5'-thioadenosine derivatives as potent and selective inhibitors of histamine N-methyltransferase.

Several new analogues of adenosine bearing a lipophilic side chain at the 5'-position have been synthesized and investigated for their ability to inhibit histamine N-methyltransferase (HNMT). The 5'-deoxy-5'-[4-(3-indolyl)but-1-yl]thio]adenosine (2e), exhibited a pI50 of 5.00 against guinea pig brain HNMT.

Inhibition of vaccinia RNA guanine 7-methyltransferase by compounds designed as multisubstrate adducts.

Several potential inhibitors of mRNA guanine 7-methyltransferase, which were designed from mechanism-based considerations, were evaluated against the vaccinia virus capping enzyme complex. Of the compounds tested, 5'-deoxy-5'[6-(2-aminopyrrolo[2,3-d]-pyrimidine-4-one) methylthio]adenosine (9) had good selective inhibitory activity against vaccinia mRNA guanine 7-methyltransferase, exhibiting an IC50 of 9.2 X 10(-5) M.

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

Multisubstrate adducts of the indole N-methyltransferase reaction have been 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 have been synthesized, together with their corresponding methylsulfonium salts. These compounds have been assayed for their ability to inhibit rabbit lung indole N-methyltransferase.