Conformational heterogeneity, self-assembly, and gas adsorption studies of isomeric hybrid peptides

Article abstract of DOI:10.1021/cg201268x

The folding and self-assembly propensities of three synthetic isomeric aliphatic-aromatic backbone hybrid peptides are illustrated. Single crystal X-ray diffraction studies of three isomeric hybrid dipeptides Boc-Phe-x-aminobenzoic acid (x = o/m/p) reveal

Full text of DOI:10.1021/cg201268x

Article
pubs.acs.org/crystal
Conformational Heterogeneity, Self-Assembly, and Gas Adsorption
Studies of Isomeric Hybrid Peptides
Sibaprasad Maity, Poulami Jana, Suman Kumar Maity, Pankaj Kumar, and Debasish Haldar*
Department of Chemical Sciences, Indian Institute of Science Education and Research - Kolkata, Mohanpur, West Bengal 741252,
India
S
* Supporting Information
ABSTRACT: The folding and self-assembly propensities of three synthetic isomeric
aliphatic−aromatic backbone hybrid peptides are illustrated. Single crystal X-ray diffraction
studies of three isomeric hybrid dipeptides Boc-Phe-x-aminobenzoic acid (x = o/m/p)
reveal that the peptides adopt unconventional conformations which self-assemble to form
diverse supramolecular architectures using hydrogen bonding interactions and other
noncovalent interactions in the solid state. The N2 sorption propensities of the isomeric
hybrid peptides in the solid state significantly vary with folding and self-assembly nature.
The peptides 1 and 2 exhibit type-III N2 sorption isotherm, though peptide 1 adsorbs 2-fold
higher N2 than does peptide 2.
Phe-x-aminobenzoic acid (x = o/m/p) adopt unconventional
conformations in the solid state and form a supramolecular
herringbone helix or single helix or corrugated sheetlike
structure in higher order assembly, directed by intermolecular
N−H···O and O−H···O hydrogen bonds. Moreover, the
peptides exhibit type-III N2 sorption isotherm. The sorption
propensities of the isomeric peptides differ significantly with
folding and self-assembly pattern.
INTRODUCTION
■
Developing biomimetic materials, such as the folded structures
of biopolymers, by the self-assembly of synthetic organic
moieties is highly interesting due to their potential application
in bioorganic chemistry and material sciences.1 The self-
assembly process requires a combination of several noncovalent
interactions such as hydrogen bonding, π−π stacking, and van
der Waals interactions between the building blocks.2 In this
context, the small peptide scaffold that can occasionally serve as
a hydrogen bond donor or acceptor is highly interesting.3 This
interest stems from their structural versatility, biocompatibility,
robustness, and accessibility by standard analytical methods.4
The folding patterns of the scaffolds mostly belong to the
RESULTS AND DISCUSSION
■
Background. Three N-terminally protected dipeptides,
Boc-Phe-x-aminobenzoic acid (x = o/m/p) containing N-
terminal L-phenylalanine and C-terminal rigid aromatic β/γ/δ
amino acids residues have been synthesized by conventional
solution-phase methodology, purified, characterized, and
studied (Figure 1). The peptides have been designed with
aromatic β, γ, δ amino acids to increase the helical pitch and
decrease the number of residues per supramolecular helical turn
(Figure 1). Colorless monoclinic crystals of peptides 1, 3, and
colorless orthorhombic crystals of peptide 2 suitable for X-ray
diffraction studies were obtained from their methanol−water
solutions by slow evaporation.
canonical folds.5 Gorbitz has reported the supramolecular left-
̈
handed double helices (Val-Ala class structures) from hydro-
phobic dipeptides from α-amino acids.3,6 Majority of the
reports of unconventional folds have exploited scaffold
combinations of aliphatic and aromatic backbone moieties.7
Huc and co-workers have reported the formation of a
herringbone helix from noncanonical folding of an aromatic−
aliphatic δ-peptides.8 Lin et al. has discussed the construction of
a two-dimensional (2D) herringbone-like zinc coordination
polymer from a helical motif.9 Tomasini et al. has reported
formation of fiberlike structures from synthetic Boc-Phe
containing di- or tripeptides.10
The conformational heterogeneity of the aliphatic−aromatic
backbone hybrid isomeric peptides was observed by the solid
state FTIR spectroscopy. The region 1800−1500 cm−1 is
important for the stretching band of amide I, the bending peak
of amide II, and the hydrogen bonded urethane groups.12
Another informative frequency range is 3500−3200 cm−1,
Over the past few years, our research group has dealt with
the supramolecular materials from short synthetic peptides.11
Herein we present the noncanonical folding and formation of
diverse supramolecular structures in the solid state from
isomeric aromatic−aliphatic backbone hybrid dipeptides (1−
3), each containing N-terminal L-phenylalanine and C-terminal
rigid aromatic β/ γ/ δ amino acids. The molecular scaffold Boc-
Received: September 26, 2011
Revised: November 15, 2011
Published: November 29, 2011
© 2011 American Chemical Society
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Article
Figure 1. The schematic presentation of the reported dipeptides 1−3.
