Design and synthesis of cyclic RGD pentapeptoids by consecutive Ugi reactions

Article abstract of DOI:10.1021/ol702521g

(Chemical Equation Presented) A new strategy for the synthesis of cyclic peptoids was developed. The approach is based on the use of consecutive Ugi reactions for the assembly of the acyclic peptoid and for the ring closure. Cyclopentapeptoid analogues of the RGD peptides were designed and synthesized using this methodology. The results confirm the versatility and efficiency of the method for the preparation of cyclic oligopeptoids.

Full text of DOI:10.1021/ol702521g

ORGANIC
LETTERS
2008
Vol. 10, No. 2
205-208
Design and Synthesis of Cyclic RGD
Pentapeptoids by Consecutive Ugi
Reactions
Otilie E. Vercillo,†,‡ Carlos Kleber Z. Andrade,‡ and Ludger A. Wessjohann*,†
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry,
Weinberg 3, D-06120 Halle (Saale), Germany, and Laborato´rio de Qu´ımica
Metodolo´gica e Orgaˆnica Sinte´tica, Instituto de Qu´ımica, UniVersidade de Bras´ılia,
CP 4478, 70910-970 Bras´ılia-DF, Brazil
wessjohann@ipb-halle.de
Received October 16, 2007
ABSTRACT
A new strategy for the synthesis of cyclic peptoids was developed. The approach is based on the use of consecutive Ugi reactions for the
assembly of the acyclic peptoid and for the ring closure. Cyclopentapeptoid analogues of the RGD peptides were designed and synthesized
using this methodology. The results confirm the versatility and efficiency of the method for the preparation of cyclic oligopeptoids.
Peptoids1,2 are a class of oligomeric N-alkyl glycines that
mimic the primary natural structure of peptides. They are
attractive non-natural molecules for drug discovery ap-
proaches because of their many biological activities and
proteolytic stability. Many peptoids have been shown to be
capable of acting as protein ligands with high affinity.3
The Ugi four-component reaction (U-4CR)4 is known to
be one of the most versatile tools for the construction of
peptoid and mixed peptoid-peptide backbones. Repetitive
or consecutive Ugi reactions have been used in the synthesis
of PNA oligomers5 and also in the synthesis of hydantoin-
imide and tetrazole derivatives.6 U-4CRs also have been used
in one-pot macrocyclizations.7-9 However, these approaches
did not allow the assembly of pure peptoid backbones in a
consecutive fashion followed by formation of the macrocycle,
as proposed in this study. In order to study sequential Ugi
reactions for the construction of defined cyclopeptoid
backbones, a convergent approach toward the synthesis of
cyclic peptoids capable of mimicking the structural complex-
ity of the cyclic RGD peptides is reported herein (RGD )
† Leibniz Institute of Plant Biochemistry.
‡ Universidade de Bras´ılia.
(1) (a) Zuckermann, R. N.; Matin, E. J.; Spellmeyer, D. C.; Stauber, G.
B.; Shoemaker, K. R.; Kerr, J. M.; Figliozzi, G. M.; Goff, D. A.; Siani, M.
A.; Simon, R. J.; Banville, S. C.; Brown, E. G.; Wang, L.; Richter, L. S.;
Moss, W. H. J. Med. Chem. 1994, 37, 2678. (b) Shin, S. B. Y.; Yoo, B.;
Todaro, L. J.; Kirshenbaum, K. J. Am. Chem. Soc. 2007, 129, 3218.
(2) Wessjohann, L. A.; Andrade, C. K. Z.; Vercillo, O. E.; Rivera, D.
G. Targets Heterocycl. Syst. 2006, 10, 24.
(3) (a) Alluri, P.; Liu, B.; Yu, P.; Xiao, X.; Kodadek, T. Mol. BioSyst.
2006, 2, 568. (b) Masip, I.; Corte´s, N.; Abad, M.-J.; Guardiola, M.; Pe´rez-
Paya´, E.; Ferragut, J.; Ferrer-Montiel, A.; Messeguer, A. Bioorg. Med. Chem.
2005, 13, 1923.
(5) (a) Do¨mling, A. Nucleosides Nucleotides 1998, 17, 1667. (b) Xu,
P.; Zhang, T.; Wang, W.; Zou, X.; Zhang, X.; Fu, Y. Synthesis 2003, 1171.
(6) Constabel, F.; Ugi, I. Tetrahedron 2001, 57, 5785.
(7) (a) Wessjohann, L. A.; Ruijter, E. Mol. DiVersity 2005, 9, 159. (b)
Wessjohann, L. A.; Voigt, B.; Rivera, D. G. Angew. Chem., Int. Ed. 2005,
44, 4785. (c) Rivera, D. G.; Wessjohann, L. A. J. Am. Chem. Soc. 2006,
128, 7122.
(8) Failli, A.; Immer, H.; Go¨tz, M. Can. J. Chem. 1979, 57, 3257.
(9) (a) Janvier, P.; Bois-Choussy, M.; Bienayme´, H.; Zhu, J. P. Angew.
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10.1021/ol702521g CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/19/2007

