Photoresponsive peptoid oligomers bearing azobenzene side chains

Article abstract of DOI:10.1039/b804802a

N-Substituted glycine peptoid oligomers were synthesized to incorporate a photoresponsive azobenzene side chain. The ability of this side chain to undergo reversible photoisomerization was established, and the cis- to trans-azobenzene thermal isomerization of this side chain was investigated. Circular dichroism studies indicated that trans- to cis-azobenzene isomerization does not significantly alter the backbone conformation in a series of peptoids thought to have well-defined structures. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b804802a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Photoresponsive peptoid oligomers bearing azobenzene side chains†
Neel H. Shah and Kent Kirshenbaum*
Received 20th March 2008, Accepted 23rd April 2008
First published as an Advance Article on the web 21st May 2008
DOI: 10.1039/b804802a
N-Substituted glycine peptoid oligomers were synthesized to incorporate a photoresponsive
azobenzene side chain. The ability of this side chain to undergo reversible photoisomerization was
established, and the cis- to trans-azobenzene thermal isomerization of this side chain was investigated.
Circular dichroism studies indicated that trans- to cis-azobenzene isomerization does not significantly
alter the backbone conformation in a series of peptoids thought to have well-defined structures.
diverse products.17–19 Additionally, peptoids have the propensity
Introduction
to form stable, ordered conformations,20–22 and a number of
these oligomers have shown biological activity.23–27 Despite their
similarities to biopolymers, however, only a small number of
peptoid oligomers have been shown to be responsive to their
environment.21,28,29 Thus far, such systems have relied on solvent
or pH changes to induce conformational changes.
Many biomolecular systems are capable of recognizing and
responding to external stimuli. Typically, an exogenous influence
such as ligand binding, a change in pH or temperature, or
absorbance of a photon can modulate biomolecular structure to
subsequently activate a biochemical signal cascade. In recent years,
extensive efforts have been made to mimic the responsiveness
of biomolecules to their environment for biosensor and other
biomedical applications.1–5 Within these novel synthetic systems,
light has emerged as a useful and convenient external stimulus due
to the fact that it can be spatially and temporally controlled. In
particular, research has focused on the irreversible photorelease
of chemically caged compounds6–9 and the reversible structural
changes of photochromic compounds such as azobenzene.10–16
Our research is focused on developing structural control in
a class of peptidomimetics known as N-substituted glycine
oligomers, or peptoids. These molecules can be readily synthesized
in a sequence-specific manner to yield a wide array of chemically
Although photosensitive functional groups have not yet been
incorporated into peptoids, many azobenzene-functionalized pep-
tides have been shown to undergo photo-induced conformational
switching, suggesting that this strategy could be extrapolated to
peptidomimetic systems.1,10,16 Here, we report the incorporation
of an azobenzene moiety into a peptoid scaffold and the ability
to reversibly photoisomerize this side chain. The introduction
of photoresponsive functionalities within this important class of
biomimetic oligomers may allow for unique structural control and
may expand the scope of their potential applications.
Results and discussion
Department of Chemistry, New York University, 100 Washington Square
East, New York, NY, 10003-6688, USA. E-mail: kent@nyu.edu; Fax: +1
212 260 7905; Tel: +1 212 998 8487
† Electronic supplementary information (ESI) available: Structures and
characterization of peptoid oligomers, RP-HPLC analysis of photoiso-
merization, and calculation of thermal isomerization rates. See DOI:
10.1039/b804802a
Synthesis of photoresponsive peptoid oligomers
Azobenzene-containing peptoids were synthesized using a mod-
ified version of the solid-phase submonomer protocol developed
by Zuckermann et al. (Scheme 1).17 Typically, N-substituted gly-
cine oligomers are generated through iterative bromoacetylation
Scheme 1 Synthesis of azobenzene-containing peptoid oligomers.
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and primary amine displacement steps. N-(p-Phenylazo-phenyl)-
glycine (Nazb) was incorporated as a monomer unit in this manner
by reacting the N-terminal bromoacetyl group of an elongating
peptoid chain with commercially available 4-aminoazobenzene.
