pH dependence of the inhibition of chymotrypsin by a peptidyl trifluoromethyl ketone

Brady, Kenneth D.; Liang, Tzyy Chyau; Abeles, Robert H.

doi:10.1021/bi00449a017

Cited by 36 publications

(36 citation statements)

References 29 publications

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“…Preliminary results indicate that the formation of the nitroso hemiketal intermediate (Scheme ) is fast (sub‐millisecond time range), which suggests that the final release of the alcohol together with the formation of the trifluoromethyl ketone derivative is rate‐limiting. Partial deprotonation of the hemiketal intermediate at neutral pH (a value of 9.125 has been reported for the p K a of related hemiketals) could accelerate such a decomposition process. The details of the kinetics of the photochemical decomposition of such o ‐nitrobenzyl ether derivatives are currently under investigation 26…”

Section: Methodsmentioning

confidence: 98%

1‐(o‐Nitrophenyl)‐2,2,2‐trifluoroethyl Ether Derivatives as Stable and Efficient Photoremovable Alcohol‐Protecting Groups

Specht

Goeldner

2004

Angew Chem Int Ed

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Section: Methodsmentioning

confidence: 98%

1‐(o‐Nitrophenyl)‐2,2,2‐trifluoroethyl Ether Derivatives as Stable and Efficient Photoremovable Alcohol‐Protecting Groups

Specht

Goeldner

2004

Angew Chem Int Ed

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“…If the kinetic experiments are not run for a sufficient length time, only the initial pre-equilibrium will be observed and the slow-binding inhibitor may appear to be much weaker than it actually is. With respect to serine proteinases, this phenomenon has been most thoroughly studied with TFMKs, 129,131,137,141,158 although some a-ketoestersl41 and some DFMKs129,140 also demonstrate slow onset of full inhibition.…”

Section: Slowbinding Inhibition By Electrophilic Pepfidyl Ketonesmentioning

confidence: 99%

Synthetic Inhibitors of Elastase

Edwards

Bernstein

1994

Medicinal Research Reviews

214

156

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For more than two decades investigators around the world, in both academic and industrial institutions, have been developing inhibitors of human neutrophil elastase. A number of very elegant and insightful strategies have been reported. In the case of reversible peptidic inhibitors, this has resulted in the identification of some extremely potent compounds with dissociation constants in the 10(-11) M range. This is quite an accomplishment considering that these low molecular-weight inhibitors are only tri- and tetrapeptides. In the case of the heterocyclic-based inhibitors, the challenge of balancing the heterocycle's inherent reactivity and aqueous stability with the stability of the enzyme-inhibitor adduct has been meet by either using a latent, reactive functionality which is only activated within the enzyme, or by incorporating features which selectively obstruct deacylation but have little effect on the enzyme acylation step. The underlying goal of this research has been the identification of agents to treat diseases associated with HNE. Several animal models have been developed for evaluating the in vivo activity of elastase inhibitors, and compounds have been shown to be effective in all of these models by the intravenous, intratrachael or oral routes of administration. However, only a very small percentage of compounds have possessed all the necessary properties, including lack of toxicity, for progression into the clinic. The peptidyl TFMK ICI 200,880 (25-12) has many of the desired characteristics of a drug to treat the diseases associated with HNE: chemical stability, in vitro and in vivo activity, a long duration of action, and adequate metabolic stability. Currently ICI 200,880 is the only low molecular-weight HNE inhibitor known to be undergoing clinical trials, and may be the compound which finally demonstrates the clinical utility of a synthetic HNE inhibitor.

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“…6. ), allowed for experimental estimation of the bound, α-fluorinated hemiketal pKa at 4.9 [32,33]. Thus, the α-fluorinated hemiketal pK a is apparently lowered by approximately 4 log units, in the active site, suggestive of favorable interactions in the oxyanion hole.…”

Section: Use Of Fluorinated Functionality For “Transition State Anmentioning

confidence: 99%

Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages

Berkowitz

Karukurichi

Salud-Bea

et al. 2008

Journal of Fluorine Chemistry

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On the one hand, owing to its electronegativity, relatively small size, and notable leaving group ability from anionic intermediates, fluorine offers unique opportunities for mechanism-based enzyme inhibitor design. On the other, the “bio-orthogonal” and NMR-active 19-fluorine nucleus allows the bioorganic chemist to follow the mechanistic fate of fluorinated substrate analogues or inhibitors as they are enzymatically processed. This article takes an overview of the field, highlighting key developments along these lines. It begins by highlighting new screening methodologies for drug discovery that involve appropriate tagging of either substrate or the target protein itself with 19F-markers, that then report back on turnover and binding, respectively, via an the NMR screen. Taking this one step further, substrate-tagging with fluorine can be done is such a manner as to provide stereochemical information on enzyme mechanism. For example, substitution of one of the terminal hydrogens in phosphoenolpyruvate, provides insight into the, otherwise latent, facial selectivity of C-C bond formation in KDO synthase. Perhaps, most importantly, from the point of view of this discussion, appropriately tailored fluorinated functionality can be used to form to stabilized “transition state analogue” complexes with a target enzymes. Thus, 5-fluorinated pyrimidines, α-fluorinated ketones, and 2-fluoro-2-deoxysugars each lead to covalent adduction of catalytic active site residues in thymidylate synthase, serine protease and glycosidase enzymes, respectively. In all such cases, 19F NMR allows the bioorganic chemist to spectrally follow “transition state analogue” formation. Finally, the use of specific fluorinated functionality to engineer “suicide substrates” is highlighted in a discussion of the development of the α-(2′Z-fluoro)vinyl trigger for amino acid decarboxylase inactivation. Here 19F NMR allows the bioorganic chemist to glean useful partition ratio data directly out of the NMR tube.

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pH dependence of the inhibition of chymotrypsin by a peptidyl trifluoromethyl ketone

Cited by 36 publications

References 29 publications

1‐(o‐Nitrophenyl)‐2,2,2‐trifluoroethyl Ether Derivatives as Stable and Efficient Photoremovable Alcohol‐Protecting Groups

1‐(o‐Nitrophenyl)‐2,2,2‐trifluoroethyl Ether Derivatives as Stable and Efficient Photoremovable Alcohol‐Protecting Groups

Synthetic Inhibitors of Elastase

Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages

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