Potent Inhibition of HhaI DNA Methylase by the Aglycon of 2-(1H)-Pyrimidinone Riboside (Zebularine) at the GCGC Recognition Domain

Abstract

A short oligodeoxynucleotide (ODN) with 2-(1H)-pyrimidinone at the HhaI DNA methyltransferase target site (GCGC) is shown to induce a level of inhibition of methyl transfer and thermal stability of the complex with the enzyme identical to that achieved with a similar ODN substituted with 5-azacytosine. The drugs responsible for these effects - zebularine and 5-azacytidine/2′-deoxy-5-azacytidine - are contrasted in terms of chemical stability and possible metabolic activation by a brief structure-activity analysis.