Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 4. Further modifications of the amino acid and base portions of S-adenosyl-L-homocysteine

Abstract

Structural analogs of S-adenosyl-L-homocysteine (L-SAH), with modifications in the amino acid or base portions of the molecule, were synthesized and evaluated for their abilities to inhibit the transmethylations catalyzed by catechol O-methyltransferase (COMT) [rat liver], phenylethanolamine N-methyltransferase (PNMT) [bovine adrenal medulla], histamine N-methyltransferase (HMT) [guinea pig brain], hydroxyindole O-methyltransferase (HIOMT) [bovine pineal gland], and indoleethylamine N-methyltransferase (INMT) [rabbit lung]. From these studies some interesting and potentially useful differences in the structural features of L-SAH needed to produce maximal binding to these methyltransferases were detected. This paper provides evidence that 8-azaadenosyl-L-homocysteine is a potent and selective inhibitor of HIOMT, whereas N6-methyladenosyl-L-homocysteine and N6-methyl-3-deazaadenosyl-L-homocysteine are selective inhibitors of INMT. S-tubercidinyl-L-homocysteine was a fairly potent, but nonselective inhibitor of all of the methyltransferases studied. The differences and the similarities in the requirements for the binding of SAH to methyltransferases, which were detected in this study and earlier studies, are described. The possibilities of utilizing differences in binding requirements for the design of SAH analogs as specific inhibitors of methyltransferases are discussed.