Date of this Version

10-8-2014

Document Type

Article

Abstract

Gemcitabine is a modified cytidine analog having two fluorine atoms at the 2?-position of the ribose ring. It has been proposed that gemcitabine inhibits RNR activity by producing a C3?? intermediate via direct H3?-atom abstraction followed by loss of HF to yield a C2?? with 3?-keto moiety. Direct detection of C3?? and C2?? during RNR inactivation by gemcitabine still remains elusive. To test the influence of 2?- substitution on radical site formation, electron spin resonance (ESR) studies are carried out on one-electron oxidized gemcitabine and other 2?-modified analogs, i.e., 2?-deoxy-2?-fluoro-2?-C-methylcytidine (MeFdC) and 2?-fluoro-2?-deoxycytidine (2?-FdC). ESR line components from two anisotropic ?-2?-F-atom hyperfine couplings identify the C3?? formation in one-electron oxidized gemcitabine, but no further reaction to C2?? is found. One-electron oxidized 2?-FdC is unreactive toward C3?? or C2?? formation. In one-electron oxidized MeFdC, ESR studies show C2?? production presumably from a very unstable C3?? precursor. The experimentally observed hyperfine couplings for C2?? and C3?? match well with the theoretically predicted ones. C3?? to C2?? conversion in one-electron oxidized gemcitabine and MeFdC has theoretically been modeled by first considering the C3?? and H3O+ formation via H3?-proton deprotonation and the subsequent C2?? formation via HF loss induced by this proximate H3O+. Theoretical calculations show that in gemcitabine, C3?? to C2?? conversion in the presence of a proximate H3O+ has a barrier in agreement with the experimentally observed lack of C3?? to C2?? conversion. In contrast, in MeFdC, the loss of HF from C3?? in the presence of a proximate H3O+ is barrierless resulting in C2?? formation which agrees with the experimentally observed rapid C2?? formation.

Originally Published In

Journal of the American Chemical Society

PMID

25296262

DOI

10.1021/ja5083156

Comments

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Download

Share

COinS
 

Rights Statement

Rights Statement

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).