corresponding to the N−H stretching vibrations of the
peptide.13 The FTIR studies show that the peptides molecules
are strongly intermolecular hydrogen bonded in the solid state
(Figure 2). Intense bands at 3316 (peptide 1) cm−1, 3312
Figure 3. (a) The hydrogen bonded dimer of peptide 1A·D; (b) top
view; and (c) side view of supramolecular noncanonical herringbone
helix.
listed in Table 1. Further, the peptide 1A molecule forms an
intermolecular hydrogen bond with peptide 1D molecule (O4−
Table 1. The Important Backbone Torsion Angles (°) of
Peptide 1−3
peptide
ϕ1
Ψ1
ϕ2
Ψ2
Peptide 1A
Peptide 1B
Peptide 1C
Peptide 1D
Peptide 2
62.05
63.63
37.97
36.38
−179.72
169.52
−161.96
177.13
37.18
−179.18
179.35
−77.82
−78.17
−59.00
−72.68
−111.66
−31.52
−31.05
135.31
158.79
152.52
−177.97
179.03
−161.15
5.33
Peptide 3A
Peptide 3B
19.04
−7.07
−177.89
H4···O9, 1.85 Å, 2.71 Å, 166°, 1 + x, y, 1 + z) and (O10−
H10A···O5, 1.90 Å, 2.71 Å, 166°, −1 + x, y, −1 + z) to form a
dimer like a traditional acid dimer (Figure 3a). Similarly, the
peptide 1B molecule forms an acid dimer with the peptide 1C
molecule. In higher order assembly, the dimeric building blocks
of peptide 1 self-assemble through intermolecular hydrogen
bonding interactions (N1−H1···O8, 2.14 Å, 2.84 Å, 155°, 1 −
x, −1/2 + y, 1 − z and (N3−H3···O8, 2.00 Å, 2.73 Å, 142°, −x,
1/2 + y, 1 − z)) to form a supramolecular herringbone like
helical architecture along the axis parallel to the crystallographic
b direction (Figure 3b,c).15 In higher order packing, the peptide
1 forms a herringbone like architecture by hydrogen bonding
interaction (Figure ESI 2).
In comparison with peptide 1, peptide 2 contains the
terminal acid functional group at the meta position, but this
change had a significant impact on the molecular conformation.
As it is evident from the solid state structure, the BOC amide
functional group adopts cis geometry (Figure 4) which is very
rare. In peptide 2, there is no intramolecular hydrogen bond
and no acid dimer formation like peptide 1. The backbone
torsion angles (Table 1) of peptide 2 are significantly different
to that of peptides 1 and 3. Moreover, in higher order packing,
the individual peptide 2 molecules are themselves regularly
interlinked through intermolecular hydrogen bonding inter-
actions (N1−H1···O4, 2.1 Å, 2.93 Å, 161°, −1 − x, 1/2 + y, 1/
2 − z and O5−H5···O2, 1.84 Å, 2.65 Å, 167°, −1 − x, −1/2 +
Figure 2. The solid state FTIR spectrum of the reported dipeptides
(a) 1, (b) 2, and (c) 3.
(peptide 2) cm−1, and 3310 (peptide 3) cm−1 were observed for
the reported peptides, indicating the presence of strongly
hydrogen-bonded NH groups.13 The characteristic IR
absorption bands at about 1516 cm−1, 1650 cm−1, 1708 cm−1
for peptide 1 and 1534 cm−1, 1685 cm−1 for peptide 2 and 3
suggest the conformational heterogeneity between the isomeric
peptides.
Crystal Structure Analysis. Peptide 1 crystallizes with four
peptide molecules in the asymmetric unit (Figure ESI 1),
whereas peptide 2 crystallizes with one peptide molecule.