arginine-glycine-aspartic acid). The RGD loop containing
peptides are the molecular attachment points of many cellular
and extracellular matrices. Along with the integrins, their
receptors, they constitute a major system for cell adhesion,10
which is crucial in many pathological processes, such as
tumor metastasis, angiogenesis, osteoporosis, and thrombosis.
Nearly half of the known integrins recognize the RGD
sequence as ligands, giving this motif a central role in cell
adhesion biology as the prototype adhesion signal.
The integrins became attractive targets for drug develop-
ment, especially those involved in cancer treatment and in
platelet aggregation. For instance, the inhibitors of the
integrin RIIbâ3, involved in platelet aggregation, are used as
antithrombotic agents,11 and the cyclic peptide, c(RGDf-
[NMe]V), an antagonist of integrin RVâ3, is in clinical tests
as an anticancer drug.12 Many cyclic RGD peptides and
nonpeptidic mimetics have been developed as highly active
and selective antagonists for different integrin receptors by
tuning the conformational bias of the macrocycle.11-17
On the basis of the pharmacophore model proposed by
Kessler and co-workers (1),18 the structure-activity relation-
ship (SAR) and docking studies on Rvâ3 integrin ligands,19,20
as well as synthetic feasibility, we designed cyclic pentapep-
toid analogues of RGD peptides (Figure 1). Thus, the main
of the amides and not to the R carbon as in peptides. The
shift of the side chains to the amide nitrogen commonly
results in increased metabolic stability. It can be done in two
different directions: (1) toward the “N-terminus” direction,
that is, to the nitrogen atom of the amino acid itself (CR f
Ni), or (2) to the “C-terminus” direction, that is, to the
nitrogen atom of the next amino acid residue (CR f Ni+1).
As shown in Figure 1, for any given R and R′, a peptoid
(“RGD”) and a retro-peptoid (“DGR”) can be formed within
a cyclic peptide; that is, four different cyclopeptoid configu-
rations with the side chain sequence of R-G-D are possible.
For the targeted cyclopeptoids 2 and 3, the CR f Ni shift
had to be followed. Also, compared to classical peptoids,
these compounds contain some amide-NH bonds that allow
H-donor interaction, albeit less than in peptides.
The retrosynthetic analysis of the peptoids (Scheme 1)
shows that the proposed compounds can be achieved
Scheme 1. Retrosynthesis
employing two consecutive Ugi four-component reactions
(U-4CRs) for the construction of the acyclic amino acid
precursor, and another Ugi three-component four-center
reaction for the peptoid macrocyclization. A general route
was developed in which the side chains of the peptoid
backbone could be easily exchanged by varying the amine,
leading to both kinds of target peptoids, the RGD- and the
DGR-like compounds.
Figure 1. Structures of RGD peptide pharmacophore model (1)
and of the cyclic pentapeptoid analogues. 2: CR f Ni shifted
peptoid; 3: retro CR f Ni shifted peptoid. Ni+1 shifted peptoids
are not shown.
A special challenge was the introduction of the guani-
dinium group. Attempts to use ethyl or propylamine with
(14) Goodman, S. L.; Ho¨lzemann, G.; Sulyok, G. A. G.; Kessler, H. J.
Med. Chem. 2002, 45, 1045.
(15) Aumailley, M.; Gurrath, M.; Mu¨ller, G.; Calvete, J.; Timpl, R.;
Kessler, H. FEBS Lett. 1991, 291, 50.
(16) Hayashi, Y.; Sato, Y.; Katada, J.; Takiguchi, Y.; Ojima, I.; Uno, I.
Bioorg. Med. Chem. Lett. 1996, 6, 1351.
innovation in this approach is the rapid access to the cyclic
skeleton, in principle, suitable to combinatorial extension,
and the fact that the side chains are attached to the nitrogen
(17) Dijkgraaf, I.; Kruijtzer, J. A. W.; Frielink, C.; Soede, A. C.; Hilbers,
H. W.; Oyen, W. J. G.; Corstens, F. H. M.; Liskamp, R. M. J.; Boerman,
O. C. Nucl. Med. Biol. 2006, 33, 953.
(18) Haubner, R.; Gratias, R.; Diefenbach, B.; Goodman, S. L.; Jonczyk,
A.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 7461.
(19) Gottschalk, K.-E.; Kessler, H. Angew. Chem., Int. Ed. 2002, 41,
3767.
(10) Rouslahti, E.; Pierschbacher, M. D. Science 1987, 238, 491.
(11) Haubner, R.; Schimitt, W.; Ho¨lzemann, G.; Goodman, S. L.;
Jonczyk, A.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 7881.
(12) Dechantsreiter, M. A.; Planker, E.; Matha¨, B.; Lohof, E.; Ho¨lzemann,
G.; Jonczyk, A.; Goodman, S. L.; Kessler, H. J. Med. Chem. 1999, 42,
3033.
(13) Wermuth, J.; Goodman, S. L.; Jonczyk, A.; Kessler, H. J. Am. Chem.
Soc. 1997, 119, 1328.
(20) Marinelli, L.; Lavecchia, A.; Gottschalk, K.-E.; Novellino, E.;
Kessler, H. J. Med. Chem. 2003, 46, 4393.
206
Org. Lett., Vol. 10, No. 2, 2008

