Search for: All records

Deferasirox (Def), an orally administered iron‐chelating drug, has drawn significant interest in repurposing for anticancer application due to the elevated Fe demand by cancer cells. But there are also concerns about its severe off target health effects. Herein Cu(II) binding is studied as a potential off target interaction. The aqueous solution stability and speciation of the ternary complex Cu(Def)(pyridine) was studied by UV‐Vis and EPR spectroscopy, ESI‐mass spectrometry, and cyclic voltammetry under physiologically relevant conditions. The complex is observed to be a redox active, mononuclear Cu(II) complex in square planar geometry. UV‐Vis spectroscopy demonstrates that at pH 7.4 the complex is quite stable (ϵ337nm =10,820 M^−1cm^−1) with a log K=16.65±0.1. Cu scavenging from the Cu transporters ceruloplasmin and albumin was also studied. Def does not inhibit ceruloplasmin activity but forms a ternary Cu(II) complex at the bovine serum albumin ATCUN site. Cu(Def)(py) displays potent but nonselective cytotoxicity against A549 cancer and MRC‐5 noncancer lung cells but the potency of the ternary protein complex was more moderate. This work elucidates potential Def toxicity from Cu complexation in the body but also cytotoxic synergy between the metal and chelator that informs on new drug design directions. 

Classical antibacterial drugs were designed to target specific bacterial properties distinct from host human cells to maximize potency and selectivity. These designs were quite effective as they could be easily derivatized to bear next-generation drugs. However, the rapid mutation of bacteria and their associated acquired drug resistance have led to the rise of highly pathogenic superbug bacterial strains for which treatment with first line drugs is no match. More than ever, there is a dire need for antibacterial drug design that goes beyond conventional standards. Taking inspiration by the body’s innate immune response to employ its own supply of labile copper ions in a toxic attack against pathogenic bacteria, which have a very low Cu tolerance, this review article examines the feasibility of Cu-centric strategies for antibacterial preventative and therapeutic applications. Promising results are shown for the use of Cu-containing materials in the hospital setting to minimize patient bacterial infections. Studies directed at disrupting bacterial Cu regulatory pathways elucidate new drug targets that can enable toxic increase of Cu levels and perturb bacterial dependence on iron. Likewise, Cu intracellular chelation/prochelation strategies effectively induce bacterial Cu toxicity. Cu-based small molecules and nanoparticles demonstrate the importance of the Cu ions in their mechanism and display potential synergism with classical drugs.