Species- or isozyme-specific enzyme inhibitors. 7. Selective effects in inhibitions of rat adenylate kinase isozymes by adenosine 5'-phosphate derivatives.
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 KM (AMP)/Ki for competitive inhibition or as KM (AMP)/KM when only KM 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.
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D009132:Muscles / Q000201:enzymology; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011817:Rabbits
D007527:Isoenzymes; D000249:Adenosine Monophosphate; D010770:Phosphotransferases; D000263:Adenylate Kinase