Super-secondary structure peptidomimetics: Design and synthesis of an α-α hairpin analogue

Article abstract of DOI:10.1080/10610278.2013.817581

The α-α helix motif presents key recognition domains in protein-protein and protein-oligonucleotide binding, and is one of the most common super-secondary structures. Herein, we describe the design, synthesis and structural characterisation of an α-α hairpin analogue based on a tetra-coordinated Pd(II) bis-(iminoisoquinoline) complex as a template for the display of two α-helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the side chains of the i and i+4 residues of two helices. 2013

Full text of DOI:10.1080/10610278.2013.817581

This article was downloaded by: [UQ Library]
On: 24 November 2014, At: 10:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Supramolecular Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gsch20
Super-secondary structure peptidomimetics: design
and synthesis of an α–α hairpin analogue
Laura Nevolaa, Johanna M. Rodrigueza, Sam Thompsonb & Andrew D. Hamiltonab
a Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT06511, USA
b Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
OxfordOX1 3TA, England, UK
Published online: 21 Aug 2013.
To cite this article: Laura Nevola, Johanna M. Rodriguez, Sam Thompson & Andrew D. Hamilton (2013) Super-secondary
structure peptidomimetics: design and synthesis of an α–α hairpin analogue, Supramolecular Chemistry, 25:9-11, 586-590,
DOI: 10.1080/10610278.2013.817581
To link to this article: http://dx.doi.org/10.1080/10610278.2013.817581
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Supramolecular Chemistry, 2013
Vol. 25, Nos. 9–11, 586–590, http://dx.doi.org/10.1080/10610278.2013.817581
Super-secondary structure peptidomimetics: design and synthesis of an a–a hairpin analogue
a
a
b
a
,
b
L a u r a N e v o l a , J o h a n n a M . R o d r i g u e z , S a m T h o mp s o n * a n d A n d r e w D . H a m i l to n
*
b
aDepartment of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06511, USA; Chemistry Research Laboratory,
Department of Chemistry, University of Oxford, Oxford OX1 3TA, England, UK
(
R
e
c
e
i
v
e
d
2
0
M
a
y
2
0
1
3
;
fi
n
a
l
v
e
r
s
i
o
n
r
e
c
e
i
v
e
d
1
1
J
u
n
e
2
0
1
3
)
T
h
e a– a
o
h
e
l
i
x
m
o
t
i
f
p
r
e
s
e
n
t
s
k
e
y
r
e
c
o
s
g
n
i
t
i
o
u
n
d
o
m
a
i
n
s
i
,
n
p
r
o
t
e
i
n
–
p
r
o
t
e
i
n
a
n
d
p
r
o
t
e
i
n
–
o
l
i
g
o
n
u
c
l
e
o
t
i
d
e
b
i
n
d
i
n
g
,
a
n
d
i
s
o
n
n e
o f
o
f
t
h
e
m
n a– a
s
t
c
o
m
m
o
n
s
u
p
e
r
-
s
e
c
o
n
d
a
r
y
t
r
u
c
t
r
e
s
.
H
e
r
e
i
n
w
e
d
e
s
c
r
i
b
e
t
h
e
d
e
s
i
g
n
,
s
y
n
t
h
e
s
i
s
a
n
d
s
t
r
u
c
t
u
r
a
l
c
h
a
r
a
c
t
e
r
i
s
a
t
i
o
a
h
a
i
r
p
i
n
a
n
a
l
o
g
u
e
b
a
s
e
d
o
n
a
t
e
t
r
a
-
c
o
o
r
d
i
n
a
t
e
d
P
d
(
I
I
)
b
i
s
-
(
i
m
i
n
o
i
s
o
q
u
i
n
o
l
i
n
e
)
c
o
m
p
l
e
x
a
s
a
t
e
m
p
l
a
t
e
f
o
r
t
h
e
d
i
s
p
l
a
y
of two a-helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the
side chains of the i and i þ 4 residues of two helices.
Keywords:
s
t
r
u
c
t
u
r
a
l
m
i
m
i
c
r
y
;
p
r
o
t
e
i
n
–
p
r
o
t
e
i
n
i
n
t
e
r
a
c
t
i
o
n
;
a
l
p
h
a
h
e
l
i
x
;
s
i
d
e
c
h
a
i
n
;
G
C
N
4
˚
Introduction
short linkers of one or two amino acids and 10 A for
many examples where the turn is formed of several amino
acids.
