Porphyrin-peptoid conjugates: Face-to-face display of porphyrins on peptoid helices

Article abstract of DOI:10.1021/ol4004564

Distance, orientation, and number controlled porphyrin-peptoid conjugates (PPCs) were efficiently synthesized. Cofacial (1, 2, and 4), slipped-cofacial (3), and unstructured (5) arrangements of porphyrins provided distinct optical and electronic propertie

Full text of DOI:10.1021/ol4004564

ORGANIC
LETTERS
2
013
Vol. 15, No. 7
670–1673
PorphyrinÀPeptoid Conjugates:
Face-to-Face Display of Porphyrins
on Peptoid Helices
1
†
Boyeong Kang, Solchan Chung, Young Deok Ahn, Jiyoun Lee, and Jiwon Seo*
†
‡
§
,‡
Department of Chemistry, and School of General Studies, Gwangju Institute of Science
and Technology, Gwangju, 500-712, South Korea, and Department of Global Medical
Science, Sungshin Women’s University, Seoul, 142-732, South Korea
jseo@gist.ac.kr
Received February 19, 2013
ABSTRACT
Distance, orientation, and number controlled porphyrinÀpeptoid conjugates (PPCs) were efficiently synthesized. Cofacial (1, 2, and 4), slipped-
cofacial (3), and unstructured (5) arrangements of porphyrins provided distinct optical and electronic properties characterized by UVÀvis and
circular dichroism spectroscopy. In addition, ECCD spectra confirmed the handedness of peptoid helices.
Porphyrins, a class of naturally occurring pigments, have
been actively investigated due to their interesting photo-
physical and chemical properties. As the judicious arrange-
ment of porphyrins has resulted in a number of interesting
molecules for applications ranging from sensors to new
control over the arrangement of porphyrinic dyes is required
to provide the desired optoelectronic properties in the
artificial LHCs. Some of the artificial LHCs showed distinct
optical properties which reflect the degree of exitonic inter-
action between porphyrin monomers in the array.
To date, most of the studies regarding interactions
4
1
optoelectronic materials, much effort has been made
1
to construct defined oligomeric porphyrin arrays, parti-
cularly, to mimic the natural photosynthetic antenna
between porphyrins are focused on two π planes arranged
in a side-by-side manner (i.e., porphyrins are on the same
2
systems. As nature utilizes optimally organized pigments
2a,5
plane).
In contrast, fewer face-to-face arrangements of
3
in the light-harvesting complexes (LHCs), a high level of
porphyrins are investigated possibly due to the lack of an
efficient scaffolding material and synthetic accessibility.
†
6
Peptides, nucleic acids, viruses, organogels, synthetic
7
8
9
Department of Chemistry, Gwangju Institute of Science and Technology.
School of General Studies, Gwangju Institute of Science and
‡
4b 2b
polymers, and dendrimers have been used as scaffolds
Technology.
§
Sungshin Women's University.
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1
0.1021/ol4004564 r 2013 American Chemical Society
Published on Web 03/08/2013

