Optically pure heterobimetallic helicates from self-assembly and click strategies

Single diastereomer, diamagnetic, octahedral Fe(II) tris chelate complexes are synthesised that contain three pendant pyridine proligands pre-organised for coordination to a second metal. They bind Cu(I) and Ag(I) with coordination geometry depending on the identity of the metal and the detail of the ligand structure, but for example homohelical (ΔFe,ΔCu) configured systems with unusual trigonal planar Cu cations are formed exclusively in solution as shown by VT-NMR and supported by DFT calculations. Similar heterobimetallic tris(triazole) complexes are synthesised via clean CuAAC reactions at a tris(alkynyl) complex, although here the configurations of the two metals differ (ΔFe,ΛCu), leading to the first optically pure heterohelicates. A second series of Fe complexes perform less well in either strategy as a result of lack of preorganisation

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

Amphipathic α-helix mimetics through asymmetric self-assembly on a metal scaffold

Chapter 1 | Reviews innate host-defence α-helices and their mimetics as potential anticancer chemotherapeutics. Introduces biologically relevant bimetallic triple metallohelices as potential non-peptide mimics, and reviews the known flexicates. Discusses the criteria such compounds would need to satisfy in order to be successful anticancer agents. Chapter 2 | Describes the discovery, synthesis and characterisation of nineteen new class Ib flexicates with varying ligand functionality. These compounds are found to be highly active and selective in cancer, with no observed activity in bacteria. Preliminary modes of action studies indicate that they do not act through DNA interactions, but cause changes to the cell cycle and induce programmed cell death. Chapter 3 | Describes the conception, synthesis and characterisation of a new asymmetric type of architecture, named a triplex metallohelix. A range of these novel complexes are found to be highly active and selective in several cancer cell lines. Possible modes of action found the triplex metallohelices do not bind or damage DNA, but do cause changes to the cell cycle, induce programmed cell death and appear to localise on the cellular membrane of colon cancer cells. Chapter 4 | Summarises the aims and results of this research project and concludes this work by discussing the perspectives of the novel metallohelices described as α-helix mimetics. Final remarks consider some possible directions that this research could take in the future. Chapter 5 | Provides details of the experimental procedures used to carry out the work in this thesis

Data for Anticancer metallohelices : nanomolar potency and high selectivity

A range of new helicate-like architectures have been prepared via highly diastereoselective self-assembly using readily accessible starting materials. Six pairs of enantiomers [Fe2L3]Cl4.nH2O (L = various bidentate ditopic ligands NN–NN) show very good water solubility and stability. Their activity against a range of cancer cell lines in vitro is structure-dependent and gives IC50 values as low as 40 nM. In an isogenic pair of HCT116 colorectal cancer cells, preferential activity was observed against cell lines that lack functional p53. Selectivity is also excellent, and against healthy human retinal pigment epithelial (ARPE19) and lung fibroblast (WI38) cells IC50 values are nearly three orders of magnitude higher. Cisplatin is unselective in the same tests. The compounds also appear to have low general toxicity in a number of models: there is little if any antimicrobial activity against Methicillin-resistant Staphylococcus aureus and Escherichia coli.; Acanthamoeba polyphaga is unaffected at 25 μg ml -1 (12.5 μM); Manduca sexta larvae showed clear evidence of systemic distribution of the drug, and rather than any observation of adverse effects they exhibited a significant mean weight gain vs controls. Investigation of the mode of action revealed no significant interaction of the molecules with DNA, and stimulation of substantial cell death by apoptosis