Given the reduced nucleophilicity of this aryl amine with respect
to the more common alkyl amines used in peptoid synthesis,
the submonomer was allowed to react for 16 hours rather than
20 minutes. Additionally, the subsequent bromoacetylation was
carried out for 90 minutes rather than 20 minutes. For those
peptoid sequences bearing N-terminal Nazb monomers, a 90
minute bromoacetylation reaction was followed by treatment
with sodium borohydride to provide the corresponding acetylated
oligomers. Overall, syntheses of azobenzene-containing peptoid
oligomers yielded crude products with >85% purity which were
subsequently purified by reverse-phase high performance liquid
chromatography (RP-HPLC).30
Kinetic stability of cis-azobenzene peptoid side chains
cis-Azobenzene is known to be thermally less stable than trans-
azobenzene, and the isomer is often short-lived, reducing the utility
of azobenzene as a photoswitch for practical applications.32,33
Thus, upon establishing the efficacy of azobenzene photoiso-
merization on a peptoid scaffold, the kinetic stability of the
unstable cis-azobenzene isomer was investigated. Absorbance
spectra of molecule 1 after trans- to cis-photoisomerization
showed that the cis-azobenzene isomer underwent rapid thermal
back-isomerization in the dark at room temperature, reconverting
to trans-azobenzene with a half-life of approximately 5 hours
(Scheme 2). Interestingly, upon acetylation of the N-terminus,
the thermal back-isomerization of resulting oligomer 2 slowed
drastically, reconverting with a half-life of over 6 days. To better
understand the nature of this disparity, a small library of oligomers
(3–9, 11, 12) with varying lengths, side chains, and N-terminal
functionalities were synthesized incorporating azobenzene at
different positions along the peptoid scaffold (Table 1 and 2).34
Photoisomerization of azobenzene-containing peptoids
The capacity for azobenzene-functionalized peptoids to photoi-
somerize was evaluated using UV–vis spectroscopy before and
after photoirradiation of the oligomers within select wavelength
ranges. An initial absorbance spectrum of peptoid trimer 1
with azobenzene at the second residue showed an intense p–p*
transition around 325 nm and a weak n–p* transition around
440 nm, characteristic of trans-azobenzene. Analytical RP-HPLC
of the compound showed the presence of only one isomer.31 Upon
irradiation between 275 nm and 375 nm to the photostationary
state, the intensity of the p–p* transition decreased while that
of the n–p* transition increased (Fig. 1a). RP-HPLC showed
two peaks representing the cis- and trans-azobenzene isomers
of peptoid 1 with distinct polarities. Integration of these peaks
indicated approximately 75% conversion from a trans- to a cis-
azobenzene side chain.31 Subsequent irradiation of the trimer
in the visible region (>400 nm) completely recovered the trans-
azobenzene-containing oligomer (Fig. 1b).
Scheme 2 Photoisomerization and thermal back-isomerization of 1.
An initial comparison of trimers 1, 3 and 5 to their acetylated
derivatives 2, 4, and 6 suggested that the drastic change in
the rate of thermal back-isomerization was simply a result of
the loss of a free N-terminal amine. This free amine could
establish an electrostatic influence or associate with a counterion
that can destabilize the nearby cis-azobenzene moiety. However,
molecule 14, which does not contain a free amine but displays
Fig. 1 Photoisomerization of a peptoid trimer monitored by UV–vis spectroscopy (a) trans- to cis- photoisomerization of 1: 0, 2, 4, 6, 8 and 10 sec
irradiation accompanied by decreasing absorbance intensity at 325 nm (b) cis- to trans- photoisomerization of 1: 0, 2, 4, 6, 8 and 10 sec irradiation
accompanied by increasing absorbance intensity at 325 nm.
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Table 1 N-Substituted glycine monomer units
Circular dichroism of photoresponsive peptoids
Peptoids rich in (S)-N-(1-phenylethyl)glycine
(Nspe)
Monomer
Designator
monomer units have been shown to populate compact helical
conformations and display distinct circular dichroism (CD)
spectra in their backbone amide absorbance region (between
195 nm and 225 nm).20 Additionally, CD has been used
to detect backbone conformational changes in peptoids by
monitoring changes in the local electronic environment around
the main-chain amide chromophores.21,29 We sought to examine
the ability of peptoids incorporating Nazb to populate stable
backbone conformations. The effect of trans- to cis-azobenzene
photoisomerization on the peptoid backbone was monitored
using CD (Fig. 2). Since distinct conformational states typically
display unique CD spectra, a change in CD spectrum upon
photoisomerization would indicate a photoswitching of the
peptoid backbone structure.
