Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks

Abstract

Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination and repair) and are dynamic structures which adopt either open or closed conformations, with the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core giving them an ideal structure to interact with the central cavities of open DNA junctions. Combining experimental studies and MD simulations we show that an Au pillarplex can bind DNA 4-way junctions (Holliday junctions) in their open form, a binding mode not accessed by synthetic agents before. The Au pillarplexes can bind designed 3-way junctions too but their large size leads them to open up and expand that junction, disrupting the base pairing which manifests in an increase in hydrodynamic size and a lower junction thermal stability. At high loading they re-arrange both 4-way and 3-way junctions into Y-shaped DNA forks to increase the available junction-like binding sites. The structurally related Ag pillarplexes show similar DNA junction binding behaviour, but a lower solution stability. This pillarplex binding contrasts with (but complements) that of the metallo-supramolecular cylinders, which prefer 3-way junctions and we show can rearrange 4-way junctions into 3-way junction structures. The ability of pillarplexes to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures where they are key interconnecting components. Studies in human cells, confirm that the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction-binders into organometallic chemistry.

Metals in Cancer Research: Beyond Platinum Metallodrugs

“…In this area, a new class of cationic supramolecular organometallic complexes (SOCs), 97 named pillarplexes, 102 has recently been reported to bind open DNA four-way Holliday junctions, creating exciting possibilities to modulate and switch such structures in biology. 103 In general, based on these intriguing results, we expect that supramolecular approaches in medicinal inorganic chemistry will foster further attention.…”

Prokaryotic DNA Crossroads: Holliday Junction Formation and Resolution

“…225 Given the widespread occurrence of HJs throughout the genome, recent studies have started to emerge, with a focus on the HJ structure as a pivotal target molecule. 223,224,226 While bioactivity research on HJs has been extensively characterized through biochemical and structural studies in eukaryotic paradigms, its extension to prokaryotes remains largely underexplored. For instance, the application of AS1411modified HJs in the form of aptamers demonstrated a targeted delivery of doxorubicin specifically to murine colon cancer cells in vitro.…”

A Golden Touch in the Design of Porphyrin Metallacages as Multifaceted Anticancer Agents

“…[39] Using NHC ligands, another family of gold-based 3D-SCCs, the so-called pillarplexes, has been proposed as 4-way junction DNA stabilizers and studied for their anticancer effects in vitro. [40] Besides the use of more stable organometallic Au-C bonds, chelation is a main strategy to stabilize gold ions in biological media, in particular in the oxidation state 3+. Amongst the chelating ligands, porphyrins have been successfully combined with Au(III) ions, [41][42][43][44] in some instances achieving potent antiproliferative agents endowed with a dual mode of action (MoA), [10,[44][45][46] based on both the potent anticancer activity of the gold center coupled to the remarkable photosensitizer properties of the free ligands for their use in photodynamic therapy (PDT).…”