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.
Current Pharmaceutical Design
Title: From a Classic Approach in Cancer Chemotherapy Towards Differentiation Therapy: Acyclic and Cyclic Seven-Membered 5-Fluorouracil O,N-Acetals
Volume: 6 Issue: 18
Author(s): J. Campos, J. F. Dominguez, M. A. Gallo and A. Espinosa
Affiliation:
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.
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Campos J., Dominguez F. J., Gallo A. M. and Espinosa A., From a Classic Approach in Cancer Chemotherapy Towards Differentiation Therapy: Acyclic and Cyclic Seven-Membered 5-Fluorouracil O,N-Acetals, Current Pharmaceutical Design 2000; 6 (18) . https://dx.doi.org/10.2174/1381612003398627
DOI https://dx.doi.org/10.2174/1381612003398627 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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