Novel derivatives of
5-fluorouracil (5-FU) possessing a broader spectrum of antitumor activity and fewer toxic side effects than
5-FU have been sought. Herein, we report three different types of
5-FU O,N-
acetals: a) a novel class of
5-fluorouracil-containing acyclonucleosides. The antitumor activities of such compounds were assessed against HEp human cells showing that (RS)-1-¿[3-(2-hydroxyethoxy)-1-cyclopentoxy]propyl¿-
5-fluorouracil 3c is 4-fold more active than 5-FU. (RS)-1-¿[3-(2-hydroxyethoxy)-1-isopropoxy]propyl¿-
5-fluorouracil 3b has important potential advantages over 5-FU because of its lower toxicity and its ability to induce myogenic differentiation in
rhabdomyosarcoma cells. Our results suggest that this
drug may be useful for differentiation
therapy in this type of
tumor; b) within the cyclic
prodrugs of 5-FU, a series of new ring-expanded isosteres (1,4-oxaheteroepanes) of
Ftorafur were synthesized. The level of diastereoselectivity in the preparation of cis and trans 1-(3-chloromethyl)-1,4-dioxepan-5-yl)-
5-fluorouracil, although modest, suggests a potentially general approach for controlling the stereochemistry of this unexplored class of reactions involving the preparation of 5-FU seven-membered O,N-
acetals; c) new 5-FU acyclic analogs containing two 5-FU moieties at both ends of the molecules with a linker having two
amide bonds have been designed and synthesized. These bis(5-FU-O,N-
acetals) show interesting
antineoplastic activities against the HT-29 cell line.