T
h
e
d
e
s
i
g
n
o
f
n
o
n
-
p
e
p
t
i
d
i
c
s
m
a
l
l
m
o
l
e
c
u
l
e
s
t
o
r
e
p
r
o
d
u
c
e
t
h
e
r
e
c
o
g
n
i
t
i
o
n
p
r
o
p
e
r
t
i
e
s
o
f
t
h
e
r
a
p
e
u
t
i
c
a
l
l
y
r
e
l
e
v
a
n
t
s
e
c
o
n
d
a
r
y
s
t
r
u
c
t
u
r
a
l
p
r
o
t
e
i
n
e
l
e
m
e
n
t
s
l i s he d fi e l d (1). With a particular emphasis on the
i
s
n
o
w
a
n
e
s
t
a
b
-
Results and discussion
moderation of protein–protein interactions, there are
many examples of peptidomimetics of a-helices (2–4)
and a growing number that mimic some of the properties
of b-strands and b-sheets (5, 6). However, there are few
non-peptidic mimics of more complex super-secondary
structures (7). The majority of approaches are based on the
modification of peptidic folding preferences via manipu-
lation of the primary sequence (8, 9). Examples include
careful positioning of non-natural a,b-dehydrophenylala-
nine to promote hydrophobic interactions (10), or the
incorporation of reactive natural amino acids, including
cysteine (11), which are responsive to an oxidative
stimulus (12). Strategies relying on the templating effect of
cyclic peptides or synthetic molecules, such as norbor-
nene, have also been explored (13, 14).
H
e
r
e
i
n
,
w
e
r
e
p
o
r
t
t
h
e
d
e
s
i
g
n
a
) bis-(iminoisoquinoline) complex that
n
d
s
y
n
t
h
e
s
i
s
o
f
a
t
e
t
r
a
-
c
o
o
r
d
i
n
a
t
e
d
P
d
(
I
I
templates the display of a range of a-helical peptidomi-
metics to reproduce the structural characteristics of an a–
a hairpin. To replicate the inter-helical loop angle v, of
approximately 08 for the parallel disposition and 1808 for
the anti-parallel hairpin, we sought a metal complex with a
square-planar coordination geometry (29, 30). Inspired by
previously reported Pd(II)-2-imino-pyridine complexes
(31, 32), and other metals with an N4 coordination
geometry, (33) we designed and synthesised bis-(imino-
isoquinoline) ligand 4 (Scheme 1).
T
h
e
s
y
n
t
h
e
s
i
s
c
o
m
m
e
n
c
e
d
w
y
i
t
h
n
i
t
r
a
t
i
o
n
o
f
1
-
m
e
t
h
y
l
-
r 2
i
s
o
q
u
i
n
o
l
i
n
e
t
o
g
i
v
e
e
x
c
l
u
s
i
v
e
l
t
h
e
5
-
n
i
t
r
o
r
e
g
i
o
i
s
o
m
e
(34), followed by selenium dioxide-mediated oxidation of
the methyl group to aldehyde 3 (35). Condensation with
1,3-diaminopropane provided di-imine 4 as a reactive
intermediate. Addition of commercially available tetrakis
(acetonitrile)palladium(II) tetrafluoroborate gave complex
5, with an immediate chromatic change in the reaction
mixture from yellow to dark orange-brown. Purification
was achieved by precipitation from acetonitrile with
O
n
e a– a
e
o
f
t
h
e
m
o
s
t
c
o
m
m
o
n
s
u
p
e
r
-
s
e
c
o
n
d
a
r
y
s
t
r
u
c
t
u
r
e
s
i
s
t
h
h
a
i
r
p
i
n
,
i
n
w
h
i
c
h
a
s
e
q
u
e
n
c
e
o
f
a
m
i
n
o
a
c
i
d
s
l
i
n
k
s
t
w
o
a
-
h
e
l
i
c
e
s
,
u
s
u
a
l
l
y
i
n
a
n
a
n
t
i
p
a
r
a
l
l
e
l
a
r
r
a
n
g
e
m
e
n
t
( 15, 16). Others include the b–a–b motif, (17, 18) a–a
corner (19), b–b corner (20) and b–b hairpin (Figure 1)
(21). Various models for a-helix packing emphasise
the importance of helix complementarity (22–24), in
which the nature of the side chains determines the packing
(or torsion) angle v (25, 26). For the a–a hairpin, De
Grado found a strong correlation between the number of
linking residues and the inter-helical distance (the average
of the orthogonal space between the axis of the two
chloroform (Scheme 1).
U
1
p
o
n
c
h
e
l
a
t
i
o
n
,
t
h
e
H
N
M
R
s
i
g
n
a
l
s
c
o
r
r
e
s
p
o
n
d
i
n
g
t
o
t
h
e
m
e
t
h
y
l
e
n
e
s
a
d
j
a
c
e
n
t
t
o
t
h
e
i
m
i
n
e
n
i
t
r
o
g
e
n
s
,
a
n
d
t
h
e
c
e
n
t
r
a
l
m
e
t
h
y
l
e
n
e
o
f
t
h
e
p
r
o
p
y
l
l
i
n
k
e
r
,
s
h
o
w
a
c
h
a
n
g
e
i
n
˚
helices) (27, 28). Distances range between 5 A for
m
u
l
t
i
p
l
i
c
i
t
y
a
t
t
r
i
b
u
t
a
b
l
e
t
o
t
h
e
i
n
t
r
o
d
u
c
t
i
o
n
o
f
*
C
o
r
r
e
s
p
o
n
d
i
n
g
a
u
t
h
o
r
s
.