However, two molecules of peptide 3 crystallize with two
molecules of methanol in the asymmetric unit (Figure ESI 1).
Interestingly, the torsion angle around the phenylalanine
residue appears to play a critical role in dictating the overall
structural features. From the crystal structure of peptide 1, it is
evident that there are two intramolecular hydrogen bonds. For
each of peptide 1 molecule in the asymmetric unit, the five-
member hydrogen bonded ring between Phe N and anthranelic
acid NH and the six-member hydrogen bonded ring between
anthranelic acid NH and anthranelic acid CO resulting a
rigid conformation in the solid state (Figure 3a).14 The
backbone torsion angles (ϕ, ψ) of peptide 1 molecules are
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Article
Å) and phenylalanine rings (shortest C−C distance 4.11 Å) in
the dimer. Each of peptide 3 dimers stacked by maintaining the
proper registry to form a corrugated sheetlike structure through
intermolecular hydrogen bonding interactions (N1−H1···O4,
2.05 Å, 2.90 Å, 169°, x, y, 1 + z and N3−H3···O9, 2.26 Å, 3.02
Å, 148°, 2 − x, −1/2 + y, 1 − z) along with the intervening
bridging methanol molecules (O5−H5···O12, 1.84 Å, 2.65 Å,
173°, x, y, −1 + z and O10−H10A···O11, 1.77 Å, 2.58 Å, 169°,
2 − x, 1/2 + y, 1 − z) (Figure 5). Hydrogen bonding data for
peptides 1−3 are also listed in Table 2. Crystal data for these
three hybrid peptides are detailed in Table 3.
Table 2. Hydrogen Bonds in Crystal Structures of Peptide
1−3
H···
A/Å
D···
A/Å
D−H···A/
interactions
Peptide 1
deg
N1−H1···O8
N2−H2···O5
N2−H2···N1
N3−H3···O3
O4−H4···O9
N4−H4D···O9
N4−H4D···N3
N5−H5···O20
N6−H6A···O14
N6−H6A···N5
N7−H7···O13
N8−H8···O17
N8−H8···N7
2.14
1.97
2.37
2.00
1.86
1.96
2.35
2.20
2.11
2.40
1.95
1.95
2.31
1.90
2.94
2.66
2.78
2.72
2.65
2.65
2.78
2.90
2.74
2.80
2.75
2.65
2.72
2.70
155
136
110
142
166
137
111
138
131
109
155
138
110
166
1 − x, −1/2+ y, 1 − z
intramolecular
Figure 4. The cis amide configuration and supramolecular helical
structures obtained from peptide 2.
intramolecular
−x, 1/2 + y, 1 − z
1 + x, y, 1 + z
intramolecular
y, 1/2 − z) and thereby form a supramolecular single helix
along the b axis (Figure 4).16
From crystal data, the asymmetric unit contains two
molecules of peptide 3 and two molecules of methanol. The
backbone torsion angles of molecules A and B of peptide 3 are
significantly different (Table 1). For peptide 3, in the
asymmetric unit, the dimer formed by intermolecular hydrogen
bonds N2−H2···O7, 2.00 Å, 2.83 Å, 164° and N4−H4···O2,
2.14 Å, 2.98 Å, 168° (Figure 5).
intramolecular
−x, 1/2 + y, 1 − z
intramolecular
intramolecular
2 − x, −1/2 + y, 1 − z
intramolecular
intramolecular
O10−
x, y, −1 + z
H10A···O5
O18−
1.88
2.70
176
x, −1 + y, z
H18A···O14
Peptide 2
N1−H1···O4
N2−H2···O3
O5−H5···O2
2.11
2.51
1.84
2.93
3.31
2.64
161
157
167
−1 + x, y, z
1 + x, y, z
−1 − x, −1/2 + y, 1/2 −
z
Peptide 3
N1−H1···O4
N2−H2···O7
N3−H3···O9
N4−H4···O2
O5−H5···O12
2.05
2.00
2.26
2.14
1.84
1.77
2.90
2.83
3.02
2.98
2.65
2.58
169
164
148
168
173
169
x, y, 1 + z
intramolecular
2 − x, −1/2 + y, 1 − z
intramolecular
x, y, −1 + z
2 − x, 1/2 + y, 1 − z
O10−
H10A···O11
O11−
1.93
2.09
2.74
2.86
171
156
intramolecular
intramolecular
H11A···O8
O12−
H12A···O3
Thermal Characterization. The TGA-DTG experiments
also support the different nature of the reported isomeric
dipeptides (Figure 6). The TGA results show no decom-
position or mass loss up to 157 and 178 °C for peptides 1 and
2, respectively. For peptide 3, there is a mass loss at 87 °C for
release of methanol and decomposition at 166 °C.
