peptides and proteins involving noncovalent interactions.1 The
mystery of how a protein sequence specifies a unique structure
and function has intrigued chemists leading to the design and
development of foldamers,2 which are synthetic oligomers with
a definite conformational backbone structure. The foldamer
approach has been extensively utilized generating diverse sets
of structures which are able to mimic secondary structure
elements like â-turns, helices, and â-pleated sheets.3 The driving
force for these efforts has been the possibility of achieving
suitable templates for the design of biologically active molecules
that compete for a variety of protein-protein4 and protein-
membrane interactions, respectively.5 These synthetic oligomers
may provide excellent starting points for the elaboration of
peptide mimics that could be designed only with difficulties on
the basis of small-molecule scaffolds.6 To extend the repertoire
of foldamer design, foldamers containing different residues of
independent conformational preferences were recently suggested.
For instance, several groups demonstrated that R,â-hybrid
peptides composed of alternately changing R- and â-amino acid
constituents showed convincing evidence for the formation of
special helix types.7 We ourselves have recently provided
theoretical insights into the helix formation propensities in R,â-,
R,γ-, and â,γ-hybrid peptides.8 Furthermore, the potential of
using unconventional foldamer building blocks for the design
of protein secondary structure mimetics has also been described.9
In this note, we describe a foldamer having proline (Pro) and
3-amino-5-bromo-2-methoxy benzoic acid (Amb) as alternating
subunits that forms repeating γ-turn conformations. Although
not so ubiquitous as â-turns, γ-turns consisting of three amino
acid residues have been implicated in several important biologi-
Enforcing Periodic Secondary Structures in
Hybrid Peptides: A Novel Hybrid Foldamer
Containing Periodic γ-Turn Motifs
Pranjal K. Baruah,† N. K. Sreedevi,† Rajesh Gonnade,‡
Sapna Ravindranathan,§ Krishnan Damodaran,
Hans-Jo¨rg Hofmann,*,| and Gangadhar J. Sanjayan*,†
DiVision of Organic Synthesis, Central Material
Characterization DiVision, and Central NMR Facility,
National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune 411 008, India, Department of Chemistry, UniVersity of
Pittsburgh, Pittsburgh, PennsylVania 15260, and
UniVersita¨t Leipzig, Institut fu¨r Biochemie, Bru¨derstrasse 34,
D-04103 Leipzig, Germany
hofmann@uni-leipzig.de; gj.sanjayan@ncl.res.in
ReceiVed October 2, 2006
(1) (a) Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. ReV.
2001, 101, 3131-3152. (b) Shi, Z.; Chen, K.; Liu, Z.; Kallenbach, N. R.
Chem. ReV. 2006, 106, 1877-1897. (c) MacKenzie, K. R. Chem. ReV. 2006,
106, 1931-1977.
This note describes the design, synthesis, and conformational
studies of a novel hybrid foldamer that adopts a definite
compact, three-dimensional structure determined by a com-
bined effect of the special conformational properties of the
foldamer constituents. The striking feature of this de novo
designed foldamer is its ability to display periodic γ-turn
conformations stabilized by intramolecular hydrogen bonds.
Conformational investigations by single-crystal X-ray studies,
solution-state NMR, and ab initio MO theory at the HF/6-
31G* level strongly support the prevalence of γ-turn motifs
in both the di- and tetrapeptide foldamers, which are
presumably stabilized by bifurcated hydrogen bonds in the
solid and solution states. The strategy disclosed herein for
the construction of hybrid foldamers with periodic γ-turn
motifs has the potential to significantly augment the con-
formational space available for foldamer design with diverse
backbone structures and conformations.
(2) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180.
(3) For representative reviews, see: (a) Smith, M. D.; Fleet, G. W. J. J.
Peptide Sci. 1999, 5, 425-441. (b) Kirschenbaum, K.; Zuckerman, R. N.;
Dill, D. A. Curr. Opin. Struct. Biol. 1999, 9, 530-535. (c) Cheng, R. P.;
Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101, 3219-3232. (d)
Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem.
ReV. 2001, 101, 3893-4011. (e) Cubberley, M. S.; Iverson, B. L. Curr.
Opin. Chem. Biol. 2001, 5, 650-653. (f) Stigers, K. D.; Soth, M. J.; Nowick,
J. S. Curr. Opin. Chem. Biol. 1999, 3, 714-723. (g) Sanford, A. R.; Yamato,
K.; Yang, X.; Yuan, L.; Han, Y.; Gong, B. Eur. J. Biochem. 2004, 271,
1416-1425. (h) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
BiodiVersity 2004, 1, 1111-1239.
(4) Kritzer, J. A.; Hodsdon, M. E.; Schepartz, A. J. Am. Chem. Soc.
2005, 127, 4118-4119.
(5) Liu, D.; Choi, S.; Chen, B.; Doerksen, R. J.; Clements, D. J.; Winkler,
J. D.; Klein, M. L.; DeGrado, W. F. Angew. Chem., Int. Ed. 2004, 43, 1158-
1162.
(6) (a) Choi, S.; Clements, D. J.; Pophristic, V.; Ivanov, V.; Vemparala,
S.; Bennett, J. S.; Klein, M. L.; Winkler, J. D.; DeGrado, D. F. Angew.
Chem., Int. Ed. 2005, 44, 6685-6689. (b) Baldauf, C.; Guenther, R.;
Hofmann, H.-J. J. Org. Chem. 2005, 70, 5351-5361.
(7) (a) Hayen, A.; Schmitt, M. A.; Ngassa, F. N.; Thomasson, K. A.;
Gellman, S. H. Angew. Chem., Int. Ed. 2004, 43, 505-510. (b) De Pol, S.;
Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew. Chem., Int. Ed. 2004,
43, 511-514. (c) Sharma, G. V. M.; Nagendar, P.; Jayaprakash, P.; Krishna,
P. R.; Ramakrishna, K. V. S.; Kunwar, A. C. Angew. Chem., Int. Ed. 2005,
44, 5878-5882.
Over the past three decades, chemists have made key strides
in learning the fundamental rules of folding propensities of
(8) (a) Baldauf, C.; Gunther, R.; Hofmann, H.-J. Biopolymers 2006, 84,
408-413. (b) Baldauf, C.; Gunther, R.; Hofmann, H.-J. J. Org. Chem. 2006,
71, 1200-1208.
(9) Acrylamide oligomers have been shown to adopt â-sheet-like
structures, see: Kendhale, A.; Gonnade, R.; Rajamohanan, P. R.; Sanjayan.
G. J. Chem. Commun. 2006, 2756-2758.
† Division of Organic Synthesis, National Chemical Laboratory.
‡ Central Material Characterization Division, National Chemical Laboratory.
§ Central NMR Facility, National Chemical Laboratory.
Department of Chemistry, University of Pittsburgh.
| Universita¨t Leipzig, Institut fu¨r Biochemie.
10.1021/jo062032w CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/23/2006
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J. Org. Chem. 2007, 72, 636-639