Ca2+ Selective Host Rotaxane Is Highly Toxic Against Prostate Cancer Cells

David B Smithrud; Lucas Powers; Jennifer Lunn; Scott Abernathy; Michael Peschka; Shuk-Mei Ho; Pheruza Tarapore

doi:10.1021/acsmedchemlett.6b00347

Ca²⁺ Selective Host Rotaxane Is Highly Toxic Against Prostate Cancer Cells

ACS Med Chem Lett. 2017 Jan 4;8(2):163-167. doi: 10.1021/acsmedchemlett.6b00347. eCollection 2017 Feb 9.

Authors

David B Smithrud¹, Lucas Powers¹, Jennifer Lunn¹, Scott Abernathy¹, Michael Peschka¹, Shuk-Mei Ho², Pheruza Tarapore³

Affiliations

¹ Contribution from the Department of Chemistry, University of Cincinnati , Cincinnati, Ohio 45221, United States.
² Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, United States; Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, United States; Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, United States; Cincinnati Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, Ohio 45220, United States.
³ Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, United States; Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, United States; Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, United States.

Abstract

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: Prostate cancer; calcium; crown ethers; rotaxanes.

Grants and funding

P30 ES006096/ES/NIEHS NIH HHS/United States