Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 8. Molecular dissections of carbocyclic 3-deazaadenosine as inhibitors of S-adenosylhomocysteine hydrolase

Abstract

A series of 9-(hydroxyalkyl)-3-deazaadenines, which are analogs of the carbocyclic derivative of 3-deazaadenosine (3-deaza-C-Ado), were synthesized. The analogs were tested as inhibitors of bovine liver S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as inhibitors of vaccinia virus (WR) replication in clone 929 mouse L cells and the results were compared to those observed for the parent compound, 3-deaza-C-Ado. 4-Amino-1-(2,3-dihydroxy-1-propyl)imidazo[4,5-c]pyridine (14), the analog which included the 1''-, 2'' and 3''-carbons of 3-deaza-C-Ado, was the most active inhibitor toward purified AdoHcy hydrolase. The inhibitory effect of 14 (Ki = 768 nM) on AdoHcy hydrolase was significantly less than that observed for 3-deaza-C-Ado (Ki = 4 nM). Analog 14 also exhibited inhibitory activity against vaccinia virus replication, but the activity was less than that observed with 3-deaza-C-Ado. 4-Amino-1-(4-hydroxy-1-butyl)imidazo[4,5-c]pyridine (15) showed little or no inhibitory activity toward AdoHcy hydrolase, but it did exhibit antiviral effects comparable to 14. Deaza-C-Ado and analog 14 may be producing their antiviral effects by altering a critical viral methylation (e.g., methylation of the 5''-cap of viral mRNA), whereas analog 15 may be acting through an alternative mechanism.