Synthesis of new series of α-cyclodextrin esters as dopamine carrier molecule

Article abstract of DOI:10.1016/j.bmc.2011.05.048

A new series of amphiphilic α-cyclodextrins were synthesized by grafting N-acylated amino acids [valine, leucine, phenylalanine, methionine, and tryptophan (3a-e)] to the primary hydroxyl groups via ester bond formation. The synthetic pathway involves sel

Full text of DOI:10.1016/j.bmc.2011.05.048

Bioorganic & Medicinal Chemistry 19 (2011) 4307–4311
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of new series of a-cyclodextrin esters as dopamine carrier molecule
Seyed Mohammad Seyedi a, Hamid Sadeghian b, , Atena Jabbari a, Amir Assadieskandar c, Hamideh Momeni a
⇑
a Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 917751436, Iran
b Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad 91389-13131, Iran
c Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, 14176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of amphiphilic a-cyclodextrins were synthesized by grafting N-acylated amino acids [valine,
Received 23 April 2011
Revised 23 May 2011
Accepted 23 May 2011
Available online 6 June 2011
leucine, phenylalanine, methionine, and tryptophan (3a–e)] to the primary hydroxyl groups via ester
bond formation. The synthetic pathway involves selective hexa-bromination of the primary hydroxyls
followed by per-substitution with the carboxylate moiety of the N-acetyl residues in the presence of
DBU (1,8-diazabicyclo[5,4,0]undec-7-ene). The ability of the synthetic compounds for the extraction of
dopamine was studied. The results showed a considerable ability of some of the amphiphilic compounds
for the extraction of dopamine into octanol phase from water. To complete the study, the binding affinity
of dopamine toward the synthetic host molecules was calculated by using of the molecular docking
technique.
Keywords:
Esterification
DBU
Extraction
Molecular modeling
Log D
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
composed of N-acylated lipophilic amino acids on the primary hy-
droxyl groups. The ability of the synthetic compounds for extrac-
tion of dopamine (Fig. 1), a hydrophilic bioorganic compound,
was then studied.
Formation of inclusion complexes is the most important ability
of cyclodextrins (CDs) leading to their development as drug carri-
ers,1 and their utility for the solubilization,2 encapsulation,3 and
transport of biologically active molecules.4 Amphiphilic cyclodex-
trin derivatives are valuable in pharmaceutical applications due
to their ability for self-organization in aqueous media. Liposomes,5
nanoparticles,6 vesicles7 and micellar aggregates8 have been pre-
pared from amphiphilic cyclodextrins to form versatile carrier
and delivery systems for hydrophilic and lipophilic drugs. These
compounds are produced by grafting various lengths of lipophilic
chains on to the primary or secondary hydroxyl groups of the glu-
copyranose units. Among these derivatizations, grafting of fatty-
acids, -alcohols and -amines to the primary hydroxyl group of
cyclodextrins are most common.6 The lipophilic chains of these
structures would make an intimate contact with biological
membranes.
2. Results and discussion
Our interest in the design and synthesis of amino acid-a-CD
derivatives emerges from our previous work in which preparation
of amphiphilic peptide b-CD as a phase transfer carrier of glucosa-
mine was reported.11 The desired structures have been synthesized
as esters of the six primary hydroyl groups of
a-CD and the car-
boxyl moiety of N-acetylated amino acids: leucine (Leu), valine
(Val), phenylalanine (Phe), methionine (Met) and tryptophan
(Trp) (Scheme 1).
In this molecular design, lipophilic amino acids were selected
for extension of the cavity of
structure.
a-CD with an external lipophilic
Furthermore, bilayer vesicles composed of amphiphilic CDs
have been shown to bind specific guests to recognize molecular
signals.9,10 This suggests that amphiphilic CDs could be used for
the development of biological receptors that may help to under-
stand the complicated mechanism of the molecular recognition
by living cells.
In this molecular design, lipophilic amino acids were selected to
extend the cavity of the -CD to provide additional room for sub-
a
strate binding. In addition, the amino groups of the appended ami-
no acids were acylated to ensure the overall structure was
amphiphilic with a polar end consisting of the secondary hydroxyl
groups, and a non-polar end consisting of the amino acid side
chains.
In this study, a new series of amphiphilic
a-cyclodextrin were
synthesized by grafting N-acetylated amino acids on to the primary
hydroxyl groups via ester bond formation. The new structures are
The synthetic pathway involves selective hexa-bromination of
the hydroxyl groups of
a
-CD,12 with N-bromosuccinamide (NBS)
and triphenylphosphine (PPh3), then substitution with the carbox-
ylate moiety of the N-acetyl amino acids in the presence of DBU
⇑
Corresponding author. Tel.: +98 05117610111; fax: +98 05117628088.
E-mail address: sadeghianh@mums.ac.ir (H. Sadeghian).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.05.048

