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Ingraham, Charles H. IV ; Stalinska, Joanna ; Carson, Sean C. , et al. SCI REP-UK,2023,13(1):12236. DOI: 10.1038/s41598-023-39236-w PubMed ID: 37507404
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Abstract: Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (- logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24 μM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7 ± 0.5 μM, which exceeds its glioblastoma IC50 (1.17 μM) by over threefold.
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CAS No. : | 42017-89-0 | MDL No. : | MFCD00792461 |
Formula : | C17H15ClO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MQOBSOSZFYZQOK-UHFFFAOYSA-N |
M.W : | 318.75 | Pubchem ID : | 64929 |
Synonyms : |
NSC 281318; FNF Acid
|
Chemical Name : | 2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropanoic acid |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 magneticnanosolidsuperacid; In cyclohexane; water; at 83 - 85℃; | In the ring with a water separator, reflux condenser, thermometer, 250 mL reaction flask fenofibrate (I) (20.0 g, 0.063 mol),isopropanol (28.0 g, 0.467 mol),with aqua cyclonexane 10 mL of hexane and magnetic nano solid superacid SO 4 / Fe 3 O 4 -Al 2 O3 -ZrO 2 -Nd 2 O 3 0.36 g, warmed to 83-85 C reflux, TLC monitoring of the reaction . After completion of the reaction, thecatalyst was separated magnetically, recovery of the catalyst. The reaction solution was cooled to 0-10 C, stirred crystallization, filtration, the filter cake rinsed with isopropanol and dried to give a white solid 22.1 g, yield 97.0%. Products byNMR, MS, IR and their structures were confirmed for our target product. |
96.6% | EXAMPLE; In a dual-jacket reactor of 250 mL (reactor A), 60 g of <strong>[42017-89-0]fenofibric acid</strong> (1 eq.; 0.188 moles) are introduced and 120 mL of isopropanol (2 volumes). The reaction mixture is heated with reflux. The reaction mixture is heterogeneous. To this suspension, are added 29.11 g of thionyl chloride (1.3 eq.; 0.245 moles) over 3 hours. The reaction mixture is homogenized while adding thionyl chloride in order to obtain a yellow solution. At the end of the addition, the reaction medium is maintained under reflux for about 4 hours (the reaction kinetics are followed by HPLC).In a reactor B, 28.58 g of K2CO3 (1.1 eq.; 0.21 mole) are introduced and 120 mL of water (2 volumes). The mixture is heated to 60-65 C.The contents of reactor A are hot-poured into the reactor B within about 1 hour. The reactor A is rinsed with 15 mL of isopropanol which are transferred to reactor B. The mixture is stirred for a minimum of 5 minutes. Stirring is stopped and the mixture is left to decant. The lower aqueous phase is removed. 134 mL of water are added to the alcoholic phase, while maintaining the temperature of the reaction mass at 60-65 C. The reaction mass is cooled to 50 C. and initiated with a few mg of fenofibrate. The mixture is maintained for about 30 minutes at 50 C. The medium crystallizes. The temperature is lowered to 0-5 C. within 2 hours and then maintained for a minimum of 30 minutes at this temperature (0-5 C.). The mixture is filtered. The cake is washed three times with 70 mL of water. It is dried for one night at 60 C. in a ventilated oven. 65.61 g of dry product are thereby obtained (yield=96.6%).Analytical results:HPLC (area %)Fenofibrate=99.98%<strong>[42017-89-0]Fenofibric acid</strong>=0.02%. | |
92.4% | With macroporous strong acid cation exchange resin D001; In water; toluene; at 110℃; | The <strong>[42017-89-0]Fenofibric acid</strong> is obtained by condensation, acidification and purification of 4-hydroxy-4-chlorobenzophenone with acetone and chloroform under the conditions of sodium hydroxide as a catalyst. <strong>[42017-89-0]Fenofibric acid</strong> (63.75 g, 0.2 mol) was added to a 500 ml flask. Isopropyl alcohol 69ml and water with toluene 100ml, After stirring and heating, after the reaction liquid reaches the specified temperature, the initial acid value of the reaction liquid is sampled and measured. At the same time, 10 g of the catalyst was added to the four-necked flask, and the timing was started, and the acid value was measured at regular intervals. In a boiling state, the water formed by the reaction is azeotropically distilled off with toluene.The aqueous phase was separated in a water separator and toluene was refluxed.As the reaction progresses, the temperature of the reaction solution gradually increases, and the temperature of the reaction solution is controlled to be within 110 C. After the reaction for a certain period of time, the reaction is stopped. The reaction solution was cooled, filtered, and neutralized with a mass concentration of 3% to 4% sodium hydroxide solution to pH = 7 to 8, and allowed to stand for stratification. The upper layer is dried with an appropriate amount of anhydrous sodium sulfate until clarification, and the clear liquid is taken. The toluene with water is distilled off under normal pressure and then under reduced pressure, and the distilled toluene is recycled. The material was cooled to 50 C, dissolved in isopropanol, cooled, filtered, and dried to obtain a yellowish crystalline powder, which was purified with isopropyl alcohol.A white solid of 66.69 g was obtained, and the esterification yield was 92.4% (based on fenofibrate acid), and the content was 99.9%. |
