Medium benzene-fused oxacycles with the 5-fluorouracil moiety: synthesis, antiproliferative activities and apoptosis induction in breast cancer cells

On the basis of the increase in lipophilicity, novel benzannelated six- and seven-membered derivatives have been synthesized, starting from 2-hydroxybenzyl alcohols, 2-hydroxybenzaldehydes, and catechol. The X-ray structure of (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil () is presented and compared with its conformational analysis at the semiempirical (AM1) and ab initio (6-31G∗) levels and NOE effects. A good agreement between both experimental and theoretical data was found showing a chair conformation for the 2,3-dihydro-5H-1,4-dioxepin ring and an axial orientation of the 5-FU moiety on the C3 position. Compounds and (RS)-1-(7-methoxy-2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil () were found to be the most potent inhibitor of MCF-7 cells growth. (RS)-1-(2,3-Dihydrobenzoxepin-2-yl)-5-fluorouracil () induced apoptosis up to 57.33% of cell population after 24 h.