Triplex metallohelices: new potent and selective compounds against colon cancer

Triplex metallohelices: new potent and selective compounds against colon cancer
R. A. Kaner,a,b A. D. Faulkner,a P. Gurnani,a S. E. Howson,a R. M. Phillips,c D. H. Simpson,a
P. Scotta*
Department of Chemistry, University of Warwick, Coventry, CV4 7AL
Institute of Advanced Study, University of Warwick, Coventry, CV4 7HS
Department of Pharmacy, University of Huddersfield, Huddersfield, HD1 3DH
There is a need to develop novel anticancer drugs which bypass
multidrug resistance and exhibit high selectivity. Host defence
peptide α-helices (a) help us to resist various diseases including
cancers and infection,2 and there is a drive to develop synthetic
functional mimics of these innate molecules.3 Metallohelices
(e.g. helicates)4 being of a similar size and charge to α-helices,5
have risen to the fore.6 Unfortunately these metal complexes are
unsophisticated in comparison to the natural systems,7 rarely
contain functional groups and invariably have high symmetry.8
Our research lab developed new water compatible
(a) Antibacterial α-helix of human
systems known as flexicates (b), which are optically pure
cathelicidin LL-37 of similar size
manner, easily functionalised and have shown great potential as
and charge density to a flexicate;1
(b) traditional symmetric flexicate
[M2(AB'-B'A)3]; (c) low symmetry,
triplex metallohelix.
extremely potent and selective9 anticancer and antimicrobial
agents. They are also found to cause significant changes to the
cell cycle and induce early apoptosis in colon cancer.10
More recently we have established a novel asymmetric architecture, which employs
directional ligands to form triplex metallohelices (c).11 These soluble, and stable compounds
show exceptional anticancer activity. They are found to act on the cell cycle and induce
apoptosis without damaging DNA. They appear to act similarly to the peptidic α-helices that
they are designed to emulate, and are highly selective against cancer cells. These compounds
take a significant step towards using metallohelix architectures as highly adaptable
peptidomimetic systems in the fight against cancer.12
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