Enzyme inhibitors XXI Hydrophobic and hydroxylic binding sites of adenosine deaminase

Recent studies have shown that the orthoand para-isomers of 9-(bromoacetamido-benzyl)adenine are good irreversible inhibitors of adenosine deaminase. In an attempt to prepare other types of irreversible inhibitors of this enzyme, a series of 9-(ω-bromoacetoxyalkyl)adenines were synthesized. However, none of these compounds were active as irreversible inhibitors although they were reversible inhibitors of this enzyme. Thus, it appears that the alkyl chain of the 9- (ω-bromoacetoxy-alkyl)adenines does not complex with the enzyme in a manner identical to the 9-substituent of 9-(p- or o-bromoacetamidpbenzyl)adenine. When the 9-(ω-hydroxy-alkyl)adenines were evaluated as reversible inhibitors of adenosine deaminase, it was found that as the alkyl chain was lengthened, the compounds became initially more potent inhibitors, then less potent, and finally more potent again as the alkyl chain was lengthened to octyl. These results can be rationalized by assuming two different modes of binding. The short chain compounds bind to a hydroxyl binding site whereas the long chain compounds bind to a hydrophpbic region which based on other data appears to extend approximately seven or eight carbons from the 9-position of adenine.