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

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 Ca 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 Ca. CEHR2 transfers Ca from an aqueous solution into CHCl to greater extent than alkali metal cations and Mg. It also transfers Ca 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.

Mechanically Interlocked Molecules for Biomedical Applications

“…In a follow‐up study, [27] the same rotaxane and a derivative with a smaller crown ether ( 13 b ) were studied for their toxicity against different types of prostate cancer cells. Prostate cancer metastasizes to skeletal sites where the Ca 2+ concentration can be as high as 40 mM.…”

Supramolecular Rotaxane‐Based Multi‐Modal Probes for Cancer Biomarker Imaging**

“…[10,11] In a biomedical context, supramolecular coordination complexes show promise in several applications [12,13] from cytotoxic drugs [14][15][16] and drug delivery vehicles, [17][18][19] through to biosensors for DNA recognition, [20] and reporter probes for diagnostic molecular imaging. [12] For example, rotaxanes loaded with cytotoxic Pt [14] or Ru [16] complexes, and others capable of selective Ca 2 + ion binding, [15] have displayed antitumour properties against human cancer cells. Rotaxanes have also been engineered with sophisticated drugrelease mechanisms [21,22] that feature enzyme-mediated disassembly and prodrug activation inside tumour cells.…”

Viologen-Based Rotaxanes from Dibenzo-30-crown-10

“…13,14 A rotaxane which selectively complexes Ca 2+ was reported to have potent anticancer properties. 15 The selective shuttling, or switching, behavior of rotaxanes has led to investigation of their use in drug delivery. 16 These hosts have also been used to construct supramolecular polymers 17−22 by self-assembly, which makes more complex topologies and structures accessible, 23 and gives rise to interesting properties, selfhealing, 24,25 and optoelectronic properties, 26 for example.…”

“…Crown ethers have been widely used as hosts in supramolecular chemistry. They have been used as the wheel components in rotaxanes and other interlocked molecular structures with functionalities such as molecular shuttles, molecular switches, − ionic sensors, switchable catalysts, − molecular muscles, , and simple mimics of ribosomes. , A rotaxane which selectively complexes Ca 2+ was reported to have potent anticancer properties . The selective shuttling, or switching, behavior of rotaxanes has led to investigation of their use in drug delivery .…”