Design of substrate-site-directed irreversible inhibitors of adenosine 5'-phosphate aminohydrolase. Effect of substrate substituents on affinity for the substrate site

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Abstract
Derivatives of adenosine 5''-phosphate (AMP) were synthesized in which the phosphoester (POCH2) grouping of AMP is replaced by PCH(R)CH2 where R is OC(O)Me, CH2NHCOMe, CH2NHCOEt, and CH2NHCOOR''(R'' = Me, Et and Pr). The 2'',3''-O-isopropylidene and 2'',3-di-O-acetyl derivatives of AMP were also prepared. All compounds were competitive inhibitors of rabbit muscle AMP aminohydrolase with enzyme-inhibitor dissociation constants (Ki values) of 330, 20, 17, 19, 16, 14, 260, and 105 .mu.M, respectively. All compounds were substrates except those in which R was CH2NHCOEt and CH2NHCOOR'' (R'' = Me, Et, and Pr). THe previously described allo and talo epimers of 5''-C-acetylaminomethyl-AMP and the allo epimer of 5''-C-propionylaminomethyl-AMP were substrates and competitive inhibitors with Ki values of 18, 47 and 42 .mu.M, respectively. The talo epimer of 5''-C-propionylaminomethyl-AMP was not a substrate and was a noncompetitive inhibitor, Ki = 205 .mu.M. 8-Bromo-AMP was a substrate (Vmax 0.03% that of AMP). Affinity for the AMP site of the aminohydrolase is retained when the above substituents (except 5''-C-propionylaminomethyl in the talo configuration) are attached to AMP and it might therefore be possible to design substrate-site-directed irreversible inhibitors for this enzyme by suitable modification of these substituents.

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