaceutical compositions containing the indole derivatives and the salts or the hydrates thereof are used for preparing SIRT2 inhibitors, drugs for treating or preventing cancers, and drugs for treating or preventing neurodegenerative diseases. The 3-substituted 5H- [1,2, 4%]Triazine [5,6-b ]]The structure of the indole derivative is shown as a formula I. The 3-substituted 5H- [1,2,4] of the invention]Triazine [5,6-b ]]The pharmaceutical composition of the indole derivative compound and the salt or hydrate thereof has the effects of treating or preventing cancers and treating or preventing neurodegenerative diseases, provides a new choice for the development of SIRT2 inhibitors, anti-tumor and anti-psychogenic diseases in the field, and has good application prospects.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to application of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative.
Background
Acetylation/deacetylation modification of histones plays an important role in gene expression regulation. Enzymes involved in deacetylation are, in addition to classical class i and ii HDACs (histone deacetylases), class iii HDACs, the Sirtuin regulator 2protein or Sirtuin family of proteins. The Sirtuin family of proteins is a family of proteins that depend on nicotinamide adenine dinucleotide (NAD +), highly conserved in the core region, sirtuins and ADP ribosyltransferases.
The mammal has seven Sirtuin proteins, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7, all of which have highly conserved NAD + binding and catalytic domains. These Sirtuin proteins have distinct subcellular locations, with SIRT1, SIRT6, and SIRT7 located primarily within the nucleus; SIRT3, SIRT4, and SIRT5 are localized in mitochondria; while SIRT2 was distributed mainly in the cytosol. The subcellular localization of these proteins also depends on cell type, state, and intermolecular interactions, etc., as SIRT1 and SIRT2 can shuttle between and interact with proteins in the nucleus and cytoplasm.
Of all Sirtuin proteins, SIRT1 and SIRT3 have been the most widely studied. In recent years, SIRT2 is becoming a new research hotspot. Various substrates of SIRT2 have been identified, including histone substrates and non-histone substrates. Among them, histone substrates mainly include histone H4K16, H3K18 and H3K56, non-histone substrates include various transcription factors (e.g., P300, FOXO3, FOXO1, HIF-1. alpha., NF-. kappa.B and PGC-1. alpha.), cell cycle-related enzymes (e.g., BubR1, CDK9 and CDH1/CDC20), metabolic enzymes (e.g., LDH-A, PEPCK, ACLY, G6PD and PGAM), cell signal-related substrates (e.g., PRLR, K-Ras, PAR-3 and TIAM1) and structural proteins (e.g., keratin 8,. alpha. -tubulin), etc. With the discovery and research of various substrates, SIRT2 has been shown to play an important role in regulating related biological processes, and also means that abnormalities in SIRT2 may cause various diseases. In fact, a series of studies have demonstrated that SIRT2 is closely related to the development of various cancers (including glioma, bladder cancer, non-small cell lung cancer, burkitt lymphoma, colon cancer, breast cancer, etc.) and nervous system diseases (including huntington's disease, parkinson's disease, etc.), etc. Therefore, SIRT2 is considered as a potential target for treating these diseases, and the development of small molecule inhibitors with high selectivity for directly targeting SIRT2 is an effective way to treat these diseases.
