Metalloporphyrin dimers bridged by a peptoid helix: Host-guest interaction and chiral recognition

Article abstract of DOI:10.3390/molecules23112741

Co-facial porphyrins have been designed to construct porphyrin tweezers with versatile molecular recognition capabilities. In this study, we synthesized metalloporphyrin-peptoid conjugates (MPPCs) displaying two metalloporphyrins on a peptoid scaffold with either achiral unfolded (1) or helical (2 and 3) secondary structures. Host-guest complexation of MPPCs was realized with various guests of different lengths and basicities, and the extent of complexation was measured by UV-vis and circular dichroism (CD) spectroscopic titration. Intermolecular and intramolecular chirality induction were observed on achiral and chiral peptoid backbones, respectively. Spectroscopic data indicated that a broad scope of achiral guests can be recognized by chiral 2; in particular, longer and more flexible guests were seen to bind more tightly on 2. In addition, chiral 2 provided a distinct CD couplet with DL-, D-, or L-Lys-OMe, which was a result of the diastereomeric host-guest complex formation. Our results indicated that MPPCs can recognize, contrast, and analyze various achiral, chiral, or racemic molecules. Based on co-facial metalloporphyrins present on peptoid scaffolds, we developed a novel class of porphyrin tweezers, which can be further utilized in asymmetric catalysis, molecular sensing, and drug delivery.

Full text of DOI:10.3390/molecules23112741

molecules
Article
Metalloporphyrin Dimers Bridged by a Peptoid Helix:
Host-Guest Interaction and Chiral Recognition
Yen Jea Lee , Boyeong Kang and Jiwon Seo *
Department of Chemistry, School of Physics and Chemistry, Gwangju Institute of Science and Technology,
Gwangju 61005, Korea; leeyeonjae@gist.ac.kr (Y.J.L.); boyeongkang2022@u.northwestern.edu (B.K.)
* Correspondence: jseo@gist.ac.kr; Tel.: +82-62-715-3675; Fax: +82-62-715-2866
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 29 September 2018; Accepted: 22 October 2018; Published: 24 October 2018
Abstract: Co-facial porphyrins have been designed to construct porphyrin tweezers with versatile
molecular recognition capabilities. In this study, we synthesized metalloporphyrin–peptoid
conjugates (MPPCs) displaying two metalloporphyrins on a peptoid scaffold with either achiral
unfolded (1) or helical (2 and 3) secondary structures. Host–guest complexation of MPPCs was
realized with various guests of different lengths and basicities, and the extent of complexation
was measured by UV-vis and circular dichroism (CD) spectroscopic titration. Intermolecular
and intramolecular chirality induction were observed on achiral and chiral peptoid backbones,
respectively. Spectroscopic data indicated that a broad scope of achiral guests can be recognized
by chiral
2; in particular, longer and more flexible guests were seen to bind more tightly on
2.
In addition, chiral
2
provided a distinct CD couplet with DL-, D-, or L-Lys-OMe, which was a
result of the diastereomeric host–guest complex formation. Our results indicated that MPPCs can
recognize, contrast, and analyze various achiral, chiral, or racemic molecules. Based on co-facial
metalloporphyrins present on peptoid scaffolds, we developed a novel class of porphyrin tweezers,
which can be further utilized in asymmetric catalysis, molecular sensing, and drug delivery.
Keywords: porphyrin; peptoid; porphyrin tweezers; co-facial porphyrin; host-guest; chiral
recognition; exciton-coupled circular dichroism
1. Introduction
In photosynthetic light-harvesting complexes, the distance between numerous pigments and
their arrangement are precisely controlled by a helical protein matrix. This spatial regulation is
directly related to the highly efficient natural photosynthetic process [
multiporphyrin arrays have been constructed as artificial light-harvesting systems [
photonic or electronic wires [ ]. Various efforts have been made to improve the function of these
1
,2]. Inspired by Nature,
3–6] or as molecular
7–9
multiporphyrin systems, including the construction of co-facial porphyrins on molecular scaffolds
such as neucleotides [10], anthrancenics [10,11], peptide [12,13], and other peptidomimetics [14–16].
