Novel Functionalized Calixarenes as Host Molecules for Complexation with Alkaline Earth Metals

Alpha-emitting radionuclides (e.g. radium-223, 224) are of high interest for cancer therapy, but currently, no stable complexing agent for radium is known. Moderate stability constants have been described for complexes of alkaline-earth metal ions with calixarenes, crown and aza crown ethers [2, 3]. By combining calixarenes with crown and aza crown ethers as well as functionalizing the remaining calixarene hydroxyl groups, higher stability constants may be achieved. In this study, we synthesized and evaluated new functionalized calixarenes as host molecules for radium. 1,3 single-bridged crowns were selectively introduced on the lower rim of 4-tert-Butylcalix[4]arene by alkylation with tosylated crown ethers or by acylation and sequential amination with aza crown ethers. The remaining phenolic hydroxyl groups were functionalized by acylation and sequential amination to prepare acetic acid amide and hydroxyl amide derivatives. The complexation was carried out by vortexing the ligand in chloroform with an aqueous BaCl2-solution as surrogate for Ra for 10 min. The barium complex was isolated from the organic layer and characterization was performed by NMR. The barium-133 and radium-224 calixcrowns were prepared similarly and stability studies performed by TLC and HPLC. 1,3-bridged crown and calix(aza)crown ethers were obtained in good yields (53 and 58%, respectively) and acetic acid amide and hydroxyl amide calixcrown derivatives were successfully prepared with yields of 66-82%. Barium was incorporated into the calixarene compounds, isolated by a two-phase extraction and the structure confirmed by NMR. Synthesis and stability of the radioactive complexes will be reported. Future studies will incorporate a targeting moiety on the upper ring. Several novel, functionalized calixarene compounds were prepared and initial complexation studies were performed with nonradioactive barium. The resulting complexes were checked by NMR and the procedure was transferred to radioactive barium-133 and radium-224. Complexation and stability was demonstrated by radiographic imaging of the developed TLC plates. These complexes show great promise for application to cancer therapy.