One-electron oxidation of gemcitabine and analogs: mechanism of formation of C3' and C2' sugar radicals.
One-electron oxidation of gemcitabine and analogs: mechanism of formation of C3' and C2' sugar radicals.
复制标题
DOI：
10.1021/ja5083156
复制
发表时间：
2014-11-05
影响因子：
15
通讯作者：
Sevilla, Michael D.
中科院分区：
文献类型：
--
作者：
Adhikary, Amitava;Kumar, Anil;Rayala, Ramanjaneyulu;Hindi, Ragda M.;Adhikary, Ananya;Wnuk, Stanislaw F.;Sevilla, Michael D.
吉西他滨是一种修改的胞苷类似物，在核糖环的2‘-位有两个氟原子。有人认为吉西他滨通过直接H3‘-原子抽提产生C3’·中间体，然后失去HF生成C2‘·带有3’-酮基部分，从而抑制RNR的活性。在吉西他滨灭活RNR的过程中，C3‘·和C2’·的直接检测仍然难以捉摸。为了测试2‘-取代对自由基位形成的影响，对单电子氧化吉西他滨和其他2’-修饰类似物2‘-脱氧-2’-氟-2‘-C-甲基胞苷(MeFdC)和2’-氟-2‘-脱氧胞苷(2’-FDC)进行了电子自旋共振(ESR)研究。来自两个各向异性β-2‘-F原子超精细耦合的电子自旋共振谱线成分证实了单电子氧化吉西他滨中C3’·的形成，但没有发现与C2‘·的进一步反应。单电子氧化的2‘-FDC对C3’·或C2‘·的生成无反应。在单电子氧化的MeFdC中，ESR研究表明C2‘·可能来自一个非常不稳定的C3’·前体。实验观察到的C2‘·和C3’·的超精细耦合与理论预测符合得很好。在单电子氧化吉西他滨和MeFdC中，C3‘·向C2’·转化的理论模型是首先考虑通过H3‘-质子去质子化生成C3’·和H3O+，然后通过这种接近的H3O+引起的HF损失生成C2‘·。理论计算表明，在吉西他滨中，在H3O+存在的情况下，C3‘·向C2’·的转化存在势垒，这与实验观察到的C3‘·向C2’·转化的情况一致。相反，在MeFdC中，在接近的H3O+存在的情况下，C3‘·的HF的损失是无障碍的，导致C2’·的形成，这与实验观察到的C2‘·的快速形成是一致的。
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 β-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.
登录
查看更多内容
影响因子：
2.9
作者：
Artin, Erin;Wang, Jun;Lohman, Gregory J. S.;Yokoyama, Kenichi;Yu, Guixue;Griffin, Robert G.;Bar, Galit;Stubbe, JoAnne
通讯作者：
Stubbe, JoAnne
影响因子：
15
作者：
Adhikary A;Kumar A;Khanduri D;Sevilla MD
通讯作者：
Sevilla MD
影响因子：
15
作者：
Adhikary A;Khanduri D;Sevilla MD
通讯作者：
Sevilla MD
影响因子：
3.3
作者：
Adhikary, Amitava;Becker, David;Palmer, Brian J.;Heizer, Alicia N.;Sevilla, Michael D.
通讯作者：
Sevilla, Michael D.
影响因子：
3.3
作者：
De Cooman, Hendrik;Vanhaelewyn, Gauthier;Callens, Freddy
通讯作者：
Callens, Freddy