87.70% | With sulfuric acid; In toluene; at 110℃;Green chemistry; | A four-necked flask, each of which has an electric stirring bar, a thermometer, a third port with a reflux condenser and a water separator, and a fourth port for feeding; To the four-necked flask was added 60 g of toluene, 18 g of isopropyl alcohol and 6 g of concentrated sulfuric acid. Then, 60 g of <strong>[42017-89-0]fenofibric acid</strong> was added with stirring, and the mixture was stirred at 400r to 500r / min using an electric stir bar, 110 C heated to reflux, so that the reaction of water from the water separator, toluene, a small amount of water and isopropyl alcohol through the reflux condenser flow back to the four-necked flask, when the reaction to the water and then enter the water separator to stop heating Stirring, the esterification reaction after leaving the liquid with 60 ~ 70 hot water washing, so that impurities and liquid layer, to retain the upper layer of material and toluene mixture, remove the lower water and impurities, and then to the liquid And the unreacted fenofibrate acid was neutralized by stirring, the alkali aqueous layer and the feed liquid were separated, and the alkali layer was neutralized with hydrochloric acid to pH = 3 to 4, Norbert acid, dried as raw material recovery; separation of alkaline water after the liquid with 60 ~ 70 hot water washing, so that impurities and liquid layer, the upper material and toluene mixed organic phase, the lower layer of NaOH The organic phase was separated and the organic phase was separated. The separated organic phase was placed in a three-necked flask equipped with a stir bar, a thermometer and a ball-type condensing tube, respectively, and subjected to atmospheric distillation to remove water and partially toluene , When the temperature rose to 115 after the relative vacuum to maintain the -0.08 ~ -0.1MPa, under vacuum distillation in addition to toluene; cooling to 60 , adding 150g isopropyl alcohol, 1g of medicinal activated carbon, heated to reflux 30min after the heat Filtration, cooling to 15 C, to obtain white-like fenofibrate, the product yield of 87.70%, prepared fenofibrate melting point of 79.4 ~ 80.3 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | A mixture of 4-chloro-4'-hydroxybezophenone (116 g, 0.500 mole) and sodium hydroxide (120 g, 3.00 mole) in acetone (1 L) was heated to reflux for 2 hours. The heating was stopped and the heating source was removed. A mixture of chloroform (179 g, 1.50 mole) in acetone (300 mL) was added drop-wise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and was acidified (to pH=l) with IN hydrochloric acid. The precipitate, which formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL toluene each). After filtration and drying under high vacuum, the experiment produced fenofibric acid (116 g, 73% yield) as a light yellow solid. 'H NMR (300 MHz, DMSO-d6): 6 = 13.22 (1H, s, br), 7.72 (4H, d, J= 8.4 Hz), 7.61 (2H, d, J= 7. 8 Hz), 6.93 (2H, d, J= 7. 8 Hz), 1.60 (6H, s). "C NMR (75 MHz, DMSO-d6) : 5 = 192.96, 174.18, 159.35, 136.84, 136.12, 131.67, 131.02, 129.12, 128. 43, 116. 91,78. 87,25. 13. | |
With sodium hydroxide; | The Fenofibric acid is obtained by condensation, acidification and purification of 4-hydroxy-4-chlorobenzophenone with acetone and chloroform under the conditions of sodium hydroxide as a catalyst. Fenofibric acid (63.75 g, 0.2 mol) was added to a 500 ml flask. Isopropyl alcohol 69ml and water with toluene 100ml, After stirring and heating, after the reaction liquid reaches the specified temperature, the initial acid value of the reaction liquid is sampled and measured. At the same time, 10 g of the catalyst was added to the four-necked flask, and the timing was started, and the acid value was measured at regular intervals. In a boiling state, the water formed by the reaction is azeotropically distilled off with toluene.The aqueous phase was separated in a water separator and toluene was refluxed.As the reaction progresses, the temperature of the reaction solution gradually increases, and the temperature of the reaction solution is controlled to be within 110 C. After the reaction for a certain period of time, the reaction is stopped. The reaction solution was cooled, filtered, and neutralized with a mass concentration of 3% to 4% sodium hydroxide solution to pH = 7 to 8, and allowed to stand for stratification. The upper layer is dried with an appropriate amount of anhydrous sodium sulfate until clarification, and the clear liquid is taken. The toluene with water is distilled off under normal pressure and then under reduced pressure, and the distilled toluene is recycled. The material was cooled to 50 C, dissolved in isopropanol, cooled, filtered, and dried to obtain a yellowish crystalline powder, which was purified with isopropyl alcohol.A white solid of 66.69 g was obtained, and the esterification yield was 92.4% (based on fenofibrate acid), and the content was 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h; | 31.8 g of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid was dissolved in 200 mL of dichloromethane, 1 mL of N,N-dimethylformamide was added and stirred, and 19.0 g of oxalyl chloride was added dropwise thereto at 0 C. The reaction was carried out at room temperature for 3 hours. The methylene chloride was removed to give 30.8 g of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionyl chloride in a yield of 91.4%. |
83.2% | With thionyl chloride; In Petroleum ether; benzene; | (a) 2-[4-(4-Chlorobenzoyl)-phenoxy]-2-methylpropionyl chloride 18.6 ml (0.25 mol) of thionyl chloride are added to a solution of 31.85 g (0.10 mol) of <strong>[42017-89-0]2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropionic acid</strong> in 100 ml of anhydrous benzene and the mixture is then heated under reflux for 1 hour 30 minutes. After cooling, the solvent and the excess chlorinating agent are driven off under reduced pressure. The residual chestnut-coloured crystalline mass is taken up in petroleum ether. After filtering, washing and drying, 28 g of the expected acid chloride are obtained, in the form of a beige powder. Instanteous melting point (Kofler) = 80-81 C. Yield = 83.2%. |
A473645[ 856676-23-8 ]
2-Hydroxy-N,N,N-trimethylethanaminium 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate
Reason: Free-salt