Abstract: The Aster proteins (encoded by the Gramd1a-c genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small mol. modulators of Asters, we identified 20α-hydroxycholesterol (HC) and U18666A as lead compounds Unfortunately, both 20α-HC and U18666A target other sterol homeostatic proteins, limiting their utility. 20α-HC inhibits sterol regulatory element-binding protein 2 (SREBP2) processing, and U18666A is an inhibitor of the vesicular trafficking protein Niemann-Pick C1 (NPC1). To develop potent and selective Aster inhibitors, we synthesized a series of compounds by modifying 20α-HC and U18666A. Among these, AI (Aster inhibitor)-1l, which has a longer side chain than 20α-HC, selectively bound to Aster-C. The crystal structure of Aster-C in complex with AI-1l suggests that sequence and flexibility differences in the loop that gates the binding cavity may account for the ligand specificity for Aster C. We further identified the U18666A analog AI-3d as a potent inhibitor of all three Aster proteins. AI-3d blocks the ability of Asters to bind and transfer cholesterol in vitro and in cells. Importantly, AI-3d also inhibits the movement of low-d. lipoprotein (LDL) cholesterol to the ER, although AI-3d does not block NPC1. This finding positions the nonvesicular Aster pathway downstream of NPC1-dependent vesicular transport in the movement of LDL cholesterol to the ER. Selective Aster inhibitors represent useful chem. tools to distinguish vesicular and nonvesicular sterol transport mechanisms in mammalian cells.
Keywords:
cholesterol ; lipid metabolism ; lipid transport
* 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.
Reference：
[1] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 8, p. 2805 - 2809
2
[ 626-40-4 ]
[ 56-81-5 ]
[ 34522-69-5 ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: at 120℃; Stage #2: at 130℃;
Step 1: A 100 mL flask was charged with 3,5-dibromoaniline (5.00 g, 19.9 mmol), sodium 3-nitrobenzenesulfonate (987 mg, 4.39 mmol), iron(ll)sulfate heptahydrate (63.2 mg, 0.658 mmol), and methanesulfonic acid (20 mL). A reflux condenser was added, and the reaction was heated in a 120 °C aluminum block.Glycerol (0.64 mL, 8.8 mmol) was added through the condenser, and the aluminum block temperature was then increased to 130 °C. Heating was continued overnight. After cooling to rt, the reaction mixture was diluted with DCM and water, cooled in an ice/water bath, and rendered alkaline by addition of a 50percent aqueous solution of NaOH. The resulting mixture was filtered over Celite® and extracted with DCM. The organicphase was dried over Na2SO4 and concentrated to a brown solid. Purification by chromatography (80 g Si gel, 0—40percent EtOAc in heptane gradient over 17 CV and then held at 40percent) afforded 5,7-dibromoquinoline as a tan solid (3.19 g, 56percent). 1H NMR (400 MHz, CDCI3) O 7.53 (dd, 1 H), 7.96 (d, 1 H), 8.29 (d, 1 H), 8.50 (d, 1 H), 8.93 (dd, 1 H). LCMS (ESI) m/z: 285.9 [M+H] (95percent). LCMS data were acquired from the reactionmixture immediately prior to workup.
