Enaminone-based mimics of extended and hydrophilic α-helices

Full text of DOI:10.1002/chem.201202120

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DOI: 10.1002/chem.201202120
Enaminone-Based Mimics of Extended and Hydrophilic a-Helices
Marc J. Adler,[a, b] Richard T. W. Scott,[a] and Andrew D. Hamilton*[a]
The pursuit of structural and functional mimics of a-heli-
ces has been a fruitful area of research over the past decade.
The evolution of scaffold design has led to the progression
from molecules that are difficult to synthesize, solubilize,
and derivatize to structural motifs that can be easily assem-
bled, elongated, and diversified. These advancements have
allowed a-helix mimics to be generated more quickly and
thus to be more easily evaluated.[1]
an aniline followed by conjugate addition to the correspond-
ing ynone-functionalized monomeric unit.[6] This paper de-
scribes how this strategy can be applied to a range of side-
chain substituents beyond the simply hydrophobic as well as
to the iterative construction of a range of extended helix
mimetics, with full structural characterization of the sequen-
tial oligomers (Scheme 1).
To this point, much a-helix mimetic research has focused
on molecules that mimic up to two turns of an a-helix con-
taining principally hydrophobic residues.[2] Although many
interesting and biologically active compounds have been
made and investigated, there has been limited synthetic
work done on either extended scaffolds[3] or those that can
be assembled in the presence of hydrophilic amino acid-like
functional groups without the use of extensive protecting
group strategies.[4]
Extended and hydrophilic helices are of considerable bio-
logical significance. For example, the seven-helix transmem-
brane bundles of G-protein-coupled receptors not only span
the width of the bilayer membrane (ꢀ8 turns), but also are
often stabilized by interhelix interactions of hydrophilic side
chains.[5] Other important elongated helices include leucine
zippers, structural motifs in the DNA-binding region of tran-
scription factor proteins.
Scheme 1. General synthesis of enaminones.
A major goal in the field of helix mimicry is the develop-
ment of scaffolds that can be easily elongated and function-
alized for use in probing the nature of these important bio-
logical molecules. Herein, an oligoenaminone-based scaffold
that can readily mimic elongated a-helices is described. The
principal advantages of the enaminone design are its ease of
synthesis and the presence of intramolecular hydrogen
bonds, which stabilize the conformation.
We first tested the ability of this synthetic route to sup-
port more polar substituents. Enaminones with free carboxy-
late groups in the lower monomer were assembled through
the reaction of aniline 1 with ynone 2 to give enaminone 3
(Scheme 2). The nitro substituent in 3 could be readily re-
duced to amino acid 4, which not only improved water solu-
bility, but also readies it for potential further elongation. A
major advantage of this route is that it is executed without
protecting groups.
A second test of the approach came for helix mimetics
with polar side chains, such as hydroxyl group containing 6.
This derivative was assembled by an analogous route (Fig-
ure 1a) and, again, in the absence of protecting groups. A
crystal structure of 6 showed that the intramolecular hydro-
gen bond was maintained in the solid state despite the pres-
ence of a nearby hydroxyl group (Figure 1b).
We have previously reported the synthesis of a-helicomi-
metic enaminones, through hydrogenation of a nitroarene to
[a] Prof. M. J. Adler, R. T. W. Scott, Prof. A. D. Hamilton
Department of Chemistry, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
Fax : (+44)1865-285002
E-mail: andrew.hamilton@chem.ox.ac.uk
[b] Prof. M. J. Adler
Department of Chemistry & Biochemistry
Northern Illinois University
1425 W. Lincoln Hwy.
The enaminone synthetic route is also amenable to ready
elongation. The first series of extended mimics was based on
an amide-terminated scaffold. The synthetic approach fol-
DeKalb, IL 60115–2828 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202120.
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projecting from a single face of
a helix in the coiled coil of the
zipper.
The synthesis of these elon-
gated mimics was accomplished
by using the iterative process
previously outlined (Scheme 4).
Crystal structures were ob-
tained for two- and four-turn
mimics of the leucine zipper
helix (17 and 20, respectively).
As in the shorter structures, the
intramolecular hydrogen bonds
are intact in these derivatives
Scheme 2. Synthesis of carboxy-terminated enaminones.
the solid state and serve to sta-
bilize the helicomimetic core.
Compound 23, which structurally mimics ten turns of a leu-
cine zipper monomer, marks the longest synthetic helix
mimetic of any type characterized to date.
