Radiosynthesis of various pyrimidine derivatives and determining their uptake into cells

Abstract

N3-substituted pyrimidine nucleoside derivatives containing either an iodovinyl moiety or an allyl group, i.e. [121]-N3-(3-iodoprop-2-en- l -yl)thymidine, (1~-711 and e21]-N3-(prop-2-enl- yl)-5-iodo-Z'-deoxyuridine, (1~_10, were synthesised and preliminarily evaluated by determining their uptake into CHO-Kl cells. Compound e~-711 was designed to be a delivery vector of 121: into the DNA of the cells, while (1~_10 was designed to serve as a control. Compound (1231]-711 was also intended to have a higher metabolic radiochemical stability than 5-iodo-Z'-deoxyuridine ([123I]_IUdR) for the therapeutic use in cancer. The synthesis of the N3-substituted intermediate precursors 411, 5 and 9 was achieved by Nalkylation of suitably' protected thymidine and 5-iodo-Z'-deoxywidine analogues, respectively. The intmediate precursors for radiolabelling, 411 and 11, were obtained by incorporating a trialkylstannyl group at the respective labelling positions prior to radioidination. (1~1-711 was recovered from (1~_6G after acid-hydrolysis of the protecting groups and 10 was obtained from direct oxidative iodination of11. The radiochemical yields ranged from 73% to 91% at the end ofthe synthesis and radiochemical purities were in excess of99"10 after HPLC purification. The cell-uptakes ofthe radiotracers were carried out and assessed by a direct comparison with the gold standard e23I]-IUdR, which is known to bephosphorylated and incorporated into the DNA of cells during the cells S-phase. The cell-uptake results of (1~_711 and (1~-10 were roughly 4% and 3% relative to [123I]-IUdR, respectively. The poor cell-uptake of (1~_10 suggested thatthe uptake into the cells is not influenced by the position of the iodine atom in the molecule, but most probably by the availability of the N3-position in its non-substituted form. As a result of its poor incorporation into cells, it was concluded that the synthesised radiotracer (1231]_711 would be a poor candidate for use in the eradication ofmalignant cells.