Triazolo-β-aza-ε-amino acid and its aromatic analogue as novel scaffolds for β-turn peptidomimetics

Article abstract of DOI:10.1039/c4cc08414d

Triazolo-β-aza-ε-amino acid and its aromatic analogue (^AlTAA/^ArTAA) in the peptide backbone mark a novel class of conformationally constrained molecular scaffolds to induce β-turn conformations. This was demonstrated for^AlTAA in a Leu-enkephalin analogue and in a designed pentapeptide wherein the FRET process was established. Restricted rotation induced chirality and turn conformation into the achiral aromatic amino acid scaffold,^ArTAA, which in a short tripeptide backbone acted as a β-turn mimic as a β-sheet folding nucleator. This journal is

Full text of DOI:10.1039/c4cc08414d

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TriazoloꢀβꢀAzaꢀεꢀAmino Acid and Its Aromatic
Analogue as Novel Scaffolds for βꢀturn
Peptidomimetics
Cite this: DOI: 10.1039/x0xx00000x
Subhendu Sekhar Bag,* Subhasish Jana, Afsana Yashmeen and Suranjan De
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Triazoloꢀβꢀazaꢀ
ε
ꢀamino acid and its aromatic analogue molecules with constrained backbone angles,
ω(i) and φ(i+1),
Al
Ar
(
TAA/ TAA) in peptide backbone mark a novel class of are expected to induce folded conformations in linear peptides.
conformationally constrained molecular scaffolds to induce βꢀ The triazolo amino acids are advantageous with respect to their
Al
turn conformations. This was demonstrated for TAA in a metabolically inertness, easy associability with biological
Leuꢀenkephalin analogue and in a designed pentapeptide targets and tolerance to various reaction conditions used in
wherein FRET process was established. Restricted rotation peptide synthesis. Moreover, the triazolo unit acts as trans
ꢀ
induced chirality and turn conformation into the achiral amide mimetic which makes the scaffolds more prone to
Ar
aromatic scaffold,
backbone acted as a
TAA, which in a short tripeptide nucleate βꢀturn structure while present in a short peptide
β
ꢀturn mimic as a
β
ꢀsheet nucleator.
backbone. Though the click chemistry has been utilised in
mimicking the protein’s secondary structures, to the best of our
knowledge, the triazolo amino acids as scaffold has not been
Introduction of a conformationally constrained nonpeptide
isostere into peptide backbones in order to achieve desirable
secondary structures along with pharmacologically viable
peptideꢀbased drug candidates is of great interest in recent
time. Among the various secondary structures, βꢀturns are
important targets for mimicry, both because they serve as
recognition sites in peptides and proteins as well as they allow a
protein chain to fold back upon itself to form a compact
structure. Considerable efforts have thus been invested in
delineating the impact of appended molecular scaffolds in one
hand and nucleating turn mimics on the other hand, on the
conformational preferences of proteins and peptides in
solution. Despite an exponential growth on the development
of constrained nonꢀpeptidic molecular scaffolds, very few
peptidomimetic drugs have been developed, necessitating an
6
explored. We envisioned that upon incorporation of
Al
Ar
TAA/ TAA into backbone a linear peptide, such as, Leuꢀ
3,7
enkephalin analogue, might adopt βꢀturn conformation.
1
2ꢀ3
3
1
c
1
c
1
ꢀ3
overhaul in the existing design principles.
As a part of our ongoing research efforts on the design of
4
unnatural biomolecular building blocks via click chemistry and
4
c
βꢀturn peptidomimetics, we report herein on the simple
synthesis and application of triazoloꢀβꢀazaꢀ ꢀamino acid (
TAA) as new and
novel constrained molecular scaffolds (Fig. 1). Similar to the
ε
1,
Al
Ar
TAA) and its aromatic analogue (2,
3jꢀk
sugar amino acids, the rigid frameworks of pseudoꢀaromatic
triazole units prompted us to use triazolo amino acids as novel
5
molecular scaffolds in peptidomimetic studies. These two
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Figure 1. (A) The constrained molecular scaffoldsꢀtriazolo amino acids (1,
acids (Glyꢀβ Ala) having conformational restriction at ωi and
Al
Ar
TAA and
2
,
TAA) and (B) structures of the designed peptidomimetics 3ꢀ5
.
