Hydrogen-bonding interactions in ferrocene-peptide conjugates containing valine

Article abstract of DOI:10.1016/j.jorganchem.2010.10.061

The synthesis and characterization of a series of ferrocene (Fc) peptide conjugates containing the amino acid valine is reported, where the peptide substituents are part of the hydrophobic sequence of the amyloid β-peptide. The hydrogen-bonding (H-bonding

Full text of DOI:10.1016/j.jorganchem.2010.10.061

Journal of Organometallic Chemistry 696 (2011) 1117e1125
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Hydrogen-bonding interactions in ferrocene-peptide conjugates containing valine
*
Samaneh Beheshti, Anas Lataifeh, Heinz-Bernhard Kraatz
Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario, Canada N6A 5B7
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and characterization of a series of ferrocene (Fc) peptide conjugates containing the amino
acid valine is reported, where the peptide substituents are part of the hydrophobic sequence of the
amyloid b-peptide. The hydrogen-bonding (H-bonding) interaction in these compounds is studied by
Received 23 September 2010
Received in revised form
27 October 2010
variable temperature 1H NMR spectroscopy. The solid-state structures, determined by single crystal X-ray
crystallography, of two of the conjugates (Fc[CO-Leu-Val-OMe]2 1 and Fc[CO-Gly-Val-OH]2 6) are
reported. Both structures are stabilized by intramolecular H-bonds exhibiting the familiar “Herrick motif”
involving the proximal amide NH and the amide CO of the adjacent amino acid. This motif is sufficiently
rigid and is maintained in solution as suggested by CD studies. However, the intermolecular H-bonding
patterns observed on conjugates 1 and 6 are significantly different resulting in very different supra-
molecular architectures. For conjugate 1, a more conventional set of head-to-tail stacking interactions
Accepted 28 October 2010
Keywords:
Ferrocene
Bioconjugate
Peptide
CD spectroscopy
Hydrogen bonding
which is stabilized by b-sheet-like H-bonding interactions between the individual molecules is observed.
However, for conjugate 6, the presence of the C-terminal acid group and presumably the flexibility of the
Gly linker enables the formation of a more open structure that contains hydrophobic channels occupied
by solvent molecules.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
engages in intramolecular interaction of the “Herrick”-type, while
the amide of the second amino acid is involved in intermolecular
The desire to control the secondary structure of peptides has
attracted much attention due to its potential importance in the
design of functional peptidic materials [1] and their role in
guiding folding, misfolding [2] and biochemical processes [3] in
proteins. For this purpose, molecular scaffolds have been
successfully exploited to guide intramolecular peptide assemblies
into specific secondary structures supported by hydrogen bonding
(H-bonding) [4]. In this context, ferrocene (Fc) having two cyclo-
pentadienyl (Cp) rings separated by 3.3 Å make it a suitable
scaffold to support the formation of inter-strand hydrogen bonds
between peptide substituents on the two Cp rings of the metal-
H-bonding interaction that ultimately leads to the formation of
larger supramolecular arrangements [10]. Recently extended
b
-
sheet-like structures were reported for Fc-dicarboxylic acid
conjugates of tripeptides. These conjugates exhibit a second inter-
strand H-bonding interaction in addition to “Herrick motif” [6].
Most Fc-di- and tri-peptide conjugates reported to date possess C-
terminal esters, while the corresponding carboxylates have rarely
been studied.
Fc-peptide conjugates adopting
b-sheet-like conformations are
potentially interesting molecular models for diseases in which
b
-
sheet structure plays a structural role such as Alzheimer’s and
Parkinson’s. Alzheimer’s disease is associated with the aggrega-
locene [5], allowing for the design of a range of b-sheet-like Fc-
foldamers [6e8]. In many of the resulting Fc-peptide conjugates
[9e12], H-bonding adjacent to the Fc group involving the amide
NH and CO of the first amino acid stabilizes the structure of the
conjugate and was first proposed by Herrick [9]. Hirao has
reported a number of examples of Fc-dicarboxylic acid conjugates
of dipeptides in which the amide of the Fc-proximal amino acid
tion of the amyloid
order to elucidate the mechanism of aggregation and folding of
, emphasis has been placed on identifying peptide sequences
which are critical for the aggregation processes [14e16]. Research
has focused on peptides containing the hydrophobic sequence
b-peptide (Ab) into fibrils in the brain [13]. In
A
b
A
b16e22 (Lys16-Leu17-Val18-Phe19-Phe20-Ala21-Glu22), which is
critical for the formation of the initial tangles, leading to the
formation of mature peptide fibrils [17]. Based on these consid-
erations, a number of hydrophobic dipeptides Leu-Val (L-V), Val-
Phe (V-F), Gly-Val (G-V) and tripeptide Val-Phe-Phe (V-F-F) were
* Corresponding author. Tel.: þ1 519 661 2111x81561; fax: þ1 519 661 3022.
E-mail address: hkraatz@uwo.ca (H.-B. Kraatz).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.10.061

1118
S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
selected and conjugated to Fc-dicarboxylic acid in an attempt to
study the interactions between the peptide substituents in
soluble bioorganometallic model systems. One of these systems
possesses Gly as the Fc-proximal amino acid in order to provide
maximum flexibility to the peptide strands, to facilitate inter-
strand interactions and reduce potential steric strain in the
resulting Fc-conjugate. We hope that these conjugates are more
soluble than these hydrophobic peptides alone, which should
ultimately enable us to study their interaction in solution and
learn about the role of the hydrophobic peptide sequence in the
2.2. Synthesis of tripeptide
2.2.1. Boc-Val-Phe-Phe-OMe
Boc-Phe-Phe-OMe (1.0 g, 2.3 mmol) was dissolved in dry CH2Cl2
and treated with trifluoroacetic acid (TFA, 3.0 mL) in CH2Cl2
(3.0 mL) for 30 min. The TFA and CH2Cl2 were removed in vacuo.
The resulting residue was redissolved in dry CH2Cl2 and cooled in
an ice bath prior to the addition of triethylamine (Et3N). To this
a solution of activated Boc-Val-OH, prepared from Boc-Val-OH
(0.41 g, 1.9 mmol), Et3N (0.40 mL), HBTU (0.87 g, 2.3 mmol) and
HOBt (0.35 g, 2.3 mmol) in dry CH2Cl2 was added. The mixture was
stirred for 12 h. The solution was washed with aqueous solutions of
saturated NaHCO3, citric acid (10%), again saturated NaHCO3 and
finally distilled water. The organic phase was collected and traces of
water were removed using anhydrous Na2SO4. The product was
purified by column chromatography (silica gel, EtOAc: hexanes 1:1)
to yield white solid compound (0.70 g, 70%). MS (ESI): calcd for
aggregation of amyloid
b. In this work, we focus on both Fc-
peptide ester and Fc-peptide acid conjugates for most systems
and report their properties including some interesting new
supramolecular interactions which were previously not observed
in Fc-peptide conjugates.