Nazb = N-(p-phenylazo-phenyl)glycine
Nspe = (S)-N-(1-phenylethyl)glycine
Nme = N-(2-methoxyethyl)glycine
Sar = N-(methyl)glycine or sarcosine
Prior to photoisomerization, pentamers 8 and 9 and hep-
tamers 11 and 12 showed qualitatively similar CD spectra to
their corresponding Nspe homo-oligomers 10 and 13. Upon
photoisomerization, the general spectral shape of each oligomer
was retained, however compounds 9 and 12, bearing N-terminal
azobenzene side chains, showed a small decrease in signal intensity,
suggesting a subtle change in backbone conformation. Since the
azobenzene side chain in these oligomers was at the N-terminus,
this change is most likely only a realignment of the terminal
residue. Surprisingly, peptoids 8 and 11, bearing azobenzene side
chains in the middle of the sequence, showed virtually no change
in their CD spectra upon photoisomerization, indicating retention
of general backbone conformation features.
The CD spectra of oligomers 8, 9, 11 and 12 were not
dramatically altered after trans- to cis-azobenzene photoisomer-
ization. These results indicate that structural perturbations in the
azobenzene side chain may not strongly influence the peptoid
backbone. Previous studies of peptoids comprising N-alkyl glycine
monomers have described conformational rearrangements in
response to pH and solvent changes,21,28,29 reinforcing the notion
that these oligomers can exhibit substantial structural plasticity.36
On the other hand, the local conformational preferences of N-
aryl glycine units, such as Nazb, have not been as carefully
defined. N-Aryl glycine monomers may exhibit distinct structural
characteristics. In particular, the presence of N-aryl glycines
may rigidify the peptoid backbone, thereby precluding dramatic
conformational rearrangements, even upon photoisomerization
of a bulky azobenzene side chain. Research in our lab is currently
focused on investigating the properties of N-aryl glycine peptoid
oligomers to better understand their structural preferences.
Table 2 Peptoid sequences and half-lives of thermal back-isomerization
Compound
Sequence
Half-lifea/hours
1
NspeNazbNspe
5.7
153.5
5.5
137.2
7.8
2
AcNspeNazbNspe
NmeNazbNme
AcNmeNazbNme
SarNazbSar
3
4
5
6
AcSarNazbSar
149.8
108.9
84.8
106.6
—
122.5
109.0
—
7
(Nspe)2Nazb(Nspe)2
Ac(Nspe)2Nazb(Nspe)2
AcNazb(Nspe)4
8
9
10
11
12
13
14
Ac(Nspe)5
Ac(Nspe)3Nazb(Nspe)3
AcNazb(Nspe)6
Ac(Nspe)7
N-methyl-p-phenylazo-acetanilide
5.0
a Half-life is based on a first-order decay.
the same core chromophore as 1–6, also showed a rapid rate of
back-isomerization. The fact that peptoid pentamer 7, bearing a
free N-terminus, had a slow rate of thermal back-isomerization
also indicated that this disparity in thermal stability cannot be
attributed exclusively to N-terminal acetylation. Additionally,
oligomers 1–6 showed that this phenomenon was not side chain
dependent. Ultimately, it was found that acetylated trimers and
longer oligomers underwent thermal back-isomerization nearly
one order of magnitude slower than non-acetylated trimers and
the small-molecule analogue 14 (Table 2).35 This trend may be
attributable to non-local stereoelectronic interactions between the
azobenzene and monomer units more than one residue away that
stabilize the cis-azobenzene state or increase the energetic barrier
to back-isomerization by destabilizing the transition state of this
process.