Co-facial porphyrins have been actively used in the design of porphyrin tweezers. Because of
their outstanding photophysical properties such as strong visible-light absorption in the Soret band
(~410 nm) and intense fluorescence emission (500–700 nm), porphyrin tweezers can readily detect
environmental changes at low concentrations (below
engineered to recognize and differentiate chirality while maintaining this intrinsic photophysical
sensitivity, and therefore, are employed frequently as a chiral sensing reagent [17 22]. By the
µM levels) [17]. Porphyrin tweezers can be
–
complexation of an achiral porphyrin tweezer with a chiral guest, the chirality of the guest can
be transferred to the host; subsequently, the interporphyrin arrangement prefers a certain chiral twist
depending on the asymmetric configuration of the guest. Furthermore, the chiral interporphyrin
Molecules 2018, 23, 2741; doi:10.3390/molecules23112741
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2741
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twist results in an exciton-coupled circular dichroism (ECCD) signal; this phenomenon is called
intermolecular chirality induction [17,23].
Chiral co-facial porphyrins are interesting molecular tweezers by virtue of their enantioselective
0
binding with chiral guests. By connecting two porphyrins with chiral linkers, such as 1,1 -bi-2-naphthol
(BINOL) [23], chiral diamine [24], or benzyl ester [25], a pre-organized chiral interporphyrin twist can
be maintained through intramolecular chirality induction. The chiral porphyrin tweezer recognizes and
differentiates chiral guests such as amino acids [26] or diamines [27], and this leads to enantioselective
host–guest binding.
Along with chirality, conformational flexibility of a porphyrin tweezer is essential for its
complexation with various substrates [11,18,25,28]. If the porphyrin tweezer is extremely rigid,
it cannot form an “induced fit” to accommodate a wide variety of guests [29]. In contrast,
if a porphyrin tweezer is extremely flexible, it will result in poor binding affinity or nonspecific
binding [30]. Because few scaffolds are capable of controlling the backbone conformational flexibility,
studies concerning the effect of backbone flexibility on the host–guest complexation are scarce.
Previously, we reported porphyrin–peptoid conjugates (PPCs) capable of modulating the
interporphyrin arrangement and distance by the position-specific incorporation of porphyrins on a
helical peptoid [14–16]. Peptoids are sequence specific peptidomimetics based on the N-substituted
glycine backbone. By inserting a monomer sequentially, peptoids can form secondary structures
such as polyproline type I (PPI)-like helix [31], ribbons [32], and square helix [33]. In related studies,
PPI-like peptoid helix possessing
α-chiral aromatic amine side chains exhibits a pitch length of
~6 Å, and a periodicity of three residues per turn [31]. More recently, the modulation of peptoid
helicity using the sergeant-and-solider effect was demonstrated [34]. The established solid phase
peptoid synthesis method [35] and efficient post-synthetic modifications [36
–41] afforded peptoids
with greater structural diversity, thereby leading to their application in various functional entities
including bioactive agents [42
ligands [48,54–59].
–47], biomimetic materials [48–51], sensors [52,53], and metal-chelating
Co-facial porphyrins on porphyrin-peptoid conjugates can act as molecular tweezers whose
structural characteristics (e.g., chirality, spatial arrangement, and conformational flexibility) can be
influenced by peptoid scaffolds [16]. This type of structural controllability can be rarely found in other
porphyrin tweezers. In addition, the tertiary amide backbone of peptoids and their dynamic cis-trans
isomerism renders the porphyrin tweezers moderately flexible to adopt various guests. In this study
we synthesized three new MPPCs with different backbone chirality and metals (Zn or Cu) (Scheme 1).
Using UV-vis and circular dichroism (CD) spectroscopy, three types of interactions between the MPPC
host and guest molecules were investigated: (1) achiral host–chiral guest, (2) chiral host–achiral
guest, and (3) chiral host–chiral guest complexations (Figure 1). The structural and chemical features
(i.e., length and basicity) of various bidentate guests were evaluated upon their complexation with
MPPCs. Moreover, using chiral MPPCs, chiral differentiation and racemate analysis were performed.
Our MPPCs provided an insight into the design of a moderately flexible chiral porphyrin tweezer that
can recognize a broad scope of guest molecules efficiently.