E
m
a
i
l
:
s
a
m
.
t
h
o
m
p
s
o
n
@
c
h
e
m
.
o
x
.
a
c
.
u
k
;
a
n
d
r
e
w
.
h
a
m
i
l
t
o
n
@
c
h
e
m
.
o
x
.
a
c
.
u
k
q 2 0 1 3 T a y l o r & F r a n c i s

Supramolecular Chemistry
5
8
7
n
S
i
n
g
l
e
-
c
r
y
s
t
a
l
X
-
r
a
y
d
i
f
f
r
a
c
t
i
o
n
w
a
s
c
a
r
r
i
e
d
o
u
t
o
s
a
m
p
l
e
s
g
r
o
w
n
a
t
r o o m t e m p e r a t u r e t h r o u g h s l o w
l
e
v
a
p
o
r
a
t
i
o
n
o
f
d
i
e
t
h
y
l
e
t
h
e
r
i
n
t
o
a
s
o
u
t
i
o
n
o
f
c
o
m
p
l
e
x
5
in acetonitrile (The Cambridge Crystallographic Data
Centre: submission number 930541). A slightly distorted
square-planar geometry at palladium was observed with a
˚
mean planar deviation of 0.053 A for the four Pd–N
contacts. N–Pd–N cis- and trans-bite angles ranged from
79.678 to 105.168 and 174.918 to 172.948, respectively. The
distance between the nitrogen atoms of the nitro
groups, which provide attachment points for helix
˚
mimetics, is 10.76 A and thus congruent with the
properties of common a–a hairpin motifs in proteins
(Figure 2, see also Supplemental information, available
online, Chapter 3).
I
n
o
r
d
e
r
t
o
a
d
a
p
t
s
c
a
f
f
o
l
d
5
f
o
r
t
h
e
d
i
s
p
l
a
y
o
f
h
e
l
i
x
mimetics, the synthesis required modification to allow nitro
group reduction and coupling prior to imine formation and
complexation. Accordingly, aldehyde 3 was protected as a
dimethyl acetal and the nitro group reduced to give amine 7
in excellent yield (86–90% over two steps). As proof of
principle, we chose commercially available 3-methyl-4-
nitrobenzoic acid 8, as a mimic of the alanine side chain and
previously synthesised biphenyl carboxylic acid 9 (36) as a
mimic of two leucine residues in the i and i þ 4 positions.
These acids were activated with thionyl chloride before
coupling to give amides 10 and 11, respectively. The
aldehyde was unmasked in good yield after treatment with a
mixture of acetic and hydrochloric acids. Di-imines were
synthesised with 1,3-diaminopropane and used for com-
plexation without further purification. Following the
procedure for the synthesis of complex 5, precipitation
F
m
B
i
o
o
g
t
t
u
r
s
e
,
m
1
w
.
i
g
(
t
C
o
l
f
o
o
o
u
c
m
r
u
o
n
f
a
l
i
t
a
n
h
n
e
i
g
)
s
C
w
om mo n s uper- se con da ry s tr uc tur al
t
i
f
t
h
h
h
e
s
o
o
r
k
–
h
e
a
–
a
h
a
i
r
p
i
n
,
h
i
g
h
l
i
g
h
t
e
d
.
t
o
r
i
t
:
a
n
e
g
l
e
o
f
2
0
8
b
e
t
w
e
e
n
t
w
o
a
-
h
e
l
i
c
e
s
.
c
y
c
l
i
c
r
i
g
i
d
i
t
y
.
I
n
a
d
d
i
t
i
o
n
,
r
e
s
o
n
a
n
c
e
s
s
c
o
r
r
e
s
p
o
n
d
i
n
g
t
o
d
n
t
h
e
a
r
o
m
a
t
i
c
a
n
d
i
m
i
n
e
h
y
d
r
o
g
e
n
u
n
d
e
r
g
o
m
a
r
k
e
d
d
o
w
n
fi
e
l
d
s
h
i
f
t
s
c
o
n
s
i
s
t
e
n
t
w
i
t
h
t
h
e
w
i
t
h
d
r
a
w
a
l
o
f
e
l
e
c
t
r
o
e
n
s
i
t
y
(
T
a
b
l
e
1
,
c
o
m
p
o
u
n
d
5
)
.
F
u
r
t
h
e
r
c
h
a
r
a
c
t
e
r
i
s
a
t
i
o
n
confirms the presence of the complex, with mass
spectrometry showing ions consistent with the free di-
cationic complex, and that of the mono-tetrafluoroborate
anion. Elemental analysis is in good agreement with the
hypothesised structure: found (calcd) C, 38.06 (38.24); H,
2.56 (2.51); N, 11.51 (11.63).
NO2
NO2
(i)
(ii)
(iii)
N
N
O
N
Me
Me
1
3
2
H
NO2
NO2
NO2
NO2
N
N
N
N
N
N
N
(iv)
Pd(II)
N
[BF4]2
H
H
H
H
4
5
(i) HNO3, H2SO4, 80%; (ii) SeO2, 70–80%;
(iii) 1,3-diaminopropane, 93%; (iv) Pd(MeCN)4(BF4)2, 70%
S
c
h
e
m
e
1
.
S
y
n
t
h
e
s
i
s
o
f
a
m
o
d
e
l
l
i
n
k
e
r
5
.

