"Triazole bridge": Disulfide-bond replacement by ruthenium-catalyzed formation of 1,5-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/anie.201008142

A good impression: A modular approach using a ruthenium(II) catalyst during peptide synthesis gives rigid and well-defined triazole bridges as tailor-made substitutes for natural disulfide bridges (see structures). The corresponding modification of the mo

Full text of DOI:10.1002/anie.201008142

DOI: 10.1002/anie.201008142
Disulfide Mimics
“Triazole Bridge”: Disulfide-Bond Replacement by Ruthenium-
Catalyzed Formation of 1,5-Disubstituted 1,2,3-Triazoles**
Martin Empting, Olga Avrutina, Reinhard Meusinger, Sebastian Fabritz, Michael Reinwarth,
Markus Biesalski, Stephan Voigt, Gerd Buntkowsky, and Harald Kolmar*
About one fourth of the peptidic macromolecular structures
deposited in the protein data base (PDB) contain at least one
disulfide bridge.[1] In nature, disulfide bonds are formed in a
milieu where oxidizing conditions prevail, for example, on the
cell surface or in the extracellular matrix. Many proteins
benefit from disulfide contributions to their conformational
stability. In particular, the defined tertiary folding of oligo-
peptides smaller than 30 residues essentially relies on macro-
cyclization through the cystine motif because of the restricted
number of noncovalent intramolecular interactions available.
Moreover, formation of the disulfide pattern results in
structural rigidity of the peptidic framework, as for example,
in the family of cystine knot miniproteins,[2] leading to
conformationally constrained scaffolds with extraordinary
thermal stability and resistance against proteolytic degrada-
tion.[2a] Hence, the discovery and development of disulfide-
bridged peptides suitable for diagnostic and therapeutic
applications remains a field of intense research.[3]
The in-vitro generation of disulfide bonds in peptides is
usually achieved post-synthetically and mediated by DMSO,
air oxygen, or other oxidizing agents. Although this reaction
step can be achieved under relatively mild conditions in
solution, it remains one of the most demanding obstacles
towards high-yield peptide synthesis, especially for disulfide-
rich species in which the controlled regiospecific formation of
several disulfide bonds is not trivial to control.[4] In addition,
to suppress unwanted intermolecular reactions of the thiol
groups of individual peptides, oxidative folding usually has to
be conducted in highly diluted solutions. In spite of the use of
gluthathione-based redox buffers, polymer-supported oxida-
tion systems, macrocyclization on the solid support and/or
orthogonal protecting groups, control over the topology of the
disulfide bridges formed is still a challenge.[4a,e,f,5]
In view of these difficulties and to improve the redox
stability of bridged peptides, several routes towards synthetic
disulfide surrogates have been developed.[6] Straightforward
approaches usually employ thioether, olefin, or alkane-based
isosters.[6a,b,d–f] However, cystathione bridges require multiple
synthetic steps and careful choice of orthogonal protection,
and dicarba bridges give cis/trans isomers during ring-closing
metathesis (RCM).[6a,b,f] Only an additional purification step
or the subsequent palladium-catalyzed hydrogenation of the
unsaturated species to the corresponding alkane leads to a
construct with defined configuration.[6b,f]
In 2004, Meldal et al. described the utility of copper(I)-
catalyzed azide–alkyne cycloaddition (CuAAC) for a tria-
zole-based disulfide replacement.[6c] Owing to the compelling
characteristics of this prototypic “click” reaction, it has been
extensively applied in peptide chemistry exploiting the almost
perfect orthogonality to side-chain reactivities.[7] The intro-
duction of 1,4-disubstituted 1,2,3-triazoles into peptides has
also been used to mimic and rigidify conformations of the
amide backbone.[7d,8] Moreover, a variety of examples of
CuAAC-based macrocyclizations of peptides in solution and
on solid supports has been reported.[6c,8d,9]
Using the same azide- and alkyne-functionalized buidling
blocks, 1,5-disubstituted 1,2,3-triazoles can be generated in
the ruthenium(II)-catalyzed variant (RuAAC) of the
CuAAC.[10] This reaction expands the range of peptidomi-
metic structures selectively accessible from the same precur-
sor and having different biological activities governed by the
architecture of the incorporated triazole.[10c,f–h]
To our knowledge, 1,5-disubstitiuted 1,2,3-triazoles have
not been taken into consideration as disulfide mimics to date.
