New therapies are needed to eradicate androgen resistant, prostate cancer. Prostate cancer usually metastasizes to bone where the concentration of calcium is high, making Ca2+ a promising toxin. Ionophores can deliver metal cations into cells, but are currently too toxic for human use. We synthesized a new rotaxane (CEHR2) that contains a benzyl 15-crown-5 ether as a blocking group to efficiently bind Ca2+. CEHR2 transfers Ca2+ from an aqueous solution into CHCl3 to greater extent than alkali metal cations and Mg2+. It also transfers Ca2+ to a greater extent than CEHR1, which is a rotaxane with an 18-crown-6 ether as a blocking group. CEHR2 was more toxic against the prostate cancer cell lines PC-3, 22Rv1, and C4-2 than CEHR1. This project demonstrates that crown ether rotaxanes can be designed to bind a targeted metal cation, and this selective cation association can result in enhanced toxicity.Keywords: calcium; crown ethers; Prostate cancer; rotaxanes;

For the past eight years, we have used online homework software as a pedagogical tool for undergraduate students (almost all are second-year students) learning organic chemistry. Being strong proponents of homework, we were surprised to find that about half of the students who complete 90% or more of the online homework assignments received less than 50% of the available points on examinations, even though comparable problems were given. Students who combined traditional pencil–paper problem solving with the online software performed better than students who solely used the online homework package. Our findings contribute to the ongoing debate between pencil–paper and computer learning with the recommendation that they should be combined to provide students with the ultimate learning tool.

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 Mg2+ or Ca2+ 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 IC50 values of 0.5 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.Keywords: apoptosis; calcium; crown ethers; magnesium; rotaxanes

Cytotoxic agents that specifically target cancer cells are in high demand. Modifying drugs with targeting groups however, can produce deleterious effects on drug pharmokinetics. In this study, platinum (Pt) was linked with host-rotaxanes to discover the effect on the cytotoxicity of Pt when carried by a highly modified rotaxane as a ligand. One host-rotaxane (Pt-BocRot) contains the basic components of a rotaxane: wheel (with a Boc protecting group), axle, and blocking group. A second rotaxane (Pt-ArgRot) contains arginine moieties on its wheel instead to potentially improve association with the phosphate groups on cell membranes or DNA backbone. The cytotoxicities of the rotaxanes and various model compounds were determined using ovarian cancer SKOV-3 cell line, which is resistant to cisplatin. We found Pt-ArgRot was slightly more cytotoxic than Pt-BocRot. Both were clearly more cytotoxic than rotaxanes without Pt and the model compounds. As importantly, they killed cells through an apoptotic mechanism. These results suggest that targeting agents for a particular cell type can be incorporated with Pt-complexes using the rotaxane architecture to improve drug specificity.

Proteins can reduce the entropic penalty for ligand association through a favorable change in configurational entropy. To investigate this process, the ΔGo, ΔHo, and ΔSo of complexes formed between host-rotaxanes and guests were determined and compared to discover the relationship between rotaxane-structure and the energies involved in guest-association in water and DMSO. Fluorescence quenching assays provided the association constants. Van't Hoff analysis of variable temperature assays gave the enthalpies of binding. The driving force for the association of a guest and a host-rotaxane can switch from being enthalpically to entropically driven with a change in the solvent or guest. This study shows that a dramatic increase in the entropy of binding can be obtained through the addition of a rotaxane-wheel to a synthetic host. An increased motion of the wheel appears to be the source of the positive binding entropy, which would be an example of favorable configurational entropy promoting complex formation.

Proteins can reduce the entropic penalty for ligand association through a favorable change in configurational entropy. To investigate this process, the ΔGo, ΔHo, and ΔSo of complexes formed between host-rotaxanes and guests were determined and compared to discover the relationship between rotaxane-structure and the energies involved in guest-association in water and DMSO. Fluorescence quenching assays provided the association constants. Van't Hoff analysis of variable temperature assays gave the enthalpies of binding. The driving force for the association of a guest and a host-rotaxane can switch from being enthalpically to entropically driven with a change in the solvent or guest. This study shows that a dramatic increase in the entropy of binding can be obtained through the addition of a rotaxane-wheel to a synthetic host. An increased motion of the wheel appears to be the source of the positive binding entropy, which would be an example of favorable configurational entropy promoting complex formation.