4308
S. M. Seyedi et al. / Bioorg. Med. Chem. 19 (2011) 4307–4311
control consisting octanol alone. The concentration of dopamine
OH
OH
was determined by using of triiodide spectrophotometric meth-
od.17 The results in Table 1 show that dopamine was extracted
effectively by 3a–d but no significant extraction was observed for
H2N
3e or
The binding affinity of dopamine toward 3a–e was calculated
and reported as estimated binding free energy ( Gb). The structures
of 3a–e were modeled via grafting the required residues to the pri-
mary hydroxyls of a -CD crystal structure followed by geometry
optimization (MM+ and PM3 methods). In the modeled molecules,
residues are aligned above the -CD ring and the cylindrical struc-
ture shape is observed in which the outer part is hydrophobic while
the head ( -CD ring) possess the hydrophilic nature. The structure
a-CD.
Figure 1. Molecular structure of dopamine.
D
(1,8-diazabicyclo[5,4,0]undec-7-ene) (Scheme 1).13–15 The re-
quired N-acetyl amino acids were synthesized via reaction of acetic
anhydride with the amino acids. The compounds were prepared in
good yields with simple workup to give the expected spectroscopic
properties and acceptable elemental analyses. The steric hindrance
of valine b-carbon might be a main cause of decrease in synthetic
yield of compound 3b.
Binding behavior of the compounds prepared was studied using
dopamine, a natural neurotransmitter, as a guest molecule. The rel-
ative binding affinity of 3a–e toward dopamine was measured
using a phase extraction method.16 The decrease in dopamine con-
centration of aqueous phase after shaking for 2 h with octanol con-
a
a
a
was stabilized by intramolecular hydrogen bonds between amide
groups. The binding affinity was estimated in AuoDockTools soft-
ware using the AUTODOCK4.0 program.18 A total of 100 docked conform-
ers of dopamine were generated for each of 3a–e. The detailed
analysis of all 100 docked models revealed that all had nearly iden-
tical orientations fixed by hydrogen bonding of the amine and hy-
droxyl groups of dopamine with the acetamide and sugar portions
of the host molecules (Fig. 2). The averages of estimated binding free
taining 3a–e and
a-CD, was determined and reported as a
fractional extraction (%E). Aqueous solutions of the dopamine
energy of docked molecules (DGb) are outlined in Table 1.
(5 mM) (pH 7.4) were separately extracted with octanol (lipid
The docking results of 3a–e, showed that the binding free en-
phase), containing 3a–e or
a
-CD, (5 mM) and compared with a
ergy of dopamine for all of the host molecules with similar
Br
O
HO
O
OH
O
O
R
7
OH
O
O
R
O
OH
O
2
DBU, RCOOH
OH O
O
OH
OH
, DMF
3
O
O
OH
OH
OH
O
O
OH
OH
O
O
OH
OH
O
1) NBS, PPh
O
O
O
O
OH
OH
OH
OH
OH
R
O
O
O
OH
O
OH
O
OH
OH
O
O
O
O
OH
OH
OH
OH
O
O
OH
OH
OH
O
R
O
O
OH
O
R
O
1
3a-e
O
RCOO :
S
NH
O
O
O
O
O
N
H
COO
N
COO
N
H
COO
N
COO
N
H
COO
H
H
a (72%)
c (72%)
b (43%)
d (65%)
e (72%)
Scheme 1. General procedure for the synthesis of amphiphilic
a-CDs (3a–e).