Figure 5. Formation of methanol mediated supramolecular corrugated
sheetlike structure from peptide 3.
N2 Gas Adsorption. In order to examine the void and
hollow in the noncanonical folded structure and self-assembly,
gas adsorption studies have been performed.17 The N2 sorption
studies with evacuated sample of peptides 1 and 2 exhibit type-
III isotherm (Figure 7). The N2 uptake of peptide 1 crystal was
found to be 22 cm3/g; however that for peptide 2 is 11 cm3/g
The peptide molecules are bound with methanol by
intermolecular hydrogen bonding interactions (O11−
H11A···O8, 1.93 Å, 2.75 Å, 171° and O12−H12A···O3, 2.09
Å, 2.86 Å, 156°) (Figure 5). There are also two π−π
interactions between Paba rings (shortest C−C distance 3.75
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Article
Table 3. Crystallographic Parameters of Peptides 1−3
Peptide 1
Peptide 2
Peptide 3
empirical
formula
C21H24N2O5
C21H24N2O5
C21H24N2O5,CH4O
formula
weight
384.42
384.42
416.47
crystal
system
monoclinic
orthorhombic
monoclinic
space group
T (K)
a/Å
P21
P212121
P21
100
100
100
10.578(4)
11.874(5)
32.517(13)
90
5.507(4)
17.177(12)
21.103(16)
9.412(8)
22.041(19)
11.901(10)
90
b/Å
c/Å
α/deg
β/deg
γ/deg
V/Å3
Z
94.155
90
109.25
90
4073.5
8
1996.3
4
2330.8
4
Figure 7. N2 sorption isotherm of (a) peptide 1 and (b) peptide 2 at
STP (P0 = 1 atm) showing the sorption is 2-fold higher for peptide 1.
−3
Dc Mg m
1.253
22876
1.279
22927
1.187
18704
reflns
collected
unique
reflns
13428
7272
4239
3074
9813
6410
observed
reflns
R1 I > 2σ(I) 0.0880
wR2 0.2402
0.0438
0.0874
0.0473
0.1509
indicating that the supramolecular herringbone like helical
packing of peptide 1 provides a larger void (3.02 nm) than the
supramolecular single helical packing of peptide 2 (2.84 nm).
On evacuation peptide 3 crystals released methanol molecules
and formed an opaque polymorph. Hence, for peptide 3, the N2
sorption study was not performed.
Morphology. To obtain insight about the morphology of
the reported isomeric peptides, field-emission scanning electron
microscopic (FE-SEM) measurements were carried out. For
FE-SEM experiments, dilute solutions (0.5 mM) of reported
peptides in methanol−water (1:1 v/v) were placed on a
microscopic glass slide and then dried under a vacuum for two
days. Figure 8 depicts the FE-SEM images of the aliphatic−
aromatic backbone hybrid isomeric peptides. From Figure 8a,b,
the micrographs show the roselike morphology for peptide 1 in
the self-assembled state. Peptides 2 and 3 exhibit twisted
fiberlike morphology (Figure 8, panels c and d respectively)
with a diameter ca. 100 nm and several micrometers in length.
Figure 8. FE-SEM images (a) and (b) exhibit roselike morphology of
peptide 1 and (c) and (d) showing twisted fiberlike morphology of
peptides 2 and 3, respectively.
CONCLUSION
■
In conclusion, we have shown that the isomeric aliphatic−
aromatic backbone hybrid peptides adopt unconventional
Figure 6. TGA of (a) peptide 1, (b) peptide 2, and (c) peptide 3. From this graph, the peptide 1 and 2 exhibit no decomposition, phase transitions,
or mass loss up to 157 and 178 °C, respectively. The crystal of peptide 3 has released methanol at 87 °C and decomposed at 166 °C.
