Small cationic a-helical peptides are emerging as agents for the treatment of cancer and infection, but are costly and suffer from unfavourable pharmacokinetics. Helical multimetallic architectures (helicates) may provide a suitably-sized scaffold for synthetic peptidomimetics, and some display relevant biological activity, but their high symmetry and modest functionality offers little scope to address biolomolecular targets. We have now established a highly stereoselective self-assembly of functionally diverse, asymmetric 'triplex' metallohelices with - like triplex DNA architectures - antiparallel arrangement of the strands. A modular sub-component self-assembly has allowed us to produce what we believe to be the most functionally diverse library of metallohelices to date, and these potential recognition elements are arranged � as confirmed by solution structural studies � by the nature of the helix fold. We believe that this takes us a significant step towards peptide a-helix-like candidates for biochemical targets in proteins and nucleic acids. Stabilised by a range of hydrophobic intramolecular interactions, these foldamers are unusually soluble and stable in biological media, with amphipathic structures akin to the active sub-units in e.g. host-defence peptides and p53. They display very high structure-dependent toxicity to human colon carcinoma cell-line HCT116 p53++ causing dramatic changes in the cell cycle population, but no DNA damage. They have rather lower toxicity to MDA-MB-468 (human breast adenocarcinoma), and remarkably they show no significant toxicity to the bacteria MRSA (USA300) and E. coli (TOP10).

Asymmetric peptidomimetic "triplex" metallohelices with high and selective activity against cancer cells

248th National Meeting (2014)

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