2. Experimental
C29H39N3O6 525.2; Found 525.6 [M]þ. 1H NMR (CDCl3):
8H, CHAr Phe), 6.96 (m, 2H, CHAr Phe), 6.51 (d,1H, NH Phe),
(d, 1H, NH Phe), 4.93 (d, 1H, NH Boc),
4.71 (m, 1H, CHa Phe),
4.70 (m, 1H, CHa Phe), 3.89 (m, 1H, CHa NH Boc),
3.65 (s, 3H,
3.03 (m, 4H, CHb2 Phe), 2.06 (m, 1H, CHb Val),
1.43
0.87 (dd, 3H, (CH3)2 Val), 0.77 (dd, 3H, (CH3)2
d
7.21 (m,
6.22
d
d
d
2.1. General remarks
d
d
d
d
d
All syntheses were carried out in air unless otherwise indicated.
Dichloromethane (CH2Cl2) used for synthesis was distilled and
dried (CaH2) prior to use. The coupling agents used for amide bond
formation, N-ethyl-N0-(3-dimethylaminopropyl) carbodiimide
hydrochloride (EDC$HCl), 1-hydroxybenzotriazole hydrate (HOBt)
and O-(1H-benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tet-
rafluoroborate (HBTU) (Advanced ChemTech) were used as
received. All amino acids used were purchased from Advanced
ChemTech. All other chemicals were used as received and
purchased from SigmaeAldrich. Fc-dicarboxylic acid (Fc[COOH]2)
was synthesized as reported previously [18]. Products were puri-
fied by column chromatography, on a column packed 15e25 cm
high with 230e400 mesh silica gel. Nuclear magnetic resonance
(NMR) spectra were recorded on a Varian Mercury 400 spectrom-
eter operating at 400.1 MHz for 1H NMR and 100.6 MHz for 13C
ester OCH3),
d
d
d
(s, 9H, CH3 Boc),
Val).
d
d
2.3. General synthesis of ferrocene-peptide conjugates (1e7)
To a stirring mixture of Fc-dicarboxylic acid (0.27 g, 1.0 mmol),
triethylamine (0.34 mL, 2.5 mmol) in dry CH2Cl2 (50 mL), HOBt
(0.33 g, 2.2 mmol) and EDC$HCl (0.42 g, 2.2 mmol) were added. In
a separate flask Boce(AA)neOCH3 in dry CH2Cl2 were deprotected
by treatment with TFA. The TFA and CH2Cl2 were removed in vacuo.
The resulting residue was redissolved in CH2Cl2, cooled in an ice
bath prior to the addition of triethylamine and is then added to the
reaction mixture. After 12 h, the reaction mixture was washed with
subsequent aqueous solutions of saturated NaHCO3, citric acid
(10%), again saturated NaHCO3 and finally distilled water. The
organic phase was collected and traces of water were removed
using anhydrous Na2SO4. After concentration of the solution under
reduced pressure, the crude product was purified by flash column
chromatography in a chloroformemethanol solvent mixture. The
solvent was then removed completely under reduced pressure and
orange solids were obtained. Complete hydrolysis of the methyl
ester moieties was performed by reacting LiOH or NaOH (3 eq.) in
H2OeTHF or H2OeMeOH.
NMR. Chemical shifts (
and 13C NMR spectra in relation to tetramethylsilane (TMS,
All 1H NMR and 13C NMR spectra are referenced to CHCl3 (signals at
¼ 7.27 and ¼ 77.00, respectively) or DMSO-d6 (signals at ¼ 2.50
and
¼ 39.50, respectively) and coupling constants J were
d
) were reported in ppm for both 1H NMR
¼ 0).
d
d
d
d
d
measured in Hz. 2D-COSY experiments were used to complete
assignments in the 1H NMR spectra. Variable temperature and
concentration dependent 1H NMR measurements have been
carried out on a Varian Inova 400 (400 MHz). Mass spectrometry
analysis was carried out using a Finnigan MAT 8400 time-of-flight
mass spectrometry (TOF-MS) using high resolution electron impact
(HR-EI) or high resolution electrospray ionization (HR-ESI). UVevis
data were recorded in CH2Cl2 and CH3OH solution (0.5 mM) on
a Cary 300 UVevis spectrophotometer (Varian) using quartz
cuvette with 1 cm patch length (200e700 nm, 1 nm resolution).
The CD spectra were recorded on a Jasco J-810 circular dichroism
spectropolarimeter using a cell with a pathlength of 1 cm. The CD
spectra are an average of three accumulations in CH2Cl2 and
CH3OH. The spectra were further smoothed using means-move-
ment algorithm with a convolution width of 25-point supplied with
the JASCO software. Ellipticity maxima (lmax) are given in nm.
2.3.1. Fc[CO-Leu-Val-OMe]2 (1)
Boc-Leu-Val-OMe (0.75 g, 2.2 mmol). Silica gel column, CHCl3:
CH3OH (92:8 v/v), Yield: (0.43 g, 60%). MS (HR-ESI): calcd for
C36H54FeN4NaO8 749.3189; found 749.3184 [M þ Na]þ. 1H NMR
3
(400 MHz, CDCl3):
d
8.40 (d, JHH ¼ 7.42 Hz, 2H, NH Leu), 6.33 (d,
3JHH ¼ 8.99 Hz, 2H, NH Val), 4.88 (s, 2H, Hcp), 4.80 (s, 2H, Hcp), 4.63
(m, br, 2H, CHa Val), 4.57 (m, br, 2H, CHa Leu), 4.42 (s, 2H, Hcp), 4.29
(s, 2H, Hcp), 3.76 (s, 6H, ester OCH3), 2.25 (m, 2H, CHb Val), 1.80 (m,
4H, CHb2 Leu), 1.45 (m, 2H, CHg Leu), 1.04 (dd, JHH ¼ 7.03 Hz, 12H,
3
(CH3)2 Val), 0.89 ( m, 12H, (CH3)2 Leu). 13C NMR (CDCl3):
d 174.8,
172.3 (COamide), 170.4 (COester), 75.9 (Cpipso), 71.5, 71.0 (Cpm), 70.1,
70.0 (Cpo), 57.3, 52.6 (CHa Leu & CHa Val), 52.1 (OCH3), 39.7 (CHg
Leu), 31.4 (CHb Val), 24.8 (CH2b Leu), 22.9, 21.4 ((CH3)2 Leu), 19.1, 18.0
Molar ellipticity coefficients (Mq) were calculated as Mq
¼
q/10
(c ꢀ l), where the ellipticity ( ) is in millidegrees, sample concen-
q
tration c (1.1 mM) and pathlength l in centimetres (1 cm), thus
giving deg cm2 molꢁ1 for Mq. The dipeptides, Boc-Leu-Val-OMe
[19], Boc-Val-Phe-OMe [20], Boc-Gly-Val-OMe [21] and Boc-Phe-
Phe-OMe [22] were prepared as described before using HBTU and
HOBt. Their spectroscopic properties were identical to those
reported in the literature.
((CH3)2 Val). UVevis: lmax (nm) (
e
(cmꢁ1 Mꢁ1)): 443 (396).