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1H NMR (DMSO-d6, 500 MHz, δppm): 12.18 (s, 1H, COOH),
8.62−8.60 (m, 1H, anthra ring proton), 8.01−8.00 (d, 1H, anthra ring
proton), 7.56−7.52 (m, 1H, anthra ring proton), 7.43−7.42 (d, 1H,
anthra ring proton), 7.31 (s, 1H, anthra NH), 7.29−7.14 (m, 5H,
phenyl ring protons), 7.19 (d, 1H, J = 5, Phe NH), 4.20−4.18 (m, 1H,
CαH Phe), 3.22−3.18 (d, 1H, J = 20 Hz, CβH Phe), 2.91−2.86 (d,
1H, J = 20 Hz, CβH Phe), 1.31 (s, 9H, Boc). 13C NMR (DMSO-d6,
125 MHz, δppm): 170.95, 169.34, 155.46, 140.54, 138.28, 133.29,
131.13, 129.03, 128.09, 126.20, 122.44, 119.26, 117.85, 78.33, 57.75,
36.69, 28.05, 27.71. FTIR (cm−1): 3316, 3279, 1708, 1683, 1659, 1587,
1516, 1451, 1396, 1299, 1252, 1167.
conformations and exhibit diverse self-assembly directed by
intermolecular hydrogen bonds. In crystals, the ortho isomer
self-assemble to form a supramolecular herringbone-like helix,
whether the meta isomer exhibits a helical tapelike structure
and para isomer shows corrugated sheetlike architecture.
Moreover, peptide 1 crystals adsorb N2 2-fold higher than
does peptide 2. Such noncanonical folding and assembly may
foster new studies for the design of useful materials.
EXPERIMENTAL SECTION
■
Anal. calcd for C21H24N2O5 (384.43): C, 65.61; H, 6.29; N, 7.29.
Found: C, 65.63; H, 6.33; N, 7.33.
General. All amino acids (L-phenylalanine, o-aminobenzoic acid, m-
aminobenzoic acid, p-aminobenzoic acid) were purchased from Sigma
chemicals. 1-Hydroxybenzotriazole (HOBt) and dicyclohexylcarbodii-
mide (DCC) were purchased from SRL.
TOF mass m/z 407.39 (M + Na)+ Mcal 384.17
(c). Boc-Phe-Maba-OMe 5. 3.714 g (14 mmol) of Boc-Phe-OH was
dissolved in 30 mL of dry DCM in an ice−water bath. H-maba-OMe
was isolated from 5.628 g (30 mmol) of the corresponding methyl
ester hydrochloride by neutralization, and subsequent extraction with
ethyl acetate and ethyl acetate extract was concentrated to 15 mL. It
was then added to the reaction mixture, followed immediately by 2.888
g (14 mmol) of DCC and 1.891 g (14 mmol) of HOBt. The reaction
mixture was allowed to come to room temperature and was stirred for
48 h. DCM was evaporated and the residue was dissolved in ethyl
acetate (60 mL) and dicyclohexylurea (DCU) was filtered off. The
organic layer was washed with 2 M HCl (3 × 50 mL), brine (2 × 50
mL), 1 M sodium carbonate (3 × 50 mL), and brine (2 × 50 mL) and
dried over anhydrous sodium sulfate, and evaporated in a vacuum to
yield compound 5 as a white solid. The product was purified by silica
gel (100−200 mesh) using n-hexane−ethyl acetate (3:1) as the eluent.
Yield: 4.574 g (11.48 mmol, 86.56%).
Synthesis. The peptides were synthesized by conventional
solution-phase methodology by using a racemization free fragment
condensation strategy. The Boc group was used for N-terminal
protection, and the C-terminus was protected as a methyl ester.
Couplings were mediated by DCC/HOBt. Deprotection of the methyl
ester was performed using the saponification method. All the
intermediates were characterized by 500 MHz and 400 MHz 1H
NMR, 13C NMR, and mass spectrometry. The final compounds were
fully characterized by 500 MHz and 400 MHz 1H NMR spectroscopy,
13C NMR spectroscopy (125 MHz, 100 MHz), mass spectrometry,
and IR spectroscopy. Peptide 1−3 were also characterized by X-ray
crystallography.
