title: 2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase.
abstract: It has been found that 2'-deoxy-2'-methyleneuridine (MdUrd), 2'-deoxy-2'-methylenecytidine (MdCyd), and 2'-deoxy-2',2'-difluorocytidine (dFdCyd) 5'-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3' to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3' to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd and dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
authors.forename: C H
authors.initials: CH
authors.lastname: Baker
authors.forename: J
authors.initials: J
authors.lastname: Banzon
authors.forename: J M
authors.initials: JM
authors.lastname: Bollinger
authors.forename: J
authors.initials: J
authors.lastname: Stubbe
authors.forename: V
authors.initials: V
authors.lastname: Samano
authors.forename: M J
authors.initials: MJ
authors.lastname: Robins
authors.forename: B
authors.initials: B
authors.lastname: Lippert
authors.forename: E
authors.initials: E
authors.lastname: Jarvi
authors.forename: R
authors.initials: R
authors.lastname: Resvick
mesh_terms: D003596:Cytosine / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003845:Deoxycytosine Nucleotides / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D003845:Deoxycytosine Nucleotides; D003841:Deoxycytidine; D003596:Cytosine; D012264:Ribonucleotide Reductases; C056034:2'-deoxy-2'-methylenecytidine; D004229:Dithiothreitol