Diheterocyclanes as synthons for the preparation of novel series of nucleoside and acyclonucleoside analogues.
Convenient synthesis of 1-[[3-(2-hydroxyethylhetero)-1-alkoxy]alkyl]-5-fluorouracils 3-8 was accomplished via the use of tin (IV) chloride, capable of a 1,4-chelation on alkoxy-1,4-diheteroepanes. Increasing the reaction time led to 5-FU seven-membered nucleoside analogues which could be considered as upper isosteres of the effective antitumour agent Ftorafur. Using 1-[[3-(2-hydroxyethoxy)-1-alkoxy]propyl]-5-fluorouracil as a parent drug, several chemical modifications on the acyclic moiety were made with the aim of obtaining new compounds showing significant antiproliferative activity in rhabdomyosarcoma (RD) cells. 14 treatment in vitro caused time- and dose-dependent growth inhibition on RD cells. Interestingly, when they were treated with doses of 35 microM and 140 microM of 14 for 6 days, they showed morphological and phetotypic differentiation with increased expression of desmin, alpha-actinin and tropomyosin. We suggest a potential role for differentiation therapy as a therapeutic approach to the treatment of rhabdomyosarcoma.
Campos
J
J
Departamento de Química Orgánica, Facultad de Farmacia, Granada, Spain.
Gómez
J A
JA
Trujillo
M A
MA
Gallo
M A
MA
Espinosa
A
A
Marchal
J A
JA
Aránega
A
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D012208:Rhabdomyosarcoma / Q000188:drug therapy
D000970:Antineoplastic Agents; D009705:Nucleosides