Reference：
[1] Green Chemistry, 2017, vol. 19, # 2, p. 390 - 396
12
[ 334-48-5 ]
[ 56-81-5 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 17863-69-3 ]
[ 17598-93-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1999, vol. 76, # 7, p. 839 - 843
13
[ 334-48-5 ]
[ 56-81-5 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 17598-93-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1996, vol. 73, # 11, p. 1521 - 1525
[2] JAOCS, Journal of the American Oil Chemists' Society, 2014, vol. 91, # 2, p. 261 - 270
14
[ 110-38-3 ]
[ 56-81-5 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 3376-48-5 ]
[ 17863-69-3 ]
[ 17598-93-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1996, vol. 73, # 11, p. 1489 - 1495
15
[ 20776-50-5 ]
[ 56-81-5 ]
[ 928839-62-7 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8217 - 8231
16
[ 6933-10-4 ]
[ 56-81-5 ]
[ 122759-89-1 ]
Yield
Reaction Conditions
Operation in experiment
25%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 120 - 130℃; for 1.5 h;
The raw materials 3,5-difluoroaniline G-1 (5.6 g, 27 mmol) and sodium 3-nitrobenzenesulfonate (7.2 g, 32 mmol) Was added to a mixed solution of concentrated sulfuric acid (15 mL) and water (6 mL) After heating to an internal temperature of 120 ° C, glycerol (7.4 g, 80 mmol) After the addition was completed, the temperature was raised to 130 ° C and reacted for 1.5h, then cooled. The reaction was poured into crushed ice, concentrated ammonia water to adjust the pH to 5 ~ 6, the precipitated solid was filtered off, washed with water, After drying, column chromatography gave 3.82 g of white solid compound G-2 in 58percent yield. A mixture of 6-bromo-7-methylquinoline (I-2) and 6-bromo-5-methylquinoline (J-1) was synthesized. Then separated by supercritical preparative chromatography (SFC), IC-H column, mobile phase: isopropanol / carbon dioxide = 18/82, detection wavelength: 254nm. The first fraction was collected as 6-bromo-7-methylquinoline (I-2) as a white solid, yield: 25percent. The second fraction was collected as a 6-bromo-5-methylquinoline (J-1) white solid in a yield of 20percent
Reference：
[1] Patent: CN105968115, 2016, A, . Location in patent: Paragraph 0492; 0518-0520
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4281 - 4290
17
[ 6933-10-4 ]
[ 56-81-5 ]
[ 122759-89-1 ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: With iron(III) sulfate; sulfuric acid In nitrobenzene for 3 h; Heating / reflux Stage #2: With water; sodium hydrogencarbonate In nitrobenzene
Intermediate 4: 6-Bromo-7-methyl-quinoline; [0304] A mixture of 4-bromo-3-methylaniline (20 g, 107.5 mmol), ferric sulfate (6.6 g, 43.4 mmol), glycerol (40.8 g, 440 mmol), nitrobenzene (8.12 g, 66 mmol), and concentrated EPO <DP n="81"/>sulfuric acid (23 ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 3h and then evaporated to remove the excess nitrobenzene. The solution was added a saturated aqueous solution of sodium bicarbonate until pH=7-8, then the solution was filtered and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The solid was purified by flash column chromatography to give a yellow solid, which was further washed with petroleum ether to give 7.5 g of 6-bromo-7-methyl-quinoline (31percent yield): 1H NMR (CDCl3): 2.60 (s, 3H), 7.36 (m, IH), 7.96 (s, IH), 8.04 (m, 2H), 8.89 (m, IH).
Stage #1: at 120℃; for 4 h; Stage #2: With water; sodium hydroxide In ethanol; ethyl acetate; nitrobenzene at 20℃;
To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0g, 12.6mmol), glycerol (4.64g, 50.0mmol), and ferrous sulfate (0.56 g, 2.0mmol) was added cone, sulfuric acid (2.2mL) dropwise. The reaction mixture was heated at 120 0C for 4hr. After cooled to RT, the reaction was diluted with ethyl acetate (15OmL), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over Na2SO4 and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo- 8-(trifluoromethyl)quinoline (1.2g, 48percent).
