Enzyme inhibitors mechanism-based

Pratt, R. F. On the definition of mechanism-based enzyme inhibitors. Bioorg. Med. Chem. Lett. 1992, 2, 1323-1326. 

Action and Design Mechanism-Based Enzyme Inhibitors, ed. T. 1. Kalman ... 

Richard B. Silverman, Structure-Based and Mechanism-Based Enzyme Inhibitor Drug Design and Drug Action, in Bioorg. Med. Chem., 4 (9), Pergamon, Oxford, UK, 1996. 

Halogenated amino acids as mechanism-based enzyme inhibitors. . 1527... 

Amino acids, peptides and proteins play essential roles in living systems. As chemists, we have the ability to fabricate new structures of great complexity. Yet frequently the synthesis and application of even the simplest chemical structures can contribute substantial information on living systems. This has certainly been true for the application of fluorine chemistry to the synthesis of fluorinated amino acids [1, 2], These molecules are not only interesting in their own right but may act as potent mechanism-based enzyme inhibitors that may have application in medicine or diagnostics, or they can be valuable probes that, incorporated into peptides or proteins, elucidate fundamental biological chemistry or uncover new aspects of biochemical structure and function [3-5],... 

Another nucleoside-derived mechanism-based enzyme inhibitor is Fluoronepla-nocin A [79]. This compound is of interest as a broad-spectrum antiviral drug which acts by irreversible inhibition of S-adenosylhomocystein hydrolase (SAH). In a first enzymatic reaction step the 3 -hydroxy group of the inhibitor is oxidized to the corresponding ketone (Scheme 4.34). This leads to depletion of the biochemical oxidizer nicotinamide adenine dinudeotide (NAD ). In the next step a nucleophilic residue of the enzyme undergoes Michael addition to the /i-fluoro a,/>-unsatu-rated ketone moiety. This is followed by fluoride elimination and thus the inhibitor stays covalently trapped in the active site and disables the enzyme permanently. 

The terminal fluoroolefine group is a useful functionality in the design of mechanism-based enzyme inhibitors [29]. The defluorinative formation of quinone methide intermediates (82) from 80 and their trapping of active enzyme has been proposed as a method for affinity labeling of (3-glycosidases as shown in Scheme 6.16 [30]. 

Kalman Tl, ed. Drug Action Design—Mechanism-Based Enzyme Inhibitors. New York Elsevier Science, 1979. 

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