1
functional groups such as cationic charges, metal
5
to display porphyrinic dyes; however, studies using a scaf-
folding material that can both precisely control the position
and relative orientation of porphyrins and provide a face-
to-face array of porphyrins have not yet been introduced.
Peptoids are a class of peptidomimetic polymers based
1
binders, a catalytic active site, and steroid hormones.
6
17
18
1
0
on oligo-N-substituted glycine backbones. The chemical
structure of peptoids differs from that of peptides only in
that side chains are attached to the backbone amide
nitrogen instead of the R-carbon. As a bioinspired material,
peptoids are monodisperse and sequence specific; there-
fore, precise control of chain length, side chain func-
tionality, and monomer sequence is possible. On the other
hand, the non-natural tertiary amide bonds render them
highly stable against proteolysis compared to their natural
1
1
counterparts. Peptoid oligomers can be readily synthe-
sized up to ∼50 monomers using a conventional solid-
1
2
phase peptide synthesis technique. These peptoid oligo-
mers, if R-chiral side chains are incorporated, can form
well-defined helical structures that are induced by local
1
3
steric and electronic interactions. The conformations
of peptoid helices have been characterized as stable poly-
proline type-I-like structures which exhibit a periodicity of
three residues per turn (i.e., helical turns are repeated for
every three residues) with a pitch length of approximately
1
3aÀc,14
˚
6
.0 A.
These unique structural features of peptoids
are proven to be useful for creating novel functional
molecules by facilitating a position-specific display of
(
7) Fendt, L.; Bouamaied, I.; Thoni, S.; Amiot, N.; Stulz, E. J. Am.
Chem. Soc. 2007, 129, 15319.
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Fantner, G.; Nelson, K. A.; Belcher, A. M. J. Am. Chem. Soc. 2010, 132,
(
Figure 1. Distance, orientation, and number controlled porphyrinÀ
1462. (b) Endo, M.; Fujitsuka, M.; Majima, T. Chem.;Eur. J. 2007, 13,
8660.
peptoid conjugates (PPCs).
(
9) Ajayaghosh, A.; Praveen, V. K.; Vijayakumar, C. Chem. Soc.
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F. E.; Bartlett, P. A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9367.
(
By employing a biomimetic molecular design approach,
our goal is to construct an array of photosensitizers
displayed on the peptoid helix and to study energy transfer
events upon various arrangements of the photosensitizers.
In due course, we present herein an efficient synthetic
strategy for a face-to-face arrangement of porphyrins on
peptoid helices. Unlike other natural or synthetic poly-
mers, peptoid helices exhibit unique stability and well-
defined structural features in various conditions such as
(
11) Miller, S. M.; Simon, R. J.; Ng, S.; Zuckermann, R. N.; Kerr,
J. M.; Moos, W. H. Drug Dev. Res. 1995, 35, 20.
12) (a) Murphy, J. E.; Uno, T.; Hamer, J. D.; Cohen, F. E.; Dwarki,
(
V.; Zuckermann, R. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1517. (b)
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(
13) (a) Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.; Armand,
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Zuckermann, R. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4303. (b)
Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.;
Barron, A. E.; Truong, K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen,
F. E.; Zuckermann, R. N.; Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A.
13e
solvents and temperature, providing an excellent scaf-
folding material. As shown in Figure 1, we designed four
porphyrinÀpeptoid conjugates (PPCs) with precisely de-
fined distance, orientation, and number of porphyrins
(1À4). Distance dependency can be examined by compar-
ing PPCs having two porphyrins positioned 1 pitch (1) and
2 pitches (2) apart. Additionally, two porphyrins in a
distorted orientation (3), three porphyrins on one face
1998, 95, 4309. (c) Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch,
J. A.; Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E. J. Am.
Chem. Soc. 2003, 125, 13525. (d) Gorske, B. C.; Bastian, B. L.; Gaske,
G. D.; Balckwell, H. E. J. Am. Chem. Soc. 2007, 129, 8928. (e) Sanborn,
T. J.; Wu, C. W.; Zuckermann, R. N.; Barron, A. E. Biopolymers 2002,
6
3, 12.
14) Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E.
J. Am. Chem. Soc. 2011, 133, 15559.
15) (a) Chongsiriwatana, N. P.; Patch, J. A.; Gzyzewski, A. M.;
(
(
(
4), and an unstructured analogue of 1 (5) were prepared.
Dohm, M. T.; Ivankin, A.; Gidalevitz, D.; Zuckermann, R. N.; Barron,
A. E. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 2794. (b) Seo, J.; Ren, G.;
Liu, H.; Miao, Z.; Park, M.; Wang, Y.; Miller, T. M.; Barron, A. E.;
Cheng, Z. Bioconjugate Chem. 2012, 23, 1069. (c) Huang, W.; Seo, J.;
Lin, J. S.; Barron, A. E. Mol. Biosyst. 2012, 8, 2626. (d) Schr o€ der, T.;
Niemeier, N.; Afonin, S.; Ulrich, A. S.; Krug, H. F.; Br €a se, S. J. Med.
Chem. 2008, 51, 376.
Preliminary spectroscopic studies such as UVÀvis and
(17) Maayan, G.; Ward, M. D.; Kirshenbaum, K. Proc. Natl. Acad.
Sci. U.S.A. 2009, 106, 13679.
(18) (a) Holub, J. M.; Garabedian, M. J.; Kirshenbaum, K. Mol.
Biosyst. 2011, 7, 337. (b) Levine, P. M.; Imberg, K.; Garabedian, M. J.;
Kirshenbaum, K. J. Am. Chem. Soc. 2012, 134, 6912.
(16) Lee, B. C.; Chu, T. K.; Dill, K. A.; Zuckermann, R. N. J. Am.
Chem. Soc. 2008, 130, 8847.
Org. Lett., Vol. 15, No. 7, 2013
1671

