Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(ii)- and even Zn(ii)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(ii) system are dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.

Department of Chemistry University of Warwick Coventry CV4 7AL UK Email

School of Applied Sciences University of Huddersfield Huddersfield HD1 3DH UK

The Czech Academy of Sciences Institute of Biophysics Kralovopolska 135 CZ 61265 Brno Czech Republic

Warwick Medical School University of Warwick Coventry CV4 7AL UK

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