5
8
8
L. Nevola et al.
1
T
a
a
b
l
e
1
.
S
e
l
e
c
t
e
d
H
N
M
R
c
h
e
m
i
c
a
l
n d t h e c o rr e s p o n d i n g P d( I I ) c o mp l e x ( 5, 16 and 17).
s
h
i
f
t
s
o
f
t
h
e
f
r
e
e
l
i
g
a
n
d
x
1
C
o
m
p
o
u
n
d
H
S
i
g
n
a
l
F
r
e
e
l
i
g
a
n
d
C
o
m
p
l
e
5
5
5
5
5
5
5
5
16
16
16
16
16
16
16
16
16
17
17
17
17
17
17
17
17
17
3
4
6
7
8
9
1
2
3
4
6
7
8
9
1
2
3
3
4
6
7
8
9
1
2
3
8
8
8
7
9
8
4
2
8
7
7
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
8
7
2
3
0
4
8
(
(
(
(
(
(
(
(
(
(
(
d
d
d
)
)
)
9
8
8
8
8
9
4
2
8
8
7
8
8
9
4
2
9
8
8
8
8
8
9
4
2
9
.
.
1
1
1
1
1
4
0
1
4
2
0
9
7
5
4
9
5
0
5
0
1
9
6
4
1
4
1
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
d
)
9
9
2
9
6
1
4
6
5
9
0
2
5
0
4
4
6
5
2
0
4
5
1
4
3
m
m
m
d
b
m
m
d
d
d
m )
d )
s )
m
m
)
)
)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6
2
t
)
8
8
d
)
)
7
7
s
)
r
)
)
)
1
1
0
2
7
7
6
8
t
)
3
2
3
4
q
d
d
d
)
)
)
)
)
)
)
F
i
g
u
r
e
2
.
( C o l o ur o n l i n e ) S i n g l e - c r ys t a l X - r a y s t r u ct u r e o f P d
( I I ) bis-(iminoisoquinoline) complex 5 (palladium grey,
7
7
8
4
0
9
(
(
(
(
t
)
tetrafluoroborate brown). The position of the tetrafluoroborate
ions is characterised by close intermolecular contacts: Pd· · ·F
˚
2.85 and 3.91 A.
8
4
d
)
7
0
2
0
s
)
1
1
1
t
)
)
)
2
4
0
(
q
)
)
7
.
0
[
[
[
[
[
7
3
3
[
(
]
]
]
]
]
m
s
)
a
a
a
a
a
d
d
d
m
d
s )
m
m
)
)
)
)
)
ligands 14 and 15 (Table 1). Electrospray mass
spectrometry and elemental analysis are also in close
agreement with calculated isotope patterns (see supporting
information).
8
.
7
0
4
(
(
(
]
b
m
m
r
)
)
)
1
1
1
4
2
.
.
)
)
A l t h o u g h w e w e r e u n a b l e t o o b t a i n d i f f r a c t io n - qu a li t y
c r y s ta l s o f c o m p l e x e s 16 or 17, a computationally derived
a
s
)
(37, 38) low-energy conformation of a four-amino acid
residue mimic 17 gave encouraging results when super-
imposed on the dimer conformation of the leucine zipper
transcription factor GCN4 (39). Given that coiled-coil a-
helical transcription factors control the expression of
myriad genes, it is an appealing strategy to use a synthetic
agent to regulate transcription, and thus influence
the translation of proteins implicated in human disease.
The Ca positions of the peptide show good agreement
with those of the oxygen atoms of the biphenyl helix
(Figure 3).
N
o
t
t
m
e
r
s
:
V
a
,
s
l
u
(
h
e
q
s
n
t
i
)
o
n
q
f
p
u
t
p
m
,
m
u
m
n
l
t
i
)
l
p
l
m
i
i
c
u
i
t
l
i
t
v
e
s
l
i
e
n
t
a
b
a
r
n
e
a
d
d
c
k
(
w
e
b
t
r
i
s
)
t
:
(
b
s
r
)
o
s
a
i
d
n
g
s
o
l
i
e
n
f
t
g
,
(
d
t
e
)
.
d
o
]
p
u
b
T
l
e
h
y
t
e
l
,
(
t
)
i
p
l
e
t
i
n
t
e
t
,
(
i
p
l
e
[
a
c h
g r o u p .
e
i
c
a
l
i
f
h
i
s
s
i
g
a
s
o
e
r
l
p
p
h
t
h
o
s
e
t
h
b
i
h
e
n
gaveatwo-aminoacidmimetic16as a darkyellow powderin
60% yield (Scheme 2).
n a cc o r d a nc e w i t h m o d e l s y s t e
m 5, the 1H NMR
spectra of complexes 16 and 17 show a similar downfield
shift of resonances when compared with those of the free
I
R2
NO2
R2
R2 =
R2
R2
13
NH
Me
NR1
O
NH
O
NH
2
O
HN
O
(v), (vi)
(i)
(iii)
(iv)
4
3
6
3
A
N
N
N
O
N
N
Pd(II)
N
7
1
8
Oi-Pr
[BF4]2
MeO
OMe
MeO
OMe
H
H
H
N
9
11
12
Oi-Pr
6 R1 = O
7 R1 = H
10 R2 = A 50 %
11 R2 = B 60 %
12 R2 = A 80 %
13 R2 = B 80 %
16 R2 = A 60 %
(ii)
B
17 R2 = B 48 %
(i) CH(OMe)3, c. p-TsOH, 90–95%; (ii) Pd/C, H2, 95%; (iii) R2CO2H: 8 or 9, SOCl2, then i-Pr2NEt, 7;
(iv) AcOH, HCl; (v) 1,3-diaminopropane; (vi) Pd(MeCN)4(BF4)2
S
c
h
e
m
e
2
.
