CN110950841A - Synthesis and application of novel triazole compounds - Google Patents
Synthesis and application of novel triazole compounds Download PDFInfo
- Publication number
- CN110950841A CN110950841A CN201911152555.7A CN201911152555A CN110950841A CN 110950841 A CN110950841 A CN 110950841A CN 201911152555 A CN201911152555 A CN 201911152555A CN 110950841 A CN110950841 A CN 110950841A
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- amino
- prmt5
- compounds
- 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.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel triazole compound shown in figure 1 and application thereof as a protein arginine methyltransferase 5 inhibitor, and discloses application of the compound in preventing and/or treating cancer-related diseases caused by abnormal activity of protein arginine methyltransferase 5.
Description
Technical Field
The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to synthesis and application of a novel triazole compound.
Background
Protein arginine methyltransferases (PRMTs) -catalyzed methylation of protein arginine is an important post-translational modification that uses S-adenosylmethionine (SAM) as a methyl donor to methylate and modify the nitrogen atom of the protein arginine side chain. The substrates of PRMTs are glycine and arginine rich proteins. The 9 human PRMTs identified (PRMT 1-9) were further subdivided into type I, type II and type III, depending on the status of the methylated arginine. Type I PRMT catalyzes the formation of monomethyl arginine (MMA) and asymmetric dimethyl arginine (aDMA), including PRMT1, PRMT2, PRMT3, PRMT4, PRMT6 and PRTM 8; type ii PRMT catalyzes the formation of MMA and symmetric dimethylarginine (sDMA), including PRMT5 and PRMT 9; type iii PRMT catalyzes the formation of MMA, including PRMT 7. PRMT5 belongs to type ii PRMT, transferring a methyl group from the SAM to the guanidine nitrogen of an arginine residue to produce MMA and sDMA. Human tissue proteomics analysis showed that PRMT1, -4 and-5 expression was more prevalent compared to PRMT2, -3, -6, -7 and-8. PRMT5 mediates various cellular processes such as transcription, RNA metabolism, signal transduction, and cell differentiation through symmetric dimethylation of multiple substrate proteins in the nucleus and cytoplasm.
Interestingly, increasing research has shown that PRMT5 is an attractive target for cancer therapy, which is overexpressed or upregulated in a variety of human cancers, including leukemia, lymphoma, breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma, or testicular cancer. Selective inhibition of PRMT5 was reported to block B cell transformation. In addition, PRMT5 controls melanoma growth through the SKI/SOX10 regulatory axis. PRMT5 is considered to be an effective target for the treatment of Mantle Cell Lymphoma (MCL), glioblastoma, multiple myeloma, and mixed leukemia (MLL) -acute myeloid leukemia.
LLY-283, Sinefungin and A9145C are reported to be SAM binding site inhibitors, EPZ015666 and its analogue GSK3326595 are substrate binding site inhibitors, EPZ015666 is the first PRMT5 inhibitor with potent activity in both in vitro and in vivo models of mantle cell lymphoma. In addition, clinical trials for GSK3326595 in phase i for the treatment of solid and non-hodgkin's lymphoma are ongoing. Although there are more than 10 PRMT5 inhibitors reported, most exhibit low potency or lack in vivo activity. Therefore, there is a need to find more effective PRMT5 inhibitors.
In view of the above, there is an urgent need in the art to develop more novel arginine methyltransferase 5 inhibitors.
Disclosure of Invention
In order to solve the problems, the invention provides a novel triazole compound, a preparation method thereof and application thereof in preventing and/or treating cancer or related diseases.
The invention is realized by the following technical scheme.
In a first aspect of the invention, triazole compounds with novel structures are provided, and the general formula is shown in figure 1, wherein R is 3-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 3- (cyclobutylamino) phenyl and 3- ((tetrahydro-2H-pyran-4-yl) amino) phenyl.
Among them, a preferred structure is shown in fig. 2.
