Dehalogenation of 5-Halouracils after Low Energy Electron Attachment:  A Density Functional Theory Investigation

Abstract

In this density functional theory investigation of the radiosensitization properties of 5-halogen-substituted uracils, the potential energy surfaces of the halouracils before and after electron attachment are investigated. The electron affinities (EA's) of uracil, halouracils, and uracilyl radical (U-yl • ) are calculated. The gas-phase adiabatic EA's of the halouracils after zero point energy (ZPE) corrections are in good agreement with those reported recently (Wetmore, S. D.; Boyd, R. J.; Eriksson, L. A. Chem. Phys. Lett. 2001, 343, 151-158). The U-yl • radical has an exceptionally high AEA of 2.34 eV and proton affinity of 9.5 eV in the gas phase, showing its reactive nature and potential to cause DNA damage when incorporated in the genome. The higher EA of the halouracils compared to that of the DNA bases supports the experimental reports on the increased probability of low-energy electrons to localize on halouracils in DNA, leading to dehalogenation reactions and DNA damage. Potential energy surfaces (PES) are calculated for dehalogenation to show the relative energy change in the dissociation of halogen from both the neutral molecule and anion radical. The PESs along the C 5 -X bond of all neutral molecules including uracil show the typical surface expected for a strong covalent bond rupture. Each of the halouracil anion radicals is found to have two thermally accessible electronic states of differing symmetries, i.e., π*(A") and σ*(A ' ), that have quite differing properties. Both the pure π* state and the σ* state feature planar geometries. The pure π* state has a PES similar to that of the neutral molecule with a strong C-X bond, while the σ* state shows far weaker C-X bonding. Moreover, there is a mixed state PES that undergoes a transition from a slightly nonplanar π* state to that of a σ* state as the C-X bond distance increases to the crossing point of the two PES. From the full PES that allows for state crossing, the lowest energy barriers for formation of the extended σ* states are estimated to be 20.80, 3.99, and 1.88 kcal/mol for F-, Cl-, and Br-substituted uracil anion radicals, respectively. The overall energetics suggest that the π* to σ* conversions are exothermic for ClU and BrU anions, with ∆H calculated to be -0.98 and -2.98 kcal/mol, ∆G, -2.32 and -3.80 kcal/mol at 298 K and 1 atm, respectively. Remarkably, for the F-U anion the lowest energy path is not the loss of fluoride ion but the detachment of HF. The sensitivity of the halouracils to low-energy electrons is found to be on the order of BrU ≈ ClU . FU, in agreement with experimental observations.

Transient Anions in Radiobiology and Radiotherapy: From Gaseous Biomolecules to Condensed Organic and Biomolecular Solids

“…The studies [157][158][159][160][161][162][163][164][165][166][167] confirmed the prediction of Zimbrick and coworkers [168] that the radiosensitizing properties of these compounds arose from DEA of solvated electrons, and further showed that DEA of higher energy (0-7eV) electrons was also involved in radiosensitization. Platinum bromide, aromatic compounds containing nitro group and other halogenated thymidine derivatives were found to play similar roles [58, 70, 71, 163-165, 169, 170].…”

Dinâmica de íons temporários de biomoléculas halogenadas

“…Medidas do espectro de transmissão eletrônica realizadas para as 5-halouracilas apontam para a existência de ressonâncias nesses sistemas [43], enquanto cálculos de estrutura eletrônica mostram para a existência de um estado ligado [44,45]. As seções de choque de dissociação são ordens de grandeza mais elevadas nas 5-halouracilas do que na uracila ou timina, além de apresentar um espectro de fragmentos muito mais rico [46][47][48][49][50][51].…”

“…Nas 5-halouracilas, fragmentos são observados já a partir de 0 eV, o que indica que as reações de dissociação correspondentes devem ser endotérmicas. Esseé um dos principais aspectos que carecem de uma melhor compre-ensão, uma vez que os cálculos existentes [44,45,48,134] riam surgir a partir da captura do elétron por fragmentos gerados da degradação térmica da molécula neutra, embora essa não deva ocorrer na faixa de temperaturas em que as mediadas foram realizadas [48]. A possibilidade usualmente mais creditadaé a de captura eletrônica em bandas vibracionalmente quentes da molécula alvo, onde a energia térmica adicional daria conta de reduzir o threshold de dissociação [48].…”

“…eV abaixo de cálculos anteriores [44,45,48,134], para todas as 5-halouracilas. Considerando que essa estabilizaçãoé superior ao desvio absoluto médio reportado para o método Um dos aspectos mais intrigantes sobre os dados de dissociação das 5-halouracilaś e a ausência do sinal de eliminação de hidrogênio na 5-bromouracila e 5-iodouracila, em contraste aos casos da uracila, 5-fluorouracila e 5-clorouracila.…”

“…Nessa energia, oátomo do hidrogênio elimi- eV, sem correção de energia de ponto zero, próxima dos valores existentes de 0,45 eV [44] e 0,37 eV [45]. Em todos os sistemas, a curvatura do potencial doânion adiabáticoé menor do que a do neutro, na vizinhança do equilíbrio da espécie neutra, e por isso a A medida que o halogênioé afastado de sua posição de equilíbrio, ocorrem uma sequência de mudanças estruturais (ver figura 4.27) e no caráter e energética doânion adiabático.…”