Glaser Rainer, Sui Yongqiang, Sarkar Ujjal, Gates Kent S
Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
J Phys Chem A. 2008 May 29;112(21):4800-14. doi: 10.1021/jp8011987.
Radicals resulting from one-electron reduction of (N-methylpyridinium-4-yl) methyl esters have been reported to yield (N-methylpyridinium-4-yl) methyl radical, or N-methyl-gamma-picoliniumyl for short, by heterolytic cleavage of carboxylate. This new reaction could provide the foundation for a new structural class of bioreductively activated, hypoxia-selective antitumor agents. N-methyl-gamma-picoliniumyl radicals are likely to damage DNA by way of H-abstraction and it is of paramount significance to assess their H-abstraction capabilities. In this context, the benzylic C-H homolyses were studied of toluene (T), gamma-picoline (P, 4-methylpyridine), and N-methyl-gamma-picolinium (1c, 1,4-dimethylpyridinium). With a view to providing capacity for DNA intercalation the properties also were examined of the annulated derivatives 2c (1,4-dimethylquinolinium), 3c (9,10-dimethylacridinium), and 4c (1,4-dimethylbenzo[g]quinolinium). The benzylic C-H homolyses were studied with density functional theory (DFT), perturbation theory (up to MP4SDTQ), and configuration interaction methods (QCISD(T), CCSD(T)). Although there are many similarities between the results obtained here with DFT and CI theory, a number of significant differences occur and these are shown to be caused by methodological differences in the spin density distributions of the radicals. The quality of the wave functions is established by demonstration of internal consistencies and with reference to a number of observable quantities. The analysis of spin polarization emphasizes the need for a clear distinction between "electron delocalization" and "spin delocalization" in annulated radicals. Aside from their relevance for the rational design of new antitumor drugs, the conceptional insights presented here also will inform the understanding of ferromagnetic materials, of spin-based signaling processes, and of spin topologies in metalloenzymes.
据报道，（N - 甲基吡啶 - 4 - 基）甲酯单电子还原产生的自由基通过羧酸根的异裂产生（N - 甲基吡啶 - 4 - 基）甲基自由基，简称为N - 甲基 - γ - 吡啶鎓基。这种新反应可为一类新型的生物还原激活的缺氧选择性抗肿瘤药物提供结构基础。N - 甲基 - γ - 吡啶鎓基自由基可能通过氢原子夺取的方式损伤DNA，评估它们的氢原子夺取能力至关重要。在此背景下，研究了甲苯（T）、γ - 甲基吡啶（P，4 - 甲基吡啶）和N - 甲基 - γ - 吡啶鎓（1c，1,4 - 二甲基吡啶鎓）的苄基C - H均裂。为了提供DNA插入能力，还研究了稠环衍生物2c（1,4 - 二甲基喹啉鎓）、3c（9,10 - 二甲基吖啶鎓）和4c（1,4 - 二甲基苯并[g]喹啉鎓）的性质。采用密度泛函理论（DFT）、微扰理论（直至MP4SDTQ）和组态相互作用方法（QCISD(T)，CCSD(T)）研究了苄基C - H均裂。尽管这里用DFT和CI理论得到的结果有许多相似之处，但也出现了一些显著差异，这些差异表明是由自由基自旋密度分布的方法差异引起的。通过证明内部一致性并参考一些可观测的量来确定波函数的质量。自旋极化分析强调了在稠环自由基中需要明确区分“电子离域”和“自旋离域”。除了与新抗肿瘤药物的合理设计有关外，这里提出的概念性见解还将有助于理解铁磁材料、基于自旋的信号传导过程以及金属酶中的自旋拓扑结构。