,

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TPP
Mmt
HN
O
HN
O
R
N
R
N
R
N
R
N
O
O
O
O
O
O
H
i, ii, iii
iv, v, vi
N
N
N
NH2
H2N
N
R
N
R
H3C
H3C
3
2
3
2
O
O
Rink-amide resin
MTPP
Molecular structures of abbreviation
HN
O
OCH3
R
N
R
N
NH N
N
N
N
O
O
O
M
vii
N
NH2
N
HN
N
N
R
H3C
Mmt
3
2
O
CH3
MPPCs 1-3
1: R = Npm, M = Zn
O
O
2
: R = Nspe, M = Zn
pm
N
spe
N
TPP
MTPP
3: R = Nspe, M = Cu
Scheme 1. Synthesis of metalloporphyrin–peptoid conjugates (MPPCs) 1−3. Reagents and Conditions:
(i) bromoacetic acid (1.2 M), DIC, DMF, mi◦crowave irradiation, 35 ◦C, 1.5 min; (ii) primary amines
(1.5–1.0 M), NMP, microwave irradiation, 80 C, 4 min; (i) and (ii) were repeated until a desired peptoid
sequence was obtained; (iii) acetic anhydride (8.4 M), pyridine, DMF, room temperature (rt), 2 h;
(iv) TFA:TIS:CH2Cl2 = 0.75:5:94.25 (v/v/v), rt, 3 min, repeated over 12 times; (v) TPP-NHS, i-Pr2NEt,
CH2Cl2, rt, overnight; (vi) 95% TFA in CH2Cl2, rt; (vii) Zn(OAc)2, i-Pr2NEt (or Cu(OAc)2 without base),
MeOH/CH2Cl2, rt, overnight.
Figure 1. Schematic illustration of host–guest complexation between metalloporphyrin-peptoid
conjugate (MPPC) and guest. Specific interactions between achiral host-chiral guest, chiral host-achiral
guest, and chiral host-chiral guest are investigated in this study.

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2. Results and Discussion
2.1. Synthesis of MPPCs
Three MPPCs of different peptoid backbones (achiral peptoid backbone with benzylamine,
Npm and right-handed helix with (S)-( )-1-phenylethylamine, Nspe) [31 60] and different metal
−
,
ions were synthesized (Scheme 1). The peptoid sequence was synthesized following the standard
solid-phase submonomer synthesis protocol [35], and tetraphenylporphyrins (TPPs) were conjugated
on the resin-bound peptoid employing the method (Scheme 1) reported previously [14,15].
Metal incorporation on the porphyrin ring was performed with zinc acetate or copper acetate in
a methanol/dichloromethane mixture. The excess metal salt was removed using an SPE cartridge
(see experimental for the detailed procedures). After the removal of excess metal salts, each MPPC
of purity exceeding 98% was analyzed by LC-MS based on the chromatogram integration by UV
detection at 220 nm (Figure S1).
2.2. Achiral Host-Chiral Guest Complexation: Intermolecular Chirality Induction
Two pigments arranged in a chiral environment exhibit ECCD [61]. Owing to the achiral peptoid
scaffold, two porphyrins of
between the two porphyrins of
between two porphyrins, thereby generating an ECCD signal [17
from a guest to a host is called chirality induction. L- or D-Lys-OMe were used to verify that
pick up one guest as a molecular tweezer, and was analyzed by CD spectroscopy (Figure 2). With the
addition of L-Lys-OMe, the ECCD signal of appeared, with the maximum at 425 nm and minimum
1
cannot generate an ECCD signal [14
, the intercalation of the chiral guest can induce the chiral orientation
18]. This type of chirality transfer
can
,60]. If a chiral guest is caught
1
,
1
1
at 432 nm, and it was a negative Cotton effect indicating a left-handed interaction between porphyrins
(Figure 2a). In the case of D-Lys-OMe, the ECCD signal exhibited a mirror image that indicates
D-Lys-OMe inducing a right-handed orientation of porphyrins (Figure 2b).
◦
Figure 2. Circular dichroism (CD) spectra of
1
(1
µ
M) in CH2Cl2 at 20 C upon the addition of L-
or D-Lys-OMe. ( ) L-Lys-OMe was added from 0 to 9 equivalents. (
a
b
) CD spectra of
1
with L- or
D-Lys-OMe (17 equivalent each) were compared.
2.3. Chiral Host–Achiral Guest Complexation
The peptoid helix is a useful tool to control the interaction between porphyrins [14–16].
