These authors contributed equally to this work An antiparallel strand arrangement in water-soluble helicates creates an amphipathic functional topology akin to that of host-defence peptides. High and selective cancer cell line toxicity is exhibited, causing dramatic changes in the cell cycle without DNA damage, and remarkably there is no significant toxicity to MRSA and E. coli.

YesEnantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that\ud of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian\ud carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line\ud HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower\ud than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is\ud probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and\ud intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy\ud and supported by circular/linear dichroism in solution. Selectivity for 50-CACATA and 50-CACTAT\ud segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are\ud stabilised, and remarkably only the L metallo-helix enantiomer stabilizes T-shaped 3WJs during gel\ud electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide\ud duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the\ud number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible\ud metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the\ud cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all\ud compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage\ud occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase,\ud and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together\ud these screening and mechanistic results are consistent with the more rigid helices acting via a DNA\ud binding mechanism while the flexible assemblies do not

New optically pure helicate-like architectures are extremely active against cancer cell lines, with IC50 values as low as 40 nM, but nearly three orders of magnitude less active against healthy cells. There is also low toxicity to microbes and amoeba.