A more preferred configuration is shown in figure 3.
The preparation method of the compound related to the invention has a preparation route shown in figure 5.
Preferably, the cancer to be prevented and/or treated is leukemia, lymphoma, breast cancer, lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma or testicular cancer.
Preferably, the related disease is a disease associated with an abnormal arginine methyltransferase 5 activity.
Has the advantages that: the compound has stronger inhibitory activity and selectivity on PRMT 5; the preparation method of the compound is simple and feasible; the compound has stronger tumor cell proliferation inhibition activity, and the targeting of PRMT5 in cells is confirmed; the raw materials are easy to obtain.
Drawings
FIG. 1 is a new class of triazole compounds.
FIG. 2 shows a preferred novel triazole compound.
More preferred novel triazole compounds are shown in FIG. 3.
FIG. 4 shows the structural design of compounds C _1 to C _ 6.
FIG. 5 is a scheme for preparing compounds C _1 to C _ 6.
FIG. 6A test of the enzyme inhibitory activity of compounds C _1 to C _6 by means of radioisotopes.
Figure 7 the selectivity of compound C _4 for PRMTs was assessed by radioisotope methods.
FIG. 8 Effect of Compounds C _1 to C _6 on Z-138 cell proliferation.
FIG. 9 dose curve of Compound C _4 for inhibition of Z-138 cell proliferation.
FIG. 10 Effect of Compound C _4 on symmetric dimethylation of Z-138 cells.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1: and designing the structures of the compounds C _ 1-C _ 6.
Obtaining compounds C _ 1-C _6 by using a traditional structure optimization mode, wherein the structure design is shown in figure 4, wherein R1Nitro, amino, cyclobutylamino and (tetrahydro-2H-pyran-4-yl) amino.
Example 2: and (3) preparing compounds C _ 1-C _ 6.
The compounds C _ 1-C _6 are synthesized by starting from 3-or 4-bromonitrobenzene, the 3-or 4-bromonitrobenzene and trimethylsilylacetylene are subjected to Sonogashaaira coupling reaction, and then potassium carbonate is used for deprotection to obtain 1-ethynyl-3-nitrobenzene or 1-ethynyl-4-nitrobenzene (an intermediate 3); treating 2- (oxido-2-ethylmethyl) -1,2,3, 4-tetrahydroisoquinoline (compound 4) with sodium azide or ammonia gas in methanol to give 1-amino-3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol or 1-azido-3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (intermediate 5); preparing compounds C _1 and 6 by using the intermediate 3 and the intermediate 5 as raw materials by a click chemistry method; and reducing C _1 and C _6 by hydrogen to obtain C _2 and C _5, and reacting C _2 and C _5 with ketone to obtain C _3, C _4 and C _ 6. The specific preparation route is shown in figure 5, wherein (a): trimethylsilylacetylene, methylidene iodide, bis (triphenylphosphine) palladium chloride, triethylamine, N, N-dimethylformamide, microwave irradiation, 120 ℃; (b): potassium carbonate, methanol, room temperature; (c) the method comprises the following steps 5 a: refluxing sodium azide and ethanol; 5 b: sealing with nitrogen and methanol at 80 deg.C; (d): copper sulfate pentahydrate, sodium ascorbate, tetrahydrofuran/water; (e): palladium on carbon, hydrogen, methanol; (f): sodium cyanoborohydride, ketone, methanol.