Disclosure of Invention
The invention provides an application of a 3-position substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative, in particular an application of a 3-position substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative and a salt or hydrate thereof, or a pharmaceutical composition containing the same in preparing a SIRT2 inhibitor, a medicament for treating or preventing cancer, and a medicament for treating or preventing neurodegenerative diseases. The 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative has a structure shown in a formula I:
wherein R is1is-H, benzyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, C3-C8 cycloalkyl or halogen;
R2is-H, C1-C10 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen, substituted C6-C12 aryl or substituted 5-12-membered unsaturated heterocycle; the unsaturated heterocycle contains 1-4 heteroatoms, and the heteroatoms are N, O or S;
the substituent of the substituted C6-C12 aryl is-H, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen, phenyl, -CF3、-NO2、-OCF3、or-NHR9;
The substituent of the substituted 5-12-membered unsaturated heterocycle is-H, C1-C8 alkyl, -CN, C1-C8 alkenyl, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen, phenyl, p-nitrophenyl, -CF3、-NO2、or-NHR9;
m=0~4;n=0~4;p=1~4;q=0~4;r=1~4。
As a preferred embodiment of the present invention, R1is-H, benzyl, C1-C8 alkyl, C1-C8 alkenyl or C1-C8 alkoxy;
R2is-H, C1-C10 alkyl, C3-C8 cycloalkyl, halogen, substituted C6-C12 aryl or substituted 5-12 membered unsaturated heterocycle; the unsaturated heterocycle contains 1-4 heteroatoms, and the heteroatoms are N, O or S;
the substituent of the substituted C6-C12 aryl is-H, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen, phenyl, -CF3、-NO2、-OCF3、or-NHR9;
The substituent of the substituted 5-12-membered unsaturated heterocycle is-H, C1-C8 alkyl, -CN, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen, phenyl, p-nitrophenyl, -NO2、or-NHR9;
m=0~4;n=0~4;p=1~4;q=0~4;r=1~4。
Preferably, R1is-H, benzyl, C1-C8 alkyl or C1-C8 alkenyl;
R2is-H, C1-C10 alkyl, C3-C8 cycloalkyl, substituted C6-C12 aryl or substituted 5-12 membered unsaturated heterocycle; the unsaturated heterocycle contains 1-4 heteroatoms, and the heteroatoms are N, O or S;
the substituent of the substituted C6-C12 aryl is-H, C1-C8 alkoxy, halogen, phenyl, -CF3、-NO2、-OCF3、or-NHR9;
The substituent of the substituted 5-12-membered unsaturated heterocycle is-H, C1-C8 alkyl, -CN, C1-C8 alkoxy, halogen, phenyl, p-nitrophenyl, -NO2、or-NHR9;
m=0~4;n=0~4;p=1~4;q=0~4;r=1~4。
Further preferably, R1is-H, benzyl, C1-C4 alkyl or C1-C4 alkenyl;
R2is-H, C1-C8 alkyl, C3-C8 cycloalkyl,Or a substituted 5-to 10-membered unsaturated heterocycle; the unsaturated heterocycle contains 1-4 heteroatoms, and the heteroatoms are N, O or S;
The substituent of the substituted 5-to 10-membered unsaturated heterocycle is-H, C1-C4 alkyl, -CN, C1-C4 alkoxy, halogen, phenyl, p-nitrophenyl, -NO2、or-NHR9;
m=0~2;n=0~2;p=1~4;q=0~4;r=1~4。
Even more preferably, R1is-H, benzyl, C1-C4 alkyl or C1-C4 alkenyl;
m=0~2;n=0~2;p=1~4;q=0~4;r=1~4。
Most preferably, R1is-H, benzyl, C1-C4 alkyl or C1-C4 alkenyl;
m=0~2;n=0~2;p=1~4;q=0~4;r=1~4。
The structural formula of the 3-position substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative is as follows:
in the application of the 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at the 3-position, the cancer comprises: glioma, bladder cancer, non-small cell lung cancer, burkitt's lymphoma, colon cancer, or breast cancer.
In the application of the 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at the 3-position, the neurodegenerative diseases comprise: huntington's disease or Parkinson's disease.
The 3-substituted 5H- [1,2,4] triazin [5,6-b ] indole derivatives and salts or hydrates thereof can be used as they are or in the form of pharmaceutical compositions. The pharmaceutical composition is a compound containing 0.1-99% of 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives and salts or hydrates thereof, and the balance is pharmaceutically acceptable medicinal carriers and/or excipients which are nontoxic and inert to human and animals.
The pharmaceutically acceptable carrier or excipient is one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical adjuvants. The compound of the 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at the 3-position and the pharmaceutical composition of the salt or hydrate thereof are prepared into various dosage forms by adopting a method accepted in the pharmaceutical and food fields: sprays, aerosols, liquid preparations or solid preparations; the liquid preparation comprises injection, suspension, emulsion, solution or syrup; the solid preparation comprises tablets, capsules, granules or medicinal granules.
