title: 2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: a novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1.
abstract: 2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses (<10microM) than decitabine at inhibiting DNA methylation, and was also associated with a 3-day delay in its effect. However, at doses > or = 10microM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.
authors.affiliation: Division of Hematology, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 6428, Los Angeles, CA, USA.
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.forename: Si Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Binh
authors.initials: B
authors.lastname: Trinh
authors.forename: Maqbool A
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Allen S
authors.initials: AS
authors.lastname: Yang
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: C530888:2'-deoxy-N4-(2-(4-nitrophenyl)ethoxycarbonyl)-5-azacytidine; D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D011355:Prodrugs; D012333:RNA, Messenger; D000077209:Decitabine; D015257:DNA-Cytosine Methylases; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D001374:Azacitidine