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Crown Ether Host-Rotaxanes as Cytotoxic Agents.

ABSTRACT: 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 ?M and 6 ?M, 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.

SUBMITTER: Smithrud DB

PROVIDER: S-EPMC3607455 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Crown Ether Host-Rotaxanes as Cytotoxic Agents.

Smithrud David B DB Wang Xiaoyang X Tarapore Pheruza P Ho Shuk-Mei SM

ACS medicinal chemistry letters 20121108 1

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 Mg<sup>2+</sup> or Ca<sup>2+</sup> on toxicity was explored because changes in the intracellular concentration of these cati ...[more]

PMID: 23538490

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