Triplex metallohelix: a new potent and selective system against colon cancer
Rebecca A. Kaner*,a Alan D. Faulkner,a Pratik Gurnani,a Suzanne E. Howson,a Roger
M. Phillips,b Daniel H. Simpson,a Nick R. Waterfieldc and P. Scotta
a
Department of Chemistry, University of Warwick, Coventry, CV4 7AL
Department of Pharmacy, University of Huddersfield, Huddersfield, HD1 3DH
c
Warwick Medical School, University of Warwick, Coventry, CV4 7AL
b
University of Warwick
Supervisor’s Name: Peter Scott
PhD began in: October 2010
There is a need to develop novel anticancer drugs which bypass multidrug resistance
and exhibit high selectivity. Peptidic α-helices are vital in host defence against various
diseases including cancers and infection,1 and there is a drive to discover synthetic
functional mimics of these innate molecules.2 Some metallohelices, being of similar
size and charge to α-helices, have risen to the fore.3 Unfortunately these complexes
are unsophisticated in comparison to the natural systems.4
We developed water compatible metallohelices known as flexicates,5,6 and while
these support external functional groups they are, like conventional helicates, highly
symmetrical.7 Asymmetric helicates have never to our knowledge been isolated.
We have discovered the first class of such a compound - the triplex metallohelix.
Comprising antiparallel strands, they are formed with excellent selectivity and have
unparalleled chemical and optical stability. Diverse functionality is supported. 8
We will report the self-assembly of single isomer complexes – no post-synthetic
resolution – from stoichiometric amounts of a directional chiral iminopyridine ligand and
M(II) cation. These compounds are found to be extremely selective against colon
cancer cells, over healthy human cells and non-mammalian model organisms. They
appear to act in a similar manner to the peptidic α-helices that they are designed to
emulate, congregating on the extracellular membrane, affecting the cell cycle and
inducing apoptosis, but not inducing DNA damage. These compounds take a
significant step towards using metallohelix architectures as highly adaptable
peptidomimetic systems in the fight against cancer.
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