Conclusions
In conclusion, we have shown that a photoresponsive azobenzene
side chain can be readily incorporated within a peptoid scaffold
and reversibly interconverted between two states. Additionally, the
kinetic stability of the thermally less stable cis-azobenzene side
chain can be significantly enhanced by elongating the oligomer
beyond trimer length, thereby allowing access to this state for
practical applications or structural studies. Ultimately, the ability
to photocontrol both the backbone and side chain conformations
of these well-ordered peptidomimetics could provide a convenient
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Fig. 2 CD spectra of (a) pentamers and (b) heptamers before and after trans- to cis- photoisomerization.
way to control their functions. Azobenzene-containing peptoids
may provide a useful scaffold for photoactive materials in optical
or sensor devices. Furthermore, the incorporation of this photore-
sponsive side chain into bioactive peptoids may provide a precise
method to modulate and probe their interactions with biological
molecules.
Fmoc protecting group was removed by treatment with 1.5 mL of
20% piperidine in DMF twice for 20 minutes. After deprotection
and after each subsequent synthetic step, the resin was washed
twice with 2 mL of DMF, twice with 2 mL of dichloromethane,
and twice again with 2 mL of DMF, one minute per wash.
Peptoid synthesis was carried out with alternating bromoacy-
lation and amine displacement steps. For each bromoacylation
step, 20 eq. bromoacetic acid (1.2 M in DMF) and 24 eq. N,N ꢀ-
diisopropylcarbodiimide (neat) were added to the resin, and the
mixture was agitated for 20 minutes. After washing, 20 eq. of
the required amine (1.0 M in DMF) were added to the resin
and agitated for 20 minutes. Incorporation of methylamine was
carried out in 50% tetrahydrofuran in DMF. Additionally, a
modified reaction time of 16 hours was used for the amine dis-
placement with 4-aminoazobenzene, and the subsequent bromoa-
cylation of the N-terminal 4-aminoazobenzene was conducted for
90 minutes.
When required, peptoid N-termini were acetylated on solid-
phase by one of two methods. For oligomers with an N-terminal
4-aminoazobenzene, acetylation was carried out in two steps.
First, the N-terminus was bromoacetylated as described above.
After washing, the bromide was displaced by adding 5 eq. of
sodium borohydride (0.25 M in dimethylsulfoxide) to the resin
and agitating the mixture for 2 hours. All other oligomers were
acetylated by adding 10 eq. of acetic anhydride (0.5 M in DMF)
to the resin and agitating the mixture for 1 hour.
Experimental
Materials
Bromoacetic acid, 4-aminoazobenzene, piperidine, and methy-
lamine in tetrahydrofuran (2.0 M) were purchased from Sigma-
Aldrich (St. Louis, MO). S-(−)-1-Phenylethylamine was pur-
chased from TCI (Portland, OR). 2-Methoxyethylamine, acetic
anhydride, sodium borohydride, iodomethane and sodium hydride
(60% w/w dispersion in mineral oil) were purchased from
Alfa Aesar (Ward Hill, MA). N,Nꢀ-Diisopropylcarbodiimide
and N,N-diisopropylethylamine were purchased from Chem-
Impex International (Wood Dale, IL). Trifluoroacetic acid was
purchased from Acros (Belgium). Fmoc-protected Rink amide
resin (0.69 mmol g−1 loading level) was purchased from Nova
Biochem (San Diego, CA).
Peptoid synthesis
Solid-phase synthesis of peptoid oligomers was carried out
in fritted syringes on Rink amide resin using a variation of
the peptoid submonomer synthesis reported by Zuckermann
et al.17 N-Substituted glycine monomers were generated from their
corresponding amine submonomers. N-(2-Methoxyethyl)-glycine
was generated by incorporation of 2-methoxyethylamine. N-
(Methyl)glycine was generated by incorporation of methylamine.
N-(4-Phenylazo-phenyl)glycine was generated by incorporation of
4-aminoazobenzene. (S)-N-(1-Phenylethyl)glycine was generated
by incorporation of S-(−)-1-phenylethylamine. All equivalencies
are given with respect to resin loading level.
Peptoid characterization and purification
Peptoid products were cleaved from the Rink amide resin by
treatment with 95% aqueous trifluoroacetic acid for 10 minutes
(40 mL g−1 resin). After filtration, the cleavage cocktail was
concentrated by rotary evaporation under reduced pressure for
large volumes or under a stream of nitrogen gas for volumes
less than 1 mL. Cleaved samples were then re-suspended in 50%
acetonitrile in water to the desired concentration.
