consider that the RMSD value will not scale linearly with the
number of positions considered. Previous reports have generally
measured the ‘goodness-of-fit’ of only three groups and not the
five substituents of molecule 22. In this scaffold the RMSD
value for the groups on one face of the molecule (i, i + 4 and
i + 8) is 0.84 Å, which compares comparably to the previously
reported benzoylurea mimic of the i, i + 4 and i + 7 side-chains
(0.67 Å).3
Notes and references
1 (a) M. J. Adler et al., in Small-Molecule Inhibitors of Protein–Protein
Interactions, L. Vassilev and D. Fry, Springer, Berlin, Heidelberg, 2011;
(b) J. A. Wells and C. L. McClendon, Nature, 2007, 450, 1001;
(c) S. Fletcher and A. D. Hamilton, Curr. Top. Med. Chem., 2007, 7, 922;
(d) S. Fletcher and A. D. Hamilton, J. R. Soc. Interface, 2006, 3, 215.
2 (a) E. Ko, J. Liu and K. Burgess, Chem. Soc. Rev., 2011, 40, 4411;
(b) J. M. Davis, L. K. Tsou and A. D. Hamilton, Chem. Soc. Rev., 2007,
36, 326.
3 (a) I. C. Kim and A. D. Hamilton, Org. Lett., 2006, 8, 1751;
(b) J. Becerril and A. D. Hamilton, Angew. Chem., Int. Ed., 2007, 46,
4471; (c) S. Marimganti, M. N. Cheemala and J.-M. Ahn, Org. Lett.,
2009, 11, 4418; (d) S. Thompson, R. Vallinayagam, M. J. Adler,
R. T. W. Scott and A. D. Hamilton, Tetrahedron, 2011, DOI: 10.1016/j.
tet.2011.11.010.
4 J. M. Rodriguez, N. T. Ross, W. P. Katt, D. Dhar, G. I. Lee and
A. D. Hamilton, ChemMedChem, 2009, 4, 649.
5 Molecular Operating Environment, MMFF94(s); Chemical Computing
Group Inc.
6 (a) S. Hirano, M. Kawasaki, H. Ura, R. Kato, C. Raiborg, H. Stenmark
and S. Wakatsuki, Nat. Struct. Mol. Biol., 2006, 13, 272; (b) I. Huber,
M. Rotman, E. Pick, V. Makler, L. Rothem, E. Cukierman and D. Cassel,
Methods Enzymol., 2001, 329, 307; (c) S. Runge, H. Thøgersen,
K. Madsen, J. Lau and R. Rudolph, J. Biol. Chem., 2008, 283, 11340;
(d) R. E. W. Hancock and A. Rozek, FEMS Microbiol. Lett., 2002, 206,
143.
1H NMR of the deprotected molecule 23 shows the benzoyl-
urea N–H resonance as a sharp singlet at 11.38 (CDCl3) and
11.46 (DMSO-d6) consistent with previous studies,8 and sup-
ports the existence of an intra-molecular hydrogen bond and thus
a linear scaffold conformation in both of these solvent systems.
In summary, we have designed a route to amphiphilic α-helix
mimetics based on the well-established benzoylurea scaffold,
and have implemented this in a modular and scalable synthesis
of molecules accurately reproducing the spatial and angular pro-
jection of five amino acid side-chains on both sides of an
α-helical strand. This represents a significant improvement in the
scope of non-peptidic peptidomimetics, allowing for mimicry of
hydrophobic and hydrophilic side-chains on two faces of an
α-helix.
7 W. Guo, J. F. Li, N. J. Fan, W. W. Wu, P. W. Zhou and C. Z. Xia, Synth.
Commun., 2005, 35, 145.
8 J. M. Rodriguez and A. D. Hamilton, Angew. Chem., Int. Ed., 2007, 46,
8614.
Acknowledgements
9 Crystal structure data for compound 22 has been deposited with the
Cambridge Crystallographic Data Centre (CCDC number 861447‡).
10 Chimera. University of California, San Francisco (supported by NIH P41
RR001081): C. C. Huang, G. S. Couch, E. F. Pettersen and T. E. Ferrin,
Pacific Symposium on Biocomputing, 1996, 1, 724.
We thank Richard T. W. Scott (X-ray crystallography), James
W. Luccarelli (modelling), The University of Oxford for funding
(ST) and Dr Martin D. Smith (Oxford) for helpful discussions.
5782 | Org. Biomol. Chem., 2012, 10, 5780–5782
This journal is © The Royal Society of Chemistry 2012