We employed a right-handed helix by incorporating Nspe into the peptoid sequence to develop chiral
porphyrin tweezers, 2 and 3 [14–16]. The CD spectra of 2 were scanned from 190–260 nm (Figure S2),
and it indicated that 2 maintained PPI-like helix in ACN, MeOH, and ACN/MeOH mixtures.
The molecular conformation of the peptoid backbone is restricted at low temperatures.
Subsequently, the co-facial porphyrins on peptoid exhibited strong interaction. Therefore,
the temperature dependence of the ECCD signal from the porphyrins indicates whether the porphyrins

Molecules 2018, 23, 2741
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are facing each other on a molecular scaffold. The temperature was controlled from 20 ◦C to
−
10 ◦C
when CD spectra of
10 ◦C), the ECCD signal of
porphyrins was introduced well on the peptoid helix of 2.
As shown in Figure S2, demonstrated a positive Cotton effect without any guest molecules
2
were obtained from 400 nm to 450 nm (Figure S2). With the low temperature
(
−
2
became stronger. This suggests that the facial arrangement of zinc
2
owing to the intramolecular chirality induction afforded by a right-handed helical peptoid (Figure S2a).
Compared to the porphyrin tweezers bearing alkyl chain or linkers reported previously, the peptoid
helix can provide a spatially defined environment between two porphyrins. Therefore, the co-facial
porphyrins of
2 was expected to exhibit different binding preferences depending on the characteristics
of the guest, such as length and basicity.
The host–guest complexations of
2
with guest molecules of different lengths and basicities
(pKa) were evaluated using CD and UV-vis spectroscopy. Various guests containing pyridyl, amino,
piperidinyl, and thiol (Figure 3) groups were used to confirm the characteristics of guests that could
be recognized by 2. During the spectroscopic titration of 2, the characteristic ECCD signal decreased
owing to the achiral guest intercalation weakening the chiral interaction of porphyrins.
a
Figure 3. Guest molecules containing nitrogen atom(s).
The pKa values of pyridine [62],
b
ethylenediamine [63], and piperidine [64] are shown on the left side of Figure. The lengths of
the molecules were computationally measured from nitrogen atom to nitrogen (or sulfur) atom for
bidentate ligands and from nitrogen to hydrogen atom for pyridine and piperidine after energy
minimization using the MM2 force field in Chem3D 16.0.
The modulation of intramolecular chirality induction by achiral bidentate guests revealed a
spectroscopic shift depending on the length of the guests. Without any guest,
absorption at 427 nm. With ethylenediamine or 1,4-diaminobutane, the maxima of the UV-vis spectra
of were blue shifted (Figure S3d–e, Table 1). These short guests may place porphyrins close together,
2 exhibited its maximal
2
inducing face-to-face-type porphyrin arrangement (i.e., H-aggregation). Longer guests such as 1,
6-diaminohexane did not exhibit a similar spectral shift. In the case of 4,40-trimethylenedipiperidine,
which is longer and bulkier than 1,6-diaminobutane, a bathochromic shift was observed with
429 nm (Table 1). Bulkier and longer guests are also recognized by , and an edge-to-edge-type
can distinguish the length and
2 at
2
porphyrin arrangement (i.e., J-aggregation) was formed. Therefore,
2
bulkiness of the guests effectively by providing spectral shifts.

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Clear isosbestic points on spectroscopic titration indicate a formation of a well-defined
supramolecular complex between a host and guest [23 65 66]. Except for pyridine, most guests
,
,
tested indicated clear isosbestic points in spectroscopic titration. When 4,4-dipyridyl and
4,40-trimethylenedipyridine were used as guests, a clear isosbestic point near 423 nm (Figure S3b,c)
appeared, indicating that a 1:1 binding is predominant. Otherwise, diamine guests exhibited different
numbers of isosbestic points; nevertheless, this type of guests demonstrated well-defined isosbestic
points. For example, 1,4-diaminobutane and 1,6-diaminohexane revealed three and two isosbestic
points, respectively (Figure S3e,f); therefore, the 1:1 to 1:3 binding mode for 1,4-diaminobutane,
and 1:1 and 1:2 binding modes for 1,6-diaminohexane can be expected. Other piperidinyl guests
exhibit one isosbestic point in each titration data near 425 nm, thus indicating the dominance of 1:1
complexation (Figure S3h,i). Interestingly, the first isosbestic points near 423–427 nm appeared with
most guests on the spectroscopic titration; therefore, we can assume that 1:1 binding complexations
with the tested guests possess a similar structural pattern. Therefore, the decreasing absorbance at
416 nm of spectroscopic titration can be employed universally to calculate the dissociation constants
(binding constants) for each complexation.
