Enzyme Inhibitors. XVIII. Studies on the Stereoselectivity of Inhibition of Adenosine Deaminase by DL-, D-, and L-9-(2-Hydroxypropyl)Adenine

Previous studies on the inhibition of adenosine deaminase with compounds that contain an asymmetric center utilized the corresponding racemic compounds. In order to determine if adenosine deaminase exhibits a stereoselectivity in complexation with one enantiomer of a dl mixture, the syntheses of d-(-) and L-( + ) isomers of 9-(2-hydroxypropy 1 )adenine (6-d and 6-l) were undertaken because the dl racemate of this compound has previously been shown to be a good reversible inhibitor of this enzyme. Enzymic evaluation of L-( + )-9-(2-hydroxypropyl)-adenine (6-L) and d-(-)-9-(2-hydroxypropyl)adenine (6-d) revealed that 6-L is a much better inhibitor of adenosine deaminase than is 6-d; the ([I]/[S])_0.5of 6-L = 0.148, whereas the ([I]/[S]_0.5of 6-d = 1.48. A rationalization for this difference in inhibitory properties is presented. Calculations based on the ([I]/[S] )0.6 of 6-L compared to the ([I]/[S] )0.5 of 9-(2-hydroxyethyl)adenine reveal that the free energy of binding of the methyl group of 6-L is -1.15 kcal, a value which cannot be accounted for on the basis of hydrophobic forces alone. Thus, the positive involvement of van der Waals forces is invoked. Based on these and other data, it is concluded that there is a specific methyl binding region on adenosine deaminase which forms a unique “tight fit” or “lock and key” type of fit with the methyl group of L-(+ )-9-(2-hydroxypropyl)adenine (6-l).