2.3.2. Fc[CO-Val-Phe-OMe]2 (2)
Boc-Val-Phe-OMe (0.83 g, 2.2 mmol). Silica gel column, CHCl3:
CH3OH (92:8 v/v), Yield: (0.47 g, 60%). MS (HR-EI): calcd for
C42H50FeN4O8 794.29781; found 792.95055 [M]þ. 1H NMR

S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
1119
(400 MHz, CDCl3):
d
8.12 (d, 3JHH ¼ 8.60 Hz, 2H, NH Val), 7.37e7.34
(COacid), 171.9, 171.4, 171.0 (COamide), 75.2 (Cpipso), 71.4, 70.8 (Cpm),
(br, m, 4H, CHAr Phe), 7.30e7.24 (br, m, 6H, CHAr Phe), 6.54 (d,
3JHH ¼ 7.42 Hz, 2H, NH Phe), 4.91 (m, 2H, CHa Phe), 4.87 (s, 2H, Hcp),
4.79 (s, 2H, Hcp), 4.45 (s, 2H, Hcp), 4.33 (s, 2H, Hcp), 4.22 (m, 2H, CHa
Val), 3.69 (s, 6H, ester OCH3), 3.26e3.13 (m, br, 4H, CHb2 Phe), 2.12
(m, 2H, CHb Val), 0.98 (dd, 3JHH ¼ 6.64 Hz, 6H, (CH3)2 Val). 13C NMR
70.1, 69.7 (Cpo), 52.5 (CH2 Gly), 52.2, 52.1 (CHa Val), 50.8, 49.7 (CHb
Val), 28.9 28.7, 27.5, 27.3 ((CH3)2 Val). UVevis: lmax (nm) (
e
(cmꢁ1 Mꢁ1)): 439 (411).
2.3.7. Fc[CO-Val-Phe-OH]2 (7)
Fc[CO-Val-Phe-OMe]2 (0.79 g, 1.0 mmol), Yield: (0.45, 60%). MS
(ESI): calcd for C40H46FeN4NaO8 789.2563 found 789.2600
(CDCl3):
d
173.1, 171.5 (COamide), 170.5 (COester), 135.4, 129.4, 128.7,
127.2 (all CHAr Phe), 76.4 (Cpipso) 71.6, 71.2 (Cpm), 70.1, 69.8 (Cpo),
60.5 (CHa Val), 53.6 (CHa Phe), 52.1 (OCH3), 38.0 (CHb2 Phe), 29.5
[M þ Na]þ. 1H NMR (400 MHz, DMSO-d6):
d 12.67 (s, br, 2H, COOH),
(CHb Val), 19.7, 19.5 ((CH3)2 Val). UVevis: lmax (nm) (
e
(cmꢁ1 Mꢁ1)):
8.47 (d, 3JHH ¼ 7.82 Hz, 2H, NH Phe), 7.85 (d, 3JHH ¼ 8.99 Hz, 2H, NH
448 (323).
Val), 7.26e7.19 (m, br, 10H, CHAr Phe), d 4.78 (s, 2H, Hcp), d 4.77 (s,
2H, Hcp),
d
4.48 (m, 2H, CHa Phe), 4.29e4.26 (m, br, 6H, Hcp þ CHa
2.3.3. Fc[CO-Gly-Val-OMe]2 (3)
Val), 3.06 (2H, CHb2 of Phe), 2.95 (m, 2H, CHb2 of Phe), 2.07 (m, 2H,
Boc-Gly-Val-OMe (0.63 g, 2.2 mmol). Silica gel column CHCl3:
CH3OH (92:8 v/v), Yield: (0.42 g, 70%). MS (EI): calcd for
C28H38FeN4O8 614.2 found 614.2 [M]þ. 1H NMR (400 MHz, CDCl3):
CHb Val), 0.89 (t, 3JHH ¼ 6.25 Hz, 12H, (CH3)2 Val). 13C NMR (CDCl3):
d
172.6 (COacid), 172.0, 168.6 (COamide), 137.4, 129.0, 128.1, 126.4 (all
CHAr of Phe), 77.0 (Cpipso), 71.6, 71.3 (Cpm), 70.0, 69.0 (CpO), 58.2,
d
¼ 8.70 (t, 3JHH ¼ 5.86 Hz, 2H, NH Gly), 6.65 (d, 3JHH ¼ 8.21 Hz, 2H,
53.5 (CHa Val & CHa Leu), 36.6 (CHb2 Phe), 29.6 (CHb Val), 19.2, 18.9
NH Val), 4.86 (s, 4H, Hcp), 4.83 (s, 4H, Hcp), 4.59 (m, 2H, CHa Val),
4.43 (s, 2H, Hcp), 4.40 (s, 2H, Hcp), 4.01 (s, 2H, CH2 Gly), 3.88 (s, 2H,
CH2 Gly), 3.78 (s, 6H, ester OCH3), 2.23 (m, 2H, CHb Val), 1.00 (dd,
((CH3)2 Val). UVevis: lmax (nm) (e M
(cmꢁ1 ꢁ1)): 434 (395).
2.4. X-ray crystallographic data collection and refinement of the
structures
3JHH ¼ 7.03 Hz, 12H, (CH3)2 Val). 13C NMR (CDCl3):
d 172.2, 171.4
(COamide), 170.6 (COester), 75.7 (ipso C Cp), 71.5, 71.3 (CHm Cp), 70.6,
70.3 (CHo Cp), 57.6 (CHa Val), 52.2 (OCH3), 42.9 (CH2 Gly), 31.35 (CHb
Orange crystals were obtained by slow diffusion of hexane into
a solution of compound 1 in CH2Cl2. Yellow brownish crystals were
grown by a slow diffusion of hexane into a methanolic solution of
compound 6 at room temperature. Both compounds were mounted
Val), 19.07, 17.86 ((CH3)2 Val). UVevis: lmax (nm) (e M
(cmꢁ1 ꢁ1)):
443 (334).
2.3.4. Fc[CO-Val-Phe1-Phe2-OMe]2 (4)
Boc-Val-Phe-Phe-OMe (1.1 g, 2.2 mmol). Silica gel column,
increasing proportions of CH3OH (2e5)% in CH3Cl, Yield: (0.54 g,
50%). MS (HR-ESI): calcd for C60H68FeN6NaO10 1111.4244; found
Table 1
Summary of crystallographic data for Fc[CO-Leu-Val-OMe]2 (1) and Fc[CO-Gly-Val-
OH]2 (6).
1111.4265 [M þ Na]þ. 1H NMR (400 MHz, CDCl3):
d 7.72 (d,
3JHH ¼ 8.21 Hz, 2H, NH Val), 7.30e7.19 (m, br, 8H, CHAr Phe), 7.03 (d,
3JHH ¼ 7.82 Hz, 2H, NH Phe1), 6.89 (m, 4H, CHAr Phe), 6.16 (d,
3JHH ¼ 7.42 Hz, 2H, NH Phe2), 4.77 (s, 2H, Hcp), 4.71 (m, br, 4H, CHa
Phe), 4.66 (s, 2H, Hcp), 4.43 (s, 2H, H of Cp), 4.37 (s, 2H, H of Cp),
4.27 (m, 2H, CHa Val), 3.66 (s, 6H, ester OCH3), 3.24 (m, 2H, CHb2
Phe), 3.03 (m, 6H, CHb2 Phe), 2.16 (m, 2H, CHb Val), 1.00 (d,
3JHH ¼ 6.64 Hz, 6H, (CH3)2 Val), 0.86 (d, 3JHH ¼ 6.64 Hz, 6H, (CH3)2
1
6
Identification code
Empirical formula
Formula weight
T/K
B10051
C36H54FeN4O8
726.68
08123
C26H34FeN4O8
586.42
150 (2)
150 (2)
0.71073
Tetragonal
P4322
16.749 (2)
16.749 (2)
12.862 (3)
90
l/Å
0.71073
Monoclinic
P21
12.5711 (5)
17.6392 (7)
17.1800 (7)
90
97.6980 (10)
90
3775.2 (3)
4
Crystal system
Space group
a/Å
b/Å
c/Å
Val). 13C NMR (CDCl3):
d 172.8, 171.1, 170.5 (COamide), 170.0 (COester),
136.3, 135.5, 129.5, 129.1, 128.7, 128.5, 127.1 (all CHAr Phe), 77.2
(Cpipso), 71.6, 71.4 (Cpm), 70.6, 69.9 (Cpo), 60.5 (CHa Val), 54.7, 53.4
(CHa Phe), 52.2 (OCH3), 38.3, 37.9 (CHb2 Phe), 30.0 (CHb Val), 19.4,
ꢂ
ꢂ
a
/
b
/
90
90
e M
(cmꢁ1 ꢁ1)): 444 (128).
