Theoretical study concerning the fragmentation pathways of radical anions of 5-fluorouracil derivatives.

BOROSKY, GABRIELA L.; PIERINI, ADRIANA B.

Lugano

Congreso; 6th World Congress of Theoretically Oriented Chemists, WATOC?02; 2002

WATOC

The release of the typical antitumour drug 5-fluorouracil from its N1-C5-linked dimer has been experimentally observed upon g-irradiation of its oxygen-free aqueous solution [1]. More recently, it was pointed out that the presence of a carbonyl group as substituent at the carbon atom bonded to N1 increases the rate of dissociation [2]. Considering the importance that the knowledge of the factors governing the fragmentation rate of this type of intermediates could have in assisting the development of antitumour drugs we undertook the study of the system. We employed ab initio methods and density functional theory to evaluate the dissociation pathways that may follow the radical anions of type 1, where R1= F, Cl, Br, I, H-C=O, CN, NO2, and R2=R3=H. The effect of different substituents R1 on the kinetic and thermodynamic of the N1-CR1R2R3 bond cleavage was evaluated. Competing fragmentation reactions such as dissociation of the C-R1 bond when R1= halogen, NO2, CN was also calculated. The results are compared with previously reported semiempirical studies [3]. [1]          Nishimoto, S. -I., Hatta, H., Ueshima, H., Kagiya, T., J. Med. Chem. 1992, 35, 2711. [2]          Mori, M., Hatta, H., Nishimoto, S. -I., J. Org. Chem. 2000, 65, 4641. Borosky, G. L., Nishimoto, S. -I., Pierini, A. B., J. Mol. Struct. (Theochem) 2000, 499 (1-3), 151.