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 and 3-deazaadenine) carbocyclic nucleosides, nucleoside 2'',3''-dialdehydes, and nucleoside 2'',3''-diols [carbocyclic-adenosine, carbocyclic-N6-methyl-adenosine, carbocyclic-3-deaza-adenosine, carbocyclic adenosine-2'',3''-dialdehyde, carbocyclic N6-methyladenosine-2'',3''-dialdehyde, carbocyclic 8-azaadenosine-2'',3''-dialdehyde, carbocyclic 3-deazaadenosine-2'',3''-dialdehyde, carbocyclic adenosine-2'',3''-diol, carbocyclic N6-methyladenosine-2'',3''-diol, carbocyclic 8-azaadenosine-2'',3''-diol and carbocyclic 3-deazaadenosine-2'',3''-diol] 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 analog (Ki = 110 .+-. 38 nM) and the 3-deazaadenine analog (Ki = 4 .+-. 0.9 nM), which were reversible, competitive inhibitors. The 2'',3''-dialdehydes produced irreversible inhibition of AdoHcy hydrolase, resulting in incorporation of 2-4 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 analog, 61 nM; 8-azaadenine analog, 57.5 nM; and 3-deazaadenine analog, 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 analog) and several nucleoside 2'',3''-dialdehydes (e.g., adenine, N6-methyladenine, 8-azaadenine and 3-deazaadenine analogs) 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.