o
φi+1 angles. On the other hand, ψi angle is restricted by 25.1
outꢀofꢀplane in addition to the fixed ωi and φi+1 angles in
We, therefore, demonstrate the synthesis of triazolo amino
scaffold
2 (Fig. 1). Therefore, both the scaffolds would expect
Al
Ar
acids, TAA
structural properties of linear peptides wherein the scaffolds
present in a peptide backbone (Fig. 1). The peptides and
ꢀturn structures as
(1) and TAA (2), and their effect on the
to show high propensity to induce short linear peptide chain to
fold back upon itself resulting in a compact conformation.
To explore the constrained property and to determine the
3
5
Al
with TAA in the backbone adopted purely
β
effect that scaffold
1 and 2 exert on the conformation of a
were determined by CD, NMR and modelling studies. A sheet
like structure with 20% turn was the result of induction by
peptide, we, next, incorporated them into (a) a linear Leuꢀ
Al
enkephalin analogue (for TAA) (3), (b) a designed tripeptide
Ar
TAA in the backbone of
ꢀturn peptide
a
designed tripeptide
4
ꢀ
.
Ar
Al
(
4
) (for TAA) and (c) a designed pentapeptide (for TAA
containing two of our triazolyl fluorescent UAAs into two
termini ( ) (Fig. 1). All the peptides were synthesized by
solution phase peptide coupling protocol. The peptide was
)
TPy
Do
Al
Interestingly, the
β
5
, (Bocꢀ Ala ꢀLeuꢀ TAA
TPhen
Do
Leuꢀ
Ala ꢀCO Me), showed a Förster resonance energy
2
5
transfer (FRET) process between the terminal unnatural
5
TPhen
Do
TPy
Do
fluorescent triazolyl amino acids,
Ala and Ala .
synthesized via a two steps coupling of amine of dipeptide,
Al
The synthesis of the aliphatic triazolo amino acid, TAA
Tphen
Do
BocNHꢀ
Ala ꢀCO(NMe)OMe (34) and acid of dipeptide,
(
1
, Fig. 1) proceeded through a novel click reaction path
TPy
Do
BocNHꢀ Ala ꢀLeuꢀCO Me
(
40
)
containing unnatural
2
followed by hydrolysis of azido ester (11) and then reduction of
the azide (12) (Scheme 1). The aromatic triazolo amino acid (
Tphen
Do
TPy
Do
fluorescent triazolyl amino acids [
respectively] with triazolo amino acid, TAA
Ala and
Ala
,
2
,
Al
(1) (ESI†,
Ar
TAA, Fig. 1) was synthesized in a similar way via a click
chemistry protocol (ESI†, Scheme S2). The amino acid
scaffolds were characterised by NMR, mass spectrometry, and
Section 2ꢀ6).
single crystal Xꢀray diffraction analysis for scaffold
2
.
Figure 2. (A) Molecular arrangement; (B) Model shape of linearly arranged “S”
Al
units (two molecules of unit cell) [CCDC 997089] and (E) UVꢀvisible and CD
Scheme 1. Synthesis of the aliphatic triazolo amino acid scaffold (
1
,
TAA).
Ar
spectra of aromatic triazolo amino acid scaffold
2 ( TAA).
o
The crystal structure analysis of scaffold
2 (mp 168 C;
Next, the secondary structure of peptide 3, a Leuꢀenkephalin
chiral space group P2 2 2 ) revealed that the aminophenyl unit
1
1 1
o
analogue, was estimated by recording its CD spectrum in
methanol which showed a strong positive band at 206 nm and a
negative band at 191 nm indicating a type II βꢀturn
was 25.1 out of plane with respect to triazole unit. Overall the
scaffold adopted a hairpin shape wherein the two hairpins
packed faceꢀtoꢀface via weak Hꢀbonding interaction leading to
8
conformation (Fig. 3A). The peptide secondary structure
“
S”ꢀshaped structure which were linked each other via
8
b
estimation using CD estima program showed 100% βꢀturn
structure in peptide the existence of which implied the
ArCH….NTriazole, ArCHꢀ bonding (side way) and hydrophobic
π
t
3
interaction through Butylꢀunits to link “S”ꢀ units linearly
possible presence of intramolecular Hꢀbonds between the
peptide strands. CD spectrum also indicated a predominantly
leading to a helical like construct (Fig. 2AꢀB and ESI†, Section
7
). More interestingly, the solid state chirality was well
type II βꢀturn conformation in fluorescent pentapeptide
5
(Fig.
