Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 9. 2',3'-Dialdehyde derivatives of carbocyclic purine nucleosides as inhibitors of S-adenosylhomocysteine hydrolase.

Abstract

A series of purine (e.g., adenine, N6-methyladenine, 8-azaadenine, 3-deazaadenine) carbocyclic nucleosides, nucleoside 2',3'-dialdehydes, and nucleoside 2',3'-diols were synthesized as potential inhibitors of bovine liver S-adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3.3.1.1) and as potential inhibitors of vaccinia virus replication. The 2',3'-dialdehydes were prepared by periodate oxidation of the corresponding carbocyclic nucleosides. Reduction of the intermediate dialdehydes with sodium borohydride afforded the corresponding 2',3'-diols. Of the nucleosides tested, the most potent inhibitors of AdoHcy hydrolase were the adenine analogue (Ki = 110 +/- 38 nM) and the 3-deazaadenine analogue (Ki = 4 +/- 0.9 nM), which were reversible, competitive inhibitors. In contrast, the 2',3'-dialdehydes produced irreversible inhibition of AdoHcy hydrolase, resulting in incorporation of two to four molecules of the dialdehyde per molecule (tetramer) of the enzyme. On the basis of an Ackermann-Potter analysis, the following "apparent" Ki values were determined for the 2',3'-dialdehydes: adenine analogue, 61 nM; 8-azaadenine analogue, 57.5 nM; and 3-deazaadenine analogue, 32 nM. The nucleoside 2',3'-diols were substantially less effective as inhibitors of AdoHcy hydrolase, requiring millimolar concentrations to achieve significant inhibition. When tested for their ability to inhibit vaccinia virus replication, several carbocyclic nucleosides (e.g., adenine and 3-deazaadenine analogues) and several nucleoside 2',3'-dialdehydes (e.g., adenine, N6-methyladenine, 8-azaadenine, and 3-deazaadenine analogues) exhibited good antiviral effects. A good correlation existed between a compound's inhibitory effects on AdoHcy hydrolase and its antiviral effects, suggesting that the inhibition of viral replication is caused by inhibition of a critical methylation reaction, e.g., methylation of the 5'-cap of viral mRNA.