ꢂ
19.3 ((CH3)2 Val). UVevis: lmax (nm) (
g
/
V/Å3
3608.1 (10)
4
1.080
0.46
1232
Z
2.3.5. Fc[CO-Leu-Val-OH]2 (5)
Fc[CO-Leu-Val-OMe]2 (0.72 g, 1.0 mmol), Yield: (0.41 g, 60%). MS
(HR-ESI): calcd for C34H50FeN4NaO8 721.2876 found 721.2889
Dcalcd/Mg mꢁ3
M/mmꢁ1
F (000)
1.279
0.45
1552
[M þ Na]þ. 1H NMR (400 MHz, DMSO-d6):
d
12.60 (s, br, 2H, COOH),
Crystal size/mm
0.09 ꢀ 0.09 ꢀ 0.09
0.25 ꢀ 0.25 ꢀ 0.08
q
range for data
collection/ꢂ
1.63e28.70
2.04e25.03
8.52, 8.50 (m, 4H, NH Leu & NH Val), d 4.83 (s, 2H, Hcp), 4.72 (s, 2H,
Hcp), 4.63 (m, 2H, CHa Leu), 4.39 (s, 2H, Hcp), 4.35 (m, 2H, CHa Val),
4.31 (s, 2H, Hcp), 2.13 (m, 2H, CHb Val), 1.75 (m, 2H, CH2b Leu), 1.61
(m, 2H, CHb2 Leu), 1.39 (m, 2H, CHg Leu), 0.94 (d, 3JHH ¼ 6.64 Hz, 12H,
Index ranges
ꢁ16 < h < 16
ꢁ23 < k < 23
ꢁ23 < l < 20
233211
ꢁ13 < h < 14
0 < k < 19
0 < l < 15
28080
3182
[R(int) ¼ 0.0580]
Multi-scan
0.894/0.966
Full least squares
matrix on F2
3182/0/178
0.985
(CH3)2 Val), 0.85 ( m, 12H, (CH3)2 Leu). 13C NMR (CDCl3):
d 174.5
Reflections collected
Independent reflections
19517
(COacid), 172.6, 168.7 (COamide), 76.6 (Cpipso), 71.1, 70.8 (Cpm), 69.5,
69.4 (Cpo), 56.9, 51.0 (CHa Leu & CHa Val), 39.7 (CHg Leu), 30.1 (CHb
Val), 24.4 (CHb2 Leu), 23.1, 20.7 ((CH3)2 Leu), 19.1, 17.9 ((CH3)2 Val).
[R(int) ¼ 0.0465]
Absorption correction
Max./Min. transmission
Refinement method
Multi-scan
0.9616/0.9608
Full-matrix least
squares on F2
19517/1/883
1.016
UVevis: lmax (nm) (
e M
(cmꢁ1 ꢁ1)): 433 (390).
Data/restraints/parameters
2.3.6. Fc[CO-Gly-Val-OH]2 (6)
Goodness-of-fit on F2
Fc[CO-Gly-Val-OMe]2 (0.65 g, 1.0 mmol). Yield: (0.36 g, 60%). MS
(HR-ESI): calcd for C26H34FeN4NaO8 609.1623 found 609.1804
Final R indices [I > 2
s
(I)]
R1 ¼ 0.0453,
wR2 ¼ 0.1155
R1 ¼ 0.0552,
wR2 ¼ 0.1225
0.849 and
R1 ¼ 0.0875,
wR2 ¼ 0.2237
R1 ¼ 0.1227,
wR2 ¼ 0.2463
0.512 and
[M þ Na]þ. 1H NMR (400 MHz, DMSO-d6):
¼ 12.69 (br, 2H, COOH),
d
R indices (all data)
8.41 (m, 2H, NH Gly), 8.35 (m, 2H, NH Val), 4.78 (s, 4H, Hcp), 4.20 (s,
Largest diffraction
peak and hole
4H, Hcp), 4.22 (s, 2H, CHa Val), 3.80 (s, 4H, CH2 Gly), 2.10 (s, 2H, CHb
ꢁ0.626 e Åꢁ3
ꢁ0.483 e Åꢁ3
Val), 0.98 (s, 12H, (CH3)2 Val). 13C NMR (DMSO-d6):
d
¼ 173.2, 173.0

1120
S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
Scheme 1. Synthesis of dipeptides, tripeptide and Fc-peptide conjugates. (i) HOBt (1.2 eq.), HBTU (1.2 eq.), Et3N (1.5 eq.), CH2Cl2. (ii) a (v/v) TFA/CH2Cl2, b Boc-AA-OH (1.2 eq.), HOBt
(1.2 eq.), HBTU (1.2 eq.), Et3N (1.5 eq.) in CH2Cl2. (iii) a (v/v) TFA/CH2Cl2, b Fc[COOH]2 (1 eq.), HOBt (2.2 eq.), EDC (2.2 eq.), Et3N (2.5 eq.), CH2Cl2 (compounds 1e3) (iv) LiOH (3 eq.) in
H2O:THF (compounds 5 and 7) or NaOH (3 eq.) in H2O:MeOH (compound 6). (v) (v/v) TFA/CH2Cl2, b Fc[COOH]2 (1 eq), HOBt (2.2 eq.), EDC (2.2 eq), Et3N (2.5 eq.), CH2Cl2 (compound 4).
on glass fibres. Data were collected at 150 K on a Bruker Kappa Apex
II diffractometer using Mo radiation for 1 and on a Nonius Kappa-
CCD area detector diffractometer with COLLECT for 6. The crystal
data and refinement parameters are summarized in Table 1.
SHELXS-97 (Sheldrick, 2008) (for 1) and SHELXTL/PC V6.14 for
Windows NT (Sheldrick, G.M., 2001)(for 6, see Supporting
information) were used to solve the structures by direct methods.
For compound 1, the final R-value was 0.0453 for 17158 reflection
3 using a molar excess of NaOH in a mixture of water/methanol
results in the formation of the Fc-peptide acid 6, while conjugates 1
and 2 can be deprotected with LiOH in a mixture of water/THF to
give the Fc-peptide acids 5 and 7. The Fc-conjugates were charac-
terized by mass spectrometry and 1H, 13C NMR and UVeVis spec-
troscopies (see Supporting information). NMR assignments were
made using 2D TOCSYand 2D HSQC and by comparison to literature
data. Selected characterization data of Fc-peptide conjugates 1e7
are summarized in Table 2. It was not possible to find a common
solvent for NMR characterization due to limited stability of
compounds 1e4 in DMSO-d6 and insolubility of compounds 5e7 in
with I > 2
s
(I). For compound 6, the final R-value was 0.0875 for
(I).
