From a classic approach in cancer chemotherapy towards differentiation therapy: acyclic and cyclic seven-membered 5-fluorouracil O,N-acetals.
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.
Campos
J
J
Discipline of Clinical Pharmacology, School of Population Health Sciences, Faculty of Medicine and Health Sciences, The University of Newcastle, New South Wales, Australia.
Domínguez
J F
JF
Gallo
M A
MA
Espinosa
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D015195:Drug Design; D005472:Fluorouracil / Q000031:analogs & derivatives*; D019073:HT29 Cells; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005472:Fluorouracil