1- (3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (4- (3-nitrophenyl) -1H-1,2, 3-triazol-1-yl) propan-2-ol (C _ 1): yellow solid (152 mg, 80%).1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.22(d, J = 7.5 Hz, 1H), 8.17 (s, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.22-7.06 (m,3H), 7.00 (d, J = 6.0 Hz, 1H), 4.73 - 4.61 (m, 1H), 4.45 (m, 1H), 4.30 (m,1H), 3.89 (d, J = 14.7 Hz, 1H), 3.69 (d, J = 14.7 Hz, 1H), 3.07 - 2.88 (m,3H), 2.87 - 2.78 (m, 1H), 2.74 (m, 1H), 2.59 - 2.39 (m, 1H).13C NMR (151MHz, DMSO-d6) delta 148.9, 144.5, 133.1, 131.8, 131.1, 128.9, 126.9, 124.2, 122.8,119.8, 67.6, 61.8, 56.5, 54.9, 51.6. formula is C20H21N5O3。
1- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) -3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (C _ 2): yellow solid (78 mg, 86%).1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.19- 6.98 (m, 7H), 6.70 (m, 1H), 4.60 (m, 1H), 4.41 (m, 1H), 4.37 - 4.29 (m,1H), 3.80 (s, 2H), 2.92 (s, 4H), 2.70 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ149.8, 149.0, 147.4, 128.9, 126.9, 126.6, 126.0, 120.5, 119.1, 114.4, 67.5,61.6, 56.3, 54.5, 51.5. HRMS (ESI+) m/z+: 350.1973 [M+ H]+Molecular formula is C20H24N5O。
1- (3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (4- (3- ((tetrahydro-2H-pyran-4-yl) amino) phenyl) -1H-1,2, 3-thiazol-1-yl) propan-2-ol (C _ 3): yellow solid (37 mg, 43%).1H NMR (300 MHz, CDCl3)δ 7.96 (s, 1H), 7.29 - 7.03 (m, 6H), 6.99 (d, J = 6.0 Hz, 1H), 6.58 (d, J =7.8 Hz, 1H), 4.59 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 4.00 (d, J = 11.6 Hz,2H), 3.81 (m, 1H), 3.67 - 3.50 (m, 4H), 2.92 (m, 3H), 2.79 - 2.67 (m, 1H),2.67 - 2.56 (m, 1H), 2.42 (m, 1H), 2.06 (m, 2H), 1.48 (m, 2H).13C NMR (151MHz, DMSO-d6) delta 148.5, 147.2, 132.0, 129.9, 128.9, 126.9, 122.5, 113.3,112.7, 109.3, 66.5, 55.3, 48.3, 33.3 HRMS (ESI +) m/z +: 434.2546 minSub-formula is C25H32N5O2。
1- (4- (3- (cyclobutylamino) phenyl) -1H-1,2, 3-triazol-1-yl) -3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (C _ 4): yellow solid (42 mg, 52%).1H NMR (400 MHz, CD3OD) δ 8.24 (s,1H), 7.15 (m, 4H), 7.07 (m, 3H), 6.60 (d, J = 6.8 Hz, 1H), 4.65 (m, 1H), 4.54- 4.41 (m, 1H), 4.36 (s, 1H), 4.07 - 3.91 (m, 1H), 3.83 (s, 2H), 2.96 (m,4H), 2.71 (d, J = 8.8 Hz, 2H), 2.44 (s, 2H), 1.87 (m, 4H).13C NMR (151 MHz,CD3OD) δ 148.3, 147.9, 133.5, 130.8, 129.2, 128.2, 126.2, 125.6, 121.9,114.1, 113.1, 109.7, 67.0, 60.7, 55.8, 54.3, 51.2, 48.7, 30.4, 28.0, 14.65.HRMS (ESI+) m/z+: 404.2439 [M + H]+Molecular formula is C24H30N5O。
1- (4- (4-aminophenyl) -1H-1,2, 3-triazol-1-yl) -3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propan-2-ol (C _ 5): yellow solid (74 mg, 83%).1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.58- 7.51 (m, 2H), 7.14 - 7.06 (m, 3H), 7.02 (d, J = 5.1 Hz, 1H), 6.79 - 6.73(m, 2H), 4.61 (m, 1H), 4.41 (m, 1H), 4.30 (m, 1H), 3.72 (s, 2H), 2.91 (t, J =5.6 Hz, 2H), 2.87 - 2.79 (m, 2H), 2.68 - 2.54 (m, 2H).13C-NMR (151 MHz, DMSO-d6) δ 149.5, 147.1, 131.8, 129.8, 128.9, 126.9, 126.6, 126.0, 122.3, 113.9,113.4, 110.9, 72.8, 60.7, 54.5, 51.5. HRMS (ESI+) m/z+: 350.1973 [M + H]+Molecular formula is C20H24N5O。
