Lead compound production irreversible inhibitors

In contrast to the inhibitors such as neostigmine and related compounds described above, where the intermediate complexes hydrolyse slowly, these toxic compounds form complexes that do not hydrolyse. The enzyme becomes irreversibly bound to the toxin and, as a result, ceases to function. These agents all have leaving groups that can be displaced by the serine hydroxyl of the enzyme, leading to stable addition products. 

As noted in Chapters 4, 5, and 7, compounds aimed at dismpting tyrosine kinases have been intensively studied as potential antitumor compounds. The quinoline-based inhibitor pelitinib (45) incorporates a Michael acceptor function in the side chain that can form a covalent bond with a nucleophile on the target enzyme. Such an interaction would result in irreversible inhibition of the target kinase. Reaction of the aniline (37) with DMF acetal leads to the addition of a carbon atom to aniline nitrogen in the form of an amidine (38). This intermediate is next reacted with nitric in acetic acid to form the nitrated product... 

The best definition of the third type of irreversible enzyme inhibitor, mechanism-based inactivators, is provided by Dr Richard Silverman, a leading authority on the subject. A mechanism-based inactivator (sometimes, much to my dismay, called a suicide substrate), he writes, is an unreactive compound that has a structural similarity to a substrate or product for an enzyme. Once at the active site of the enzyme, it is converted into a species that generally forms a covalent bond to the enzyme, producing inactivation. Although both quiescent affinity labels and mechanism-based inactivators can be mistaken for... 

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