Table 1. Results of spectroscopic titration for binding constant determination (complexation of 2 with
guest molecules).
ECCD
UV-vis
λ
(nm) a
max
−6
Guests
Kd (10 M)
R2
Length (Å)
λ
max/λmin (nm) a
Without guest
Pyridine b
4,4 -Dipyridyl
-
-
1.5
7.9
-
430/423
430/423
Nd c
427
428
427
427
424
426
427
430
427
429
427
3.8
6.9
10
3.8
6.3
8.8
3.9
7.3
9.8
4.1
0.84
0.99
0.98
0.94
0.99
0.99
0.99
0.99
0.99
0.99
0
0
4,4 -Trimethylenedipyridine
Ethylenediamine
0.83
0.83
0.55
0.074
9.2
0.10
0.019
0.95
433/427
Nd c
1,4-Diaminobutane
1,6-Diaminohexane
Piperidine
434/423
435/427
434/425
Nd c
435/428
435/427
b
0
4,4 -Bipiperidine
0
4,4 -Trimethylenedipiperidine
Cysteamine
a
With the highest equivalence of guest, the spectral maximum and minimum were recorded. No isosbestic point
c
was observed. The maximum and minimum of the ECCD spectra could not be determined.
The dissociation constant, Kd was calculated with the UV-vis titration with a broad scope of
dinitrogen guests. As the addition of guests increased, the absorbance at 416 nm (a shoulder of
Soret band) decreased (Figure S3). The decreasing absorbance at 416 nm was fitted using nonlinear
regression (detail in experimental section). Consequently, the longer, more flexible and basic are the
guests, the stronger is the binding (Figure 4). According to a structural study of porphyrin-peptoid
conjugates by Kang and co-workers, the interporphyrin distance was expected to be ~6 Å based
on molecular simulation and spectroscopic analysis [15]. Therefore, we expected that the optimal
length of guest will be approximately 6 Å, e.g., 4,4-dipyridyl and 1,4-diaminobutane. However, longer
guests such as 4,40-trimethylenedipyridyl, 1,6-diaminohexane, and 4,40-trimethylene-dipiperidine
demonstrated stronger binding with lower Kd compared to shorter guests such as 4,40-dipyridyl,
1,4-diaminobutane, and 4,40-bipiperidine (Figure 4 and Table 1). Considering that two porphyrins
were connected onto the peptoid backbone through a relatively flexible n-butyl linkage, we speculated
that, because of its inherent flexibility [15,16], 2 binds effectively by adopting longer and more flexible
guests that possess higher degrees of freedom. Thermodynamically, the zinc ion creates a strong
coordination with basic nitrogen possessing higher pKa. This explains why piperidinyl guests display
lower Kd values than pyridyl guests.
Cysteamine is a drug for cystinosis that results from overaccumulation of cysteine
(or disulfide-linked dicysteine) in the cells, and is a potent candidate for treating neurodegenerative
diseases such as Huntington’s and Parkinson’s diseases [67]. Therefore, we chose cysteamine as a

Molecules 2018, 23, 2741
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biologically interesting guest for
UV-vis spectroscopy (Figure 5).
2
. The complexation of
2
and cysteamine was evaluated by CD and
Figure 4. Comparison of Kd values for the complexation of 2 and guests.
Figure 5. Titration of
2 (0.27 µ a) CD and (b)
M) with cysteamine in CH2Cl2 at 20 ◦C monitored by (
UV-vis spectroscopy.
Cysteamine with one amino group exhibited a Kd of 9.5
value of ethylenediamine. We conclude that the thiol of cysteamine also binds to the zinc porphyrin
of . CD and UV-vis spectra with cysteamine demonstrated distinguishable CD profiles (Figure 5),
×
10−7 M, which was similar to the
2
compared to other spectra with nitrogen containing guests (Figure S3). As the equivalents of cysteamine
increased, the CD maxima were shifted from 430 nm to 435 nm, and the spectrum intensity was

Molecules 2018, 23, 2741
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increased. This difference can be considered as a sulfur binding effect on the porphyrin tweezer.
