Species- or Isozyme-Specific Enzyme Inhibitors. 7. Selective Effects in Inhibition of Rat Adenylate Kinase Isozymes by Adenosine 5'-Phosphate Derivatives.

Article abstract of DOI:10.1021/jm00349a008

Monosubstituted derivatives of adenosine 5'-phosphate (AMP) with substituents of 1-3 atoms or group replacements at any of 11 positions have been synthesized and examined as substrates and inhibitors of the rat muscle adenylate kinase isozyme (AK-M), and the rat AK II and III isozymes predominant in poorly differentiated hepatoma tissue and normal liver tissue, respectively.Inhibition indexes of the compounds were expressed as K_M(AMP)/K_i for competitive inhibition or as K_M (AMP)/K_M when only K_M was available.Substituents at N(1), N⁶, or C(8) or on ionizable phosphate oxygen reduced inhibition below measurable levels; 2'-deoxy-AMP and adenosine 5'-sulfate had identical inhibition indexes with all three isozymes; compounds with substituents at C(2), O(2'), O(3'), C(4'), C(5'), or O(5') had higher inhibition indexes with AK-M than with AK II or III and the same or similar indexes for AK II and III.The most effective and / or selective inhibitors were 2-NHMe-AMP (index with AK-M, 0.2; index ratio, AK-M/AK III, 9.1), 2'-O-Me-AMP (index with AK-M, 0.14; index ratio, AK-M/AK III, 8.2), 2',3'-O-CMe2-AMP (index with AK-M, 0.25; index ratio, AK-M/AK II, 6.6), 4'-allyl-AMP (index with AK-M, 0.97; index ratio, AK-M/AK III, 8.1), and 5'(S)-Et-AMP (index with AK-M, 0.64; index ratio, AK-M/AK II, 11.2).The study provides additional evidence that the attachment of simple substituents to various atoms in turn of a substrate is a potentially useful approach in early stages of the attempted design of isozyme-selective inhibitors.