On the basis of the ionophore model, polyether analogues 4 and 6 were designed and synthesized to mimic the naturally occurring annonaceous acetogenins corossolin (2) and bullatin (5), which were discovered as members of a large family of novel polyketides with cytotoxicity, antitumoral, and other biological activities since 1982. The preliminary screening shows that they have compatible cytotoxicity with the corresponding natural annonaceous acetogenins. These results open a potential way to find more active antitumor agents with simplified structures based on natural annonaceous acetogenins.