Toward the synthesis of isozyme-specific enzyme inhibitors. Potent inhibitors of rat methionine adenosyltransferases. Effect of one-atom elongation of the ribose-P.alpha. bridge in two covalent adducts of L-methionine and .beta.,.gamma.-imido-ATP
- 1 February 1988
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 31 (2) , 384-389
- https://doi.org/10.1021/jm00397a020
Abstract
With 2'',3''-O-isopropylideneadenosine or its N6-benzoyl derivative as starting material, synthetic routes to two novel adducts of L-methionine and .beta.,.gamma.-imido-ATP have been devised. One adduct, 14 (2:3 mixture of 6'' epimers), had a P.alpha.OCH(R1)CH2 system [R1 = CH2-L-SCH2CH2CH(NH2)CO2H] in place of the P.alpha.OC(5'')H2 system of ATP, while the other, 16 (2:3 mixture of 5'' epimers), had a P.alpha.OCH2CH2CH(R2) system [R2 = L-SCH2CH2CH(NH2)CO2H]. The ribose-P.alpha. bridge in 14 and 16 contained one more methylene group than in two homologous methionine-ATP adducts studied previously. Adduct 14 was a potent inhibitor of the rat M-2 (normal tissue) and M-T (Novikoff ascitic hepatoma) variants of methionine adenosyltransferase and gave competitive kinetics vs MgATP (Ki = 0.39 and 0.63 .mu.M, respectively) or vs L-methionine (Ki = 2.2 and 2.7 .mu.M). Adduct 16 was likewise a potent inhibitor competitive vs MgATP (Ki = 0.44 and 0.81 .mu.M, respectively) or L-methionine (Ki = 2.1 and 1.5 .mu.M). The kinetic data indicate that 14 and 16 inhibit by binding simultaneously to the MgATP and L-methionine substrate sites and that the extra methylene group facilitates the interaction of their methionine residues with these methionine sites.This publication has 14 references indexed in Scilit:
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