1- (3, 4-dihydroisoquinolin-2 (1H) -yl) -3- (4- (4- ((tetrahydro-2H-pyran-4-yl) amino) phenyl) -1H-1,2, 3-triazol-1-yl) propan-2-ol (C _ 6): yellow solid (35 mg, 42%).1H NMR (400 MHz,CD3OD) δ 8.13 (s, 1H), 7.59 (m, 2H), 7.11 (m, 4H), 6.74 (m, 2H), 4.60 (m,1H), 4.41 (m, 2H), 3.97 (m, 2H), 3.89 (m, 2H), 3.55 (m, 3H), 3.00 (m, 4H),2.80 (m, 2H), 2.02 (m, 2H), 1.52 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 147.9,128.9, 126.9, 126.7, 113.0, 66.5, 65.4, 48.3, 35.9, 33.3. HRMS (ESI+) m/z+:434.2546 [M + H]+Molecular formula is C25H32N5O2。
Example 3: inhibitory activity of the compounds C _ 1-C _6 on PRMT 5.
The compounds were tested for enzyme inhibitory activity by means of radioisotopes. The specific experimental steps are as follows:
(1) preparing 1x experiment buffer (modified Tris-HCl buffer);
(2) diluting the compound to the desired concentration in a 96-well plate;
(3) preparing a protein solution, and using 1x experiment buffer solution;
(4) adding a substrate into 1x experiment buffer solution to prepare a substrate solution;
(5) will 23H]Preparation of [ 2 ], [ SAM ] by adding to 1X test buffer3H]-a SAM solution;
(6) adding SAM to 1x experiment buffer solution to prepare cold SAM solution;
(7) removing 10. mu.L of the protein solution into a 96-well plate containing the compound;
(8) incubation for 15 minutes at room temperature;
(9) add 10. mu.L of substrate solution to each well;
(10) to each well was added 10. mu.L of3H]-the SAM solution initiates the reaction;
(11) incubation at room temperature for 240 min;
(12) add 10. mu.L of cold SAM solution to each well to stop the reaction;
(13) transferring 40 mu L of reaction mixed solution to a GF/B plate, and washing for 3 times by using triple distilled water in vacuum;
(14) reading data on a Microbeta liquid scintillation/luminescence counter;
(15) the inhibition rate was calculated according to the formula% Inh = (maximum signal-compound signal)/(maximum signal-minimum signal) × 100, the maximum signal being obtained from the reaction of the enzyme and the substrate and the minimum signal being obtained from the substrate. Data were plotted after processing using GraphPadPrism 5.0. EPZ015666 was used as a positive control. The experimental results are shown in fig. 6, and the results show that the compound C _4 has greater PRMT5 inhibitory activity.
Example 4: selectivity of compound C _ 4.
The selectivity of the compound C _4 to other PRMTs was evaluated by a radioisotope method, and the results of the experiment are shown in FIG. 7, which shows the IC of the compound C _4 to PRMT1, PRMT4 and PRMT650Values were all greater than 200 μ M, indicating that it is a selective PRMT5 inhibitor.
Example 5: effect of Compounds C _1 to C _6 on cell proliferation.
Cell culture: the culture medium for Z-138 cell culture is RPMI 1640 + 10% fetal bovine serum, and 100U/mL penicillin and 100. mu.g/mL streptomycin are added to the culture medium to prevent bacterial contamination, and 5% CO is added at 37 deg.C2The cells are cultured under the saturated humidity condition, and the cells for experiments are all in the exponential growth phase.