In a typical oligomer synthesis, 100 mg of resin with a
loading level of 0.69 mmol g−1 was swollen in 2 mL of N,N ꢀ-
dimethylformamide (DMF) for 30 minutes. Following swelling, the
Peptoid oligomers were characterized by analytical reversed-
phase high performance liquid chromatography (RP-HPLC) using
an analytical C18 column on a Beckman Coulter System Gold
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HPLC system. Products were detected by UV absorbance at
214 nm during a linear gradient from 5 to 95% solvent B (0.1%
trifluoroacetic acid in HPLC-grade acetonitrile) in solvent A (0.1%
trifluoroacetic acid in HPLC-grade water) in 10 minutes with
a flow rate of 0.7 ml min−1. The expected molecular mass of
each product was confirmed using liquid chromatography/mass
spectrometry (LC/MS) on an Agilent 1100 Series LC/MSD Trap
XCT with an electrospray ion source in positive ion mode.30
Peptoid products were purified to >95% purity using the same
RP-HPLC apparatus described above with a preparatory C18
column. Products were detected by UV absorbance at 230 nm
during a linear gradient from 5 to 95% solvent B in solvent A in
50 minutes with a flow rate of 2.5 ml min−1. Compounds were then
lyophilized to powders.
Circular dichroism spectroscopy of azobenzene derivatives
All CD spectroscopy experiments were carried out in capped
1 mm path-length quartz cuvettes on 50 lM solutions of each
compound in methanol or acetonitrile. CD spectra were obtained
using an Aviv Stopped Flow CD Spectropolarimeter Model
202SF. CD spectra were obtained for each compound before and
after irradiation between 275 nm and 375 nm for 2 minutes.
Acknowledgements
We thank Professor Vladimir Shafirovich for the use of his xenon
light source and Dr Robert Cerpa for his helpful discussions.
This work was supported by a National Science Foundation
CAREER Award (CHE-0645361) and the NYU College of Arts
and Science Dean’s Undergraduate Research Fund. We also thank
the NCRR/NIH for a Research Facilities Improvement Grant
(C06RR-165720) at NYU.
Synthesis and purification of N-methyl-4-phenylazo-acetanilide
(14)
Acetic anhydride (44 lL, 46.9 mmol) and N,N-diisopropyl-
ethylamine (122 lL, 70.4 mmol) were added to a solution of 4-
aminoazobenzene (50 mg, 23.5 mmol) in dichloromethane (1 mL)
and the mixture stirred at room temperature for 1 hour. The
solvent was then evaporated under a stream of nitrogen gas, and
the resulting residue was re-dissolved in diethyl ether (8 mL). The
ether solution was washed twice with 5% aqueous citric acid (5 mL
per wash). The organic layer was then dried, and the solvent was
removed under reduced pressure.
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acetanilide) was then re-dissolved in N,N-dimethylformamide
(2 mL). Iodomethane (36.5 lL, 58.7 mmol) and sodium hydride in
mineral oil (1.97 mg, 58.7 mmol) were added to the solution and
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pound in methanol. Photoisomerization of azobenzene derivatives
was monitored using an Agilent 8453 UV–Visible spectropho-
tometer. Each sample was irradiated with the appropriate wave-
lengths of UV or visible light for successive one second intervals,
obtaining an absorbance spectrum in between each interval.
Thermal cis- to trans- isomerization of azobenzene derivatives was
monitored using a Varian Cary 50 UV–Vis spectrophotometer.
Absorbance was measured before photoirradiation. Then samples
were irradiated from 275 nm to 375 nm for 2 minutes, and
then placed in the dark spectrophotometer chamber. Typically,
absorbance was measured each minute for the first 10 minutes,
every 10 minutes for the following 20 minutes, and then every
30 minutes until the sample was scanned for a minimum of
6 hours.
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oligomers were characterized by electrospray mass spectrometry and
purified by RP-HPLC (ESI pages S3–S7)†.
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35 See ESI pages S8–S9 for calculations used to determine the rates of
thermal back-isomerization of azobenzene-derivatives†.
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31 RP-HPLC was monitored at an isosbestic wavelength (273 nm).
See ESI page S8 for chromatographs of
irradiation†.
1
before and after
37 1H-NMR spectrum of 14 in CDCl3 can be found in the ESI on page
S7†.
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