p-Nitrophenyl and cholesteryl-N-alkyl carbamates as inhibitors of cholesterol esterase.

Hosie, L; Sutton, Larry D.; Quinn, Daniel M.

doi:10.1016/s0021-9258(19)75920-1

Cited by 98 publications

(33 citation statements)

References 18 publications

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“…The values of K C and k 3 can be quantified applying the method described by Hosie et al and Feaster et al Following this approach, the carbamate-mediated inhibition described in Figure is known to undergo apparent first order kinetics: in which A is the activity of the enzyme at a specific time t , A 0 the activity at t = 0, A ∞ the activity at t = ∞ and k obs represents the apparent first order rate constant. Plotting of k obs against the inhibitor concentration [PC] yields a hyperbolic curve described by Rearrangement of eq into a double reciprocal form with 1/ k obs as a function of 1/[PC] results in a linear plot: in which k 3 can be determined from the y -intercept and K C from the slope.…”

Section: Resultsmentioning

confidence: 99%

“…The constant k 3 represents the carbamolyation rate of the inhibitor from the reversible complex (EPC) to the carbamoylated enzyme E−C. The last step is the recovery of the enzyme through slow hydrolysis of E−C and The values of K C and k 3 can be quantified applying the method described by Hosie et al 62 and Feaster et al 63 Following this approach, the carbamate-mediated inhibition described in Figure 3 is known to undergo apparent first order kinetics:…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode

et al. 2016

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Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds with the 2-thiophenyl compound 2p as the most potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety onto the active site under release of the phenolic tetrahydroquinazoline scaffolds that themselves act as neuroprotectants. By combination of kinetic data with molecular docking studies, a plausible binding model was probed describing how the tetrahydroquinazoline scaffold guides the carbamate into a close position to the active site. The model explains the influence of the carrier scaffold onto the affinity of an inhibitor just before carbamate transfer. This strategy can be used to utilize the binding mode of other carbamate-based inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode

et al. 2016

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“…Most of the esterase enzymes are typically serine-protease and have an almost similar enzymatic pocket for biodegradation of aliphatic ester units. To study the role of enzyme–inhibitor on the FRET process, 4-nitrophenyl carbamate derivative was chosen because it has been explored in the past as an inhibitor for hydrolysis caused by porcine pancreatic cholesterol esterase enzyme. , For this purpose, 4-nitrophenyl-N-octyl carbamate was synthesized following reported procedure (see Figure S15) and employed as an inhibitor to study its effect on FRET phenomena. The substrate (P CUR+NR ) and the enzyme (horse liver esterase enzyme) and the inhibitor (p-nitrophenyl-N-octyl carbamate) were incubated together, and their FRET emission was monitored (see Figure e).…”

Section: Resultsmentioning

confidence: 99%

Enzyme-Responsive Theranostic FRET Probe Based on l-Aspartic Amphiphilic Polyester Nanoassemblies for Intracellular Bioimaging in Cancer Cells

Saxena

Pradeep

Jayakannan

2019

ACS Appl. Bio Mater.

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The present study reports one of the first attempts on the design and development of an enzymatic-biodegradable theranostic fluorescence resonance energy transfer (FRET) probe constructed on l-amino acid polymer nanoassemblies and demonstrates the proof-of-concept in live cell bioimaging. l-Aspartic acid was converted into amide or carbamate pendants containing bis-carboxylic acid ester monomers, and they were subjected to melt polymerization along with commercial diols to produce amphiphilic aliphatic polyesters. Nanoparticles of size <200 nm were obtained because of self-assembly of these amphiphilic polyesters in an aqueous medium. These nanoparticles exhibited excellent encapsulation capability for green-fluorescent anti-inflammatory drug curcumin (CUR) and highly luminescent red-fluorophore Nile red (NR) to yield a CUR-NR theranostic FRET probe. Detailed photophysical studies were carried out to demonstrate photoexcitation energy transfer from CUR to NR for the occurrence of the FRET phenomena. The theranostic FRET probe was found to be very stable at extracellular environment and underwent biodegradation at the intracellular regions for delivery of the loaded cargoes. As a result, the theranostic FRET probe functioned as turn-on at the extracellular level and became turn-off at the intracellular level under lysosomal enzyme-responsiveness. The polymer nanoparticle was nontoxic to cells, whereas its CUR encapsulated nanoparticle showed relatively good cytotoxicity in breast cancer cell lines. Live cell confocal microscopy studies using lysotracker staining confirmed the colocalization of CUR as well as NR within the polymer nanoparticles in the lysosomes for enzymatic-biodegradation. Selective photoexcitation experiments in the confocal microscope were carried out to study the FRET probe action in cancer cells. Time-dependent FRET imaging directly supported the occurrence of FRET at the intracellular level and enabled the real-time drug release studies. The present approach opens natural resource-based biodegradable theranostic FRET probes for bioimaging application.

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“…Structure-activity correlations. The inhibitory activity of 2a-2e and 1a-1e against CEase was investigated according to Hosie et al 21 with some modifications and the results are summarized in Table 3. Compared with phosphaisocoumarins A, B (Table 3) and other known CEase inhibitors (Fig.…”

Section: Biologymentioning

confidence: 99%

“…CEase (porcine) was from Worthington, p-nitrophenyl butyrate (pNPB) was from Sigma. The CEase inhibition was assayed according to Hosie et al 21 with some modifications. CEase activity was measured by following the hydrolysis of the colorimetric substrate pNPB.…”

Section: Assay Procedures and Determination Of Inhibitor Ic 50mentioning

confidence: 99%

A new synthesis of fully phosphorylated flavones as potent pancreatic cholesterol esterase inhibitors

Peng

Wei

et al. 2011

Org. Biomol. Chem.

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Five flavones possessing one to four phenolic groups were fully phosphorylated efficiently and the obtained compounds showed excellent pancreatic cholesterol esterase (CEase) inhibitory activities with IC(50) in the nanomolar range, which were much more potent than their parent compounds. The inhibition mechanism and kinetic characterization studies indicate that they are irreversible competitive inhibitors.

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p-Nitrophenyl and cholesteryl-N-alkyl carbamates as inhibitors of cholesterol esterase.

Cited by 98 publications

References 18 publications

Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode

Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode

Enzyme-Responsive Theranostic FRET Probe Based on l-Aspartic Amphiphilic Polyester Nanoassemblies for Intracellular Bioimaging in Cancer Cells

A new synthesis of fully phosphorylated flavones as potent pancreatic cholesterol esterase inhibitors

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