stacking
was also evident
maintained in methanol solution as was revealed from the
8
3
A). Moreover, the signature of aromatic
interaction between Phe and Tyr in peptide
from the appearance of a positive band at 217 nm.
tripeptide containing the aromatic scaffold in the backbone
showed a broad negative peak at 221 nm and a positive peak at
38 (characteristic of tyrosine) indicating a βꢀsheet like
πꢀπ
appearance of two distinct UVꢀvisible absorption bands at 234
3
ꢂꢃ
and 297 nm, specific rotation (
ꢀ
ꢄ ꢅ. ꢆ) and the CD spectra
ꢁ
8a,c
The
with a signature of turn conformation (Fig. 2C). Therefore, the
origin of chirality was the restricted rotation of outꢀofꢀplane
aminophenyl unit about C(aminophenyl)ꢀC(triazole) bond both in solid
and solution. The maintenance of the chiral turn conformation
in both the solid and solution phase motivated us to use the
4
2
8
b
structure with 20% turn conformation (Fig. 3A). The less
propensity of the tripeptide for adopting a fully turn structure
might be because of short peptide chain length and high rigidity
of the scaffold which in the turn conformation might be
acting as a βꢀturn mimic as βꢀsheet folding nucleator.
4
triazolo amino acid
2 as a scaffold for peptidomimetic study.
A comparison of the backbone bonds and the dihedral
Al
2
angles of the dipeptide isostere
1
(
TAA) with those of a
fixes ωi
transꢀamide bond) and φi+1 angles at about 180 . Accordingly,
3
gꢀh
natural dipeptide showed that the triazole unit of
1
o
To probe the intramolecular Hꢀbonding in all peptides we
used IR and variable temperature NMR (VT NMR)
(
peptidomimetic
1 could be used to replace two adjacent amino
2
| Chem. Commun., 2014, 00, 1-4
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DOI: 10
C
.1
O
0
M
39
M
/C4
U
C
N
C
I
0
C
8
A
41
T
4
I
D
ON
spectroscopy. Thus, the presence of intramolecular Hꢀbonded The NOESY and ROESY spectra of peptide 4 revealed that
and free amide ꢀNH stretching absorptions at 3281ꢀ3313 and the scaffold itself remained in a hairpin shape with interactions
ꢀ
1
3
409ꢀ3440 cm , respectively, in the IR spectra of all the among the TriazoleꢀCH/AromaticꢀH; PheNH/ AromaticꢀH;
9
peptides also supported the turn structures (ESI†, Section 8).
From the VTꢀNMR experiment, strong intramolecular Hꢀ NOESY and ROESY spectra of peptide
bonding involving the amide NH (of Phe) at i+3 was observed interaction between H (of
AromaticꢀH/TyrꢀOH leading to overall turn like shape. The
showed the
5
TPy
Do
TPhen
Do
Ala )/OMeꢀH (of
Ala )/CH2(Nꢀterminal) of scaffold, triazoleꢀCH,
4 containing LeuNH (Cꢀterminal); CH2(Nꢀterminal) of scaffold/LeuNH
Ala );
α
Do
TPy
in peptide
ESI†, Section 8). The amide NHs of tripeptide
the aromatic amino acid scaffold showed medium to weak which supported the turn structure with the pyrene inside the
intramolecular Hꢀbonding ability. The amide NH (of scaffold) loop closer to the triazole unit of the scaffold (ESI†, Section 8).
3
supporting the type II βꢀturn structure in peptide
3
TPyArꢀH (of
1
0
(
(Cꢀterminal)
2
and LeuꢀNH of both the termini in peptide
5
showed strong
To gain insight into the conformation observed in peptide 3ꢀ
intramolecular Hꢀbonding supporting the βꢀturn structure.
