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*
a
Department of Chemistry, University of Warwick, Coventry, CV4 7AL
b
Institute of Advanced Study, University of Warwick, Coventry, CV4 7HS
c
Department of Pharmacy, University of Huddersfield, Huddersfield, HD1 3DH
There is a need to develop novel anticancer drugs which bypass
multidrug resistance pathways (namely DNA damage) and
(a)
exhibit high selectivity against tumours over healthy tissue. In
particular the prognosis for those suffering from colon cancer,
especially at later stages, is poor. The development of novel
(b)
pharmaceuticals that successfully tackle these key issues is
paramount.
Host defence peptide α-helices (a) help us to resist
(c)
various diseases including cancers and infection, but suffer from
poor pharmacokinetics as drug targets; therefore there is a drive
to develop synthetic systems which mimic the function of these
(a) Antibacterial α-helix of human
innate
cathelicidin LL-37 of similar size
metallohelices (e.g. helicates) – being of a similar size, shape
and charge density to a flexicate;
(b) traditional 3-fold symmetric
molecules.
Among
other
mimetics
strategies,
and charge to α-helices – have risen to the fore. Unfortunately
flexicate [M2(AB'-B'A)3]; (c) mixed-
these metal complexes are unsophisticated in comparison to the
ligand, low symmetry, triplex
natural systems, rarely contain functional groups and invariably
metallohelix.
have high symmetry.
Our research lab developed new water compatible systems known as flexicates (b),
which form in an optically pure manner, are easily functionalised and have shown great
potential as extremely potent and selective anticancer and antimicrobial agents. They are
found to cause significant changes to the cell cycle and induce early apoptosis in colon cancer.
More recently we have established a novel asymmetric architecture, which employs
directional ligands to form triplex metallohelices (c). These soluble, stable, and
functionalisable compounds show exceptional activity as anticancer agents. They are found
to act on the cell cycle and induce apoptosis without damaging DNA: they appear to act in a
similar manner to the peptidic α-helices that they were designed to emulate. They have also
been found to be extremely selective against colon cancer cells over healthy cells. These
compounds take a significant step towards using metallohelix architectures as highly
adaptable peptidomimetic systems in the fight against cancer.