an ω-guanidinium group, unprotected or protected with either
2×Boc or 2×Cbz, were unsuccessful in the Ugi reactions.
Some of the problems encountered were migration of the
protecting group to the free amine or cyclization to a cyclic
guanidinium, as observed previously in another context.21-23
Therefore, monoprotected ethylene and propylene amino
alcohols or diamines were used to synthesize SGD and KGD
type peptoids that could allow the introduction of the
guanidinium moiety after the synthesis of the central mac-
rocycle (Scheme 2). Of many methods tried for the guanidi-
Scheme 4. Synthesis of Cyclopeptoid 2
Scheme 2. Synthesis of Protected SGD-, KGD-, and
DGK-like Peptoids
The first Ugi reaction (Scheme 4) was performed using
amine 16 as the amino component, furnishing ester 17 in
68% yield. After hydrolysis of ester 17, the resulting acid
was used in a subsequent Ugi reaction to give ester 18 in
high yield (85%). The amino acid precursor for the cycliza-
tion was obtained from 18 after ester hydrolysis and Cbz
deprotection and was reacted with tert-butyl isocyanide and
paraformaldehyde under pseudo-high-dilution conditions to
avoid oligomerization, giving cyclopeptoid 2 in 33% yield
(combined yield after four steps) after removal of the
protecting groups with 1:1 TFA/CH2Cl2.
nylation, none was successful for these compounds.21,24 Thus
a new set of guanidinium protective groups had to be
employed. For this purpose, amine 16 was synthesized from
azide 12 after dimethoxybenzyl (Dmb) protection and
introduction of the guanidinium moiety with the 2,2,5,7,8-
pentamethyl-6-sulfonyl (pmc) protected 1H-pyrazole car-
boxamidine 14 (Scheme 3). This new set of mixed protecting
The retro-peptoid 3 was achieved likewise by changing
the order of addition of the amines of the two initial Ugi
reactions (Scheme 5). Glycine tert-butyl ester hydrochloride
Scheme 5. Synthesis of Retro-Cyclopeptoid 3
Scheme 3. Synthesis of Amine 16
(4c) was used in the first Ugi reaction (Scheme 5) to furnish
ester 8c (84% yield), followed by amine 16 in the second
U-4CR to give ester 19 (53% yield). The cyclization of the
amino acid, prepared from peptoid ester 19, was carried out
under the standard conditions to give peptoid 3 in 21% yield
(four steps) after treatment with 1:1 TFA/CH2Cl2 to remove
the protecting groups.
The approach proposed herein has been shown to be
straightforward and opens the possibility for a combinatorial
strategy toward a wide range of cyclic peptoids. By choosing
groups was suitable, and no migration or cyclization was
observed.
(21) Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.; Goodmann,
M. J. Org. Chem. 1998, 63, 8432.
(22) Guery, S.; Schmitt, M.; Bourguignon, J.-J. Synlett 2002, 2003.
(23) Wagner, J.; Kallen, J.; Ehrhardt, C.; Evenou, J.-P.; Wagner, D. J.
Med. Chem. 1998, 41, 3664.
(24) Gers, T.; Kunce, D.; Markowski, P.; Izdebski, J. Synthesis 2004,
37 and references cited therein.
Org. Lett., Vol. 10, No. 2, 2008
207

the proper amino and carbonyl components in the first two
U-4CRs and isocyanide and carbonyl component in the Ugi
three-component four-center reaction used for the cyclization,
a variety of different peptoids can be obtained. We could
demonstrate that even the most awkward amino acid side
chain combination, carboxylate and guanidinium, can be
achieved. The results confirm the versatility and efficiency
of this method for the preparation of cyclic pentapeptoids
but potentially also higher homologues.
as studies to include a Passerini-3CR to form depsipeptoids2
are in progress.
Acknowledgment. The authors thank Dr. Ju¨rgen Schmidt
for the HRMS spectra, Daniel G. Rivera and Prof. Bernhard
Westermann (all at Leibniz Institute of Plant Biochemistry)
for helpful and fruitful suggestions, and the DAAD, CNPq,
Finatec, and HWP/LSA for financial support.
It is noteworthy that this is the first report of peptoid
synthesis where the peptoid backbone and the macrocycle
closure are performed consecutively employing the Ugi four-
component reaction. Further experiments to evaluate the
biological activity of compounds 2 and 3 and their com-
parison with the activity of the known RGD peptides as well
Supporting Information Available: General procedures
and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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