Abstract
meso-(p-acetamidophenyl)-calix[4]pyrrole 3 was found to exhibit remarkable cytotoxicity towards A549 cancer cells. A comparative study including the isomer of 3 meso-(m-acetamidophenyl)-calix[4]pyrrole 5, as well as molecules containing ‘fragments’ of these structures, demonstrated that both the calix[4]pyrrole and the acetamidophenyl units are essential for high cytotoxicity. Although calix[4]pyrroles and other anion-complexing ionophores have recently been reported to induce apoptosis by perturbing cellular chloride concentrations, in our study an alternative mechanism has emerged, as proven by the isolation of covalent DNA adducts revealed by the 32P postlabelling technique. Preliminary pharmacokinetic studies indicate that 3 is able to cross the Blood-Brain-Barrier, therefore being a potential drug that could kill primary and brain metastatic cancer cells simultaneously.
Introduction
Calix[n]pyrroles are macrocyclic compounds made up of pyrrole units linked at their 2,5-positions by quaternary carbon atoms1. meso-Octamethyl-calix[4]pyrrole 1 (Fig. 1) has been known for over a century2, but interest in this compound (and its congeners) rapidly developed only following the discovery of its ability to form complexes with anions3 and neutral molecules4 that can accept hydrogen bonds from the pyrrole NH units. Since these seminal papers, a vast number of calixpyrrole derivatives have been synthesised and investigated as selective ligands for different anions1,5, for sensing applications6, in the assembly of novel materials7,8 and devices9,10. When developing our early work on heterocyclophanes11 and calixarenes12 that can bind biologically relevant species, we reported the ability of meso–p-aminophenylcalix[4]pyrrole 2 to form a cytotoxic trans-Pt(II) complex in which the calix unit appears to assist the delivery of the toxic metal to DNA via the preliminary binding of the phosphate residues13. In this work, we propose a mechanism by which ‘free’ non-Pt(II) coordinated calixpyrrole 2 is released within the cell when the metal leaves the aminophenyl coordination site of 2 to form new bonds with nitrogen atoms of the nucleobases. Since tests conducted with ‘free’ 2 did not reveal any significant cytotoxicity when this was used at concentrations analogous to that of its Pt(II) complex, it was evident that 2 acted merely as a vector capable of delivering the toxic metal to DNA. To the best of our knowledge, this is the first report on the use of a calixpyrrole derivative for potential biomedical applications as a drug-delivery system.