Novel analogues of 5-fluorouracil - Synthesis, X-ray crystallography, and cytotoxic effects in normal human peripheral blood lymphocytes and colon adenocarcinoma Ht 29

The aim of many studies is to discover new chemicals as potential antitumor agents. We have prepared novel analogues of 5-fluorouracil (5-Fu): 5-uracilmethylphosphonic acid (5-umpa), dimethyl 5-uracilmethylphosphonate (5-umpm), diethyl 5-uracilmethylphosphonate (5-umpe) and a K⁺ (K ⁺/5-umpa, 1) and Na⁺ (Na⁺/5-umpa, 2) complex of 5-umpa. Complexes 1 and 2 have infinite chain structures built up by H-bonded pairs of 5-umpa- and {(H₂O)K(μ-OH₂) ₃K(OH₂)}²⁺ and {(H₂O) ₂Na(μ-OH₂)₂Na(OH₂) ₂}²⁺ entities. The alkali metal ions bind directly to the exocyclic oxygen atoms O(2) and O(4) of the nucleobase moiety and indirectly, i.e. through hydrogen-bond interactions involving metal-coordinated water molecules, to the phosphonate group. The new derivatives were tested for their antiproliferative and cytotoxic effects on normal human peripheral blood lymphocytes and HT 29 cancer lines in vitro using the tetrazolium salt (MTT) assay. The IC₅₀ values were evaluated (the drug concentration inhibiting 50 % of the cell growth after 72 h exposure of cells to the drug). The results indicate that 5-umpa, 5-umpm, 5-umpe, and the K⁺ and Na⁺ complexes of 5-umpa do not exert toxic effects on regular lymphocytes and on the colon adenocarcinoma HT 29 cell line (IC₅₀ > 1 mM), in comparison with 5-Fu. However, an atypical course of survival curves was observed after treatment of HT 29 cells with 5-umpa, 5-umpm and the Na⁺ complex of 5-umpa. These observations suggest that it is very important to continue the studies in different biological systems in vitro and in vivo using various experimental protocols.