We expect MPPCs to be applied as a sensor platform for thiol containing molecules.
The metal species in a metalloporphyrin tweezer is important for the selection of interaction
between the metal and guests. Copper (II) was known to strongly bind with oxygen [68]; however,
copper porphyrin-peptoid conjugate
4,4 -dipyridyl (Figure S5). The binding event of
3
did not show specific binding with 1,4-butanediol nor with
with 1,4-butanediol could not be clearly demonstrated
0
3
when UV or CD spectroscopy were used (Figure S5b). Therefore, we focused on the host–guest effect
between the zinc porphyrin peptoid conjugate 2 and nitrogen-containing guests in this study.
2.4. Chiral Host–Chiral Guest Complexation
The chiral host can be utilized in the analysis of racemic guest by forming diastereomeric
complex, and used practically as a NMR shift reagent to analyze racemic compounds [25]. Hence,
we investigated chiral porphyrin tweezer
UV-vis spectroscopy. DL-, L-, and D-Lys-OMe were used as the model racemic or enantiomeric guests.
First, with each pure enantiomer, the complexation of was evaluated. With D-Lys-OMe, a positive
2 to analyze the racemic compounds based on CD and
2
Cotton effect was observed (Figure 6a); meanwhile, the ‘’M-shape” ECCD signal appeared upon
binding with L-Lys-OMe (Figure 6b). As shown in the complexation of the achiral host and chiral
guest complexation section, L-Lys-OMe induced a negative Cotton effect with 1 (Figure 2). Chiral 2
showed the positive Cotton effect without any guest (Figure S1). Owing to the opposite preference
of peptoid backbone and guest amino acid for the orientation of co-facial porphyrins, a diminished
ECCD signal is observed (Figure 6b). In addition, the M-shape ECCD signal of
(equivalence higher than 1) suggests the possible equilibrium of two (or more) conformers giving
different exciton coupling signals [24]. With the highest equivalents of L- and D-Lys-OMe, did not
exhibit the mirror image of ECCD (Figure 7b), unlike achiral that exhibited the mirror image shown
2 with L-Lys-OMe
2
1
in Figure 2b. These non-mirror images of the ECCD spectra indicate that the host–guest complexes
(i.e., 2 with L-Lys-OMe and 2 with D-Lys-OMe), are diastereomeric to each other.
Figure 6. CD and UV-vis spectral change of
2 (1 µ a) D-Lys-OMe and (b)
M in CH2Cl2, 20 ◦C) with (
L-Lys-OMe.
UV-vis and CD spectra were measured using racemic amino acid complexed with 2. As shown in
Figure 7a, L-, D-, and racemic samples provided the same UV-vis spectra; however, ECCD demonstrated
all distinct spectral signatures. Interestingly, the value of [(A) + (B)]/2 was almost the same as the
measured CD value of 2 complexed with racemic Lys-OMe (Figure 7b).

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Figure 7. (a) UV-vis and (b) CD spectra of 2 (1 µM in CH2Cl2) with 17 equivalences of L-Lys-OMe,
D-Lys-OMe or racemic Lys-OMe.
3. Materials and Methods
3.1. Abbreviations
Trifluoroacetic acid (TFA); triisopropylsilane (TIS); N,N-dimethylformamide (DMF);
N,N0-diisopropylcarbodiimide (DIC); N-methyl-2-pyrrolidone (NMP); acetonitrile (ACN);
5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin N-hydroxysuccinimide ester (TPP-NHS); methanol
(MeOH); benzylamine (Npm); (S)-(−)-1-phenylethylamine (Nspe).