1968 reflection with I > 2
s
3. Result and discussion
CDCl3. The appearance of amide signals at the
characteristic signals of Fc moiety at the 4e5 region shows the
successful synthesis of Fc-peptide conjugates. For compounds 5e7,
the appearance of a broad resonance around 12.60 reveals
deprotection of ester groups and formation of the Fc-peptide acids.
The presence of a set of Cp signals in a ratio of 1:1:1:1 follows
the typical pattern of a disubstituted Fc corresponding to the four
inequivalent Cp protons, except for compound 6 which exhibits
a ratio of 2:2. This is presumably due to the presence of the Gly
proximal to the Fc group reducing the effect of chiral induction of
the distal amino acid on the Fc core resulting in accidental magnetic
equivalence. Similar signal ratio (2:2) was reported for Fc[CO-Gly-
d 6e9 region and the
d
The dipeptides Leu-Val (L-V), Val-Phe (V-F), Gly-Val (G-V) and
the tripeptide Val-Phe-Phe (V-F-F), mimicking part of the hydro-
phobic sequence of the Ab16e22 fragment, and their Fc-conjugates
were prepared according to Scheme 1. All peptides were synthe-
sized in reasonable yields from Boc-protected amino acids and
amino acid esters by standard solution peptide coupling method
using HBTU and HOBt as the coupling reagents [19e22] (Scheme 1).
Next, the peptides were coupled to Fc-dicarboxylic acid using
EDC/HOBt as coupling reagent, resulting in the formation of desired
Fc-peptide conjugates (1e4). Ester deprotection of Fc-peptide ester
d
Table 2
Selected spectroscopic parameters of Fc-peptide conjugates 1e7.
Compound
Mass (m/z) Found (calcd)
1H NMR (ppm)
of NH
d
of Cp protons
13C NMR (ppm)
d of COeNH
d
1
2
3
4
5
6
7
[M þ Na]þ 749.3184 (749.3189)
[M]þ 792.95055 (794.29781)
[M]þ 614.2 (614.2)
8.40, 6.33
8.12, 6.54
8.70, 6.65
7.72, 7.03, 6.16
8.52, 8.50
8.41, 8.35
8.47, 7.85
4.88, 4.80, 4.42, 4.29
4.87, 4.79, 4.45, 4.33
4.86, 4.83, 4.43, 4.40
4.77, 4.66, 4.43, 4.37
4.83, 4.72, 4.39,4.31
4.78, 4.20
174.8, 172.3
173.1, 171.5
172.2, 171.4
172.8, 171.1, 170.5
172.6, 168.7
[M þ Na]þ 1111.4265 (1111.4244)
[M þ Na]þ 721.2889 (721.2876)
[M þ Na]þ 609.1804 (609.1623)
[M þ Na]þ 789.2600 (789.2563)
171.9, 171.4, 171.0
172.0, 168.6
4.78, 4.77, 4.29, 4.26

S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
1121
Scheme 2. Labelling scheme used for assignments of amide protons of compounds
1e4, there are only two type of amide protons in compounds 1e3 (NHa and NHb),
while for compound 4, there are three different amide protons (NHa, NHb and NHc).
presumably due to the involvement of these protons in intra-
molecular H-bonding interactions. In order to investigate the
H-bonding ability of the systems, variable temperature (VT) 1H
NMR measurements were carried out in CDCl3 for compounds 1e4.
A series of VT 1H NMR of Fc[CO-Leu-Val-OMe]2 (1) in the temper-
ature range of 243e303 K is shown in Fig. 2. As the temperature
increases the resonance of the amide NHs shift for upfield. The
assignment of amide NH protons is shown in Scheme 2 and the
result of the VT 1H NMR is summarized in Table 3 (see Supporting
information for plots of chemical shifts versus temperature).
The amide protons that are involved in intramolecular or
intermolecular hydrogen bonding experience temperature depen-
dent chemical shifts [25]. For example, the temperature coefficients
of compound 1 (see Fig. 2) reveal the involvement of both amide
protons in H-bonding (ꢁ3.7 ppb Kꢁ1 for NHa and ꢁ4.7 ppb Kꢁ1 for
NHb). The trend for compounds 2e4 are similar but the NH prox-
imal to Fc displays a higher temperature dependence suggesting
stronger H-bonding. Overall, our values compare favourably with
other temperature behaviour observed for Fc-peptide conjugates
involved in H-bonding interactions [11,26].
Fig. 1. 1H NMR spectra of Fc[CO-Leu-Val-OMe]2 1 (a), 1H NMR spectra of Fc[CO-Val-
Phe-Phe-OMe]2 4 (b) (c ¼ 5 mM, CDCl3). * Denotes the residual CHCl3. For compound 4,
the residual CHCl3 signal is overlapped with the aromatic H of the Phe residue.
Characteristic signals of Fc are observed at
d
4e5. Two amide resonances at
d
8.40 and
6.33 for conjugate 1 and three amide resonances at
d 7.72, 7.03 and 6.16 for conjugate 4
is observed.
OH]2 [12a]. Representative 1H NMR spectra of compounds 1 and 4
are shown in Fig.1. The -protons are observed at 4.63 and 4.57 for
conjugate 1 and 4.71 ( -proton signals of two Phe residues are
overlapping) and at 4.27 for conjugate 4. As is expected for these
conjugates, two ( 8.40 and 6.33), and three ( 7.72, 7.03, 6.16)
a
d
d
a
d
d
d
separate resonance for the amide NHs are observed for conjugates 1
and 4, respectively.
In general, the involvement of amide protons in H-bonding will
cause deshielding of these protons beyond d 7.00 [23,24]. As shown
Next it was important to evaluate the nature of the H-bonding
interactions. For this purpose, the concentration effect of Fc-
peptide conjugate on the chemical shift of the amide NH was
monitored. Generally, amide NH that is involved exclusively in
intermolecular H-bonding should exhibit more significant
concentration dependent chemical shifts compared to those
involved in intramolecular H-bonding interactions. Our results
show that the chemical shifts of the proximal amide NHa in Fc-
conjugates 1 (see Fig. 3) and 4 (see Supporting information) did not
change appreciably with concentration in the range of 1e40 mM. In
contrast, the resonances of NHb in conjugate 1 (see Fig. 3) and NHb
and NHc in conjugate 4 (see Supporting information) are greatly
affected by concentration and shift to lower field at higher
concentration. These results suggest the engagement of amide
protons NHb in compound 1, NHb and NHc in compound 4 in
intermolecular H-bonding interactions. Unfortunately, the insolu-
bility of compounds 5e7 in CDCl3 prevented us from studying their
H-bonding behaviour. These compounds are soluble only in
in Fig. 1, the amide protons NHa proximal to the Fc group in
conjugates 1 and 4 are shifted more downfield in comparison to the
amide protons that are far from Fc. This downfield shift is
Table 3
Summary of VT 1H NMR results for compounds 1e4 (NMR spectra were recorded in
CDCl3 solution in the temperature range of 243e303 K at a Fc-peptide concentration
of 10 mM).