The administration route of the pharmaceutical composition of the compound of the 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at the 3-position and the salt or hydrate thereof is oral administration, sublingual administration or mucosal dialysis; the injection comprises intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.
The compound of the invention is found to have high selectivity for the inhibitor of the deacetylase family for the first time, in particular for the SIRT2 subtype in the SIRT family. The 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative compound and the salt or hydrate pharmaceutical composition thereof have the effects of treating or preventing cancers and neurodegenerative diseases, provide a new choice for the development of SIRT2 inhibitors, anti-tumors and anti-psychogenic diseases in the field, and have good application prospects.
Drawings
Figure 1 activity-dose relationship of compound 12 against SIRT2, and SIRT1 and SIRT 3. Wherein% inhibition represents the percentage of inhibition and Log [ Cpd ] represents the Log of the concentration of the compound.
FIG. 2 Activity-dose relationship of Compound 63 against SIRT2, and SIRT1 and SIRT 3. Wherein% inhibition represents the percentage of inhibition and Log [ Cpd ] represents the Log of the concentration of the compound.
FIG. 3 shows the in vitro cell viability inhibition of compound 12 against human breast cancer cell line MCF-7 and the inhibition of intracellular substrate protein. (A) The in vitro cell viability inhibition effect of the compound 12 on MCF-7; (B) effect of compound 12 on the level of acetylation of MCF-7 intracellular substrates. Wherein viatility represents cell viability, α -tubulin represents α -tubulin, and Ac- α -tubulin represents acetylated α -tubulin.
Detailed Description
Enzyme Activity inhibition assay of the Compound of example 1
The aim of this experiment was to test the inhibitory activity of compounds on deacetylase in vitro. The experiment adopts a fluorescence intensity detection method to carry out in vitro activity inhibition test on SIRT 2. AK-7 is a reference molecule (or referred to as a positive control). IC for deacetylase inhibitory Activity of test Compound50(half inhibitory concentration) or the inhibition rate of the test compound against the SIRT2 activity of the deacetylase at concentrations of 100 μ M and 10 μ M. IC (integrated circuit)50Values can be calculated from the inhibition of deacetylase activity by the test compound at a range of different concentrations.
1.1 Experimental materials
Human SIRT2 enzyme (BPS Biotechnology Co., Ltd., product number 50013), modified Tris-Buffer (Tris-labeled Buffer), 100% DMSO (dimethyl sulfoxide), NAD (nicotinamide adenine dinucleotide), acetylated peptide substrate, trypsin and enzyme labeling instrument (Synergy MX), which were provided by Shanghai Ruizhi chemical Co., Ltd., China.
All 5H- [1,2,4] triazin [5,6-b ] indole derivatives substituted in the 3-position of the test were purchased from Specs (Netherlands) and Chemdiv (Russia). Compound AK-7 was purchased from medchemexpress (USA). The structural formula of AK-7 is:
in vitro experiments, 10mM stock solution is prepared from 100% DMSO, and is stored in a refrigerator at-20 ℃ in the dark for later use, and the stock solution is diluted to the required concentration by using complete culture solution when in use.
1.2 test methods
The human SIRT2 enzyme is mixed with the test buffer solution, and small molecule compounds with different concentrations dissolved by the percent 100DMSO are added, shaken and mixed evenly. The mixture was then incubated at room temperature for 15 minutes. And adding a polypeptide substrate containing NAD and acetylation to promote the reaction. After 240 minutes of incubation at room temperature, the trypsin solution was added and incubation continued for 90 minutes at room temperature. Then using a microplate reader at the excitation wavelength (. lamda.)ex) Is 360nm, and has an emission wavelength (lambda)em) The fluorescence intensity was measured at 460 nm. The calculation is made by the following formula:
wherein Y is the inhibition rate, X is the concentration of the compound, Max is the negative control Signal value (no inhibition at all), Min is the positive control Signal value (complete inhibition), Signal is the Signal value of the corresponding well, Inh% is the percentage of inhibition, IC in the formula50Is the concentration of the compound corresponding to an inhibition ratio of 50% (expressed in molar concentration M, and calculated as LogIC in the formula so as to match the X unit)50)。
1.3 test results of inhibitory potency of Compounds
The compounds of the invention were tested for SIRT2 inhibition by the test methods described above, with the inhibition values for a particular fraction of the compounds shown in table 1.