And (3) detecting cell proliferation activity: adjusting the cell concentration to 1X 105Performing inoculation on a 24-well culture plate with 1 mL of each well volume, establishing a control group and an experimental group, adding DMSO into the control group, adding PRMT5 small molecule inhibitor into the experimental group to make the final concentration reach 0-200 mu M, and placing at 37 ℃ and 5% CO2The cells were cultured in an incubator, the amount of viable cells was measured every four days using CellTiter-Glo kit, and data was recorded on day 8. The experimental result is shown in figure 8, and the result shows that the compound shows effective concentration-dependent anti-Z-138 cell proliferation activity, the compound C _4 has the strongest proliferation inhibition effect on Z-138 cells, and IC502.60. + -. 0.81. mu.M, the relevant dose curve is shown in FIG. 9.
Example 6: effect of compound C _4 on cell symmetric dimethylation.
Exponentially growing Z-138 cells were incubated with different concentrations of compound C _4 for 4 days, the cells were collected and dissolved in 100 μ L of lysis buffer, total cell lysates were separated by 4-12% polyacrylamide gel electrophoresis and transferred onto PVDF membranes, then blocked with blocking solution (5% skim milk, 1% tween 20 PBS buffer), then primary antibodies [ SDMA (CST, 13222s), GAPDH (CST, 5174) and SmD3 (Sigma, HPA001170-100UL) ] were added to the blot, incubated overnight at 4 ℃, the next day, washed three times with PBST, incubated with anti-rabbit secondary antibody (HRP labeled) for 2 hours, and finally the signal was detected using the ChemiScope3400 imaging system (Clinx Science Instruments). The experimental results are shown in fig. 10, and it is known that different concentrations of compound C _4 have different inhibitory effects on the symmetric dimethylated arginine substrate SmD3 in Z-138 cells, and show that the concentration-dependent inhibition intensity of SmD3me2S is shown. Since SmD3 is one of the substrate proteins of PRMT5, it can be concluded that Compound C _4 targets PRMT5 in the cell.
Claims (6)
1. A general formula of the novel triazole compound is shown in figure 1, wherein R is 3-nitrophenyl, 3-aminophenyl, 4-aminophenyl, 3- (cyclobutylamino) phenyl and 3- ((tetrahydro-2H-pyran-4-yl) amino) phenyl.
2. The compound of claim 1, wherein the compound of figure 3.
3. A process for the preparation of a compound according to claim 1 or 2, wherein the desired product is prepared by the route of figure 5, wherein R is2Is nitro or amino, R3Is azido or amino.
4. Use of a compound according to claim 1 for the prophylaxis and/or treatment of cancer or a related disease.
5. The use according to claim 4, wherein the cancer to be prevented and/or treated is leukemia, lymphoma, breast cancer, lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma AML, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma or testicular cancer.
