Crown Ether Host-Rotaxanes as Cytotoxic Agents

Highly toxic bacterial ionophores are commonly used in veterinary medicine, but their therapeutic index is too narrow for human usage. With the goal of developing ionophores with a broader therapeutic index, we constructed highly derivatized synthetic ionophores. The toxicities of crown ether host-rotaxanes (CEHRs) against the SKOV-3 cell line were measured. The effect of Mg 2+ or Ca 2+ on toxicity was explored because changes in the intracellular concentration of these cations can cause cell death through apoptosis. We found that Boc-CEHR is highly toxic and Arg-CEHR is slightly less toxic with IC 50 values of 0.5 and 6 μM, respectively, in standard growth medium. Increasing the concentration of Ca 2+ resulted in greater toxicity of the CEHRs, whereas increasing the concentration of Mg 2+ was less effective on reducing IC 50 . Cell death occurs mainly through apoptosis. Although preliminary, these results suggest that the CEHRs deliver Ca 2+ and perhaps Mg 2+ into cells inducing apoptosis.