Herein, we report the facile introduction of 1,4- and 1,5-
disubstituted 1,2,3-triazoles into a monocyclic variant of the
sunflower trypsin inhibitor-I (SFTI-1[1,14], 1;[11] Figure 1) and
show that the macrocyclic peptidomimeticum 2 with the “1,5”
substitution pattern retains nearly full biological activity in
contrast to the “1,4” variants 3 and 4.
[*] M. Empting, Dr. O. Avrutina, Dr. R. Meusinger, S. Fabritz,
M. Reinwarth, Prof. Dr. H. Kolmar
Clemens-Schꢀpf-Institut fꢁr Organische Chemie und Biochemie
Technische Universitꢂt Darmstadt
Petersenstrasse 22, 64287 Darmstadt (Germany)
Fax: (+49)6151-16-5399
E-mail: kolmar@biochemie-tud.de
Homepage: http://www.chemie.tu-darmstadt.de/kolmar
Prof. Dr. M. Biesalski
Ernst-Berl-Institute fꢁr Technische und Makromolekulare Chemie
Technische Universitꢂt Darmstadt (Germany)
S. Voigt, Prof. Dr. G. Buntkowsky
Eduard-Zintl-Institut fꢁr Anorganische und Physikalische Chemie
Technische Universitꢂt Darmstadt
The choice of 1 as the model peptide for the investigation
of triazole-based disulfide replacements had several reasons.
SFTI-1 is a small, though very potent, inhibitor of trypsin.[11,12]
Therefore, the influence of different modes of macrocycliza-
tion on the bioactivity of the corresponding synthetic variant
can be routinely examined by serine protease inhibition
assays.[3e,6e,11,12c,13]
Petersenstrasse 22, 64287 Darmstadt (Germany)
[**] This research was supported by the Deutsche Forschungsgemein-
schaft through grant Ko 1390/9-1, LOEWE—Soft Control and by
BMBF.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008142.
Angew. Chem. Int. Ed. 2011, 50, 5207 –5211
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5207

Communications
The alignment of the deduced structures of peptidomi-
metics 2–4 with disulfide-bridged peptide 1 gave insight into
the steric requirements of the proposed triazole bridges and
allowed their tendency to disturb the parent backbone
conformation to be investigated (Figure 2b–d). The incorpo-
ration of 1,4-disubstituted 1,2,3-triazoles led to increased
distances between the Ca atoms of residues 3 and 11
compared to those of the corresponding cysteines in 1
(Figure 2c,d). In the case of the 1,5-disubstituted species the
spacing remained essentially the same (Figure 2a,b). Owing
to the planar and rigid architecture resulting in low degrees of
structural freedom for the aromatic heterocycle, the “1,4”
substitution pattern renders compounds 3 and 4 unable to
adopt the native conformation of 1 properly, thereby forcing
the residues 3 and 11 into more remote positions. In contrast,
the “1,5” pattern of 2 seems to be compatible with the
intrinsic geometry of 1. Therefore, a significant difference
between the inhibitory activities of compounds 2, 3, and 4
depending on the mode of macrocyclization was expected.
SFTI-1[1,14] (1) was synthesized by microwave-assisted
Fmoc-SPPS with subsequent DMSO mediated oxidation
(Supporting Information). Compounds 3 and 4 were synthe-
sized in a similar way using commercially available SPPS
building blocks Fmoc-l-propargylglycine (Fmoc-Pra-OH)
and Fmoc-l-azidoalanine (Fmoc-Aza-OH) or Fmoc-l-azido-
homoalanine (Fmoc-Aha-OH) yielding the linear precursors
Figure 1. Chemical formula of monocyclic SFTI-1[1,14] (1),[11]
[Ala3(&1),Ala11(&2)]SFTI-1[1,14][(&1-CH2-1,5-[1,2,3]triazolyl-&2)] (2),
[Ala3(&1),Ala11(&2)]SFTI-1[1,14][(&1-1,4-[1,2,3]triazolyl-&2)] (3), and
[Ala3(&1),Ala11(&2)]SFTI-1[1,14][(&1-CH2-1,4-[1,2,3]triazolyl-&2)] (4).