Reference：
[1] Patent: WO2010/91310, 2010, A1, . Location in patent: Page/Page column 101
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5521 - 5527
With rabbit 3-hydroxyhexobarbital dehydrogenase (AKR1C29); NADPH; In aq. phosphate buffer; ethyl acetate; at 37℃; for 0.5h;pH 7.4;Enzymatic reaction;Catalytic behavior; Kinetics;
General procedure: The reaction was conducted at 37°C in a 2.0-mL reaction mixture, containing coenzyme (1-mM NADP+ or 0.1-mM NADPH), substrate (0.05?0.1mM), enzyme (0.1?0.3mg), and 0.1-M potassium phosphate, pH 7.4. The substrate and products were extracted into 4-mL ethyl acetate 30min after the reaction was started at 37°C. The products of oxidoreduction of steroids [25] and reduction of PGD2 [28], farnesal [29] and 4-oxo-2-nonenal [18] were analyzed by TLC, as described. The reduced products of TBE were identified by the HPLC methods [23]. The products of 3HB oxidation, 3OB reduction, 5beta-androstane-3alpha,17beta-diol oxidation and 5beta-androstan-3alpha-ol-17-one reduction were analyzed by the liquid chromatography?electrospray ionization-mass spectrometry (LC?ESI-MS) using a Hewlett-Packard HP 1100 Series LC/MSD system attached with a diode array detector and a column (Mightysil RP-18 GP 5mum, 4.6mm×250mm, Kanto Chemical Co., Tokyo, Japan). Separations were carried out at a flow rate of 0.5mL/min and 40°C using the following mobile phases: 25percent acetonitrile aqueous solution containing 0.1percent formic acid for 3OB and alpha/beta-3HBs, and 80percent acetonitrile aqueous solution containing 0.1percent formic acid for the two steroids. 3OB, alpha-3HB, beta-3HB, 5beta-androstan-3alpha-ol-17-one and 5beta-androstane-3alpha,17beta-diol were detected by monitoring their total ions (m/z 249.1, 251.1, 251.1, 289.4 and 291.4, respectively) in the negative ESI mode, and eluted at the retention times of 20.1, 17.6, 16.8, 14.9 and 12.7min, respectively. The detection limits of 3OB, alpha/beta-3HBs and the two steroids were 0.1, 0.1 and 1nmol, respectively.
platinum on carbon; In water; for 3h;Direct aqueous phase reforming;
Direct aqueous phase reforming (APR) experiments were conducted in 100-ml stirred reactors with draft-tube gas-induction impeller (Parr Series 4590). Reaction tests for direct bio-based feedstock aqueous phase reforming (APR) entailed filling the reactor with 60-grams of solvent (deionized water, or a mixture of DI water and isopropanol (IPA), and 3-3.5 grams of bio-based feedstock comprising biomass (bagasse, or pine sawdust)). One (1) gram of acetic acid was optionally charged to facilitate biomass hydrolysis.[0098] Bagasse was milled via a 1-mm grate. Dry, debarked Loblolly pine was ground via blender (Thomas Scientific of Swedesboro, NJ) and sieved to less than 30 mesh. Dry solids fraction was determined by vacuum drying at 80 °C to 82 °C. One gram of aqueous phase reforming catalyst (reduced 5percent Pt/C catalyst at 50percent moisture, or powdered 1.9percent Pt/A1203) was charged to the reactor, which was charged with 4200 kPa of hydrogen or nitrogen. To minimize degradation of hydrolysate to heavy ends, each reactor was typically heated with a staged temperature sequence of one hour at, 160 °C, 190 °C, 225 °C, and finally 250 °C, before leaving overnight at the final setpoint.[0099] Comparison tests were also conducted with glucose or sorbitol fed directly to the reaction in place of biomass, to simulate and quantify conversion of model hydrolysate to APR intermediates. Glucose is one of the sugars readily leached from biomass in hot water, while sorbitol is readily formed via hydrogenation of glucose, where platinum or other catalysts capable of hydrogenation are present.