(a). Boc-Phe-Anthra-OMe 4. 3.714 g (14 mmol) of Boc-Phe-OH
was dissolved in 30 mL of dry DCM in an ice−water bath. H-Anthra-
OMe was isolated from 5.628 g (30 mmol) of the corresponding
methyl ester hydrochloride by neutralization, and subsequent
extraction with ethyl acetate and ethyl acetate extract was concentrated
to 15 mL. It was then added to the reaction mixture, followed
immediately by 2.888 g (14 mmol) of dicyclohexylcarbodiimide
(DCC) and 1.891 g (14 mmol) of HOBt. The reaction mixture was
allowed to come to room temperature and was stirred for 48 h. DCM
was evaporated and the residue was dissolved in ethyl acetate (60 mL)
and dicyclohexylurea (DCU) was filtered off. The organic layer was
washed with 2 M HCl (3 × 50 mL), brine (2 × 50 mL), 1 M sodium
carbonate (3 × 50 mL), and brine (2 × 50 mL) and dried over
anhydrous sodium sulfate, and evaporated in a vacuum to yield
compound 4 as a white solid. The product was purified by silica gel
(100−200 mesh) using n-hexane−ethyl acetate (3:1) as the eluent.
Yield: 4.574 g (10.68 mmol, 76.35%).
1H NMR (CDCl3, 500 MHz, δppm): 8.05 (s, 1H, Maba ring
proton), 7.93 (s, 1H, Maba NH), 7.76−7.74 (d, 1H, J = 10, Maba ring
proton), 7.66−7.64 (d, 1H, J = 10, Maba ring proton), 7.34 (m, 1H,
Maba ring proton), 7.312−7.170 (m, 5H, phenyl ring protons), 5.15
(d, 1H, J = 10, Phe NH), 4.46 (m, 1H, Phe CαH), 3.89 (s, 3H, -OMe
Hs), 3.16−3.14 (d, 2H, J = 10 Hz, Phe CβH), 1.42 (s, 9H, Boc Hs).
13C NMR (CDCl3, 125 MHz, δppm): 168.76, 165.58, 136.46, 135.45,
129.87, 128.27, 128.05, 127.86, 126.15, 124.57, 123.42, 119.89, 51.20,
37.18, 27.24, FTIR (cm−1): 3333.12, 3063.82, 2980.51, 1718.59,
1686.15, 1593.36, 1522.11, 1432.64, 1367.88, 1301.66, 1271.09,
1234.46, 1164.25, 1102.38, 1083.92, 1048.41, 1022.13. Anal. Calcd
for C22H26N2O5 (398.45): C, 66.32; H, 6.58; N, 7.03. Found: C,
66.31; H, 6.56; N, 7.05.
(d). Boc-Phe-Maba-OH 2. To 4.382 g (11.0 mmol) of Boc-Phe-
Maba-OMe, 25 mL of MeOH and 15 mL of 2 M NaOH were added,
and the progress of saponification was monitored by thin layer
chromatography (TLC). The reaction mixture was stirred. After 10 h,
methanol was removed under a vacuum; the residue was dissolved in
50 mL of water and washed with diethyl ether (2 × 50 mL). Then the
pH of the aqueous layer was adjusted to 2 using 1 M HCl, and it was
extracted with ethyl acetate (3 × 50 mL). The extracts were pooled,
dried over anhydrous sodium sulfate, and evaporated under a vacuum
to obtain the compound as a white solid.
1H NMR (CDCl3, 400 MHz, δppm): 11.410 (s, 1H, NH Anthra),
8.72−8.70 (d, 1H, J = 8 Hz, anthra ring proton), 8.00−7.98 (d, 1H, J =
8 Hz, anthra ring proton), 7.54−7.53 (m, 1H, anthra ring proton),
7.26−7.25 (m, 5H, phenyl ring proton), 7.22 (m, 1H, anthra ring
proton), 5.05 (d, 1H, J = 6 Hz, Phe NH), 4.57 (m, 1H, CαH Phe),
3.86 (s, 3H, OMe), 3.21−3.20 (d, 2H, J = 10 Hz, CβH Phe), 1.43 (s,
9H, Boc). 13C NMR (CDCl3, 100 MHz, δppm): 170.534, 168.169,
155.183, 140.719, 136.305, 134.531, 130.784, 129.306, 128.658,
126.913, 122.82, 120.363, 115.405, 80.146, 56.863, 52.257, 38.461,
28.268. FTIR (cm−1): 3305, 3272, 2927, 1724, 1700, 1672, 1585, 1527,
1508, 1448, 1298, 1272.
Yield 4.005 g (10.15 mmol, 92.3%).
Melting point: 170 °C.