&=Conjunction of peptide backbone and the corresponding macro-
cyclization motif.
Craik and co-workers intensely investigated the structure
and proteolytic stabilities of monocyclic and linear variants of
SFTI-1 and demonstrated the importance of the disulfide
bridge in maintaining the inhibitory activity of open-chain
species.[12a,b,14] Furthermore, Roller et al. and Rolka et al. have
shown that disulfide replacements are tolerated depending on
the steric demand at residue 3 (Figure 1).[6e,12c,15]
5
([Aza3,Pra11]SFTI-1[1,14]) and ([Aha3,Pra11]SFTI-1-
6
A
solution structure of SFTI-1[1,14] (PDB code:
[1,14]), respectively (Scheme 1a,b). CuAAC-mediated mac-
rocyclization of unprotected peptides 5 and 6 was performed
in diluted solution after acidic cleavage from the support.
As expected, RuAAC conditions appeared incompatible
to solution-phase macrocylization of unprotected peptide 6
leading to an undefined mixture of side products. Instead, the
1,5-disubstituted 1,2,3-triazole was successfully installed
during SPPS using [Cp*RuCl(cod)] as the catalyst and
microwave irradiation to give compound 2, though in low
yield (2.1% according to initial resin load, Scheme 1c).
Purified peptides 1–6 were characterized by RP-HPLC, ESI-
MS, IR-, and NMR-spectroscopy.
1JBN)[12a] enabled possible triazole-based linkages within
the peptide chain to be modeled and to evaluate their fit into
the parent disulfide-bridged template 1 (Figure 2).
Though a formation of an intramolecular triazole bridge
proceeds without change of the molecular mass and cannot be
detected by standard mass spectrometry, the azide group
gives a prominent IR absorption band around 2100 cmÀ1 [16]
.
This band is sufficiently separated from the main IR signals
commonly found in peptides, and it absence products 2, 3, and
4 thus indicates the generation of triazoles (Figure 3a). 2D
HSQC NMR spectroscopy studies enabled to discriminate
1,4- from 1,5-disubstituted 1,2,3-triazoles by measuring the
chemical shifts of the H,13C coupling signal assigned to the
unique carbon-bound proton found in both heterocycles
(Figure 3b).
1
Figure 2. Structure and overlays of energy-minimized 3D models of
SFTI-1 variants 1–4 showing the region of the disulfide bridge and the
corresponding triazole-based substitutes. a) 1, b) 1 and 2, c) 1 and 3,
d) 1 and 4.[12a] Models were aligned at the respective carbonyl, Ca, Cb,
and amide nitrogen atoms of residue 11. The root mean square
deviations (RMSD) calculated for the respective carbonyl, Ca, Cb, and
amide nitrogen atoms of residues 3 and 11 at the compared structures
are given in ꢃ. Measured distances between the Ca atoms of residues
3 and 11 of the corresponding model are shown as dashed lines and
values are given in ꢃ. Blue nitrogen, light gray carbon atoms of 1, dark
gray carbon atoms of 2–4, red oxygen, yellow sulfur, hydrogen atoms
are omitted for clarity (for details see the Supporting Information).
The signals correlating to the single proton and the
corresponding carbon nucleus at position 5 or 4 in the 1,4- or
1,5-disubstituted 1,2,3-triazole bridges of compounds 2, 3, and
4 were found in the aromatic region between d = 7.8–7.3 ppm
(1H) and d = 135–120 ppm (13C). The 2D NMR spectroscopy
procedure enabled them to be distinguished from protons not
bound to carbon and from the intrinsic phenyl multiplet
1
arising from the side chain of residue 12. The measured H
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Angew. Chem. Int. Ed. 2011, 50, 5207 –5211

Figure 3. a) Superimposed IR transmission spectra of peptides
4 (c) and 6 (a), respectively, and assigned asymmetric NNN
stretch band of the azide group of 6 at 2110 cmÀ1. b) 2D HSQC NMR
spectra (1H,13C heteronuclear correlations) showing the aromatic
region of the peptides 1–4. Corresponding structural formula and
1H,13C chemical shifts for signals assigned to the unique carbon-bound
proton of 1,4- and 1,5-disubstituted 1,2,3-triazoles are shown.