S
y
n
t
h
e
s
i
s
o
f a– a
be considered as mimics of alanine and leucine amino acid side chains.
h
a
i
r
p
i
n
m
i
m
e
t
i
c
s
b
e
a
r
i
n
g
t
w
o
1
6
a
n
d
f
o
u
r
1
7
,
s
i
d
e
-
c
h
a
i
n
g
r
o
u
p
s
.
T
h
e
m
e
t
h
y
l
a
n
d
i
s
o
-
p
r
o
p
o
x
y
g
r
o
u
p
s
m
a
y

Supramolecular Chemistry
5
8
9
H
N
N
N
Pd(II)
N
H
[BF4]2
HN
O
NH
O
i-PrO
i-PrO
Oi-Pr
Oi-Pr
17
F
i
g
u
r
e
3
.
(
C
o
l
o
u
r
o
n
l
i
n
e
)
S
u
p
e
r
i
m
p
o
s
i
t
i
o
n
o
f
a
l
o
w
-
e
n
e
r
g
y
c
spheres) and the GCN4 dimer (pdb: 2ZTA; blue ribbon and yellow spheres).
o
n
f
o
r
m
a
t
i
o
n
o
f
f
o
u
r
-
r
e
s
i
d
u
e
b
i
s
-
h
e
l
i
x
m
i
m
e
t
i
c
1
7
(
g
r
e
e
n
s
t
i
c
k
s
a
n
d
r
e
d
(
(
(
(
(
(
2
3
4
5
6
7
)
)
)
)
)
)
A
z
z
a
r
i
t
o
,
V
.
;
L
o
n
g
,
K
.
Chem. 2013, 5, 161–173.
;
M
u
r
p
h
y
,
N
.
S
.
;
W
i
l
s
o
n
,
A
.
J
.
N
a
t
.
Conclusions
W
t
e
h
a
v
e
d
e
s
i
g
n
e
d
,
s
y
n
t
h
e
s
i
s
e
d
o
a
n
d
s
P d ( II ) bis-(iminoiso-
t
r
u
c
t
u
r
a
l
l
y
c
h
a
r
a
c
-
T
h
o
10, 5780–5782.
m
p
s
o
n
,
S
.
;
H
a
m
i
l
t
o
n
,
A
.
D
.
O
r
g
.
B
i
o
m
o
l
.
C
h
e
m
.
2
0
1
2
,
e
r
i
s
e
d
a
s
i
m
p
l
e
l
i
n
k
e
r
b
a
s
e
d
n
a
quinoline) complex that reproduces the geometric
characteristics of a peptidic hairpin motif. Two amino
groups allow for the attachment of a diverse array of
peptidomimetics via amide bond formation. The approach
was exemplified by the linking of a-helical mimics of the i
and i þ 4 positions to replicate the structure of an a–a
hairpin. However, the synthetic strategy is flexible and
convergent, and in principle allows for the display of
homo- or hetero-dimeric combinations of helical peptido-
mimetics to produce a wide range of super-secondary
structural mimics. Improved aqueous solubility may be
aided by the use of recently reported helix mimics that
contain a greater number of heteroatoms in the scaffold, or
the inclusion of side-chain mimics bearing polar groups.
T h
W
o
.
m
H
p
a
s
m
o
n
,
S
n
.
;
V
a
D
l
l M
. Tetrahedron 2012, 68, 4501–4505.
i
n
a
y
a
g
a
m
,
R
.
;
A
d
l
e
r
,
.
J
.
;
S
c
o
t
t
,
R
.
T
.
.
;
i
l
t
o
,
A
.
S
D
u t h e r e l l , C . L . ; T h o mp s o n , S . ; S c o t t , R . T . W . ; H a m i l t o n , A
. Chem. Commun. 2012, 48, 9834–9836.
J
a
m
i
e
s
o
n
,
A
.
G
.
;
R
u
s
s
e
l
l
,
D
Commun. 2012, 48, 3709–3711.
.
;
H
a
m
i
l
t
o
n
,
A
.
D
.
C
h
e
m
.
K
u
l
i
t
k
t
o
,
v
,
.
O
.
W
V
.
;
T
a
h
o
m
p
s
o
n
,
S
.
v
;
o
X
,
u
,
H
H
.
;
I
n
i
c
a
n
r
v
i
t
o
,
D
C
.
D
.
