DIHETEROCYCLANES AS SYNTHONS FOR THE PREPARATION OF NOVEL SERIES OF NUCLEOSIDE AND ACYCLONUCLEOSIDE ANALOGS

Convenient synthesis of ydroxyethylhetero)-1-alkoxy]alkyl]-5-fluoroura cils 3-8 was accomplished via the use of tin (IV) chloride, capable of a 1,4-chelation on alkoxy-l,4-diheteroepanes. Increasing the reaction time led to 5-FU seven-membered nucleoside analogues which could be c onsidered as upper isosteres of the effective antitumour agent Ftorafu r. Using -(2-hydroxyethoxy)-1-alkoxy]propyl]-5-fluorouracil as a paren t drug, several chemical modifications on the acyclic moiety were made with the aim of obtaining new compounds showing significant antiproli ferative activity in rhabdomyosarcoma (RD) cells. 14 treatment in vitr o caused time- and dose-dependent growth inhibition on RD cells. Inter estingly, when they were treated with doses of 35 mu M and 140 mu M of 14 for 6 days, they showed morphological and phetotypic differ entiat ion with increased expression of desmin, alpha-actinin and tropomyosin . We suggest a potential role for differentiation therapy as a therape utic approach to the treatment of rhabdomyosarcoma.