Neighbouring-group participation as the key step in the reactivity of acyclic and cyclic salicyl-derived O,O-acetals with 5-fluorouracil.: Antiproliferative activity, cell cycle dysregulation and apoptotic induction of new O,N-acetals against breast cancer cells

The reaction between o- (hydroxymethyl)phenoxyacetaldehyde dimethyl acetals, or 3-methoxy-2,3-dihydro-5H-1,4-benzodioxepins with 5-fluorouracil (5-FU), has been studied. The intramolecular cyclization may be explained through a neighboring group attack to give a 2-(5-fluorouracil-1-yl)oxyranium ion that can be attacked by the silylated benzylic hydroxy group to yield the benzannelated seven-membered O,N-acetals. The formation of a macrocyclic trans-bis(5-FU O,N-acetal) is also reported. Such a compound arrested the human MCF-7 breast cancer cells at the G(o)/G(1) phase of the cell cycle. On the contrary, the acyclic nitro O,N-acetal seems to work as a 5-FU prodrug, because it arrested cancer cells at the S phase as the well-known prodrug Ftorafur does. (C) 2003 Elsevier Ltd. All rights reserved.