From 5-fluorouracil acyclonucleosides to benzo-fused six- and seven-membered rings linked to pyrimidine and purine bases: the shift from differentiating anticancer agents to apoptotic inducers

Abstract

Background: (RS)-1-{[3-(2-Hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil proved to be a good differentiating agent against rhabdomyosarcoma cells. Objective: As lipophilicity is known to affect the anticancer activity, the synthesis of a wide range of 5-fluorouracil derivatives linked to benzo-fused seven-membered rings was undertaken. Methods: The decision was then made to change 5-fluorouracil for uracil, with the prospect of finding an antiproliferative agent endowed with a new mechanism of action. Later on, pyrimidines were substituted for purines. Completing a structure–activity relationship study, a series of isosteric seven-membered derivatives were prepared. Results/conclusion: Finally, molecules were designed in which both structural entities (such as the benzoheterocycle and the purine) were linked through a strong C–C bond. The anticancer activity for the most active compounds was correlated with their capability to induce apoptosis.

Keywords::

• 5-fluorouracil
• apoptosis
• benzo-fused six- and seven-membered rings
• breast cancer
• differentiation
• purines
• pyrimidines