Compound
1H NMR,
d
NeH
Dd/DT, NH (ppb/K)
(ppm)/CDCl3
1
2
3
4
NHa (8.40), NHb (6.33)
NHa (8.12), NHb (6.54)
NHa (8.70), NHb (6.65)
NHa (7.72), NHb (7.03),
NHc (6.16)
NHa (ꢁ3.7), NHb (ꢁ4.7)
NHa (ꢁ6.8), NHb (ꢁ1.8)
NHa (ꢁ5.1), NHb (ꢁ4.3)
NHa (ꢁ6.9), NHb Phe1 (ꢁ2.6),
NHc Phe2 (ꢁ1.2)
Fig. 2. VT 1H NMR of Fc[CO-Leu-Val-OMe]2 1 (c ¼ 10 mM, the temperature range
243e303 K). The temperature coefficients of compound 1 reveal the involvement of
both amide protons in hydrogen bonding (ꢁ3.7 ppb Kꢁ1 for NHa and ꢁ4.7 ppb Kꢁ1 for
NHb, see Supporting information for plot of chemical shift versus temperature).
* Denotes the residual CHCl3.

1122
S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
Fig. 4. CD spectra of Fc[CO-Leu-Val-OMe]2 (1) (-) in CH2Cl2, Fc[CO-Val-Phe-Phe-OMe]2
(4) in CH2Cl2 (- - -) and Fc[CO-Leu-Val-OH]2 (5) in CH3OH (/) (c ¼ 1.1 mM). A positive
Cotton effect at Fc region (484 nm for 1, 483 nm for 4 and 485 nm for 5) is indicative
for a P-helical configuration of the peptide strands around Fc moiety as a result of two
inter-strand H-bonds between peptide chains.
Fig. 3. Concentration dependent 1H NMR of Fc[CO-Leu-Val-OMe]2 1 showing amide
region (concentration range 1e40 mM). The chemical shift of the proximal amide NHa
did not change appreciably with concentration while the resonance of NHb is affected
by concentration and shift to lower field at higher concentration. * Denotes the
residual CHCl3.
420 nm are characteristic of metal-centered transitions. The CD
spectral patterns for all conjugates correlate nicely with results
reported for other Fc-peptide conjugates possessing a “Herrick
conformation” [29,30].
In order to investigate the structures of the Fc-conjugates, single
crystal diffraction studies were carried out on compounds 1 and 6.
Compound 1 was crystallized by slow diffusion of hexanes to
a dichloromethane solution in the monoclinic space group P21 with
two independent molecules Fe1 and Fe2 in the unit cell. One of
these molecules (molecule with Fe1) is presented in Fig. 5a
(molecule with Fe2 is shown in Supporting information). The single
crystal X-ray structure of Fc-conjugate 1, shown in Fig. 5a,
confirmed the presence of close contacts between the amide
oxygen CO of Leu and the amide nitrogen NH on the Leu of the
adjacent Cp ring (d(N2/O6) ¼ 2.934(3) Å and d(N3/O3) ¼ 3.071
(3) Å (Fig. 5a)). This pattern is in accord with “Herrick” H-bonding
involving two intramolecular H-bonds. Compound 6 also was
crystallized by slow diffusion of the hexanes in a solution of
methanol in the tetragonal space group P4322. An ORTEP view of
conjugate 6 is shown in Fig. 5b. Again, the structure is stabilized by
two C2-symmetrical intramolecular H-bonds between CO (Gly) and
NH (another Gly) of each dipeptide chain (d(N8/O110) ¼ 2.840
(5) Å). Similar structural features have been reported for other Fc-
dipeptide conjugates in the solid state [9,11,26]. In addition to
intramolecular H-bonding interactions, the compounds also do
engage in intermolecular H-bonding interactions giving rise to
supramolecular assemblies.
It is important to emphasize that there are significant differ-
ences between the two compounds at the supramolecular level.
And here there are significant differences between the two Fc-
peptide conjugates. In the case of compound 1, molecules arrange
head-to-tail fashion forming infinite chains linked by intermolec-
ular H-bonding interactions between podant peptide chains of
adjacent Fc-peptide molecules resulting in the formation of a 14-
membered intermolecular H-bonded ring between the Fc-peptide
conjugates (see Fig. 6b). N/O distances between Fe1 and Fe2 are d
(N5/O4) ¼ 2.846 (3) Å; d(N1/O12) ¼ 3.015 (3) Å, whereas they
are d(N4/O130) ¼ 2.967 (3) Å and d(N80/O5) ¼ 2.930 (3) Å for Fe1
and Fe20. Similar intermolecular H-bonding distances were repor-
ted for other Fc-dipeptide conjugates [11,26].
solvents that directly compete with the H-bonding of the peptide
substituents (DMSO or CH3OH).
Next, the helicity of the Fc-conjugates was examined by circular
dichroism (CD) spectroscopy [27e31]. The helicity of the Fc group is
induced by the restricted rotation about the Cp(centroid)-Fe-Cp
(centroid) axis as a result of inter-strand H-bonding between the
two podant peptide chains on the two Cp rings [29]. Generally, for
Fc-dicarboxylic acid peptide conjugates, a positive Cotton effect at
the absorption of the Fc at about 480 nm is associated with
a P-helical structure (generally induced by
a negative Cotton effects are interpreted as being indicative of
a M-helical structure (induced by -amino acids). In general, three
L-amino acids) while
D
different conformations have been reported for Fc-peptide conju-
gates in solution based on the presence of two intramolecular
H-bonds (“Herrick” conformation), one intramolecular H-bond
(“semi-Herrick’’ or van Staveren conformation) and no intra-
molecular H-bond involving the Fc-proximal amides [29e31]. The
CD spectra of compounds 1e4 (in CH2Cl2), 5e7 (in CH3OH) were
measured and the results are summarized in Table 4. Fig. 4 shows
the CD spectra of compounds 1, 4 and 5.
As expected for L-amino acid conjugates of Fc-dicarboxylic acid,
a positive Cotton effect is observed at 484, 483 and 485 nm for 1, 4
and 5 respectively which indicates an ordered P-helical confor-
mation of the Fc moiety, presumably as a result of sufficiently
strong inter-strand H-bonds between the peptide strands to
maintain P-helicity. Other bands observed between 300 and
Table 4
Summary of CD data of ferrocene-peptide conjugates in CH2Cl2 and CH3OH*
(c ¼ 1.1 mM).
