Potent inhibition of HhaI DNA methylase by the aglycon of 2-(1H)-pyrimidinone riboside (zebularine) at the GCGC recognition domain.
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.
Marquez
Victor E
VE
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Maryland 21702, USA. marquezv@dc37a.nci.nih.gov
Eritja
Ramon
R
Kelley
James A
JA
Vanbemmel
Dana
D
Christman
Judith K
JK
D000970:Antineoplastic Agents / Q000378:metabolism*; D003562:Cytidine / Q000031:analogs & derivatives; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors; D004247:DNA / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors*; D017434:Protein Structure, Tertiary; D011741:Pyrimidine Nucleosides / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011741:Pyrimidine Nucleosides; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D004247:DNA; C037664:DNA modification methylase HhaI; D015257:DNA-Cytosine Methylases; D004248:DNA (Cytosine-5-)-Methyltransferases; D003564:Cytidine Deaminase