Propargylic Sulfone-Armed Lariat Crown Ethers: Alkali Metal Ion-Regulated DNA Cleavage Agents

Abstract

Alkali metal ion concentrations within cells are regulated during the cell cycle and may be significantly altered in cancer cells versus normal cells. Thus, the selective destruction of cancer cells might be achieved by agents that marry alkali metal ion recognition elements, such as crown ethers, with DNA-cleaving moieties. We have prepared a series of propargylic sulfone-armed lariat crown ethers, which bind sodium and potassium ions and exhibit little affinity for lithium ions, as determined by a picrate extraction assay. We have investigated the supercoiled DNA cleavage efficiency of these lariat crown ethers in the presence of various alkali metal ions. Monomeric propargylic sulfone-armed crown ethers 9b and 10b cleave DNA at physiologically relevant pH and exhibit modest increases in DNA cleavage efficiency in the presence of potassium and sodium as compared to lithium. In Tris-containing buffer, the monomeric lariat crown ether 10b cleaves DNA in a sodium ion-dependent fashion, producing 66% more DNA cleavage in the presence of 5.7 mM sodium than in the absence of added sodium. The dimeric propargylic sulfone-armed lariat crown ether 11 cleaves DNA over 10-fold better in the presence of potassium than in the presence of lithium. While the level of metal ion discrimination exhibited by these compounds is rather modest, they do represent the first successful attempt to marry molecular recognition of specific alkali metal ion with covalent modification of DNA.