;
S
c
o
R
T
.
.
;
S
r
a
o
g
i
,
I
.
;
N
e
l
a
L
.
;
a
m
l
t
o
,
A
.
.
;
E
u
r
J. Org. Chem. 2013, 2013, 3433–3445.
a
(
(
8
9
0
1
2
3
)
)
)
)
)
)
R
a
n
g
a
n
a
t
h
a
n
,
D
.
;
H
a
r
i
d
a
s
,
V
.
J. Org. Chem. 2000, 65, 4415–4422.
;
N
a
g
r
a
j
,
R
.
;
K
a
r
l
e
,
I
.
L
.
K
a
r
l
l
a
e
r
,
a
I
.
L
.
P
;
F ,
. J. Am. Chem. Soc. 1991, 113, 3952–3956.
l
i
p
p
e
n
-
A
n
d
e
r
s
o
n
J
.
L
.
;
S
u
k
u
m
a
r
,
M
.
;
U
m
a
,
K
.
;
B a
R ama gopal, U.A .; Ra makumar , S.; Sahal, D.; Chauha n, V.S.
m
,
(
(
(
(
1
1
1
1
Proc. Nat. Acad. Sci. USA. 2001, 98, 870–874.
. Biopolymers
2001, 59, 301–304.
K
a
r
l
e
,
I
.
L
.
;
R
a
n
g
a
n
a
t
h
a
n
,
D
.
;
L
a
k
s
h
m
i
,
C
B a r t h e , P . ; R o u m e s ta nd , C . ; R o c h e t t e , S . ; V i t a , C . Protein
Sci. 2000, 9, 942–955.
R
B
a n g a n a t ha n, D . ; H a r i d a s , V . ; K u r u r , S . ; N ag a r a j , R . ;
i k s h a pa th y , E . ; K u n w a r , A . C . ; S a r m a , A . V . S . ; V a i r a m a n i ,
Supplemental Information
S
u
p
p
l
e
m
e
n
t
a
l
I
n
f
o
r
m
a
t
i
o
n
i
s
a
v
a
i
l
a
b
l
e
o
n
l
i
n
e
,
c
o
m
p
r
i
s
i
n g
n
M . J. Org. Chem. 2000, 65, 365–374.
R a n g a n a t ha n, D . ; K u r u r , S . ; K a r l e , I . L . Biopolymers 2000,
e
x
p
e
r
i
m
e
n
t
a
l
p
r
o
c
e
d
u
r
e
s
a
n
d
c
o
m
p
o
u
n
d
c
h
a
r
a
c
t
e
r
i
s
a
t
i
o
(
1
4
)
d
a
t
a
(
1
H
,
1
3
C
,
I
R
,
H
R
M
S
&
X
-
r
a
y
)
.
54, 249–261.
( 1 5 )
( 1 6 )
( 1 7 )
( 1 8 )
E
E
fi
fi
m
m
,
o
o
S
v
v
,
,
A
A
.
.
V
V
o
. Protein Eng. 1991, 4, 245–250.
. FEBS Lett. 1994, 355, 213–219.
R M
S t e r n b e r g, M . J . E . ; T h o r n to n , J . M . J. Mol. Biol. 1976, 105,
a
o
.
T
.
;
R
s
s
m
a
n
n
,
.
G
.
J
.
M
o
l
.
B
i
o
l
.
1
9
7
3
,
7
6
,
2
4
1
–
2
5
6
.
Acknowledgements
367–382.
T
h
d
c
s
e
a
t
u
h
i
t
e
t
h
o
U
f
l
r
s
n
r
t
h
a
e
n
k
i
y
t
y
a
h
e
o
a
s
N
f
a
O
i
t
i
x
o
f
a
n
o
n
a
r
d
l
d
I
n
f
r
s
o
H
t
i
r
t
u
f
y
t
e
u
e
s
n
o
f
n
H
e
a
D
o
l
t
r
k
h
(
C
G
h
x
M
6
t
r
9
o
d
8
p
)
5
h
f
0
e
o
)
r
r
( 1 9 )
( 2 0 )
( 2 1 )
( 2 2 )
( 2 3 )
E
E
fi
fi
m
m
o
o
v
v
,
,
A
A
.
.
a
V
V
. FEBS Lett. 1984, 166, 33–38.
. FEBS Lett. 1991, 284, 288–292.
a
n
i
v
r
s
t
d
i
g
,
r
i
s
I
n
a
h
r
v
o
o
X
-
r
a
s
n
n
l
y
s
s
D
a
d
n
P
e
a
c
c
(
O
f
o
S
C
C
u
n
,
Z
.
;
J
i
n
g
,
B
. J. Protein Chem. 1996, 15, 675–690.
. Acta Crystallogr. 1953, 6, 689–697.
h o t h ia , C . ; L e v i t t , M . ; R i c h a r d s o n, D . Proc. Nat. Acad.
h
i
e
l
p
f
u
d
i
s
c
u
s
i
o
.
r
i
c
k
,
F
Sci. USA. 1977, 74, 4130–4134.
