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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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Surveying the scope of aromatic decarboxylations catalyzed by prenylated-flavin dependent enzymes
Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh
Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.
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Purchased from AmBeed: 27916-43-4 ; 2438-05-3 ; 501-89-3 ; 42287-94-5 ; 776-79-4 ; 53473-36-2 ; 7251-61-8 ; 42287-97-8 ; 1621-91-6 ; 37718-11-9 ; 288-13-1 ; 86-73-7 ; 104-53-0 ; 2018-90-8 ; 87-66-1 ; 135-19-3 ; 1664-57-9 ; 289-80-5 ; 693-95-8 ; 55-22-1 ; 102-93-2 ; 1477-50-5 ; 1632-76-4 ; 4780-79-4 ; 16642-79-8 ; 3581-89-3 ; 501-97-3 ; 771-50-6 ; 98-98-6 ; 619-64-7 ; 100-51-6 ; 402-45-9 ; 59-67-6 ; 93-60-7 ; 273-53-0 ; 2084-13-1 ; 51-17-2 ; 2459-09-8 ; 2459-07-6 ; 95-16-9 ; 459-31-4 ; 90-05-1 ; 150-76-5 ; 103-25-3 ; 271-44-3 ; 6293-56-7 ; 2550-26-7 ; 288-32-4 ; 501-52-0 ; 2001-32-3 ; 1592-38-7 ; 95-15-8 ; 91-19-0 ; 1122-61-8 ; 3724-19-4 ; 20173-24-4 ; 118-31-0 ; 6125-24-2 ; 60-12-8 ; 90-15-3 ; 120-72-9 ; 822-36-6 ; 288-47-1 ; 288-42-6 ; 2038-57-5 ; 38628-51-2 ; 1929-29-9 ; 15009-91-3 ; 1505-50-6 ; 581-40-8 ; 616-47-7 ; 1571-33-1
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La Rosa, Chris ; Sharma, Pankaj ; Dar, M Junaid ; Jin, Yiru ; Qin, Lingli ; Roy, Anuradha , et al.
Abstract: CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and CYP51 from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of CYP51 but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of CYP51. Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC50 values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over CYP51 that inhibited both enzymes with IC50 values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of CYP51 and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.
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CAS No. : | 6293-56-7 |
Formula : | C7H9NO |
M.W : | 123.15 |
SMILES Code : | OCCC1=CC=CN=C1 |
MDL No. : | MFCD00831047 |
InChI Key : | YPWSASPSYAWQRK-UHFFFAOYSA-N |
Pubchem ID : | 80515 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
51% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h; | To a solution of <strong>[39998-25-9]methyl 2-(pyridin-3-yl)acetate</strong> (15.1 g, 100 mmol, 1 equiv) in anhydrous THF (180 mL) was added LiAlH4 (4.l8 g, 110 mmol, 1.1 equiv) in portions at 0C. The reaction mixture was stirred at 0C for 1 hour. Then the reaction was quenched carefully with 10% NaOH (aq.), filtered, and extracted with DCM (3 * 150 mL). The combined organic phase were washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the title compound 2-(pyri din-3 -yl)ethanol as a yellow oil (6.1 g, 51% yield). LC-MS: m/z 124.1 (M+H)+ |
Into a 500-mL flask to which a nitrogen gas introduction tube, thermometer, and Dimroth condenser had been attached were introduced 21.29 g (0.141 mol) of the <strong>[39998-25-9]methyl 3-pyridylacetate</strong> obtained above and 250 mL of anhydrous methanol. The contents were stirred at room temperature. The atmosphere in the flask was replaced with nitrogen, and 15.62 g (0.372 mol) of sodium borohydride was added to the contents little by little. The resultant mixture was heated and reacted for further 3.5 hours with refluxing. Thereafter, the liquid reaction mixture was cooled to room temperature, and 100 mL of water was added thereto to hydrolyze the excess sodium borohydride remaining unreacted. The methanol was distilled away under vacuum. Thereafter, an extraction operation using 100 mL of chloroform was conducted twice, and the resultant organic phase was washed with 100 mL of saturated aqueous sodium chloride solution and dried by adding anhydrous sodium sulfate thereto. The anhydrous sodium sulfate was removed by decantation. Thereafter, vacuum distillation was conducted to obtain 12.59 g (0.102 mol) of 3-pyridylethanol. |
Tags: 3-(2-hydroxyethyl)pyridine | Pyridines | Alcohols | Organic Building Blocks | Heterocyclic Building Blocks | 6293-56-7
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