circular dichroism (CD) spectroscopy revealed interesting
characteristics of the PPCs. The structurally well-defined
PPCs will provide a useful platform to understand the
optoelectronic behavior of porphyrins and to develop an
artificial LHC.
purified to >97% purity by preparative reversed-phase
HPLC, and the molar mass was identified by ESI-MS.
The sequences and structures of five PPCs (1À5) and
corresponding control peptoids for a CD spectroscopy
study (6À9) are provided in Figure S1 and Table S1
(
Supporting Information). The peptoid nonamers and
dodecamers were synthesized by microwave-assisted solid-
12b
phase synthesis according to the submonomer protocol.
For conjugates 1À4, R-chiral side chain Nspe (or (S)-(À)-1-
phenylethylamine) was used to induce a helical fold, and
Nlys (or 1,4-diaminobutane) was incorporated at the position
of porphyrin conjugation. To obtain 5, Npm (or benzyl-
amine) was used instead of Nspe. Once the desired sequence
was reached, N-terminal amine was acetylated, and then the
methyoxytrityl (Mmt) group was deprotected by repeated
treatments of 0.75% TFA in dichloromethane (Scheme 1).
Scheme 1. Synthesis of PorphyrinÀPeptoid Conjugates (PPCs)
Figure 2. UVÀvis absorption spectra of 1À5. TPP-ME (5-(4-
methoxycarbonylphenyl)-10,15,20-triphenylporphyrin or tetra-
phenylporphyrin methyl ester) is used as a porphyrin monomer
control. (a) 100 μM in acetonitrile. (b) Q-band increase as
increasing concentration of 1 in acetonitrile. (c) Concentration
dependent color change of 1.
Similar to porphyrin monomers such as TPP-ME, UVÀvis
absorption spectra of all the PPCs showed a strong Soret
band at λmax 410À415 nm and Q-bands at λ
645À
max
6
50 nm (Figure 2a). The Soret bands of 1À4 are noticeably
broadened; particularly, a nonzero absorption coefficient
between 400 and 700 nm is observed for 4, which can be
advantageous for light-harvesting over a broad spectral
2
1
range. All conjugates except 2 showed a bathochromic
shift (red shift) around 438 nm, and the shift became
stronger as the concentration of the conjugate solution
increased (see Supporting Information Figure S4). In the
Q-band region, a stronger absorption around 640À
6
60 nm was observed for PPC 1 as the concentration
Tetraphenylporphyrin (TPP) carboxylic acid (or 5-(4-
carboxyphenyl)-10,15,20-triphenylporphyrin) was pre-
pared according to Lindsey’s protocol (see Supporting
Information). Initially, coupling of TPP carboxylic acid
to resin bound Nlys primary amine was attempted using an
HATU/DIEA system; however, only a poor yield was ob-
served. Successful porphyrin conjugation was accomplished
when we employed a N-hydroxysuccinimide (NHS) ester/
DIEA conjugation method. The structure of TPP-NHS (or
increased (Figure 2b). The concentration dependent bath-
ochromic shift provides typical evidence of porphyrin
J-aggregation in solution and suggests the existence of
self-assembled species via edge-to-edge interaction as well
as the excitonic coupling of the transition dipole moments
1
9
22
of the chromophores. Interestingly, even at high con-
centrations (up to 1.0 mM) PPC 2 showed no red-shifted
absorption as TPP-ME did not (Supporting Information
Figures S4ÀS5).
5-(4-carboxyphenyl succinimidyl ester)-10,15,20-triphenyl-
porphyrin) is shown in Scheme 1. All crude peptoids were
Upon dilution of the solutions containing 1 and 3, we
noticed a striking color change from green to bright purple
20
(
19) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827.
20) Boisbrun, M.; Vanderesse, R.; Engrand, P.; Oli ꢀe , A.; Hupont, S.;
Regnouf-de-Vains, J.; Frochot, C. Tetrahedron 2008, 64, 3494.
(21) Balaban, T. S.; Bhise, A. D.; Fischer, M.; Linke-Schaetzel, M.;
Roussel, C.; Vanthuyne, N. Angew. Chem., Int. Ed. 2003, 42, 2140.
(22) W u€ rthner, F.; Kaiser, T. E.; Saha-M o€ ller, C. R. Angew. Chem.,
Int. Ed. 2011, 50, 3376.
(
1
672
Org. Lett., Vol. 15, No. 7, 2013

