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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors
Giri R. Gnawali ; Koichi Okumura ; Karolina Perez ; Rosa Gallagher ; Julia Wulfkuhle ; Emanuel F. Petricoin , et al.
Abstract: Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-chloro (GRG-1-34, 6e), 4-Bromo (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1–34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5 h after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.
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Keywords: Quinoline derivatives ; Pim kinase ; Antitumor activity ; mTORC
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Purchased from AmBeed: 180748-30-5 ; 4837-01-8 ; 589-10-6 ; 6627-60-7 ; 31106-82-8 ; 1260903-05-6 ; 872577-05-4 ; 865156-50-9 ; 188637-63-0 ; 103-67-3 ; 3731-51-9 ; 164341-39-3 ; 67938-76-5 ; 22921-76-2 ; 1241725-81-4 ; 131052-62-5 ; 184637-50-1
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CAS No. : | 589-10-6 |
Formula : | C8H9BrO |
M.W : | 201.06 |
SMILES Code : | BrCCOC1=CC=CC=C1 |
MDL No. : | MFCD00000234 |
InChI Key : | JJFOBACUIRKUPN-UHFFFAOYSA-N |
Pubchem ID : | 68526 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362+P364 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetonitrile; for 16.0h;Heating / reflux; | A solution of commercially available 4-methoxy-2-oxo-l,2-dihydro-pyridine-3- carbonitrile (4.0 g, 0.0266 mol), beta-bromophenetole (5.62 g, 0.0279 mol) and K2CO3 (11.0 g, 0.0799 mol) in CH3CN (150 ml) was heated at reflux for 16 hours. The reaction mixture was then filtered off and the filtrate concentrated in vacuo. The residue was recrystallised from ethylether to yield intermediate compound 17 (7 g, 97 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 55℃; for 21h; | To a solution of lH-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (0.5 g, 2.9 mmol) and l-(2- bromoethoxy)benzene (0.74 g, 3.7 mmol) in DMF (15 mL) was added K2CO3 (1.2 g, 8.6 mmol). After stirring at room temperature for 16 hr, the mixture was heated to 55 0C for 5 hr then cooled to room temperature and diluted with ethyl acetate (100 ml) and washed with water (3 X 50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (20% ethyl acetate/hexane, then ethyl acetate) to provide 0.63 g (75%) of methyl l-(2-phenoxyethyl)-lH-indole-6-carboxylate. 1H νMR (300 MHz, DMSO) S 8.26 (d, IH, J <n="142"/>= 1.0 Hz), 7.67-7.62 (m, 3H), 7.23 (td, 2H, J= 7.6 Hz5 J= 1.0 Hz), 6.92-6.84 (m, 3H), 6.55 (dd, IH, J- 3.0 Hz, J= 0.6 Hz), 4.66 (t, 2H, J= 4.9 Hz), 4.28 (t, 2H, J = 4.9 Hz), 3.86 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | Example 110 N'-[1-imadazol-1-yl-1-[1-(2-phenoxyethyl)imidazol-2-yl]methylidene]-N,N-dimethylhydrazine (compound Nos. 111, 112) To a solution of <strong>[33543-78-1]ethyl imidazole-2-carboxylate</strong> (0.505 g, 3.60 mmol) in N,N-dimethylformamide (6 ml) were added beta-bromophenetole (0.804 g, 4.00 mmol) and potassium carbonate (0.598 g, 4.32 mmol), and the mixture was stirred at 80°C for 1 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give ethyl 1-(2-phenoxyethyl)imidazole-2-carboxylate (0.869 g, 3.34 mmol, yield 93percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Step 2 : 5-(4-Methoxyphenyl)-l-(2-phenoxyethyl)pyridin-2(lH)-one; According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)-(lH)-pyridin-2- one (leq, 0.30mmol, 60mg) in TEtaF (3mL) was added K2CO3 (10eq, 3.00mmol, 0.4Ig). The reaction was stirred at room temperature for 30 minutes then l-(2- bromoethoxy)benzene (3eq, 0.90mmol, 0.18g) was added. The reaction was stirred at 60C for 12 hours. After concentration of the solvent, acetonitrile (3mL) was added followed by K2CO3 (10eq, 3.00mmol, 0.4Ig) and l-(2-bromoethoxy)benzene (10eq, 3.00mmol, 0.60g) then the reaction was microwaved for 5 minutes at 180C. