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Kappler F , Hampton A
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
Journal of Medicinal Chemistry. 1990 ;33(9) :2545-2551
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The synthesis is described of a methyl-C5' adduct of L-methionine and ?,?-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.
00222623 (ISSN) Cited By: 8; Export Date: 30 May 2006; Source: Scopus CODEN: JMCMA Language of Original Document: English Correspondence Address: Hampton, A.; Institute for Cancer Research; Fox Chase Cancer Center Philadelphia, PA 19111, United States Chemicals/CAS: methionine adenosyltransferase, 9012-52-6, Adenosine Triphosphate, 56-65-5; Enzyme Inhibitors; Isoenzymes