One-Electron Oxidation of Gemcitabine and Analogs: Mechanism of Formation of C3鈥?and C2鈥?Sugar Radicals
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- 作者：Amitava Adhikary ; Anil Kumar ; Ramanjaneyulu Rayala ; Ragda M. Hindi ; Ananya Adhikary ; Stanislaw F. Wnuk ; Michael D. Sevilla
- 刊名：Journal of the American Chemical Society
- 出版年：2014
- 出版时间：November 5, 2014
- 年：2014
- 卷：136
- 期：44
- 页码：15646-15653
- 全文大小：463K
- ISSN：1520-5126
文摘
Gemcitabine is a modified cytidine analog having two fluorine atoms at the 2鈥?position of the ribose ring. It has been proposed that gemcitabine inhibits RNR activity by producing a C3鈥测€?intermediate via direct H3鈥?atom abstraction followed by loss of HF to yield a C2鈥测€?with 3鈥?keto moiety. Direct detection of C3鈥测€?and C2鈥测€?during RNR inactivation by gemcitabine still remains elusive. To test the influence of 2鈥? substitution on radical site formation, electron spin resonance (ESR) studies are carried out on one-electron oxidized gemcitabine and other 2鈥?modified analogs, i.e., 2鈥?deoxy-2鈥?fluoro-2鈥?C-methylcytidine (MeFdC) and 2鈥?fluoro-2鈥?deoxycytidine (2鈥?FdC). ESR line components from two anisotropic 尾-2鈥?F-atom hyperfine couplings identify the C3鈥测€?formation in one-electron oxidized gemcitabine, but no further reaction to C2鈥测€?is found. One-electron oxidized 2鈥?FdC is unreactive toward C3鈥测€?or C2鈥测€?formation. In one-electron oxidized MeFdC, ESR studies show C2鈥测€?production presumably from a very unstable C3鈥测€?precursor. The experimentally observed hyperfine couplings for C2鈥测€?and C3鈥测€?match well with the theoretically predicted ones. C3鈥测€?to C2鈥测€?conversion in one-electron oxidized gemcitabine and MeFdC has theoretically been modeled by first considering the C3鈥测€?and H3O+ formation via H3鈥?proton deprotonation and the subsequent C2鈥测€?formation via HF loss induced by this proximate H3O+. Theoretical calculations show that in gemcitabine, C3鈥测€?to C2鈥测€?conversion in the presence of a proximate H3O+ has a barrier in agreement with the experimentally observed lack of C3鈥测€?to C2鈥测€?conversion. In contrast, in MeFdC, the loss of HF from C3鈥测€?in the presence of a proximate H3O+ is barrierless resulting in C2鈥测€?formation which agrees with the experimentally observed rapid C2鈥测€?formation.