3.2. Materials and Reagents
The solvents and reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA),
Acros Organics (Geel, Belgium), Alfa Aesar (Haverhill, MA, USA), or TCI (Tokyo, Japan) and used
without further purification. Rink amide MBHA resin (typical loading level 0.52 mmol/g), DMF and
NMP were purchased from Merck Millipore (Darmstadt, Germany). Bromoacetic acid, TIS, piperidine,
CH2Cl2, benzylamine, (S)-(
)-1-phenylethylamine, Zn(OAc)2, Cu(OAc)2, pyridine, 4,40-dipyridyl,
−
4,40-trimethylene-dipyridine, ethylenediamine, 1,4-diaminobutane, 1,6-diaminohexane, piperidine,
4,40-bipiperidine, 4,40-trimethylenedipiperidine, cysteamine, 1,4-butanediol and Amberlyst A21 free
base were purchased from Sigma Aldrich. DIC, L-Lys-OMe
·
2HCl, D-Lys-OMe 2HCl, and i-Pr2NEt
·
were purchased from TCI. Acetonitrile (ACN) and TFA were purchased from Acros Organics. Oasis®
6cc Vac cartridge HLB (60 µm (LP), 6cc/500 mg) was purchased from Waters (Milford, MA, USA).
3.3. Synthesis of MPPCs
Porphyrin-peptoid conjugates were synthesized by following a previously reported method
(Scheme 1) [14
Zinc incorporation was performed using zinc acetate (Zn(OAc)2, 40 equiv., 64
(129.25 g/mol, 7 equiv., 11 mol, 14 mg) and peptoid (1.6 mol) in 3 mL of CH2Cl2/MeOH (3:1, v/v).
,
15]. Zinc and copper ions were metallated on the porphyrin peptoid conjugates.
µmol, 12 mg), i-Pr2NEt
µ
µ
The reaction mixture was stirred continuously overnight, and then, excess zinc acetate was removed by
water extraction. Copper ion incorporation was performed using copper acetate (Cu(OAc)2, 20 equiv.,
65 µmol, 12 mg) and peptoid (3.3 µmol after passing a pipette containing silica to remove TFA salt
of peptoid) in CH2Cl2. The stock solution of 0.1 M Cu(OAc)2 was prepared in MeOH. The reaction
mixture was stirred continuously overnight at room temperature. The crude metallated porphyrin
peptoid conjugates were purified using solid-phase extraction (SPE). Hydrophilic lipophilic balance
(HLB) SPE cartridge (Sorbent: Oasis® HLB 60
µm (LP), 6cc/500 mg) was used. After equilibration
with 3 mL water, the sample dissolved in 10% MeOH (in water) was loaded. A wash was followed

Molecules 2018, 23, 2741
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by 10 mL methanol to remove excess salts. The 4 mL MeOH/CH2Cl2 1:3 v/v and 5 mL CH2Cl2 was
eluted, and the fractions were collected and analyzed using LC-MS.
3.4. Liquid Chromatography-Mass Spectrometry (LC-MS)
The purity of the product was confirmed by using an LC-MS system. The LC and mass data of
peptoids were obtained from an Agilent LC-MS system (Agilent Technologies, Santa Clara, CA, USA)
that is equipped with 1260 Infinity LC (Agilent Technologies, Santa Clara, CA, USA) and 6120 SQ
bundle system (Agilent Technologies, Santa Clara, CA, USA) with an atmospheric pressure ionization
(API)-electrospray ion source (Agilent Technologies, Santa Clara, CA, USA). A Poroshell 120 EC-C18
(2.7
µ
m, 4.6 mm
×
50 mm) column (Agilent Technologies, Santa Clara, CA, USA) was installed with
the LC-MS system. Because each synthesized compound exhibited different solubilities depending
on the LC solvents, each compound was analyzed under different conditions (detailed conditions are
described in Figure S1). The mass data were obtained with the positive mode (Table S1).
3.5. Desalting of D/L-Lys-OMe·2HCl
To employ D/L-Lys-OMe as a model chiral guest, desalting of D/L-Lys-OMe
using Amberlyst A21. Further, 600 mg of Amberlyst A21 was washed with MeOH and water;
subsequently, 100 mg of D/L-Lys-OMe 2HCl dissolved in 3 mL ethanol/water (5:1, v/v) was added into
·
2HCl was performed
·
Amberlyst A21. After 1 h, the solution was filtered and evaporated. The obtained free D/L-Lys-OMe
was used in spectroscopic titration.
3.6. Spectroscopic Titration
CD spectra and UV-vis spectra were obtained by adding the guest to a sample containing MPPCs
continuously. CD and UV-vis spectra were recorded using a Jasco model 810 spectrometer (Jasco, Inc.,
Easton, MD, USA) with the scan speed of 100 nm/min, 1 nm data pitch, and band width of 1 nm.