5
molecular dynamics (MD) simulations were carried out using
Schrodinger Macromodel (Maestro vs. 9.0) software package
9
b, 11
with OPLS 2005 force field.
minimum energy conformations out of 20 generated structures
revealed that the peptide took type II βꢀturn structure
stabilized by backbone Hꢀbonding involving the carbamate
CO at i and the amide NH (of Phe) at i+3 and
The superimposition of eight
3
>
aromatic−aromatic stacking which was also supported by CD,
3
IR and VTꢀNMR study (Fig. 4A). The folded conformation
with close proximity of the parallelly oriented Phe and Tyr
suggested that the peptide
3
might serve as a potential ligand
for the δꢀreceptor. The short chain tripeptide showed some
turn structure having backbone Hꢀbond between carbamate
C=O at i and amideꢀNH (of scaffold) at i + 2 which is also
possible as was revealed from a VTꢀNMR study reflecting turn
structure. The existence of 20% turn structure in peptide
1
2
4
Figure 3. (A) CD spectra of peptides 3ꢀ5 in methanol. (B) Representative
example of some important interactions observed in tetrapeptide 3.
>
Next, the solution conformations of βꢀturn peptides
were determined by studying, in detail, their H NMR spectra in
3ꢀ5,
1
4
revealed from the CD spectroscopic study was thus supported
by macromodel study. Moreover, it was stabilized by a second
side chain Hꢀbonding involving –OH of Tyr at Nꢀterminus and
amide NH of Phe at Cꢀterminus (ESI†, Section 10). The type II
βꢀturn structure as was evident from spectroscopic studies was
DMSOꢀ
peptide
d
3
6. Thus, from the coupling of side chain protons of
in H NMR spectra it was observed that the Leuꢀ side
1
chain was very rigid and adopted predominantly one single
conformation about χ and χ with an antiꢀrelationship between
βH(proꢀS) and γH. Strong ROESY interaction between Leuβꢀ
H/CH2(Cꢀterminal) of scaffold also supported this observation. The
1
2
also supported by a MD simulation for peptide
5 (Fig. 4B).
cross peak in the ROESY spectrum between LeuC
αH and
Leu CH (proꢀS) provided additional evidence of the rigidity of
δ
3
the Leu sideꢀchain. The Phe and Tyrꢀside chains also showed
their rigidity as well as the presence of one single conformation
about χ . The NOESY and ROESY spectra of peptide
3
1
revealed the interactions among the aromatic hydrogens of Tyr
and Phe suggesting their close proximity as well as rigidity in
one single conformation. The presence of NOESY cross peak
th
between H (i )/NH (i+1) also revealed a typeꢀII βꢀturn
α
conformation (Fig. 3B, and ESI†, Section 8).
Figure 5. Steady state (A) and time resolved (B) fluorescence spectra of donor
chromophore in absence or in presence of acceptor showing a FRET process in
pentapeptide
5 in methanol.
Finally, we examined the possibility of photophysical
interaction between the terminal triazolyl unnatural amino acids
in fluorescent pentapeptide
fluorescence spectra of the
5 in methanol. The UVꢀvisible and
TPhen
Do
Ala containing dipeptide (34
)
TPy
Do
and
Ala
containing dipeptide (40) revealed that the
fluorescence spectrum of former overlapped significantly with
the absorption spectrum of the latter (ESI†, Section 12).
Figure 4. Molecular dynamics simulated clustering of conformers within 21 Moreover, the peptide
5
containing these two amino acids could
kJ/mole from the global minima of peptide
3
(A) and
5
(B).
ꢋꢈꢌ
TPhen
Do
selectively be excited at 300 nm (
ꢇ
of
Ala ) where
ꢈꢉꢊ
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Ch
D
e
O
m
I: 1
i
0
ca.1
l
0
C
39
o
/
m
C4
m
CC
u
0
n
8
i
4
c
1
a
4
t
D
ion
TPy
Do
there was very low absorbance of
Ala . Therefore, these Electronic Supplementary Information
(
ESI
)
available: [Synthesis,
4
d
1
two triazolyl amino acids should form a FRET pair in our characterisation data, spectroscopic data, macromodel study and H and
1
3
designed pentapeptide
5
Do
where the conceptual donor amino acid
Ala acted as FRET donor and acceptor,
C NMR spectra]. See DOI: 10.1039/b000000x/
TPhen
Do
TPy
Ala and
1
2
3
(a) D. S. Kemp, Trends Biotechnol., 1990, 8, 249. (b) R.