C h o t h ia , C . ; L e v i t t , M . ; R i c h a r d s o n, D . J. Mol. Biol. 1981,
145, 215–250.
E fi m o v, A . V . FEBS Lett. 1999, 463, 3–6.
References
(
(
2
2
4
5
)
)
(
1
)
A
d
l
e
r
,
M
.
J
.
;
J
a
Top. Microbiol. Immunol. 2011, 348, 1–23.
m
i
e
s
o
n
,
A
.
G
.
;
H
a
m
i
l
t
o
n
,
A
.
D
.
C
u
r
r
.

5
9
0
L. Nevola et al.
(
(
(
2
2
2
6
7
8
)
)
)
L
E
W
e
n
a
e
g
l
,
e
t
S
.
;
D
,
C
h
.
i
;
r
i
D
S
k
j
e
;
i
G
a
n
r
e
,
a
G
.
,
a
S
W
d
. Biophys. J. 2004, 86, 1105–1117.
. Proteins 2005, 61, 325–337.
. Proc. Nat. Acad. Sci. USA.
O
c
h
s
e
n
f
e
l
d
,
C
.
;
B
r
o
w
n
,
S
.
T
.
;
G
i
l
b
e
r
t
,
A
.
T
.
B
.
;
S
l
i
p
c
h
e
n
k
o
,
;
;
;
;
;
;
;
l
,
.
E
d
o
.
,
F
W
L
L
H
.
V
.
;
L
e
v
c
h
e
n
k
o
,
S
.
V
.
;
O
’
N
e
i
l
l
,
D
.
P
.
;
D
i
S
;
t
a
s
i
o
,
J
r
,
R
N
S
.
.
.
A
A
H
.
.
.
.
.
.
.
e
r
s
R
.
F
.
.
D
G
r
o
.
F
o
c
h
a
n
,
R
.
C
.
;
W
i
a
n
g
,
T
.
;
B
e
r
a
n
,
G
.
J
.
O
.
B
e
s
l
e
y
,
2006, 103, 13658–13663.
Y
V
e
r
b
e
r
t
,
J
.
M
.
;
L
n
,
C
.
Y
.
;
V
a
n
V
o
o
r
h
i
s
,
T
.
;
C
h
i
e
n
,
(
(
2
3
9
0
)
)
a
a
e
m
n
k
a
d
a
,
S
.
C
o
o
r
d
.
C
h
e
m
.
R
e
v
.
1
9
6
6
,
1
,
4
1
5
–
4
3
7
.
S
o
d
t
,
A
.
;
S
t
e
e
l
e
,
R
.
P
.
;
R
a
s
s
o
l
o
v
,
V
.
A
.
;
M
a
s
l
e
n
,
P
.
E
J
S
,
t
A
e
i
n
, ,
. J. Am. Chem. Soc. 1984, 106, 4486–4492.
G
.
C
.
;
V
a
n
K
o
t
e
n
,
G
.
;
V
r
i
e
z
e
K
.
;
B
r
e
v
a
r
d
,
C
.
;
;
K
o
r
a
m
,
b
a
t
h
,
P
.
P
.
;
A
d
a
m
,
s
o
n
,
R
.
D
.
;
A
u
s
t
i
n
,
B
.
;
B
a
k
e
r
,
S
p
.
L
B
D
H
y
r
d
E
.
F
.
C
.
;
D
D
a
c
h
s
e
l
H
.
;
D
o
e
r
k
s
e
n
,
R
.
J
.
;
D
r
e
u
w
,
A
(
(
(
3
3
3
1
2
3
)
)
)
Z
h
a
n
g
,
W
.
;
S
u
n
,
W
.
-
H
.
;
W
u
,
B
.
;
Z
h
a
n
g
,
S
.
;
M
a
,
H
.
;
L
i
,
Y
.
u
n
i
e
t
z
,
B
.
D
.
;
u
t
o
i
,
A
.
D
.
;
F
u
r
l
a
n
i
,
T
.
R
.
;
G
w
a
l
t
n
e
y
,
S
.
R
Che n, J.; H ao, P. J. Organomet. Chem. 2006, 691, 4759–4767.
P e la g a t t i , P . ; C a r c e l l i, M .; C o s ta , M .; I a n e l l i , S . ; P e l i z z i , C . ;
R
e
y
d
e
n
,
A
.
;
H
i
r
a
t
a
,
S
.
;
H
s
u
,
C
-
P
.
;
K
e
d
z
i
o
r
a
,
G
.
;
K
h
a
l
l
W
i
u
l
i
n
,
R
.
Z
.
;
K
l
u
n
z
i
n
g
e
r
,
P
.
;
L
e
e
,
A
.
M
.
;
L
e
e
,
M
.
S
.
;
L
i
a
n
g
,
.
Z
.
;
o
a
e
o
g
n
t
d
o
n
t
g
l
i
n
n
,
r
o
,
D
. J. Mol. Catal. A: Chem 2005, 226, 107–110.
J
L
o
t
a
n
,
I
.
;
N
a
i
r
,
N
.
;
P
e
t
e
r
s
,
B
.
;
P
r
o
y
n
o
v
,
E
.
I
.