Complementary packing of the isopropyl side groups is
evident in the crystal structure of compound 17 (Figures 3),
which contains two enaminone molecules in each asymmet-
ric unit. The interlocking character of these interactions is
closely analogous to the packing observed in solid-state
structures of leucine zipper dimers.
In addition to two intramolecular hydrogen bonds and
many intermolecular hydrophobic contacts, the structure of
the pentamer 20 shows a distinctive conformation. The scaf-
fold structure lies in two distinct planes defined by the
lower three rings at an angle to the upper two (Figure 4).
The side chains project at different angles from the scaffold
and, reminiscent of the side chains of an a-helix, cover a
considerable amount of three-dimensional space. Access to
conformations of this type in the solid state bodes well for
the structural mimicry of extended single faces of a-helices
in solution.
Figure 1. a) Synthesis and b) crystal structure of hydroxyl-bearing enami-
none 6.
lowed our earlier strategy of converting the 2-alkoxy-4-ni-
troarylcarboxylic acid monomer into its ynone derivative,
followed by nucleophilic attack by the 2-alkoxy-4-amino-ar-
ylcarboxamide lower component.[6] Reduction of the free
nitro group followed by conjugate addition to a second
ynone unit gave the double-enaminone series 7–11 with a
variety of hydrophobic substituents (Scheme 3).
Spectroscopic investigation of compounds 7–14 showed
that, in all cases, the intramolecular hydrogen bonds are
intact in solution, as was evidenced by the pronounced
1H NMR analysis downfield shifts of all enaminone NH pro-
tons (ꢀ13 ppm). A low-energy structure (as determined by
molecular modeling by using the MOE program) of nitroe-
naminone 9 displays excellent overlap between its side
chains and the relevant residues on a key helix in the thymi-
dylate synthase–dihydrofolate reductase (TS–DHFR)
enzyme complex of Cryptosporidum hominis;[8] studies on
the functional mimicry of this helix are in progress
(Figure 2).
We were also interested in the use of extended enami-
nones as structural mimics of leucine zipper protein do-
mains. These motifs offer elegant examples of residue-spe-
cific hydrophobic interactions as stabilizing forces in pro-
tein–protein complexes. To this end, we undertook the itera-
tive synthesis of ester-terminated elongated enaminones
containing hydrophobic substituents to imitate the leucines
Scheme 3. Synthesis of elongated amidoenaminones.
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Enaminone-Based Mimics of a-Helices
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Figure 4. a) X-ray crystal structure of 20 from three different angles,
highlighting the b) intramolecular hydrogen bonds and c),d) planarity of
the structure.
Figure 2. Stereoview of the overlap of a low-energy structure of 9 with
C. hominis TS–DHFR crossover helix.
This publication details the synthesis of a variety of enam-
inones, demonstrating molecules of this type to be versatile
scaffolds for the mimicry of an array of a-helices. In addi-
tion to incorporating hydrophobic and hydrophilic side
chains, we have shown that molecules capable of mimicking
up to ten turns of an a-helix can be assembled and charac-
terized. This work serves to expand the toolkit for small-
molecule peptide mimicry.
Experimental Section
Synthesis of all enaminones and precursors was performed according to
previously published synthetic routes.[6] Full characterization for all com-
pounds can be found in the Supporting Information. CCDC-871189 (6),
CCDC-871188 (17), and CCDC-871187 (20) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Scheme 4. Synthesis of elongated helix mimics.
Acknowledgements
The authors would like to thank the University of Oxford and Northern
Illinois University for funding, and Dr. Sam Thompson, Dr. Hannah Lin-
gard, Dr. Andrew Jamieson, and Ian Jones for helpful discussions.
Keywords: a-helix
·
enzymes
·
hydrogen bonds
·
peptidomimetics · synthesis design
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Figure 3. a) X-ray crystal structure of dimeric asymmetric unit of 17 in
b) stick and c) spacefill views.
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Received: June 14, 2012
Published online: && &&, 0000
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Enaminone-Based Mimics of a-Helices
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Synthetic molecules capable of the
mimicry of a-helices that are elongated
and/or contain hydrophilic side chains
have been largely elusive. However,
the oligophenylenaminone structure
can surmount both of these challenges
(see scheme).
Peptidomimetics
M. J. Adler, R. T. W. Scott,
A. D. Hamilton* .............. &&&& — &&&&
Enaminone-Based Mimics of Extended
and Hydrophilic a-Helices
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!