1H NMR (DMSO-d6, 500 MHz, δppm): 12.99 (b, 1H, COOH),
10.18 (s, 1H, Maba NH), 8.15 (s, 1H, Maba ring proton), 7.77−7.75
(d, 1H, J = 10, Maba ring proton), 7.57−7.55 (d, 1H, J = 10, Maba
ring proton), 7.38 (m, 1H, Maba ring proton), 7.26−7.13 (m, 5H,
phenyl ring protons), 7.12−7.11 (d, 1H, J = 5, Phe NH), 4.26−4.21
(m, 1H, Phe CαH), 2.95−2.91 (d, 1H, J = 20 Hz, Phe CβH), 2.79−
2.75 (d, 1H, J = 20 Hz, Phe CβH), 1.25 (s, 9H, Boc Hs). 13C NMR
(DMSO-d6, 125 MHz, δppm): 171.044, 167.11, 155.39, 139.10,
137.87, 131.25, 129.20, 128.99, 128.03, 126.28, 124.07, 123.33, 119.99,
78.10, 56.63, 37.31, 28.13. FTIR (cm−1): 3297.96, 2982.59, 2928.18,
1683.92, 1547.43, 1397.10, 1259.57, 1217.22, 1166.72, 1050.72. Anal.
Calcd for C21H24N2O5 (384.43): C, 65.61; H, 6.29; N, 7.29. Found: C,
65.63; H, 6.31; N, 7.28.
Anal. Calcd for C22H26N2O5 (398.45): C, 66.32; H, 6.58; N, 7.03;
Found: C, 66.40; H, 6.55; N, 7.05.
(b). Boc-Phe-Anthra-OH 1. To 4.183 g (10.5 mmol) of Boc-Phe-
Antra-OMe, 25 mL of MeOH and 15 mL of 2 M NaOH were added,
and the progress of saponification was monitored by thin layer
chromatography (TLC). The reaction mixture was stirred. After 10 h,
methanol was removed under a vacuum; the residue was dissolve in 50
mL of water, and washed with diethyl ether (2 × 50 mL). Then the
pH of the aqueous layer was adjusted to 2 using 1 M HCl and it was
extracted with ethyl acetate (3 × 50 mL). The extracts were pooled,
dried over anhydrous sodium sulfate, and evaporated under a vacuum
to obtain the compound as a white solid.
Yield 3.690 g (9.60 mmol, 91.45%).
Melting point: 162 °C
TOF mass m/z 384.47 (M)+ Mcal 384.17
426
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Crystal Growth & Design
Article
(e). Boc-Phe-Paba-OMe 6. 3.714 g (14 mmol) of Boc-Phe-OH was
dissolved in 30 mL of dry DCM in an ice−water bath. H-Paba-OMe
was isolated from 5.628 g (30 mmol) of the corresponding methyl
ester hydrochloride by neutralization, and subsequent extraction with
ethyl acetate and ethyl acetate extract was concentrated to 15 mL. It
was then added to the reaction mixture, followed immediately by 2.888
g (14 mmol) of DCC and 1.891 g (14 mmol) of HOBt. The reaction
mixture was allowed to come to room temperature and was stirred for
48 h. DCM was evaporated and the residue was dissolved in ethyl
acetate (60 mL) and DCU was filtered off. The organic layer was
washed with 2 M HCl (3 × 50 mL), brine (2 × 50 mL), 1 M sodium
carbonate (3 × 50 mL), and brine (2 × 50 mL) and dried over
anhydrous sodium sulfate and evaporated in a vacuum to yield
compound 6 as a white solid. The product was purified by silica gel
(100−200 mesh) using n-hexane−ethyl acetate (3:1) as eluent.
Yield: 4.203 g (10.55 mmol, 75.36%).
adsorption isotherm. From the N2 gas adsorption at low P/P0, the
following pore size distribution of the sample was obtained using the
NLDFT method. The pore size distribution curve of peptide 1 exhibits
one peak at 3.02 nm. From the Brunauer−Emmett−Teller (BET)
equation, the BET surface areas were calculated as 22 m2 g−1. This
analysis was done for compound 2 also. The pore size distribution
curve of peptide exhibits one peak at 2.84 nm. From the Brunauer−
Emmett−Teller (BET) equation, the BET surface areas were
calculated as 11 m2 g−1.
Scanning Electron Microscopy. The morphologies of the
reported materials were investigated by field emission scanning
electron microscopy (FE-SEM). For the SEM study, the correspond-
ing peptide solution in methanol−water (1:1 v/v) at a concentration
of 0.5 mM were drop-cast on microscopic glass slides, dried under a
vacuum for 2 days, and coated with platinum. The micrographs were
taken in an SEM apparatus (JEOL microscope JSM-6700F).