Compound
lmax/nm (Mq ꢀ 103/deg cm2 molꢁ1
)
1
2
3
4
5*
6*
7*
484 (þ6.5)
481 (þ6.2)
481 (þ6.0)
483 (þ3.9)
485 (þ3.5)
488 (þ1.9)
479 (þ3.8)
418 (ꢁ2.6)
417 (ꢁ1.6)
417 (ꢁ1.2)
416 (ꢁ1.1)
419 (ꢁ1.9)
419 (ꢁ1.0)
411 (ꢁ0.92)
356 (ꢁ6.0)
356 (ꢁ5.3)
356 (ꢁ5.5)
357 (ꢁ3.3)
358 (ꢁ3.5)
358 (ꢁ1.0)
358 (ꢁ3.5)
310 (þ13.1)
309 (þ12.0)
305 (þ12.5)
310 (þ7.8)
311 (þ6.8)
306 (þ3.5)
312 (þ6.7)
For compound 6, the presence of Gly as the Fc-proximal amino
acid provides the maximum flexibility to the peptide strands. The
allowed torsion angles for Gly occupies larger region in the

S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
1123
Fig. 5. a, b) ORTEP diagram of Fc-peptide conjugates Fc[CO-Leu-Val-OMe]2 (1) and Fc[CO-Gly-Val-OH]2 (6); ellipsoids are drawn at the 30% probability level. Hydrogen atoms are
omitted for clarity; H-bonds are shown dashed. Intramolecular H-bonding distances are N2/O6, 2.934(3) Å and N3/O3, 3.071(3) Å for Fc-peptide conjugate 1 (a) and N8/O110and
N80/O11, 2.840 (5) Å for compound 6 (b). The intramolecular H-bonding patterns are identical in both compounds. However the orientation of second amino acids are different in
these two compounds probably due to the flexibility of Gly as the first amino acid and engagement of C-terminal carboxylates of conjugate 6 in extensive intermolecular H-bonding
(see Fig. 7).
Ramachandran plot compared to Leu [32], which presumably gives
rise to the significant differences in the relative disposition of the
second amino acid in conjugates 1 and 6 as shown in Fig. 5.
Presumably the flexibility of the Gly residue as well as the presence
of the free acid group in compound 6 play a role, resulting in
different intermolecular H-bonding interactions for conjugate 6.
The FceC]O establishes intermolecular H-bonding interaction
with the acid OeH of an adjacent neighbouring molecule with
a distance of d(O7/O1600) ¼ 2.558 (5) Å (Fig. 7b). A similar H-
bonding pattern was reported for Fc[CO-Gly-OH]2 [12a]. The Val NH
groups are also involved in intermolecular H-bonding with Val CO
groups of a neighbouring molecule with a d(N12/O15000) ¼ 3.043
(6) Å (Fig. 7b).
Crystalpackingof conjugate 6 shows the formation of hydrophobic
channels formed by the interplay of intermolecular H-bonding inter-
actions. However, these are not empty but occupied by three hexane
Fig. 6. ORTEP diagram of conjugate 1 showing intramolecular H-bonding interactions (a), ORTEP diagram of conjugate 1 showing 1-D intermolecular H-bonding (b). Hydrogen
atoms are omitted for clarity and dashed lines represent H-bonds. Ellipsoids are drawn at the 30% probability level. Each dipeptide strand forms a 14-membered intermolecular
H-bonded ring with the podant dipeptide chain of another molecule of the different type, resulting infinite chains of Fe1 and Fe2 through out the lattice. The intermolecular H-bond
distances are d(N5/O4) ¼ 2.846 (3) Å, d(N1/O12) ¼ 3.015(3) Å, d(N4/O130) ¼ 2.967(3) Å and d(N80/O5) ¼ 2.930(3) Å.

1124
S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
Fig. 7. ORTEP diagram of 6 showing intramolecular H-bonds (a), ORTEP diagram of 6 showing 1-D intermolecular H-bonds (b). Hydrogen atoms are omitted for clarity and dashed
lines represent H-bonds. Ellipsoids are drawn at the 30% probability level. Flexibility of Gly as first amino acid and involvement of C-terminal of peptide strands in free acid H-bonds
would cause different intermolecular H-bond patterns for 6. Intermolecular H-bonds are between the FceC]O moieties and the acid OeH of adjacent neighbours
(d(O7/O1600) ¼ 2.558 (5) Å) and valine NH groups with valine CO groups of neighbour molecules (d(N12/O15000) ¼ 3.043 (6) Å). Crystal packing of Fc-peptide conjugate 6 showing
the formation of hydrophobic voids at the center of the stacks (c). The major void space in the structure of 6 is occupied by three hexane molecules along the columnar void (see
Supporting information).
molecules along the columnar void (Fig. 7c and see supporting
information).
between Cp rings is (2.5ꢂ, 2.1ꢂ) for 1 and (6.3ꢂ) for 6 and confirms the
co-planarity of two Cp rings. The twist angle between the planes of
Some selected structural parameters of conjugate 1 and 6 are
summarized in Table 5. The torsion angle between the substituents
the amide bonds and the Cp rings (
5.4ꢂ) for 1 and (5.7ꢂ) for 6 resulting the electronic interactions
between the -system of amides and Cp rings. Our result compare
with results reported for Fc-dipeptide conjugates [11,26].
b
) are small (5.3ꢂ/2.2ꢂ and 6.2ꢂ/
(u
), 73.5ꢂ and 70.6ꢂ for 1 and 72.9ꢂ for 6 are close to the value
p
observed for 1,20-disubstituted conformations [29]. The tilt angle (
q)
Table 5
Structural parameters of 1 and 6.
Compound
Angle (ꢂ)
u
q
b
FeeC (Å)
Cpeamide (CeC)b
Amide (C]O)b
Amide (CeN)b
1 (Fc 1)
1 (Fc 2)
6
73.5
70.6
72.9
2.5
2.1
6.3
5.3/2.2a
6.2/5.4a
5.7
2.020 (2)e2.053 (3)
2.023 (2)e2.067 (3)
1.994 (7)e2.041 (11)
1.482 (3)/1.472 (4)a
1.484 (4)/1.479 (3)a
1.446 (8)
1.250(3)/1.230 (3)a
1.240(3)/1.234 (3)a
1.252 (6)
1.336 (4)/1.347 (3)a
1.343 (3)/1.350(3)a
1.358 (6)
a
Disubstituted derivative the first values corresponds to the substituent with higher atomic label (see Supporting information for atomic labelling).
Amide proximal to Fc.
b

S. Beheshti et al. / Journal of Organometallic Chemistry 696 (2011) 1117e1125
1125
4. Conclusion
Supporting information related to this article can be found
online at doi:10.1016/j.jorganchem.2010.10.061.
The synthesis and spectroscopic properties of a series of Fc-
peptide ester and Fc-peptide acid conjugates containing hydro-
phobic amino acids from part of hydrophobic region of amyloid
beta peptide are reported. There are evidences that H-bonds play
an important role in the stability of beta amyloid aggregates
[33,34]. The presence of H-bonds in our compounds is confirmed
in solution and some cases solid states using spectroscopic
References
[1] D.J. Hill, M.J. Mio, R.B. Prince, T.S. Hughes, J.S. Moore, Chem. Rev. 101 (2001)
3893e4011.
[2] J.J. Osterhout, Protein Pept. Lett. 12 (2005) 159e164.
[3] J.D. Sadowsky, M.A. Schmitt, H.S. Lee, N. Umezawa, S.M. Wang, Y. Tomita,
S.H. Gellman, J. Am. Chem. Soc. 127 (2005) 11966e11968.
[4] T. Moriuchi, T. Hirao, Chem. Soc. Rev. 33 (2004) 294e301.
[5] D.R. van Staveren, N. Metzler-Nolte, Chem. Rev. 104 (2004) 5931e5985.
[6] S. Chowdhury, G. Schatte, H.-B. Kraatz, Angew. Chem. Int. Ed. 47 (2008) 7056e7059.
[7] S. Chowdhury, G. Schatte, H.-B. Kraatz, Angew. Chem. Int. Ed. 45 (2006) 6882e6884.
