Approaches to Isozyme-Specific Inhibitors. 17. Attachment of a Selectivity-Inducing Substituent to a Multisubstrate Adduct. Implications for Facilitated Design of Potent, Isozyme-Selective Inhibitors

Article abstract of DOI:10.1021/jm00171a032

The synthesis is described of a methyl-C5' adduct of L-methionine and β,γ-imido-ATP bearing a 6-S-n-Bu group in place of the 6-NH2 group of the parent adduct.The latter is a potent multisubstrate inhibitor in a model system consisting of the M-2 and M-T isozymes of rat methionine adenosyltransferase.When attached to ATP, the 6-S-n-Bu group induces selectivity for M-T inhibition by elevating affinity for the ATP site of M-T but not of M-2.In the above adduct it exerted a similar effect, expressed by selectivity and increased inhibitory potency toward M-T.This affords a second illustration of the ability of this approach to generate, relatively readily, a potent inhibitor with moderate isozyme selectivity.An overview is given of extensive evidence from the present series of studies that moderate (ca. 10-fold) isozyme selectivity is often exhibited by substrate derivatives bearing a single short substituent at a variety of atoms.This, together with features of another feasible approach to isozyme-selective inhibitor design, suggests an approach that has potential to facilitate the design of potent inhibitors that are both isozyme-selective and selective for a given metabolic conversion.It comprises (1) evaluation of the above type of substrate derivatives as inhibitors of a chemotherapeutically significant set of isozymes (target and nontarget), (2) attempted derivation of a potent multisubstrate adduct inhibitor of the isozymes, (3) attachment to such an adduct of one or more selectivity-inducing substituents revealed in the first step, and, if desired, (4) systematic modification of substituents with a view to obtaining enhanced potency and/or isozyme-selectivity.