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Understanding Ribonucleotide Reductase Inactivation by Gemcitabine
Author(s) -
Cerqueira Nuno M. F. S. A.,
Fernandes Pedro A.,
Ramos Maria J.
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700260
Subject(s) - ribonucleotide reductase , gemcitabine , deoxycytidine , chemistry , monomer , cytotoxicity , combinatorial chemistry , biochemistry , drug , biophysics , pharmacology , in vitro , biology , chemotherapy , organic chemistry , genetics , protein subunit , gene , polymer
Abstract This paper focuses on the inhibition of ribonucleotide reductase (RNR) by gemcitabine, 2′,2′‐difluoro‐2′‐deoxycytidine (dFdC), a deoxycytidine analogue that is a very active drug against solid tumors and is currently commercialized as gemzar. RNR inactivation is reductant‐dependent and occurs in a very different way from that of other known substrate analogues. In the presence of reductants monomer R1 of RNR is inhibited, whereas in the absence of reductants the radical is lost and monomer R2 is inhibited. As inside the cell reductants are available, it is likely that R1 inactivation is the most favorable mechanism responsible for drug cytotoxicity. This inhibition pathway has been unknown to date, but we have conducted a theoretical study that has led us to the first proposal of a mechanism for RNR inhibition by dFdC in the presence of reductants.