[8] S. Chowdhury, K.A. Mahmoud, G. Schatte, H.-B. Kraatz, Org. Biomol. Chem. 3
(2005) 3018e3023.
[9] R.S. Herrick, R.M. Jarret, T.P. Curran, D.R. Dragoli, M.B. Flaherty, S.E. Lindyberg,
R.A. Slate, L.C. Thornton, Tetrahedron Lett. 37 (1996) 5289e5292.
[10] (a) T. Moriuchi, T. Nagai, T. Hirao, Org. Lett. 7 (2005) 5265e5268;
(b) T. Moriuchi, A. Nomoto, K. Yoshida, A. Ogawa, T. Hirao, J. Am. Chem. Soc.
123 (2001) 68e75;
techniques. The solid-state structures of Fc[CO-Leu-Val-OMe]2
and Fc[CO-Gly-Val-OH]2 confirmed formation of “Herrick”
conformation (anti-parallel -sheet like). However, there are
1
6
b
significant differences between two compounds at the supramo-
lecular level in the solid state. The flexibility of Gly as an Fc-
proximal amino acid and the presence of the free acid group give
rise to the significant differences in intermolecular H-bonding
interactions of compound 6. In compound 1, the intermolecular
H-bonding interactions arrange molecule in a head-to-tail fashion
forming infinite chains, while crystal packing of 6 shows the
formation of hydrophobic channels resulting from involvement of
free acid and NH Val in intermolecular H-bonds. This particular
association of Fc-peptide conjugates is as of yet unprecedented
for this class of compounds and has to be compared with Gha-
(c) A. Nomoto, T. Moriuchi, S. Yamazaki, A. Ogawa, T. Hirao, Chem. Commun.
(1998) 1963e1964;
(d) T. Moriuchi, T. Hirao, Acc. Chem. Res. 43 (2010) 1040e1051.
[11] D.R. van Staveren, T. Weyhermüller, N. Metzler-Nolte, DaltonTrans. (2003)
210e220.
[12] (a) F.E. Appoh, T.C. Sutherland, H.-B. Kraatz, J. Organomet. Chem. 689 (2004)
4669e4677;
diri’s cyclic octapeptides composed of alternating D- and L- amino
(b) X. De Hatten, T. Weyhermüller, N. Metzler-Nolte, J. Organomet. Chem. 689
(2004) 4856e4867.
[13] A.T. Petkova, R.D. Leapman, Z. Guo, W.M. Yau, M.P. Mattson, R. Tycko, Science
307 (2005) 262e265.
acids forming flat rings that associate into continuous peptide
tubes with an inner diameter of 7e8 Å [35]. More work in this
area is necessary to probe the generality of this assembly pattern
for Fc-peptide acids. The Fc-peptide systems reported here may
[14] T.H.J. Huang, P.E. Fraser, A. Chakrabartty, J. Mol. Biol. 269 (1997) 214e224.
[15] H. Inouye, P.E. Fraser, D.A. Kirschner, Biophys. J. 64 (1993) 502e519.
[16] P.E. Fraser, J.T. Nguyen, W.K. Surewicz, D.A. Kirschner, Biophys. J. 60 (1991)
1190e1201.
[17] (a) C. Wurth, N.K. Guimard, M.H. Hecht, J. Mol. Biol. 319 (2002) 1279e1290;
(b) J.P.Melchor,L.McVoy,W.E.vanNostrand,J.Neurochem.74(2000)2209e2212;
(c) A.K. Mehta, K. Lu, W.S. Childers, Y. Liang, S.N. Dublin, J. Dong, J.P. Snyder,
S.V. Pingali, P. Thiyagarajan, D.G. Lynn, J. Am. Chem. Soc. 130 (2008) 9829e9835.
[18] V. Rapic’, K. Schlogl, B. Steinitz, J. Organomet. Chem. 94 (1975) 87e98.
[19] B. Kamber, Helv. Chim. Acta 54 (1971) 398e422.
[20] P. Rzepecki, T. Schrader, J. Am. Chem. Soc. 127 (2005) 3016e3025.
[21] J. Wonnemann, M. Oberhoff, G. Erker, R. Frohlich, K. Bergander, Eur. J. Inorg.
Chem. (1999) 1111e1120.
[22] T. Matoba, T. Hata, Agric. Biol. Chem. 36 (1972) 1423e1431.
[23] J.S. Nowick, E.M. Smith, G. Noronha, J. Org. Chem. 60 (1995) 7386e7387.
[24] J.S. Nowick, D.L. Holmes, G. Mackin, G. Noronha, A.J. Shaka, E.M. Smith, J. Am.
Chem. Soc. 118 (1996) 2764e2765.
have a potential to interact with the hydrophobic part of A
are now exploring the interaction of some of the Fc-peptide
conjugates with different fragments of A in solution and on
surfaces. Work is also under way to study longer peptide frag-
ments of A , their assembly properties and their potential to
interact with A
b. We
b
b
b
.
Acknowledgments
This work was funded by Natural Science and Engineering
Research Council of Canada (NSERC) and the University of Western
Ontario (UWO).
[25] C.N. Kirsten, T.H. Schrader, J. Am. Chem. Soc. 119 (1997) 12061e12068.
[26] T. Moriuchi, A. Nomoto, K. Yoshida, T. Hirao, J. Organomet. Chem. 589 (1999)
50e58.
[27] J. Lapic’, S. Djakovic’, M. Cetina, K. Heinze, V. Rapic’, Eur. J. Inorg. Chem. (2010)
106e114.
Appendix. Supporting information
[28] J. Lapic’, D. Siebler, K. Heinze, V. Rapic’, Eur. J. Inorg. Chem. (2007) 2014e2024.
[29] S.I. Kirin, H.-B. Kraatz, N. Metzler-Nolte, Chem. Soc. Rev. 35 (2006) 348e354.
[30] A. Lataifeh, S. Beheshti, H.-B. Kraatz, Eur. J. Inorg. Chem. (2009) 3205e3218.
[31] S.I. Kirin, U. Schatzschneider, S.D. Köster, D. Siebler, N. Metzler-Nolte, Inorg.
Chim. Acta 362 (2009) 894e906.
[32] S. Hovmöller, T. Zhou, T. Ohlson, Acta Crystallogr. D58 (2002) 768e776.
[33] I. Kheterpal, S. Zhou, K.D. Cook, R. Wetzel, Proc. Natl. Acad. Sci. U. S. A 97
(2000) 13597e13601.
[34] J.J. Balbach, Y. Ishii, O.N. Antzutkin, R.D. Leapman, N.W. Rizzo, F. Dyda, J. Reed,
R. Tycko, Biochemistry 39 (2000) 13748e13759.
[35] (a) M.R. Ghadiri, J.R. Granja, R.A. Milligan, D.E. Mcree, N. Khazanovich, Nature
366 (1993) 324e327;
Additional molecular drawings (ORTEP) of conjugates 1 and 6.
Additional spectroscopic information, including VT NMR, variable
concentration NMR, and 13C NMR spectroscopies of some Fc-
peptides. Pictorial representation showing the columnar voids and
residual electron density for Fc-conjugate 6. CCDC 793939 (conju-
gate 1) & 793940 (conjugate 6) contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(b) M. Engels, D. Bashford, M.R. Ghadiri, J. Am. Chem. Soc. 117 (1995) 9151e9158.