Authors: Campos, J.; Dominguez, J.F.; Gallo, M.A.; Espinosa, A.

Source: Current Pharmaceutical Design, Volume 6, Number 18, 1 December 2000 , pp. 1797-1810(14)

Publisher: Bentham Science Publishers

Abstract:

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.

Keywords: Cancer Chemotherapy; 5 fluorouracil; incurable tumors; Multidrug Resistance MDR; Drudg design; fluorinated pyrimidine; pharmacokinetic parameters; Chelation Control; Regiospecificity; chelative Lewis acid; Acyclic Symmetrical; Antitumor Activity; Biological cycle; rhabdomyosarcoma cell line; Fluorescence Activated Cell Sorting; Vimentin and desmin

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612003398627

Publication date: 2000-12-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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