[00100] A batch reaction time of 20 hours under these conditions corresponds to a weight hourly space velocity (g-feed/g-catalyst/h) of about 3, for a comparable continuous flow reactor. A 0.5-micron sintered metal filter attached to a dip tube allowed liquid samples to be taken throughout the course of reaction, without loss of biomass or catalyst. Samples were analyzed by an HPLC method based on combined size and ion exclusionchromatography, to determine unreacted sorbitol, and amount of C3 and smaller polyols formed: glycerol (Gly), ethylene glycol (EG), and 1,2-propylene glycol (PG). Additional GC analysis via a moderate polarity DB-5 column were conducted to assess formation of C6 and lighter oxygenates (e.g., ketones, aldehydes, alcohols), as well as alkane and alkene products. A separate GC equipped with thermal conductivity and flame ionization (FID) detectors for refinery gas analysis, were used for detection of H2, C02, and light alkanes C1-C5. GC-mass spec was used to characterize select APR reaction product mixtures. Examples 1-3[00101] Batch APR reactions with sugar cane bagasse as biomass feed, and with a comparison of 25percent sorbitol as feed, were performed as described above. 1.7percent acetic acid was added to simulate catalysis of hydrolysis by recycle acid. Products formed from this concentration of acetic acid were subtracted from total product formation, to calculate the net production of liquid fuels from bagasse. This result shown in Table 1 shows the critical importance of concerted APR reaction with hydrolysis of biomass. In the absence of concerted aqueous phase reforming, the hydrolysate undergoes irreversible degradation (presumably to heavy ends), and cannot be reverted to liquid fuels upon subsequent APR and condensation. Converted reaction may be effected by direct inclusion of APR catalyst in the hydrolysis reactor, or via a pump around loop to recirculate liquid between a biomass contactor, and an APR catalytic reactor. Table 1: Direct APR of Biomass
In water; at 375℃; under 760.051 Torr; for 6h;Inert atmosphere; Flow reactor;
The dehydrocyclization activities of Zn?Cr?Ocatalysts calcined at different temperatures were performedat 375°C and atmospheric pressure in a fixedbedvertical quartz reactor (i.d = 8 mm, length =450 mm) placed in a two zone furnace operated in adown flow mode. In the first zone maintained at300°C the reaction mixture was preheated whereas inthe second zone containing the catalyst bed the reactortemperature was set at 375°C. Temperatures in theboth zones were monitored by a temperature controller-cum-programmer using a K-type thermocouple.Glycerol (Fluka) and EDA (SDFCL, India) wereused. Nitrogen (IOLAR-I grade, BOC, India) wasused as a carrier gas. The catalytic activities were measured using ?18/+23 sieved (BSS) particles. The carbonmass balance was done based on the inlet and outletconcentration of the organic moiety. Prior to thereaction, the calcined catalyst (about 0.2 g) wasreduced in a flow of 5percent H2 and 95percent Ar (30 mL min?1)at 400°C for 5 h. The catalytic activities were measuredunder strict kinetic control. An aqueous glycerol solution(20 wtpercent in H2O) was used with a glycerol to EDAmole ratio of 1 :1 , at a flow rate of 5 mL h?1 (10 mmolglycerol + 10 mmol EDA + 200 mmol H2O), alongwith N2 as a carrier gas at a flow rate of 1800 mL h?1.The feed mixture mole ratio is glycerol : EDA : H2O :N2= 1 : 1 : 20 : 8. The product mixture was analyzed bygas chromatograph (Shimadzu, GC-17A) via a flameionization detector (FID) using a ZB-5 capillary columnat a ramping rate of 10°C min?1 from 60 to280°C. The mass balance for all the measurements was>95percent. The samples were analyzed by GC-MS(QP5050A Shimadzu) using a ZB-5 capillary columnwith EI mode.
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; sodium 3-nitrobenzenesulfonate; In water; at 50 - 135℃;Cooling with ice; Reflux;
Ice bath under conditions of 250 mLOf the three bottles by adding concentrated H2SO441 g (22 mL),Stir by addingSodium nitrobenzene sulfonate17.5 g (78 mmol),Boric acid2.4 g (39 mmol),FeSO4 · 7H2O 1.4 g (5 mmol)Glycerol 12.5 mL,2-amino-6-methylpyridine (4.3 g, 40 mmol)Mixed evenly after adding 22.5mL 50 warm water,in135 ° CUnder reflux2-3h,After cooling; with 50percent NaOH solution transferred to alkaline, filter,The aqueous solution was extracted three times with chloroform and the organic layer was dried over anhydrous MgSO4,The solvent was removed by rotary distillation to give the crude product which was recrystallized from cyclohexane to give 2-methylnaphthyridine,Ie probe reagent;The concentrated sulfuric acid concentration is 95-98percent;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
