Quadruply Stranded Metallo-Supramolecular Helicate [Pd₂(hextrz)₄]⁴⁺ Acts as a Molecular Mimic of Cytolytic Peptides

Abstract

Metrics & MoreArticle RecommendationsABSTRACT: [Pd 2 (hextrz) 4 ] 4+ is a quadruply stranded helicate, a novel bioinorganic complex designed to mimic the structure and function of proteins due to its high stability and supramolecular size.We have previously reported that [Pd 2 (hextrz) 4 ] 4+ exhibited cytotoxicity toward a range of cell lines, with IC 50 values ranging from 3 to 10 μM. Here we demonstrate that [Pd 2 (hextrz) 4 ] 4+ kills cells by forming pores within the cell membrane, a mechanism of cell death analogous to the naturally occurring cytolytic peptides.[Pd 2 (hextrz) 4 ] 4+ induced cell death is characterized by an initial influx of Ca 2+ , followed by nuclear condensation and mitochondrial swelling. This is accompanied by progressive cell membrane damage that results in the formation of large blebs at the cell surface. This allows the efflux of molecules from the cell leading to loss of cell viability. These data suggest that it may be possible to design metallo-supramolecular complexes to mimic the cytotoxic action of pore forming proteins and peptides and so provide a new class of drug to treat cancer, autoimmune disorders, and microbial infection.

High‐Throughput Computational Evaluation of Low Symmetry Pd2L4Cages to Aid in System Design**

“…Since first being reported over twenty years ago, [4] lantern‐type Pd 2 L 4 cages,[ 5 , 6 , 7 ] assembled from “naked” Pd II ions and ditopic ligands (L), have become an extensively studied class of metal‐organic polyhedra (MOPs). [ 8 , 9 , 10 , 11 , 12 ] Wide‐ranging applications for these cages have been investigated, including in drug delivery,[ 13 , 14 , 15 ] biomedicine,[ 16 , 17 , 18 , 19 , 20 , 21 ] catalysis,[ 22 , 23 , 24 , 25 ] and guest encapsulation/recognition. [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ] To simplify the self‐assembly process, most previous reports have focussed on high‐symmetry systems derived from single, symmetrical ligands.…”

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity

“…Others have examined DNA binding and nuclease activity ( Childs et al, 2006 ), and the cytotoxicity of related double-stranded complexes ( Holtze et al, 2006 ; Allison et al, 2018 ). In addition, quadruple-stranded helicates have been shown to be cytotoxic ( Mcneill et al, 2015 ; Ahmedova et al, 2016a ; Ahmedova et al, 2016b ; Schmidt et al, 2016 ; Vasdev et al, 2018 ; Ahmedova et al, 2020 ) and in some cases the modes of action of the complexes have been studied ( Mcneill et al, 2020 ).…”

Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host–guest chemistry

“…These shifts are consistent with hydrogen bonding between the chloride ligands of CP and the α-protons of the pyridyl groups (H a ) of HC . 20–24 Additionally, the amide proton (H i ) also shifts upon the additional of the CP consistent with a hydrogen bonding interaction between the amide CO units and the ammine ligands of the CP. CP did not show any sign of interaction with the small IC system.…”

“…17–19 Furthermore, M 2 L 4 systems have shown potential as biomedical therapeutics and drug delivery systems. 20–24…”