X-ray Crystallography. Intensity data were collected with MoKα
radiation at 100 K using Bruker APEX-2 CCD diffractometer. Data
were processed using the Bruker SAINT package and the structure
solution and refinement procedures were performed using
SHELX97.18 The non-hydrogen atoms were refined with anisotropic
thermal parameters. The hydrogen atoms were included in geometric
positions and given thermal parameters equivalent to 1.5 times those
of the atom to which they were attached. The data have been
deposited at the Cambridge Crystallographic Data Centre with
reference numbers CCDC 813384, 813385, and 813386 for peptides
1, 2, and 3 respectively.
1H NMR (CDCl3, 400 MHz, δppm): 8.10 (b, 1H, NH Paba), 7.97−
7.95(d, 2H, J = 8 Hz, paba ring protons), 7.47−7.45(d, 2H, J = 8 Hz,
paba ring protons), 7.29−7.26(m, 5H, phenyl ring protons), 5.10 (d,
1H, J = 6 Hz, Phe NH), 4.46−4.46 (m, 1H, CαH Phe), 3.89 (s, 3H,
OMe), 3.16−3.14 (d, 2H, J = 8 Hz, CβH Phe), 1.42 (s, 9H, Boc). 13C
NMR (CDCl3, 100 MHz, δppm): 170.238, 166.520, 155.927, 141.606,
136.371, 130.622, 129.201, 128.744, 127.075, 125.626, 118.942,
80.813, 56.634, 51.971, 38.270, 38.270, 28.211. FTIR (cm−1): 3347,
2952, 1716, 1670, 1521, 1434, 1407, 1367, 1318, 1284, 1177, 1162,
1112.
Anal. calcd for C22H26N2O5 (398.45): C, 66.32; H, 6.58; N, 7.03.
Found: C, 66.37; H, 6.51; N, 7.06.
(f). Boc-Phe-Paba-OH 3. To 4.183 g (10.5 mmol) of compound
Boc-Phe-OMe, 25 mL of MeOH and 15 mL of 2 M NaOH were
added, and the progress of saponification was monitored by thin layer
chromatography (TLC). The reaction mixture was stirred. After 10 h,
methanol was removed under vacuum; the residue was dissolved in 50
mL of water, and washed with diethyl ether (2 × 50 mL). Then the
pH of the aqueous layer was adjusted to 2 using 1 M HCl and it was
extracted with ethyl acetate (3 × 50 mL). The extracts were pooled,
dried over anhydrous sodium sulfate, and evaporated under a vacuum
to obtain compound 3 as a white solid.
ASSOCIATED CONTENT
* Supporting Information
Additional information as noted in the text; crystallographic
information files. This information is available free of charge via
the Internet at http://pubs.acs.org/.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: deba_h76@yahoo.com, deba_h76@iiserkol.ac.in.
■
Yield 3.740 g (9.73 mmol, 92.68%).
Melting point: 192 °C
1H NMR (DMSO-d6, 500 MHz, δppm): 12.78 (b, 1H, COOH),
10.33 (s,1H, NH Paba), 7.91−7.89 (d, 2H, J = 10 Hz, paba ring
protons), 7.71−7.69 (d, 2H, J = 10 Hz, paba ring protons), 7.33−7.15
(m, 5H, phenyl ring protons), 6.55−6.53 (d,1H, J = 10 Hz, NH Phe),
4.01 (m, 1H, CαH Phe), 3.01−2.98 (d, 1H, J = 15 Hz CβH Phe),
2.85−2.82 (d, 1H, J = 15 Hz CβH Phe), 1.32 (s, 9H, Boc). 13C NMR
(DMSO-d6, 125 MHz, δppm): 171.37, 166.89, 155.42, 142.92, 137.78,
131.18, 129.05, 128.09, 126.31, 118.55, 112.55,78.15, 56.66, 37.27,
28.13. FTIR (cm−1): 3310, 2974, 2928, 1686, 1601, 1560, 1534, 1411,
1250, 1172.
ACKNOWLEDGMENTS
■
This research was funded by the DST (SR/FT/CS-041/2009),
New Delhi, India. S.M., P.J., and S.K.M. thank the C.S.I.R, New
Delhi, India, for a fellowship.
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