N,O-diacylhydroxylamines—structures in crystals and solutions

Schraml, Jan; Sýkora, Ján; Fiedler, Pavel; Roithová, Jana; Mindl, Jaromír; Blechta, Vratislav; Cı́sařová, Ivana; Exner, Otto

doi:10.1039/b403728f

Cited by 8 publications

(6 citation statements)

References 31 publications

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“…15 N NMR spectroscopy of 15 N-labelled 1 showed that this compound is an O-(rather than N-)acylated hydroxamate (11). This result is in accord with structural studies of similar O-acyl hydroxamates (22) and will be assumed to be true for all of the present compounds, as shown in the structural diagrams above. They are thus likely to be weak N-H acids (23).…”

Section: Resultssupporting

confidence: 90%

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Pelto

Pratt

2008

Biochemistry

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The class C serine β-lactamase of Enterobacter cloacae P99 is irreversibly inhibited by Oaryloxycarbonyl hydroxamates. A series of these new inhibitors has been prepared to investigate the kinetics and mechanism of the inactivation reaction. A pH-rate profile for the reaction indicated that the reactive form of the inhibitor is neutral rather than anionic. The reaction rate is enhanced by electron-withdrawing aryloxy substituents and by hydrophobic substitution on both aryloxy and hydroxamate groups. Kinetics studies show that the rates of loss of the two possible leaving groups, aryloxide and hydroxamate are essentially the same as the rate of enzyme inactivation. Nucleophilic trapping experiments prove, however, that the aryloxide is the first to leave. It is likely, therefore, that the rate-determining step of inactivation is the initial acylation reaction, most likely of the active site serine, yielding a hydroxamoyl-enzyme intermediate. This then partitions between hydrolysis and aminolysis by Lys 315, the latter to form an inactive, cross-linked active site. A previously described crystal structure of the inactivated enzyme shows a carbamate cross-link of Ser 64 and Lys 315. Structure-activity studies of the reported compounds suggest that they do not react at the enzyme active site in the same way as normal substrates. In particular, it appears that the initial acylation by these compounds does not involve the oxyanion hole, an unprecedented departure from known and presumed reactivity. Molecular modeling suggests that an alternative oxyanion hole may have been recruited, consisting of the side chain functional groups of Tyr 150 and Lys 315. Such an alternative mode of reaction may lead to the design of novel inhibitors.For decades now, β-lactams have been one of our most effective weapons against bacterial infections (1). These drugs, although still the first line of attack in many clinical situations, have been compromised to a considerable degree by bacterial resistance to them (2). Among various sources of resistance that have arisen in bacteria, the most generally troublesome is the production of β-lactamases. These enzymes very effectively catalyze the hydrolysis and thus destruction of β-lactams before they can reach their cellular targets (3).The threat posed by β-lactamases to the efficacy of β-lactam antibiotics has been tackled by pharmaceutical companies in several ways. One approach that has been quite successful to date is that of including a β-lactamase inhibitor with a β-lactam antibiotic in combination therapies. For many years now, such combinations, using the now-classical β-lactamase inhibitors clavulanic acid, sulbactam and tazobactam, have been used to advantage (4). Since these inhibitors are themselves β-lactams, however, it is perhaps not surprising to find that certain β-lactamase mutants are capable of hydrolyzing them quite effectively. Such mutants have †

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Section: Resultssupporting

confidence: 90%

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Pelto

Pratt

2008

Biochemistry

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“…was added dropwise and the reaction mixture stirred at room temperature for 16 h, diluted with ethyl acetate and washed with water and NaHCO 3 . The collected organic phases were dried with anhydrous MgSO 4 and evaporated under reduced pressure to afford the desired product as a white solid; yield: 759 mg (86%); mp 157–158 °C (reported: mp 154–157 °C);40 1 H NMR (300 MHz, DMSO): δ =12.67 (bs, 1 H), 8.16–8.09 (m, 2 H), 7.92–7.89 (m, 2 H), 7.79–7.71 (t, J =7.5 Hz, 1 H), 7.64–7.53 (m, 5 H); 13 C NMR (75 MHz, DMSO,): δ =164.87, 164.37, 134.35, 132.34, 130.95, 129.48, 129.13, 128.68, 127.40, 126.88; ESI‐MS: m/z =242 (M + +1).…”

Section: Methodsmentioning

confidence: 99%

Lossen Rearrangements under Heck Reaction Conditions

et al. 2014

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The classical Lossen rearrangement converts activated hydroxamic acids to isocyanates that form numerous products upon their reaction with nucleophiles. We report a simple and highly efficient method of using Heck reaction conditions to initiate Lossen rearrangements of hydroxamic acids. In addition, Lossen rearrangements occur in the presence of palladium(II) acetate or triethylamine, components of the Heck reaction, alone. A potential mechanism is provided to explain this reactivity and these results show that Heck reactions and Lossen rearrangements occur under the same conditions and may provide new methods for facile initiation of Lossen rearrangements.

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“…Schraml et al [282] have Schiff bases are a group of nitrogen-containing compounds showing tautomeric equilibria. Schraml et al [282] have Schiff bases are a group of nitrogen-containing compounds showing tautomeric equilibria.…”

Section: Tautomerismmentioning

confidence: 99%

15N NMR Spectroscopy in Structural Analysis: An Update (2001 - 2005)

Marek¹,

Lyčka²,

Kolehmainen³

et al. 2007

COC

130

110

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Since our previous review article (Curr. Org. Chem. 2002, 6, 35), significant improvements and an array of 15 N NMR applications in structural analysis have been published. This report aims to update coverage of improvements in methodology and various types of applications published over the period 2001 -2005. Substantial progress in cryogenic probe technology and the commercial availability of cryoprobes have facilitated the measurement of 15 N NMR parameters.The number of solid-state applications has increased significantly during the past few years. In contrast to our previous review, this article covers 15 N solid-state studies. The 15 N NMR chemical shifts of organic molecules are routinely measured by using cross-polarization magic-angle spinning (CP/MAS) techniques. The principal values of the chemical shift tensors can also be determined. 1 H-15 N and 2 H-15 N distance measurements made by means of 1 H detection are currently used in NMR crystallography.User friendly quantum chemical programs allow for the routine calculation of 15 N chemical shielding and indirect spinspin coupling constants, especially using density functional theory (DFT).Applications of 15 N NMR spectroscopy in various fields of chemistry are summarized here. Major sections represent tautomerism, complexation, protonation, and hydrogen bonding. The other topics comprise N-alkylation, N-oxidation, regioisomerism, and changes in configuration or conformation.

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N,O-diacylhydroxylamines—structures in crystals and solutions

Cited by 8 publications

References 31 publications

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Lossen Rearrangements under Heck Reaction Conditions

15N NMR Spectroscopy in Structural Analysis: An Update (2001 - 2005)

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