Multisubstrate adducts as potential inhibitors of S-adenosylmethionine dependent methylases: inhibition of indole N-methyltransferase by (5H-deoxyadenosyl)[3-(3-indolyl)propyl-1-yl]methylsulfonium and (5'-deoxyadenosyl)[4-(3-indolyl)but-1-yl]methylsulfonium salts

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Abstract
Multisubstrate adducts of the indole N-methyltransferase reaction were designed in which a structural moiety representing the nucleophilic methyl acceptor is attached through the sulfur atom to the 5-(methylthio)adenosine and/or methionine moieties of the methyl donor, S-adenosyl-L-methionine. Indole derivatives attached through a 4-(3-indolyl)butyl sulfide or a 3-(3-indolyl)propyl sulfide linkage to 5''-thioadenosine or homocysteine were synthesized, together with their corresponding methylsulfonium salts. These compounds were assayed for their ability to inhibit rabbit lung indole N-methyltransferase. The adenosylsulfonium salts (5''-deoxyadenosyl) [4-(3-indolyl)but-1-yl]methylsulfonium perchlorate and (5''-deoxyadenosyl) [3-(3-indolyl)prop-1-yl]-methylsulfonium perchlorate inhibited of this enzyme with Ki''s [inhibition constant] of 12 and 44 .mu.M, respectively. Neither of these compounds was effective in inhibiting the methylation of 3,4-dihydroxybenzoic acid, catalyzed by purified porcine catechol O-methyltransferase.