Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Compound 1 was previously reported to be a potent inhibitor of cPLA(2)alpha in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC(50) of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-gamma-linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA(2)alpha inhibition. The IC(50)s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA(2)alpha and represent well-validated starting points for further optimization.
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PMID:Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization. 1639 99

Triplet-excited riboflavin ((3)RF*) was found by laser flash photolysis to be quenched by polyunsaturated fatty acid methyl esters in tert-butanol/water (7:3, v/v) in a second-order reaction with k approximately 3.0 x 10(5) L mol(-1) s(-1) at 25 degrees C for methyl linoleate and 3.1 x 10(6) L mol(-1) s(-1), with DeltaH(double dagger) = 22.6 kJ mol(-1) and DeltaS(double dagger) = -62.3 J K(-1) mol(-1), for methyl linolenate in acetonitrile/water (8:2, v/v). For methyl oleate, k was <10(4) L mol(-1) s(-1). For comparison, beta-casein was found to have a rate constant k approximately 4.9 x 10(8) L mol(-1) s(-1). Singlet-excited flavin was not quenched by the esters as evidenced by insensitivity of steady-state fluorescence to their presence. Density functional theory (DFT) calculations showed that electron transfer from unsaturated fatty acid esters to triplet-excited flavins is endergonic, while a formal hydrogen atom transfer is exergonic (DeltaG(o)(HAT) = -114.3, -151.2, and -151.2 kJ mol(-1) for oleate, linoleate, and linolenate, respectively, in acetonitrile). The reaction is driven by acidity of the lipid cation radical for which a pK(a) approximately -0.12 was estimated by DFT calculations. Absence of electrochemical activity in acetonitrile during cyclic voltammetry up to 2.0 V versus NHE confirmed that DeltaG(o)(ET) > 0 for electron transfer. Interaction of methyl esters with (3)RF* is considered as initiation of the radical chain, which is subsequently propagated by combination reactions with residual oxygen. In this respect, carbon-centered and alkoxyl radicals were detected using the spin trapping technique in combination with electron paramagnetic resonance spectroscopy. Moreover, quenching of (3)RF* yields, directly or indirectly, radical species which are capable of initiating oxidation in unsaturated fatty acid methyl esters. Still, deactivation of triplet-excited flavins by lipid derivatives was slower than by proteins (factor up to 10(4)), which react preferentially by electron transfer. Depending on the reaction environment in biological systems (including food), protein radicals are expected to interfere in the mechanism of light-induced lipid oxidation.
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PMID:Light-induced oxidation of unsaturated lipids as sensitized by flavins. 2037 18

The elusive neutral bicarbonate radical and the carbonate radical anion form an acid/conjugate base pair. We now report experimental studies for a model of bicarbonate radical, namely, methyl carbonate (methoxycarbonyloxyl) radical, complemented by DFT computations at the CAM-B3LYP level applied to the bicarbonate radical itself. Methyl carbonate radicals were generated by UV irradiation of oxime carbonate precursors. Kinetic EPR was employed to measure rate constants and Arrhenius parameters for their dissociation to CO2 and methoxyl radicals. With oleate and cholesterol lipid components, methyl carbonate radicals preferentially added to their double bonds; with linoleate and linolenate substrates, abstraction of the bis-allylic H atoms competed with addition. This contrasts with the behavior of ROS such as hydroxyl radicals that selectively abstract allylic and/or bis-allylic H atoms. The thermodynamic and activation parameters for bicarbonate radical dissociation, obtained from DFT computations, predicted it would indeed have substantial lifetime in gas and nonpolar solvents. The acidity of bicarbonate radicals was also examined by DFT methods. A noteworthy linear relationship was discovered between the known pKa's of strong acids and the computed numbers of microsolvating water molecules needed to bring about their ionization. DFT computations with bicarbonate radicals, solvated with up to eight water molecules, predicted that only five water molecules were needed to bring about its complete ionization. On comparing with the correlation, this indicated a pKa of about -2 units. This marks the bicarbonate radical as the strongest known carboxylic acid.
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PMID:Bicarbonate and Alkyl Carbonate Radicals: Structural Integrity and Reactions with Lipid Components. 2662 82