TABLE 1 Dual concentration inhibition of SIRT2 by some of the test compounds
As can be seen from table 1, the above compounds show a better structure-to-activity correspondence, and a total of 29 tested compounds show a better inhibitory effect (> 50%) at the tested concentration of 100 μ M. The structure I of the 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative is shown, and the substitution of substituent groups R1 and R2 has great influence on the activity. When R1 has no substituent, the series of compounds has poor inhibition effect on targeting SIRT 2; however, when R1 has a substituent, the inhibition effect of the series of compounds targeting SIRT2 is obviously enhanced; the substitution of the substituent R2 also has great influence on the activity, and particularly, the introduction of a hydrophobic group can obviously improve the activity of the series of compounds for targeting SIRT 2.
Table 2 IC of partial Compounds for SIRT2 in vitro50Value of
Compound (I) | ID number | Molecular molar mass | IC50(μM) |
AK-7 | AK-7 | 437.35 | 12 |
12 | AG-205/37150065 | 475.57 | 1.3 |
46 | 8010-5857 | 434.54 | 5.8 |
50 | 3698-0126 | 434.54 | 4.6 |
51 | 4249-0012 | 489.62 | 16 |
63 | 5471-0050 | 438.57 | 2.1 |
64 | 5471-0051 | 436.55 | 6.3 |
78 | D026-0012 | 535.63 | 5.4 |
The 3-substituted 5H- [1,2,4] of the invention]Triazine [5,6-b ]]Of the indole derivatives, IC was found for 7 compounds50Less than 10 μ M, with Compound 12 targeting the IC of SIRT250At 1.3. mu.M, a better inhibitory activity was shown.
Example 2 in vitro enzyme levels of Compounds 12 and 63 subtype Selective test experiments against SIRT1 and SIRT3 of the same family
The purpose of this experiment was to test the inhibitory activity of compounds against SIRT1, SIRT2 and SIRT3, SIRT sirs in vitro. IC for deacetylase inhibitory Activity of test Compound50(median inhibitory concentration). IC (integrated circuit)50Values can be calculated from the inhibition of deacetylase activity by the test compound at a range of different concentrations.
2.1 materials of the experiment
Human SIRT1 enzyme (BPS Biotechnology Co., Ltd., product number 50012), human SIRT2 enzyme (BPS Biotechnology Co., Ltd., product number 50013), human SIRT3 enzyme (Cayman Co., product number 10011194), Tris-Buffer modified as a Buffer, 100% DMSO (dimethyl sulfoxide), NAD (nicotinamide adenine dinucleotide), acetylated peptide substrate, trypsin and microplate reader (Synergy MX), which were provided by Shanghai Ruizi chemical Co., Ltd. (China).
All 5H- [1,2,4] triazin [5,6-b ] indole derivatives substituted in the 3-position of the test were purchased from Specs (Netherlands) and Chemdiv (Russia). In vitro experiments, 10mM stock solution is prepared from 100% DMSO, and is stored in a refrigerator at-20 ℃ in the dark for later use, and the stock solution is diluted to the required concentration by using complete culture solution when in use.
