A Generic Approach for the Catalytic Reduction of Nitriles.

Caddick, Stephen; Judd, Duncan B.; Lewis, Alexandra K. de K.; Reich, Melanie; Williams, Meredith

doi:10.1002/chin.200343051

Cited by 10 publications

(12 citation statements)

References 16 publications

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“…64 Attempts to reduce the nitrile with LiAlH4, BH3 or cobalt(II) chloride/sodium borohydride 65 suffered, in some cases, from competing reduction of the thiazole, but more generally from the difficulty in isolating the primary amine 8, as noted earlier. Ultimately, an in situ protection of the primary amine obtained by nickel boride reduction 66 of nitrile 11, provided the t-butyl carbamate 12, which was much easier to isolate and purify, in good yield. Protonolysis then provided the dihydrochloride 13, which was used directly in subsequent steps.…”

Section: Hnmentioning

confidence: 99%

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

et al. 2016

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The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.

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Section: Hnmentioning

confidence: 99%

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

et al. 2016

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“…In addition, we evaluated some novel peptides containing β 2homoamino acids. The Boc-protected amino acids were prepared according to the general methods described by Pataj [41] and Caddick. [42] The first step of this synthesis (Scheme 1) was the Knoevenagel condensation between methylcyanoacetate (I), and the aldehydes in the presence of piperidine and methanol, to give the alkenes in 36-95% yield.…”

Section: (A) Synthetic Analogues Of Kp-10mentioning

confidence: 99%

Beta amino acid‐modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity

Camerino

Liu

Moriya

et al. 2016

Journal of Peptide Science

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Kisspeptin analogues with improved metabolic stability may represent important ligands in the study of the kisspeptin/KISS1R system and have therapeutic potential. In this paper we assess the activity of known and novel kisspeptin analogues utilising a dual luciferase reporter assay in KISS1R-transfected HEK293T cells. In general terms the results reflect the outcomes of other assay formats and a number of potent agonists were identified among the analogues, including β(2) -hTyr-modified and fluorescently labelled forms. We also showed, by assaying kisspeptin in the presence of protease inhibitors, that proteolysis of kisspeptin activity within the reporter assay itself may diminish the agonist outputs. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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“…Reduction of a nitrile group to a primary amine is a transformation well known and important to synthetic chemistry (1)(2)(3)(4). Its unique biological equivalent is the reaction catalyzed by QueF enzymes (5).…”

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confidence: 99%

“…The enzymes of the Q pathway, QueF in particular, due to its apparent uniqueness, therefore represent promising drug targets to combat bacterial infections selectively. Moreover, due to the hazardous conditions required in the chemical reaction (1)(2)(3)(4), "greener" routes of nitrile reduction are highly demanded. A biocatalytic route going by the QueF mechanism presents an interesting option.…”

mentioning

confidence: 99%

Kinetic Analysis and Probing with Substrate Analogues of the Reaction Pathway of the Nitrile Reductase QueF from Escherichia coli

Jung

Czabany

Wilding

et al. 2016

Journal of Biological Chemistry

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The enzyme QueF catalyzes a four-electron reduction of a nitrile group into an amine, the only reaction of this kind known in biology. In nature, QueF converts 7-cyano-7-deazaguanine (preQ) into 7-aminomethyl-7-deazaguanine (preQ) for the biosynthesis of the tRNA-inserted nucleoside queuosine. The proposed QueF mechanism involves a covalent thioimide adduct between preQ and a cysteine nucleophile in the enzyme, and this adduct is subsequently converted into preQ in two NADPH-dependent reduction steps. Here, we show that the Escherichia coli QueF binds preQ in a strongly exothermic process (ΔH = -80.3 kJ/mol; -TΔS = 37.9 kJ/mol, K = 39 nm) whereby the thioimide adduct is formed with half-of-the-sites reactivity in the homodimeric enzyme. Both steps of preQ reduction involve transfer of the 4-pro-R-hydrogen from NADPH. They proceed about 4-7-fold more slowly than trapping of the enzyme-bound preQ as covalent thioimide (1.63 s) and are thus mainly rate-limiting for the enzyme's k (=0.12 s). Kinetic studies combined with simulation reveal a large primary deuterium kinetic isotope effect of 3.3 on the covalent thioimide reduction and a smaller kinetic isotope effect of 1.8 on the imine reduction to preQ 7-Formyl-7-deazaguanine, a carbonyl analogue of the imine intermediate, was synthesized chemically and is shown to be recognized by QueF as weak ligand for binding (ΔH = -2.3 kJ/mol; -TΔS = -19.5 kJ/mol) but not as substrate for reduction or oxidation. A model of QueF substrate recognition and a catalytic pathway for the enzyme are proposed based on these data.

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A Generic Approach for the Catalytic Reduction of Nitriles.

Cited by 10 publications

References 16 publications

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

Beta amino acid‐modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity

Kinetic Analysis and Probing with Substrate Analogues of the Reaction Pathway of the Nitrile Reductase QueF from Escherichia coli

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