6. The use according to claim 4, wherein the related disease is a disease caused by abnormal activity of protein arginine methyltransferase 5.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911152555.7A CN110950841A (en) | 2019-11-22 | 2019-11-22 | Synthesis and application of novel triazole compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911152555.7A CN110950841A (en) | 2019-11-22 | 2019-11-22 | Synthesis and application of novel triazole compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110950841A true CN110950841A (en) | 2020-04-03 |
Family
ID=69977988
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911152555.7A Pending CN110950841A (en) | 2019-11-22 | 2019-11-22 | Synthesis and application of novel triazole compounds |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110950841A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113855803A (en) * | 2021-09-23 | 2021-12-31 | 复旦大学附属眼耳鼻喉科医院 | Use of PRMT5 inhibitor for preparing hearing protection medicine |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105339351A (en) * | 2013-03-14 | 2016-02-17 | Epizyme股份有限公司 | Arginine methyltransferase inhibitors and uses thereof |
WO2016034675A1 (en) * | 2014-09-03 | 2016-03-10 | Ctxt Pty Ltd | Tetrahydroisoquinoline derived prmt5-inhibitors |
CN105452226A (en) * | 2012-12-21 | 2016-03-30 | Epizyme股份有限公司 | Teatrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof |
US20170088541A1 (en) * | 2012-12-21 | 2017-03-30 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
US20170210751A1 (en) * | 2014-06-25 | 2017-07-27 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
WO2017153520A1 (en) * | 2016-03-09 | 2017-09-14 | Ctxt Pty Limited | Benzopiperidine derivatives and their use in the treatment of cancer and hemoglobinopathies |
CN108570059A (en) * | 2017-03-09 | 2018-09-25 | 中国科学院上海药物研究所 | A kind of compound and its preparation and application with PRMT5 inhibitory activity |
CN109081808A (en) * | 2018-09-11 | 2018-12-25 | 济南大学 | Anilid class compound of the one kind containing tetrahydroisoquinoline structure, purposes and preparation method thereof |
CN109400545A (en) * | 2018-12-24 | 2019-03-01 | 济南大学 | A kind of 5 inhibitor of arginine methyltransferase and its application |
WO2019173804A1 (en) * | 2018-03-09 | 2019-09-12 | Pharmablock Sciences (Nanjing), Inc. | Inhibitors of protein arginine methyltransferase 5 (prmt5), pharmaceutical products thereof, and methods thereof |
CN110234342A (en) * | 2016-12-01 | 2019-09-13 | 葛兰素史密斯克莱知识产权发展有限公司 | Combination treatment |
WO2019180628A1 (en) * | 2018-03-22 | 2019-09-26 | Aurigene Discovery Technologies Limited | Imidazolidin-2-one compounds as prmt5 modulators |
CN110650950A (en) * | 2017-03-17 | 2020-01-03 | 阿古诺治疗有限公司 | Compounds for treating or preventing PRMT5 mediated diseases |
CN110950801A (en) * | 2019-11-13 | 2020-04-03 | 济南大学 | Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline |
-
2019
- 2019-11-22 CN CN201911152555.7A patent/CN110950841A/en active Pending
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105452226A (en) * | 2012-12-21 | 2016-03-30 | Epizyme股份有限公司 | Teatrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof |
US20170088541A1 (en) * | 2012-12-21 | 2017-03-30 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
CN105339351A (en) * | 2013-03-14 | 2016-02-17 | Epizyme股份有限公司 | Arginine methyltransferase inhibitors and uses thereof |
US20170210751A1 (en) * | 2014-06-25 | 2017-07-27 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
WO2016034675A1 (en) * | 2014-09-03 | 2016-03-10 | Ctxt Pty Ltd | Tetrahydroisoquinoline derived prmt5-inhibitors |
WO2017153520A1 (en) * | 2016-03-09 | 2017-09-14 | Ctxt Pty Limited | Benzopiperidine derivatives and their use in the treatment of cancer and hemoglobinopathies |
CN110234342A (en) * | 2016-12-01 | 2019-09-13 | 葛兰素史密斯克莱知识产权发展有限公司 | Combination treatment |
CN108570059A (en) * | 2017-03-09 | 2018-09-25 | 中国科学院上海药物研究所 | A kind of compound and its preparation and application with PRMT5 inhibitory activity |
CN110650950A (en) * | 2017-03-17 | 2020-01-03 | 阿古诺治疗有限公司 | Compounds for treating or preventing PRMT5 mediated diseases |