2.2 test methods
Mixing human SIRT1, SIRT2 and SIRT3 with test buffer solution, adding small molecule compounds dissolved in 100% DMSO at different concentrations, shaking, and mixing. The mixture was then incubated at room temperature for 15 minutes. The reaction is then driven by the addition of a substrate comprising NAD and acetylated polypeptide. After 240 minutes of incubation at room temperature, the trypsin solution was added and incubation continued for 90 minutes at room temperature. Then using a microplate reader at the excitation wavelength (. lamda.)ex) Is 360nm, and has an emission wavelength (lambda)em) The fluorescence intensity was measured at 460 nm. The calculation is made by the following formula:
wherein Y is the inhibition rate, X is the concentration of the compound, Max is the negative control Signal value (no inhibition at all), Min is the positive control Signal value (complete inhibition), Signal is the Signal value of the corresponding well, Inh% is the percentage of inhibition, IC in the formula50Is the concentration of the compound corresponding to an inhibition ratio of 50% (expressed in molar concentration M, and calculated as LogIC in the formula so as to match the X unit)50)。
2.3 test results
FIGS. 1 and 2 show that compound 12 and compound 63 strongly inhibit SIRT 2. The results of the activity test showed that compound 12 and compound 63 had little activity targeting SIRT1 and SIRT3 (IC)50>300. mu.M). The results show that compound 12 and compound 63 have better activity-dose dependence on SRIT2 and better selectivity for SIRT1 and SIRT 3.
EXAMPLE 3 in vitro cell viability inhibition of Compound 12 against human Breast cancer cell line MCF-7 and inhibition of intracellular substrate protein
The objective of this experiment was to examine the anti-malignant cell proliferation properties of compound 12 on cells in vitro and the level of the intracellular substrate α -tubulin. Human breast cancer MCF-7 cells cultured in a laboratory are added with medicine for a certain time and then detected by an MTT (tetramethylazozolium) colorimetric method and a Western Blot (Western Blot) method.
3.1 Experimental materials
3.1.1MTT colorimetric method
The main reagents are as follows: DMEM is available from Gibco BRL (Invitrogen Corporation, USA), fetal bovine serum from Gibco BRL (Invitrogen Corporation, USA), penicillin and streptomycin double antibody from Hyclone (Thermo Scientific, American), Tetramethylazo salt (MTT) and Sodium Dodecyl Sulfate (SDS) from Sigma (USA).
3.1.2Western Blot (Western Blot)
The main reagents are as follows: DMEM was purchased from Gibco BRL (Invitrogen Corporation, USA), fetal bovine serum was purchased from Gibco BRL (Invitrogen Corporation, USA), cyan and streptomycin dual antibodies were purchased from Hyclone (ThermoScientific, American), alpha-tubulin, acetylated alpha-tubulin antibodies were purchased from Sigma (American), horseradish peroxidase-labeled secondary antibody was purchased from Shanjin bridge, Beijing, and developing substrate was purchased from Millipore.
3.1.3 cell lines and culture
The cell line used in this experiment, human breast cancer MCF-7 cells, was purchased from ATCC (American type cultureselection) in USA and stored in this laboratory. MCF-7 cells were cultured in DMEM complete medium containing 10% fetal bovine serum, 100U/mL penicillin, 100. mu.g/mL streptomycin at 5% CO2And cultured at 37 ℃.
3.2 Experimental methods
3.2.1 cell lines and culture
The cell concentration was adjusted to 1 × 10 with the use of whole cell culture5Cell suspension/mL, 200 μ L cell suspension per well was seeded in 96-well plates and cultured overnight. The next day, the suspension cells were centrifuged and the supernatant discarded, and then the cells were treated with a gradient concentration of test compound. Setting a negative control group without drug and a solvent control group with the same volume, wherein the concentration of DMSO is 0.1%, each dose group is provided with 3 multiple wells, and the concentration of DMSO is 5% CO at 37 DEG C2Culturing for 72 hours, adding 20 μ L of MTT reagent with the concentration of 5mg/mL into each well, culturing for 2-4 hours, discarding the supernatant, adding 50 μ L of 20% SDS (m: v) solution into each well, incubating overnight at 37 ℃, measuring the absorbance (A) value (A value is in direct proportion to the number of living cells) by using a microplate reader (λ 570nm), taking the average value, and obtaining the relative cell proliferation inhibition rate (control group A570-experiment group A570)/control group A570 × 100%. the experiment is repeated for 3 times<0.05 is a difference, which is statistically significant. IC was used for inhibition of cell proliferation by each of the following compounds50Or inhibition rate.