(
Figure 2c), which provides visual evidence for the con-
upon porphyrin conjugation, where the degree of structural
disruption became severe as the number of porphyrins
increased from two to three. It is interesting to note that
the molecular weight of porphyrins takes up roughly 50%
of the whole PPC’s molecular weight in 1, 3, and 4;
however, only 4 showed severe structural disruption.
The through-space coupling of porphyrins in a chiral
environment gives rise to exciton-coupled circular dichro-
ism (ECCD), which is identified by a bisignate CD signature
centration dependent red-shifted absorption and J-aggregate
formation. In contrast, the solution containing 2 stays bright
purple in all the concentrations we used (up to 1.0 mM).
PPCs with a disrupted structure (4) and an unstructured
peptoid scaffold (5) (Figure 3a) showed poor solubility in
acetonitrile, and the bright purple solution of 4and 5at lower
concentrations formed precipitates as the concentration
increased higher than 0.2 mM.
24
at the Soret region of porphyrin. As shown in Figure 3b,
the ECCD spectra were observed for PPCs 1 and 3 with an
intense sign of the split Cotton effect. These couplets reflect
the chirality between the transition dipole moments of
interacting porphyrins. Three PPCs showed little or no
ECCD: (1) dodecameric PPC 2 with two porphyrins posi-
˚
tioned farther apart (∼12 A); (2) dodecameric PPC 4 with
severely disrupted peptoid secondary structure; and (3)
nonameric PPC 5 with an unstructured peptoid scaffold.
Handedness of the peptoid helix can be determined by
the ECCD of PPCs. As Takei et al. reported with their
porphyrin displayed helical polyisocyanides, the positive
CD couplet (a positive-to-negative pattern going from
longer to shorter wavelength) indicates a right-handed
2
5
helix. Their conclusion perfectly agrees with an earlier
study on peptoids that found peptoid helices composed of
26
Nspe submonomers form a right-handed helix, which is
confirmed by our ECCD spectra.
In summary, we employed the peptoid helix as a scaf-
folding material to construct a precisely defined cofacial,
slipped-cofacial, and unstructured array of porphyrins.
The degree of J-aggregation, color change, and excitonic
coupling between porphyrins could be modulated by dis-
tance, orientation, and number controlled porphyrinÀ
peptoid conjugates. Further spectroscopic and mechanism
studies are currently underway, and eventually we antici-
pate this study can offer new insight into the design of
artificial photosynthetic complexes.
Figure 3. Circular dichroism (CD) spectra of 1À9 in acetonitrile
2
(
50μM) were recorded as per-residue molar ellipticity (deg cm /dmol)
at (a) 190À260 nm and (b) 350À500 nm. Data were aquired at
room temperature.
CD spectra were measured at 190À260 nm to monitor
the peptoid backbone carbonyl nfπ* (∼220 nm) and
πfπ* (∼192 and 202 nm) transitions (Figure 3a). As
expected, peptoids without porphyrins (6À9) exhibited
typical polyproline type-I (PPI) like CD signatures with
Acknowledgment. This work was supported by the
National Research Foundation of Korea grant funded
by the Korean Government (2011-0014890).
1
3a
two negative Cotton effects at 202 and 220 nm, and PPC
, which used 100% achiral side chains, showed no net CD
5
signal. The maintenance of helical folds was observed for 1
and 3 after porphyrin conjugation; particularly, the CD
spectrum of 3 indicated a decreased contribution from
trans-amide-containing conformers (202 nm) and in-
creased contribution from cis-amide-containing confor-
mers (220 nm), which suggests that the slipped-cofacial
porphyrin arrangement provided an increased population
Supporting Information Available. Detailed procedures
for the synthesis, characterization, and purification of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
24) Person, R. V.; Monde, K.; Humpf, H.; Berova, N.; Nakanishi,
K. Chirality 1995, 7, 128.
(25) Takei, F.; Hayashi, H.; Onitsuka, K.; Kobayashi, N.; Takahashi, S.
Angew. Chem., Int. Ed. 2001, 40, 4092.
2
3
of PPI type helical conformers. Unlike nonamers, dode-
cameric PPCs (2 and 4) showed disrupted helical integrity
(
26) Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack, R. L., Jr;
Dill, K. A.; Zuckermann, R. N.; Cohen, F. E. Fold. Des. 1997, 2, 369.
(
23) Wu, C. W.; Sanborn, T. J.; Zuckermann, R. N.; Barron, A. E.
J. Am. Chem. Soc. 2001, 123, 2958.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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