Enzyme Inhibitors. IX. Hydrophobic Interactions of Some 9-Alkyladenines with Adenosine Deaminase^1,2

Enzyme Inhibitors XXIV: Bridging Hydrophobic and Hydrophilic Regions on Adenosine Deaminase

“…for CloHzaNO: C, 69.30; H, 13. Enzyme Assay-Adenosine deaminase (Type I, calf intestinal mucosa) was purchased'. The assay procedure for the study Of reversible inhibitors was previously described (2)(3)(4)(5) and is a modification of the procedure of Kaplan (12) based on the method of Kalckar (13)' a General procedures are given for the synthesis of the various types of compounds. The physical constants and analytical data for the compounds are given in Tables I1 and 111. 'The melting points, unless noted otherwise, were taken in open capillary tubes on a Mel-Temp apparatus and are uncorrected.…”

“…Analyses were performed by Galbraith Microanalytical Laboratories, Knoxville, Tenn. 5 Sigma Chemical Co.…”

“…By the use of different inhibitors, it was possible to show the presence on adenosine deaminase of a specific methyl binding region (2), a hydroxyl binding site (3,4), and a large hydrophobic region (5) which are important in forming complexes with the 9-substituent of the 9-substituted adenines.…”

“…It should be possible to obtain information concerning the identity or nonidentity of inhibitor binding sites by incorporating in one inhibitor the moieties that contribute to binding in two different inhibitors. 9-n-Alkyladenines (I) constitute a class of inhibitors in which the 9-substituent forms complexes with the large hydrophobic region on adenosine deaminase (5) hibitors (I and 11) complexes to the same site on the enzyme, and the accessory binding regions (hydrophobic and hydroxyl binding sites) are spatially closely associated with the site to which the adenine moiety binds, one would predict that an inhibitor bearing an alkyl chain and the 2-hydroxyethyl group at the 9-position of adenine (111) would be a potent inhibitor of adenosine deaminase. The purposes of this paper are: (a) to describe the synthesis of some 9-( 1-hydroxy-2-alky1)- Data taken from Average of two determinations.…”

Irreversible enzyme inhibitors 98 Hydrophobic interactions with succinoadenylate kinosynthetase and 9-substituted adenines

“…If the dichloroacetamido group was simulating the binding of the phosphate group (lo), it was predicted that IX should have a better ground state conformation for optimum binding than VIII (4, 9). The emergence of hydrophobic bonding (11) to such enzymes as adenosine deaminase (12), dihydrofolic reductase (13), thymidine phosphorylase (14), guanine deaminase (15), and others (11) suggested the possibility that V, VI, and VIII might have additional binding to succinoadenylate due to a hydrophobic interaction by part of the pentyl group. Therefore additional studies were performed on the mode of binding of the pentyl group of V, VI, and VIII; the results are reported in this paper, along with inhibition studies on V I I and IX.…”