2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase.
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.
Baker
C H
CH
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
Banzon
J
J
Bollinger
J M
JM
Stubbe
J
J
Samano
V
V
Robins
M J
MJ
Lippert
B
B
Jarvi
E
E
Resvick
R
R
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
D003845:Deoxycytosine Nucleotides; D003841:Deoxycytidine; D003596:Cytosine; D012264:Ribonucleotide Reductases; C056034:2'-deoxy-2'-methylenecytidine; D004229:Dithiothreitol