;
P
i
e
n
i
a
z
e
k
,
P
.
H
o
,
M
.
.
M
;
M
o
t
r
e
e
n
o
,
V
.
;
I
P
r
I
i
e
t
o
a
,
c
M
.
J
.
.
;
.
M
S
o
a
l
n
d
d
r
h
e
s
i
,
m
K
,
E
.
;
;
A
.
;
R
h
e
e
,
T
.
M
.
;
R
i
t
c
h
i
e
,
J
.
;
R
o
s
t
a
W
,
E
.
;
S
h
e
r
r
i
l
l
,
C
.
D
. ;
. ;
. ;
S
l
e
n
E
A
P
.
;
e
i
s
r
m
a
n
n
,
.
;
s
a
,
C
J
. Angew. Chem. Int. Ed. 2001, 40, 879–884.
;
e
r
.
J
.
R
e
,
,
S
i
m
m
o
n
e
W
t
t
,
A
.
C
.
;
S
u
b
o
t
n
i
k
,
J
.
E
.
;
o
o
d
c
o
c
k
,
I
I
I
,
H
.
L
(
(
3
3
4
5
)
)
V l
Heterocycles 1997, 45, 1519–1528.
a
n
e
l
l
e
.
;
R
a
t
h
e
l
o
t
,
P
.
;
M
a
d
o
n
a
d
o
,
J
.
;
C
r
o
z
e
t
,
M
.
P
.
Z
h
a
n
,
g
,
.
;
W
B
e
l
l
,
A
.
T
.
;
C
h
a
k
r
a
b
o
r
t
y
,
A
.
K
.
;
C
h
i
p
m
a
n
,
D
.
M
K
e
i
l
F
.
J
.
;
a
r
s
h
e
l
,
A
.
;
H
e
h
r
e
,
W
W
.
J
.
;
S
c
h
a
e
f
e
r
,
H
.
F
.
; ,
. Phys.
K
o
n
g
T
M
G
a
.
v
J
z
a
a
.
r
e
s
,
F
.
,
.
.
X
C
K
;
.
.
.
L
;
S
;
a
A
.
l
C
-
B
a
o
a
r
a
o
z
n
.
a
,
C
n
D
j
.
i
L
H
,
K
.
F
d
A
e
l
.
l
o
;
d
B
m
i
a
A
g
n
h
,
a
P
.
m
,
E
.
C
o
.
;
e
B
i
s
A
D
h
.
.
o
S
L
p
,
J
.
;
K
r
y
l
o
v
,
A
.
I
.
;
G
i
l
l
,
P
.
M
.
.
;
H
e
a
d
-
G
o
r
d
o
n
,
M
;
B
r
,
i
t
t
;
G
n
r
l
t
.
;
.
L
.
;
G
t
z
,
. ;
;
Chem. Chem. Phys. 2006, 8, 3172.
y
r
i
z
l
e
M
u
,
,
Y
.
;
a
n
n
,
.
L
;
H
e
r
t
z
o
g
,
.
(
3
8
)
)
C
o
r
n
e
l
l
,
W
e
.
D
.
;
C
i
e
p
l
a
k
,
P
.
;
B
a
l
y
,
C
.
I
.
;
G
o
u
l
d
,
I
.
R
F
.
;
M
e
r
z
,
I
g
n
r
,
D
.
M
g
D
.
G
.
;
O
t
t
,
R
.
J
J. Med. Chem. 2006, 49, 7095–7107.
.
;
P
e
a
t
,
A
.
J
.
;
Z
h
o
u
,
H
.
-
Q
.
,
,
K
.
M
.
;
F
r
g
u s
W
o
n
,
D
.
M
.
;
S
p
e
l
l
m
e
y
e
r
,
D
.
C
.
;
o
x
,
T
.
;
C
a
l
d
w
e
l
l
,
J
.
.
;
K
o
l
l
m
a
n
,
P
.
A
.
J
.
A
m
.
C
h
e
m
.
S
o
c
.
1
9
9
5
,
(
(
3
3
6
7
)
)
R
A
o
d
r T
. ChemBioChem 2009, 10, 829–833.
i
g
u
e
z
,
J
.
M
.
;
N
e
v
o
l
a
,
L
.
;
R
o
s
s
,
N
.
.
;
L
e
e
,
G
.
;
H
a
m
i
l
t
o
n
117, 5179–5197.
m
.
D
(
3
9
O
s
539–544.
h
e
a
,
E
.
;
K
l
e
m
,
J
.
;
K
i
m
,
P
.
;
A
l
b
e
r
,
T
.
S
c
i
e
n
c
e
1
9
9
1
,
2
5
4
,
S
p
a
A
r
;
t
a
n
(
A
m
b
e
.
r
f
o
r
c
e
fi
a
e
,
l
d
)
;
F
W
;
a
v
e
f
u
,
n
c
Y
t
i
o
n
,
K
I
n
c
m
.
,
I
n
r
v
i
n
e
C
S
h
a
o
,
Y
;
M
o
l
n
r
L
.
.
J
u
n
g
.
;
u
s
s
a
n
,
J
.
;