the substituents in the position of the hydrophobic side chains
of the LXXLL motif. In their preliminary studies, heteroaro-
matic groups were introduced to better approximate the
hydrophilicity of the coactivator peptide backbone.7 Several
compounds in this initial series bound with low micromolar
affinity to the ERR, establishing the feasibility of using
proteomimetics to effectively mimic the NR box. However,
none of the previous scaffolds or the proteomimetics
provided functionality that accounted for the charge clamp
interactions.
In this study, we have designed a small series of
compounds based on a bipolar bis-4,4′-oxyphenyl scaffold
that addresses both the substitution pattern of the hydrophobic
core and the electronic interactions of the charge clamp
(Figure 1). Each compound in the series contains a tertiary
amine and a carboxylic acid connected by an ether linkage
to the biphenyl core.
These terminal moieties represent the heteroatoms of the
coactivator peptide backbone that are capable of interacting
with the charged residues of the receptor. Additionally, the
ether linker should improve bioavailability. Our strategy
involved the initial preparation of the unsubstituted bipolar
bis-4,4′-oxyphenyl scaffold (1a) to test the binding efficacy
of the scaffold itself. We then prepared the target compounds
bearing symmetrically substituted isopropyl (1b), sec-butyl
(1c), and tert-butyl (1d) groups at the 3 and 3′ positions to
mimic the hydrophobic leucine side chains of the NR box.
The benzyl derivative (1e) was also prepared to evaluate the
effect of sterically demanding substituents on ERR binding
affinity.
Figure 1. Proteomimetics of the NR box. (a) The NR box forms
an R helix and consists of an LXXLL residue pattern. (b) Bis-4,4′-
oxyphenyl scaffold (energetically minimized). Note the rotation of
the biaryl core. (c) Target compounds 1a-e with varying 3,3′
substitution.
any amino acid. When bound to the surface of a receptor,
the first and third leucine residues of the NR box project
downward into a hydrophobic groove. Flanking this groove
are residues (lysine and glutamic acid) that are aligned with
the intrinsic dipole of the R-helical backbone of the NR box
peptide, creating a “charge clamp” that locks the coactivator
in place.5
Competitive blockade of this binding site would prevent
recruitment of the transcription apparatus and could ef-
fectively halt cell proliferation. An ideal NR modulator of
this type should mimic the disposition of the hydrophobic
groups of the LXXLL motif as well as the polar functional
groups that constitute the charge clamp of the NR box
binding site. Initial efforts to mimic the NR box employed
short helical peptides, constrained peptides, and peptidomi-
metics. Recently, the focus has shifted to the development
of small molecule scaffolds that possess pharmaceutical
potential due to the low molecular weight, improved bio-
availability, and potential for high binding selectivity of these
compounds.4
Our overall synthetic strategy utilized a combinatorial
approach starting from simple, commercially available alkyl-
substituted phenols (Scheme 1). Our initial objective was to
prepare the individual amino and carboxy termini and ligate
the para-substituted aryl subunits using conventional aryl-aryl
coupling techniques. The ortho-substituted phenols under-
went selective bromination at the para position using
tetrabutylammonium tribromide.8 These compounds served
as precursors for both aryl subunits of our scaffold. The
carboxy terminus was appended under Williamson ether
conditions using ethyl bromoacetate while the amino termi-
nus was added using N,N-dimethylethanolamine via the
Mitsunobu reaction. The Suzuki reaction was selected for
the biaryl coupling. Suzuki reactions involve the coupling
of activated boronic acids or esters with halogenated
compounds in the presence of a palladium catalyst and
generally tolerate a wide range of functional groups. Aryl
lithiation and Grignard reactions were evaluated for preparing
the arylboronic acids before ultimately settling on the
Miyaura reaction to generate the appropriate boronate ester
precursors for the Suzuki coupling. Suzuki reactions between
the two fully functionalized aryl subunits unfortunately
resulted in low and irreproducible yields. Additionally, the
presence of the tertiary amine affected the polarity of the
An R-helical proteomimetic approach, described by Hamil-
ton, et al.,6 provides an alternative to small molecular
scaffolds. In this approach, bi- and triaryl scaffolds replicate
the R-helical rotation of the peptide backbone and display
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Geistlinger, T. R.; Guy, R. K. Methods Enzymol. 2003, 364, 223–246. (d)
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