WO2019173804A1 (en) * | 2018-03-09 | 2019-09-12 | Pharmablock Sciences (Nanjing), Inc. | Inhibitors of protein arginine methyltransferase 5 (prmt5), pharmaceutical products thereof, and methods thereof |
WO2019180628A1 (en) * | 2018-03-22 | 2019-09-26 | Aurigene Discovery Technologies Limited | Imidazolidin-2-one compounds as prmt5 modulators |
CN109081808A (en) * | 2018-09-11 | 2018-12-25 | 济南大学 | Anilid class compound of the one kind containing tetrahydroisoquinoline structure, purposes and preparation method thereof |
CN109400545A (en) * | 2018-12-24 | 2019-03-01 | 济南大学 | A kind of 5 inhibitor of arginine methyltransferase and its application |
CN110950801A (en) * | 2019-11-13 | 2020-04-03 | 济南大学 | Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline |
Non-Patent Citations (2)
Title |
---|
许晓双等: "蛋白质精氨酸甲基转移酶抑制剂的研究进展", 《江苏医药》, vol. 44, no. 9, 30 September 2018 (2018-09-30), pages 1068 - 1071 * |
黄美玲等: "蛋白质精氨酸甲基转移酶5抑制剂的研究进展", 《现代肿瘤医学》, vol. 27, no. 8, 30 April 2019 (2019-04-30), pages 1432 - 1435 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113855803A (en) * | 2021-09-23 | 2021-12-31 | 复旦大学附属眼耳鼻喉科医院 | Use of PRMT5 inhibitor for preparing hearing protection medicine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Zhong et al. | Recent progress in the research of cold-inducible RNA-binding protein | |
Cho et al. | RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation | |
Lleonart | A new generation of proto-oncogenes: cold-inducible RNA binding proteins | |
Kang et al. | Energy stress-induced lncRNA HAND2-AS1 represses HIF1α-mediated energy metabolism and inhibits osteosarcoma progression | |
Iiizumi et al. | RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer | |
Wang et al. | Role of transcriptional corepressor CtBP1 in prostate cancer progression | |
Yang et al. | FOXP4-AS1 participates in the development and progression of osteosarcoma by downregulating LATS1 via binding to LSD1 and EZH2 | |
Nishimoto et al. | JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein–protein interaction in human colon cancer cells | |
Zhu et al. | Thymidine kinase 1 silencing retards proliferative activity of pancreatic cancer cell via E2F1‐TK 1‐P21 axis | |
CN109081808B (en) | Acyl aniline compound containing tetrahydroisoquinoline structure, application and preparation method thereof | |
Yu et al. | Promotion of LncRNA HOXA11-AS on the proliferation of hepatocellular carcinoma by regulating the expression of LATS1. | |
US20110190507A1 (en) | Thiophene-carboxamides useful as inhibitors of protein kinases | |
CN109400545B (en) | Arginine methyltransferase 5 inhibitor and application thereof | |
CN110950841A (en) | Synthesis and application of novel triazole compounds | |
CN111018832A (en) | Preparation and application of imidazolone compounds containing tetrahydroisoquinoline structure | |
Gong et al. | The role and mechanism of action of tRNA-derived fragments in the diagnosis and treatment of malignant tumors | |
Thapa et al. | Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents | |
CN102575236B (en) | Inhibition of histone acetyltransferases by CTK7A and methods thereof | |
Khushal et al. | Synthesis, Carbonic Anhydrase II/IX/XII Inhibition, DFT, and Molecular Docking Studies of Hydrazide‐Sulfonamide Hybrids of 4‐Methylsalicyl‐and Acyl‐Substituted Hydrazide | |
CN110950801A (en) | Preparation and application of sulfanilamide and benzothiazole compounds containing tetrahydroisoquinoline | |
CN112601734A (en) | Oximido naphthoquinone compound and preparation method and application thereof | |
EP3122735B1 (en) | 3-phenyl-7-hydroxy-isocoumarins as macrophage migration inhibitory factor (mif) inhibitors | |
CN108689960A (en) | 5- benzylidenes -2- phenyl thiazoles ketone compounds and its preparation and application | |
AU2014298433B2 (en) | 2-benzoylaminobenzamide derivatives as Bcl-3 inhibitors | |
US20220184195A1 (en) | Inhibition of histone methyl transferases to treat cancer |
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 | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200403 |
|
WD01 | Invention patent application deemed withdrawn after publication |