Hirschmann, Angew. Chem. Int. Ed. Engl., 1991, 30, 1278. (c) J.
P. Schneider and J. W. Kelly, Chem. Rev., 1995, 95, 2169. (d) L.
R. Whitby and D. L. Boger, Acc. Chem. Res., 2012, 45, 1698.
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523, 407. (b) J. S. Nowick, Acc. Chem. Res., 2008, 11, 1319. (c)
W. A. Loughlin, J. D. A. Tyndall, M. P. Glenn, T. A. Hill and D.
P. Fairlie, Chem. Rev., 2010, 110, PR32ꢀPR69.
respectively. With this observation we turned our attention to
1
3
study the FRET process in detail. Thus, when excited at
TPhen
Do
absorption maximum of the donor,
Ala
(λex = 300 nm), it
was observed that the fluorescence intensity of the acceptor,
TPy
Do
Ala , increased from that of the free acceptor emission by
almost fourꢀfive times in presence of donor in peptide . On the
5
TPhen
Do
other hand, the fluorescence intensity of the donor,
in peptide decreased almost three times of that of the free
donor fluorescence in presence of acceptor,
ratiomatric change in fluorescence intensity of donor/acceptor
Ala ,
(a) C. M. Wilmot and J. M. Thornton, J. Mol. Biol., 1988, 203,
5
2
3
21. (b) R. A. Wiley and D. H. Rich, Med. Res. Rev., 1993, 13,
27. (c) Y. L. Angell and K. Burgess, Chem. Soc. Rev., 2007, 36,
TPy
Do
Ala . This
1674. (d) R. F. Hirschmann, K. C. Nicolaou, A. R. Angeles, J. S.
Chen and A. B. Smith, Acc. Chem. Res., 2009, 42, 1511. (e) A.
Basak, S. S. Bag and A. Basak, Bioorg. Med. Chem.,
TPhen
Do
revealed the visual evidence of FRET process from
to
Ala
TPy
Do
13c
Ala in peptide 5 (Fig. 5A). The calculated Förster
2
005, 13, 4096. (f) S. Hanessian, X. Luo and R. Schaum,
radius (R ), the efficiency of energy transfer (E) and the donorꢀ
0
Tetrahedron Lett., 1999, 40, 4925. (g) K.Y. Tsang, H. Diaz, N.
Graciani and J. W. Kelly, J. Am. Chem. Soc., 1994, 116, 3988. (h)
A. A. Fuller, D. Du, F. Liu, J. E. Davoren, G. Kroon, E. T.
Powers, P. Wipf, M. Gruebele and J. W. Kelly, Proc. Natl. Acad.
Sci., 2009, 106, 11067. (i) R. R. Gardner, G. B. Liang and S. H.
Gellman, J. Am. Chem. Soc., 1999, 121, 1806. (j) Gruner, S. A.
W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102,
491. (k) J. Xie, N. Bogliotti, Chem. Rev., 2014, 114, 7678.
acceptor distance (r) were found to be 31 Å, 85% and 28 Å,
respectively. The occurrence of FRET process was also evident
from a time resolved fluorescence study wherein we observed a
TPhen
Do
decrease in donor life time (
Ala ; λex = 293 nm, λem = 370
nm) from 13.7 ns to 2.0 ns. More interestingly, the lifetime of
TPy
Do
acceptor ( Ala ; λex = 293 nm, λem = 400 nm) in presence of
donor was found to increase from 18.2 ns (in absence of donor)
to 19.0 ns (in presence of donor) evidencing the FRET process
4
(a) S. S. Bag, S. Talukdar and S. K. Das, Curr. Protocols Nucleic
Acids Chem., 2014, 58:1.32.1ꢀ1.32.27. (b) S. S. Bag, S. Talukdar,
R. Kundu, I. Saito and S. Jana, Chem. Commun., 2014, 50, 829.
1
3d
(
Fig. 5B, and ESI†, Section 13).
(c) S. S. Bag, S. Jana, A. Yashmeen, K. Senthilkumar and R. Bag,
Chem. Commun., 2014, 50, 433.
