Flexicates: Towards α-helix Functionality through Unsymmetrical Self-Assembly
Rebecca A. Kaner*, Dr. Suzanne E. Howson, Alan D. Faulkner and Prof. Peter Scott
Department of Chemistry, University of Warwick, Coventry, UK, CV4 7AL
PhD began: October 2010
We will present new strategies to generate optically pure compounds
with unprecedented, α-helix-like complexity via iron-templated selfassembly.
Protein -helices I are employed in binding events with proteins,
nucleic acids and membranes. They are a major component of most
host-defence peptides2 and mediate key protein handshakes in cancer.3
As therapeutic agents, however, they tend to rapidly degrade leading to
poor pharmacokinetics and so synthetic mimics are being developed
which include more favourable properties.4
The metal-templated triple bimetallic helicates II are of a similar size
and charge to -helices and some bind to biomolecules,5 but they rarely
contain functional groups and have much higher symmetry (Cn).
Overall, the chemistry is currently not sophisticated enough to deliver
molecules that fulfil the criteria which would allow them to be
considered as practical -helix mimics in biomedical chemistry.6
I
II
III
(a) Antibacterial α-helix of human
cathelicidin LL-37 of similar size and
charge density to a flexicate;1 (b)
traditional 3-fold symmetric helicate
[M2(AB'-B'A)3]; (c) mixed-ligand, low
symmetry, functionalized flexicate.
We recently developed a series of optically and diastereochemically
pure monometallic complexes [M(AB)3]2+ 7,8 and this project tethers
these with various linkers to create water stable, optically pure
structures [M2(AB'-B'A)3]4 which we call flexicates by analogy
with the related helicates. They have potential in the biological
regime as antimicrobial9 and anticancer agents, with selectivity
and activity determined by the exact functionality of the
organic ligand. Initial IC50 values have shown that flexicates
have a similar activity to Cisplatin with a significantly better
selectivity profile and we will report many new functional
complexes.
Current synthetic approaches to self-assembly invariably lead
to either symmetrical complexes (as II) or more commonly
mixtures. Most excitingly we have devised functional
L1 X: CH2OH, L2 X: CH2Naph
unsymmetrical flexicates III using carefully designed
directional ligands ABCD. This new approach has allowed us to take hitherto unfeasible steps
towards -helix-like complexity in a readily-assembled large molecule, and thus make major progress
in the development of very novel drug candidates.
L3 (AB'-B'A)
L4 (AB-CD)
DFT calculated structure of [M2(AB-CD)2(CD-BA)]4+ and MD calculated structure of [M2(AB'-B'A)3]4+
1.
2.
3.
4.
X. Li, et al., J. Am. Chem. Soc., 2006, 128, 5776-5785.
R. E. W. Hancock and H.-G. Sahl, Nat. Biotech., 2006, 24,
1551-1557.
R. E. Moellering et al., Nature, 2009, 462, 182-188.
H. Yin and A. D. Hamilton, Angew. Chem. Int. Ed., 2005,
44, 4130-4163.
5.
6.
7.
8.
9.
M. J. Hannon, Chem. Soc. Rev., 2007, 36, 280-295.
S. E. Howson and P. Scott, Dalton Trans., 2011, 40, 1026810277.
S. E. Howson, et al., Chem. Commun., 2009, 1727-1729.
S. E. Howson, et al., Dalton Trans., 2011, 40, 10416-10433.
S. E. Howson, et al., Nat. Chem., 2012, 4, 31-36.