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10g SiO2) using CEta2Cl2/AcOEt (80/20) as the eluent to afford 5-(4-methoxyphenyl)-l- (2-phenoxyethyl)pyridin-2(lH)-one (0.13mmol, 42mg, 44%) as a yellow oil. Rf= 0.29 (CEta2Cl2/AcOEt 90/10); LC (XTerra RP18, 3.5mum, 3.0x50mm Column): RT = 4.31min; MS m/z (CI) [MH]+= 322; 1H NMR (500MHz, CDCl3) delta 3.86 (s, 3H), 4.33- 4.37 (m, 2H), 4.38-4.43 (m, 2H), 6.67 (d, J=10.1Hz, 1H), 6.87-6.90 (m, 2H), 6.95-6.99 (m, 3H), 7.25-7.30 (m, 2H), 7.32-7.35 (m, 2H), 7.59-7.62 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; | General procedure: The mixture of phenol (700 mg, 3.78 mmol), beta-bromophenetole (836 mg, 4.16 mmol) and cesium carbonate (1.838 mg, 5.67 mmol) in DMF (8 mL) was stirred overnight at 50° C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and purified by recrystallization or flash chromatography. The compound 25b was prepared by using the general procedure H, as given in Example 9, starting from compound 25a as pale yellow solid in 80percent yield. 1H NMR (400 MHz, CDCl3) delta 7.86 (d, J=2.3 Hz, 1H), 7.77-7.66 (m, 2H), 7.33-7.26 (m, 2H), 7.00-6.93 (m, 3H), 4.49 (dd, J=5.6, 3.5 Hz, 2H), 4.41 (dd, J=6.0, 3.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) delta 158.37, 133.68, 129.55, 121.38, 120.28, 116.91, 114.73, 108.08, 68.58, 66.18. HRMS (ESI) calculated for C14H12BrNO4 [M+H]+: 359.9842. Found: 359.9855. |
50% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 24h; | To a solution of <strong>[52427-05-1]2-bromo-5-nitrophenol</strong> (9g, 0.041 28 mol) in anhydrous DMF (90 mL) at room temperature was added sodium hydride (1.82 g, 0.0454 mol). After stirring the resulting solution for 10 min, (2-bromoethoxy)benzene (9.96g, 0.04954 mol) was added slowly. The reaction was then stirred for 24 h and then quenched with water and diluted with DCM (150 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization from ethyl acetate to afford the title compound (6.95 g, 50percent yield). 1H NMR (399 MHz, DMSO) delta 7.94 (s, 1H), 7.87 (d, J=8.1Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.29 (t, J=6.8 Hz, 2H), 6.99 (d, J=7.6 Hz, 2H), 6.95 (s, 1H), 4.57 (s, 2H), 4.37 (s, 2H). 13C NMR (100 MHz, DMSO) delta 158.22, 155.20, 147.77, 133.77, 129.54, 120.87, 119.20, 116.83, 114.56, 108.28, 68.56, 66.10. HRMS (ESI) calcd for C14H12BrNO4 [M+Na]+ 359.9842; found 359.9855. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Alternate synthesis: l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Sodium hydride (60percent>, 6.3 g, 1.0 eq) was added to a solution of lH-pyrazole-4- carbaldehyde (15 g, 156 mmol) in DMF (150 ml) at 0°C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using a hexane/EtOAc gradient (10: 1 to 0: 100). Pure fractions were combined and evaporated under reduced pressure to yield l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (24 g, 71percent). | |
71% | Sodium hydride (60percent, 6.3 g, 1.0 eq) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (15 g, 156 mmol) in DMF (150 ml) at 0° C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a hexane/ EtOAc gradient (10:1 to 0:100). Pure fractions were combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (24 g, 71percent). |