V. V. Rostovtsev, L. G. Green, V. V. Fokin and Sharpless, K. B.
Angew. Chem., Int. Ed., 2002, 41, 2596.
(a) A. Tam, U. Arnold, M. B. Soellner, R. T. Raines, J. Am.
Chem. Soc., 2007, 129, 12670. (b) A. Dirksen and P. E. Dawson,
Curr. Opin. Chem. Biol., 2008, 12, 760. (c) Y. L. Angell and K.
Burgess, Chem. Soc. Rev., 2007, 36, 1674.
Conclusions
In conclusion, the easily accessible aliphatic and aromatic
triazolo amino acids and , respectively, were introduced for
the first time, as βꢀturnꢀmimetic constrained molecular
scaffolds. The structural and conformational analysis of Leuꢀ
5
6
1
2
7
8
J. V. Aldrich, In Burger’s Medicinal Chemistry and Drug
Discovery, Vol. 3; M. E. Wolff, Ed.; John Wiley & Sons: New
York, 1996, 321ꢀ441 and references therein.
(a) R. W. Woody, In Circular Dichroism. Principles and
Applications; K. Nakanishi, N. Berova and R. W. Woody, Eds.,
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Biochem. Biophys. Res. Commun., 1971, 44, 1285. (c) M. J.
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and D. J. Pochan, Biochemistry, 2008, 47, 4597.
(a) K. Oh and Z. Guan, Chem. Commun., 2006, 3069. (b) A.
FeherꢀVoelger, J. BorgesꢀGonzlez, R. Carrillo, E. Q. Morales, J.
GonzlezꢀPlatas and T. Martn, Chem. Eur. J., 2014, 20, 1.
H. Kessler, Angew. Chem., Int. Ed. Engl., 1982, 21, 512.
(a) MacroModel, Version 9.9 Schrodinger, LLC, New York, NY,
enkephalin analogue peptide
3 and fluorescent peptide 5 by
various spectroscopic techniques and MD simulation studies
established wellꢀdefined type II βꢀturn structure induced by the
novel βꢀturnꢀmimetic constrained molecular scaffold, the
triazolo amino acid
process in peptide
1
5
. Moreover, we established the FRET
containing a new class of fluorescent
unnatural triazolyl amino acids at the two termini. Under study
are the explorations of turn mimetic and other analogues in
details and the sequence specific DNA binding event of tetraꢀ
amides of these molecular scaffolds which might lead to the
generation of a new family of distamycin analogues.
2
9
1
1
0
1
2
1
012. (b) I. W. Kolossvry and C. Guida, J. Am. Chem. Soc.,1996,
18, 5011.
This work was funded to S. S. Bag by the CSIR [01(2330)/09/EMRꢀII],
Govt. of India. SJ and AY are thankful to CSIR for their fellowships. We
are thankful to Professor S. Ghosh and Mr. Mohitosh Dey, Department of
Biotechnology, for using the CD spectropolarimeter facility.
1
2
T. Yamazaki, D. F. Mierke, O. E. SaidꢀNejad, E. R. Felder and M.
Goodman, Int. J. Pept. Protein Res., 1992, 39, 161.
13 (a) T. Förster, Discuss. Faraday Soc., 1959, 7. (b) J. M. G.
Rogers, L. G. Lippert and F. Gai, Anal. Biochem., 2010, 399,
1
82. (c) R. J. Nedumparaa, P. J. Manua, C.P.G. Vallabhanb,
V.P.N. Nampooria, P. Radhakrishnana, Opt. Laser Tech., 2008,
0, 953. (d) C. Banerjee, N. Kundu, S. Ghosh, S. Mandal, J.
Notes and references
Bioorganic Chemistry Laboratory, Department of Chemistry, Indian
Institute of Technology Guwahati, North Guwhatiꢀ781039, Assam, India.
4
Fax:
+91ꢀ361ꢀ258ꢀ2349;
Tel:
+91ꢀ361ꢀ258ꢀ2324.Eꢀmail:
Kuchlyan and N. Sarkar, J. Phys. Chem., B 2013,117, 9508.
ssbag75@iitg.ernet.in
4
| Chem. Commun., 2014, 00, 1-4
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