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 (CEHR's) against the SKOV-3 cell line were measured. The effect of Mg²⁺ or Ca²⁺ on toxicity was explored because changes in the intracellular concentration of these cations can cause cell death through apoptosis. We found Boc-CEHR is highly toxic and Arg-CEHR is slightly less toxic with IC₅₀ values of 0.5 μM and 6 μM, respectively, in standard growth medium. Increasing the concentration of Ca²⁺ resulted in greater toxicity of the CEHRs, whereas increasing the concentration of Mg²⁺ was less effective on reducing IC₅₀. Cell death occurs mainly through apoptosis. Although preliminary, these results suggest that the CEHRs deliver Ca²⁺ and perhaps Mg²⁺ into cells inducing apoptosis.