All spectra were averaged over three measurements with a 1 cm path length cuvette. As a representative
example, CD and UV-vis spectra of 2 mL of 0.27
addition of 1 mM or 0.1 mM guest solution. The guests were dissolved in 0.27
µ
M
2
in CH2Cl2 was obtained with the sequential
in CH2Cl2 to
µ
M 2
prohibit the dilution of the host samples. The concentration of the guest stock solution was adjusted
accordingly based on the pKa of the guest.
3.7. Calculation of Dissociation Constant
The dissociation constant of the complexation was evaluated by applying a nonlinear curve
fitting with an equation used in the previous porphyrin tweezer study into the binding isotherm
from spectroscopic titration [23,69]. In this study, the spectral change of UV-vis absorbance at 416 nm
was plotted along with the added guest concentration (Figure S4). Subsequently, the obtained plot
was fitted with the nonlinear curve equation of 1:1 binding mode (Equation (1)), where [G] and [H]
represent the total concentration of the host and guest, respectively. The parameter Asat implies the
absorbance at 416 nm when the complexation is saturated:
ꢀ
ꢁ
q
2
∆A416 nm
=
A
sat(Kd + [G] + [H]) − (A2sat([G] + [H] + Kd)2 − 4A2sat[G][H] /2[H]
(1)
4. Conclusions
In this work, we incorporated metal ions (Zn2+ and Cu2+) in co-facial porphyrins present on
a peptoid backbone to construct chiral or achiral metalloporphyrin tweezers. First, the chirality
transfer from the D- or L-amino acid guest to achiral porphyrin tweezer
porphyrin tweezer , a broad range of achiral dinitrogen guests with different lengths and basicities
were complexed. The longest and most basic guest tested in this study showed the lowest dissociation
constant value (Kd). With a racemic amino acid sample, chiral formed a mixture of two diastereomeric
1 was observed. Using chiral
2
2

Molecules 2018, 23, 2741
11 of 14
complexes (
2
+ D-Lys-OMe and
2
+ L-Lys-OMe). When compared to copper-incorporated MPPCs
(3
), the zinc-incorporated MPPCs (1 and 2) exhibited clear spectral changes that helped in the
recognition of complexation. The zinc porphyrin-peptoid conjugates, as a novel class of porphyrin
tweezer, pose several unique aspects, taking advantage of structural characteristics of backbone
peptoids: (1) inter-porphyrin distance can be changed, (2) chirality can be modulated via peptoid
helicity modulation, and (3) flexibility between two porphyrins can be tuned. The development of
finely-engineered porphyrin tweezers using the MPPC platform is currently a topic of our study,
which can potentially be used as sensors, catalysts or delivery carriers.
Supplementary Materials: The following are available online, Figure S1: LC-MS chromatograms of compound
1
–
3
with UV detection at 220 nm, Figure S2: Temperature dependent CD spectra (
a
) and UV-vis spectra (
with dinitrogen guests, Figure S4:
with 4,40-dipyridyl, Figure S5: The CD and
3 (0.27 µ
M in CH2Cl2) with 4,40-dipyridyl and 1,4-butanediol, Table S1: MS data of
b) of
2
(0.27
µM) in CH2Cl2, Figure S3: CD and UV-vis spectroscopic titration of 2
A representative non-linear fitting for the host-guest titration of
UV-vis spectral change of
metalloporphyrin-peptoid conjugates.
2
Author Contributions: Conceptualization, Y.J.L. and J.S.; methodology, Y.J.L. and B.K..; software, Y.J.L.; validation,
Y.J.L.; formal analysis, Y.J.L.; investigation, Y.J.L.; resources, B.K.; data curation, Y.J.L.; writing—original draft
preparation, Y.J.L. and J.S.; writing—review and editing, Y.J.L., B.K. and J.S.; visualization, Y.J.L.; supervision, J.S.;
project administration, J.S.; funding acquisition, J.S.
Funding: This research was financially supported by the Creative Materials Discovery Program
[NRF-2018M3D1A1052659] and by the National Research Foundation of Korea [NRF-2018R1A2B6007535], which is
funded by the National Research Foundation (NRF) under the Ministry of Science and ICT.
Acknowledgments: J.S. thanks Min Su Han and Hohjai Lee for helpful discussions.
Conflicts of Interest: The authors declare no conflict of interest.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
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