Understanding ribonucleotide reductase inactivation by gemcitabine

• Type: Article in International Scientific Journal
• Date: 2007

Authors

Nuno M F S A Cerqueira (Author) FCUP; Pedro A Fernandes (Author) FCUP; Maria L Ramos (Author) FCUP

Journal

Title: Chemistry - A European Journal

Vol. 13

Pages: 8507-8515

ISSN: 0947-6539

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 110 Citations

Scopus - 112 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-004-CQ0

DOI: 10.1002/chem.200700260

Abstract (EN): 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 gernzar. 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9