Scheme 1. a) Non-natural amino acid building blocks Fmoc-l-azidoala-
nine (Fmoc-Aza-OH), Fmoc-l-azidohomoalanine (Fmoc-Aha-OH),
Fmoc-l-propargylglycine (Fmoc-Pra-OH) and the catalyst for RuAAC
mediated macrocyclization. b) Synthesis of peptidomimetics 3 and 4
bridged by 1,4-disubstituted 1,2,3-triazole. c) Synthesis of peptidomi-
metic 2 bridged by 1,5-disubstituted 1,2,3-triazole. DIEA=N,N-diiso-
propylethylamine, Fmoc=Fluorenylmethoxycarbonyl, NaAsc=sodium
ascorbate, TFA=trifluoroscetic acid, Cp*=C5Me5, cod=cycloocta-
diene, SPPS=solid-phase peptide synthesis.
Table 1: Summary of Kiapp values determined for compounds 1–6.
Entry
Bridging motif
Kiapp [nm][a]
Relative
activity[b]
1
2
cystine
1.48Æ0.1
2.4Æ0.14
1
1.6
1,5-disubstituted
1,2,3-triazole
1,4-disubstituted
1,2,3-triazole
1,4-disubstituted
1,2,3-triazole
–
3
4
1908Æ261
742Æ88
1288
501
and 13C chemical shifts were in good agreement with reported
data[10d] and displayed a significant difference between the
“1,4” and “1,5” substitution pattern confirming the proposed
constitution of RuAAC and CuAAC products 2, 3, and 4
(Figure 3b).
5
6
1916Æ205
1293
9347
–
13845Æ1835
The inhibitory activity of peptides 1–6 was determined by
kinetic studies using active-site titrated trypsin (see Figure 4
and the Supporting Information).[17]
[a] Standard error of the nonlinear regression is given. [b] Relative
activities are calculated as the ratios of the Kiapp values for the respective
compound to that of peptide 1.
The determined Kiapp values for compounds 1–6 are
summarized in Table 1. Peptidomimetic 2 with the “1,5”
substitution pattern displayed an inhibitory potency in nano-
molar range, which is comparable to that of the disulfide-
bridged parent peptide 1. In contrast, monocyclic SFTI-1
variants 3 and 4 produced by CuAAC macrocyclization
showed a dramatic decline in inhibitory activity against
trypsin. Two main issues could provide a plausible explan-
ation for this finding. First, the rigidity of the 1,2,3-triazole
formed prevents the “1,4” pattern from having a proper fit
into the parent structure, thereby increasing the bridging
distance of the peptide backbone. Though significant toler-
ance of the monocyclic SFTI-1 backbone towards the length
of the connecting element has been recently reported for non-
rigid, flexible linkers,[15] the impact of structurally constrained
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Communications
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&
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^
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In conclusion, we demonstrated the utility of a 1,5-
disubstituted 1,2,3-triazole bridge as a disulfide replacement.
Owing to its redox stability and dissimilarity to common
building blocks of nature, improved pharmacokinetic proper-
ties can be expected for this disulfide surrogate. Since, for a
range of bioactive molecules the preference of 1,5-disubsti-
tuted 1,2,3-triazoles over the 1,4 species may turn out to be
not so explicit as for the structures described, a modular
approach towards tailor-made heterodetic compounds can be
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Received: December 23, 2010
Revised: February 21, 2011
Published online: May 4, 2011
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Keywords: click chemistry · disulfide bridges · peptidomimetics ·
SFTI-1 · trypsin inhibition
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