Reaction of (Trifluoromethyl)trimethylsilane with Oxazolidin-5-ones:  Synthesis of Peptidic and Nonpeptidic Trifluoromethyl Ketones

Walter, Magnus W.; Adlington, Robert M.; Baldwin, Jack E.; Schofield, Christopher J.

doi:10.1021/jo980443+

Cited by 41 publications

(18 citation statements)

References 33 publications

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“…48 Dess-Martin periodinane (DMP) alcohol oxidation 49, 50 yielded the corresponding ketone derivative 9 as a mixture of the ketone and hydrate forms in a 2:1 molar ratio as determined by 19 F-NMR, 51 as similarly observed for other trifluoromethyl ketones solubilized in polar solvents. 52 Deprotection with trifluoroacetic acid (TFA) in methylene chloride generated 10 in 93% yield (ketone:hydrate 15:1 molar ratio by 19 F-NMR). 53 …”

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confidence: 99%

Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8

Ilies

Dowling

Lombardi

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report the synthesis and biological evaluation of the trifluoromethylketone analogue of L-arginine, (S)-2-amino-8,8,8-trifluoro-7-oxo-octanoic acid (10). While this novel amino acid was initially designed as a potential inhibitor of human arginase I, it exhibits no measurable inhibitory activity against this enzyme. Surprisingly, however, 10 is a potent inhibitor of human histone deacetylase 8, with IC50 = 1.5 ± 0.2 μM. Additionally, 10 weakly inhibits the related bacterial enzyme, acetylpolyamine amidohydrolase, with IC50 = 110 ± 30 μM. The lack of inhibitory activity against human arginase I may result from unfavorable interactions of the bulky trifluoromethyl group of 10 in the constricted active site. Since the active site of histone deacetylase 8 is less constricted, we hypothesize that it accommodates 10 as the gem-diol, which mimics the tetrahedral intermediate and its flanking transition states in catalysis. Therefore, we suggest that 10 represents a new lead in the design of an amino acid or peptide-based inhibitor of histone deacetylases with simpler structure than previously studied trifluoromethylketones.

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confidence: 99%

Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8

Ilies

Dowling

Lombardi

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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“…The third RSÀ X series (RS = Cbz-Ala-Ala; X = OH, H, CH 3 , COCH 3 ) was studied on the serine protease elastase. The syntheses of the aldehyde, the methyl ketone, and the methyl diketone derivatives (X = H, CH 3 , and COCH 3 , respectively) followed the approach of Angelastro et al [9] The trifluoromethyl ketone TS analogue (X = CF 3 ) was prepared according to Walter et al [10] The corresponding inhibition constants are presented in Tables 1 and 2. The same trend is observed for all three different recognition sites CbzPhe, Cbz-Gly-Leu-Phe, and Cbz-Ala-Ala in all examined enzymes; the stability of the TC as a function of varied CS fragment decreases in the following order:…”

Section: Experimental Validation Of the Conceptmentioning

confidence: 99%

“…Cbz-Phe-CF 3 was prepared according to Walter et al [10] and characterized according to Schofield et al [32] Cbz-Gly-Leu-Phe-NA C H T U N G T R E N N U N G (CH 3 Cbz-Gly-Leu-Phe-CH 3 (77 % yield): Enzyme inhibition assays: All enzymatic assays were carried out at 25 8C by following substrate hydrolysis spectrophotometrically. For competitive inhibition assays, solutions of substrate (at the indicated concentration in 20 mL DMSO) and inhibitor (varying concentrations in 20 mL DMSO) were dissolved in buffer (940 mL).…”

Section: Synthesismentioning

confidence: 99%

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

et al. 2006

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A transition-state analogue inhibitor that covalently reversibly binds to an enzyme formally consists of two parts: the chemical site, CS and the recognition site, RS. We have experimentally and theoretically demonstrated that the trend of binding affinity in a series of isoselective inhibitors (with identical RS and different CS fragments) depends mainly on their CS fragments. Isoselective inhibitors have the same affinity trend toward different enzymes of the same family with a common catalytic mechanism. Thus, very good correlation between experimentally determined and theoretically calculated Ki values was demonstrated. A practical outcome is the application of the described method as a tool for an expert analysis in virtual screening of inhibitor libraries and in the design of new enzyme inhibitors.

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“…The reaction took place directly in the NMR tube without addition of any other reagent. A slight adaptation of the method was necessary for the analysis of a-amino-acids that behave in solution as zwitterions: according to the procedure of Walter et al [27], 1 was reacted with the aamino-acid in presence of one equivalent of NaOH, directly in CD 3 OD (instead of water) to ensure a good solubility for all the reagents. The influence of the solvent on the performances of the method was also investigated on compound 6 in CD 3 OD, DMSO-d 6 , CD 3 CN, C 6 D 6 and pyridined 5 .…”

Section: Methodsmentioning

confidence: 99%

Signal separation and determination of the enantiomeric purity of primary amines with (−)-myrtenal – a 13C NMR study

Dufrasne¹,

Gelbcke²,

Galanski³

2006

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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Abstract1R -((/)-myrtenal was tested as a chiral derivatising agent for the determination of the enantiomeric purity of aliphatic primary amines, b-aminoalcohols, b-diamines and a-amino-acids. Derivatisation procedure consists in mixing one equivalent each of the amine and 1R -((/)-myrtenal directly into the nuclear magnetic resonance (NMR) tube before addition of the appropriate deuterated solvent and, for a-amino-acids, one equivalent of NaOH was added to neutralise the acidic function. Diastereoisomeric imines were completely formed after 12 h and analysed by 1 H-NMR except for N -methyl b-diamines for which imidazolidines were obtained. The method gave satisfactory results only for a-and b-arylalkylamines for which CDCl 3 could be advantageously replaced by C 6 D 6 or pyridine-d 5 in order to increase the difference between the chemical shifts. The main advantage of the procedure is its simplicity as it does not involve steps such as activation, heating, solvent evaporation and isolation of the product. Its limitations are the limited series of compounds susceptible to be analysed and the small difference between the chemical shifts of the diastereoisomeric imines obtained. #

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Reaction of (Trifluoromethyl)trimethylsilane with Oxazolidin-5-ones: Synthesis of Peptidic and Nonpeptidic Trifluoromethyl Ketones

Cited by 41 publications

References 33 publications

Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8

Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

Signal separation and determination of the enantiomeric purity of primary amines with (−)-myrtenal – a 13C NMR study

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