3.2.2Western Blot (Western Blot)
The cells to be tested are cultured on a plate and expanded to an appropriate cell density. Test compounds of different concentrations were added to cell culture medium containing 40nM trichostatin A, with equal volumes of solvent as a blank control, compound AK-7 as a positive control and compound 65 as a negative control, at 37 deg.C, 5% CO2The culture was carried out under the conditions for 6 hours. After 6 hours, cells were harvested and washed with pre-cooled PBS. The cells are then lysed by adding a cell lysis solution. And (3) detecting the protein concentration of the protein suspension obtained after the cracking by using a BCA method, adding a proper protein loading buffer solution, uniformly mixing, and heating at 100 ℃ for 10min to fully denature the protein. The samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and after membrane transfer the PVDF membrane was incubated with the antibody overnight at 4 ℃. Then incubated for 1h at 37 ℃ with a secondary antibody labeled with horseradish peroxidase. Protein expression was detected by exposure to horseradish peroxidase substrate.
3.3 results of the experiment
Using the above experimental methods, proliferation inhibitory activity test and Western Blot (Western Blot) were performed on human breast cancer MCF-7.
FIG. 3A shows the proliferation inhibitory activity of compound 12 on MCF-7 at various concentrations, and compound 12 can kill MCF-7 cells and inhibit MCF-7 proliferation in human breast cancer in a dose-dependent manner.
Western Blot results As shown in FIG. 3B, Compound 12 significantly increased the acetylation level of α -tubulin (α -tubulin) in a dose-dependent manner.
Claims (13)
- The application of a 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at the position 3, in particular to the application of the 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at the position 3 and a salt thereof, or a pharmaceutical composition containing the derivative and the salt thereof in preparing a SIRT2 inhibitor; the inhibitor is used for treating and/or preventing breast cancer; the 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative has a structure shown in a formula I:wherein R is1Is benzyl, C1-C4 alkyl or C1-C4 alkenyl;R15is-H; r18Is phenyl; r19Is C1-C4 alkyl; r20Is C1-C4 alkyl;m=0;n=0;
- 3.3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives, in particular to 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives and salts thereof, or pharmaceutical compositions containing the derivatives and the salts thereof in the preparation of drugs for treating or preventing breast cancer; the 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative has a structure shown in a formula I:wherein R is1Is benzyl, C1-C4 alkyl or C1-C4 alkenyl;R15is-H; r18Is phenyl; r19Is C1-C4 alkyl; r20Is C1-C4 alkyl;m=0;n=0;
- 5. use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 1 or 3, characterized in that: the 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives and salts thereof are used in the form of pharmaceutical compositions.
- 6. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 5, characterized in that: the pharmaceutical composition is a compound containing 0.1-99% of 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivatives and salts thereof, and the balance is pharmaceutically acceptable medicinal carriers and/or excipients which are nontoxic to human and animals.
- 7. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 6, characterized in that: the pharmaceutically acceptable carrier or excipient is one or more of solid, semi-solid and liquid diluents.
- 8. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 1 or 3, characterized in that: the compound of 5H- [1,2,4] triazine [5,6-b ] indole derivative substituted at 3-position and the pharmaceutical composition of the salt thereof are prepared into the following dosage forms by adopting a method accepted in the pharmaceutical field: sprays, liquid preparations or solid preparations; the liquid preparation comprises suspension, emulsion, solution or syrup; the solid preparation comprises tablets, capsules or granules.
- 9. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 8, characterized in that: the spray comprises an aerosol.
- 10. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 8, characterized in that: the solution includes an injection.
- 11. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 8, characterized in that: the granule comprises granules.
- 12. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 6, characterized in that: the administration route of the pharmaceutical composition is oral administration, sublingual administration, injection or mucosal dialysis; the injection comprises intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection.
- 13. Use of a 3-substituted 5H- [1,2,4] triazine [5,6-b ] indole derivative according to claim 12, characterized in that: the intravenous injection comprises an intravenous drip.
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