S. M. Seyedi et al. / Bioorg. Med. Chem. 19 (2011) 4307–4311
4309
Table 1
Extraction content (%E), octanol–water distribution coefficient (log D), and average of
3. Conclusion
estimated free energy of binding (D
Gb kcal molꢀ1) for compounds 3a–e
In summary, we have synthesized a new series of hydrophobic
esters of a-cyclodextrins as a carrier and lipid solubilizer for dopa-
ꢀ
Compd
%E
Log D
D
Gb
mine. By considering the external hydrophobicity and terminal
hydrophilicity of these molecular structures, this type of cage-mol-
ecule could be a precursor for the design and synthesis of other
similar molecules as carriers for desired biological compounds.
3a
3b
3c
3d
3e
ꢀ8.91 0.27
ꢀ8.95 0.33
ꢀ8.81 0.29
ꢀ8.99 0.31
ꢀ8.71 0.35
—
29.8 0.7
25.5 0.9
31.8 0.5
30.7 1.1
12.0 0.3
4.3 0.4
1.19 0.03
1.06 0.04
1.28 0.04
1.13 0.05
0.91 0.02
ꢀ1.8 0.07
a-CD
4. Experimental
4.1. Chemicals and instruments
orientations are almost equal. This could explain the similarity of
3a–d extraction contents. The somewhat lower affinity of 3e is also
consistent with the extraction results.
Melting points were recorded on an Electrothermal type 9100
melting point apparatus. 1H NMR (500 MHz) was obtained by
using a Bruker Avance DRX-500 Fourier transformer spectrometer.
Chemical shifts are reported in ppm (d) downfield from tetrameth-
ylsilane (TMS). The IR spectra were obtained on a 4300 Shimadzu
Spectrometer. Elemental analysis was obtained on a Thermo Finn-
igan Flash EA microanalyzer. All spectrophotometric measure-
ments were carried out using an Spekol 1500 spectrophotometer.
To explore the origin of these effects, the octanol–water distri-
bution coefficient (log D) of the hosts’ 3a–e was measured using
a shake flask method (Table 1).19 It was concluded that the more
lipophilic host molecules have a higher capability of extracting
dopamine to the octanol phase. The results could rationalize
the low extraction ability of 3e. Self aggregation of tryptophan
residue included into the CD cavity or conformational perturba-
tion organized by torsional strains formed via steric hindrance
of indol portions of tryptophans in 3e, could be the two main fac-
tors in decrease of octanol extraction ability of dopamine in com-
parison with the other host molecules. The phase transfer
properties of 3a–e therefore mainly depend on the side chain
molecular structure of the host since the host molecules have
similar binding affinity toward dopamine; the least lipophilic
and bulky derivative (3e) transfers the smallest proportion of
the guest molecule.
4.2. Molecular modeling and docking study
4.2.1. Structure optimization
Structures of compounds 3a–e were simulated by grafting de-
sired residues on all primary hydroxyl of the X-ray structure of
a-CD and minimized under molecular mechanic MM+ and semi-
empirical PM3 method (convergence limit = 0.01; Iteration lim-
it = 50; RMS gradient = 0.1 kcal molꢀ1; Fletcher–Reeves optimizer
algorithm) in HyperChem7.5.20
Figure 2. Side (upper) and top (lower) views of docked models of dopamine in the cavity of 3b (Val = valine residue). Hydrogen bonding is shown by dashed green lines. The
colors stand as follows: blue = nitrogen; red = oxygen; gray = carbon; white = hydrogen.

4310
S. M. Seyedi et al. / Bioorg. Med. Chem. 19 (2011) 4307–4311
The crystal structure of
binding protein was retrieved from RCSB Protein Data Bank (PDB
entry: 3CK7).
a
-CD complexed with cyclodextrin-
12H, 6CHCH2CH(CH3)2), 1.60–1.70 (m, 6H, 6CHCH2CH(CH3)2), 1.84
(s, 18H, 6CH3-acetyl), 3.32–3.41 (m, 12H, H-2, H-4), 3.85–3.87 (m,
12H, H-3 and H-5), 4.20–4.26 (m, 18H, 6NCHCO and 2H-6), 4.81 (s,
6H, H-1), 5.57–5.73 (m, 12H, OH-2 and OH-3), 8.31–8.33 (m, 6H,
6NH). 13C NMR (DMSO-d6/CDCl3) d 21.49, 23.26, 24.65, (CH3 and
CH isobutyl, CH3 acetyl), 40.48 (CH2 isobutyl), 50.81 (HNCHCO),
63.69, 69.78, 72.26, 73.19 (C6, C5, C3, and C2), 82.21 (C4), 102.33
4.2.2. Molecular docking
Automated docking simulation was implemented to dock dopa-
mine into the cavity of 3a–e with AutoDockTools 4.0 version
1.5.418 using a Lamarckian genetic algorithm.21 This method has
been previously shown to produce binding models similar to the
experimentally observed models.14,22 The torsion angles of the li-
gands were identified, hydrogens were added to the macromole-
cule, bond distances were edited and solvent parameters were
added to the structure. Partial atomic charges were then assigned
to the host molecules as well as ligands (Gasteiger for the ligands
and Kollman for the host molecules).
(C1), 170.08 (CONH), 172.60 (COO). IR (KBr disc)
m 1738 (C@O es-
ter) and 1682 (C@O amide) cmꢀ1
.
Anal. Calcd for C84H138N6O42: C, 52.99; H, 7.25; N, 4.41. Found:
C, 52.00; H, 7.10; N, 4.25.
4.4.2. Hexakis [6-O-(N-acetyl-L-valyl)]-a-cyclodextrin (3b)
White solid (0.28 g, 43%), mp: 190–192 °C; 1H NMR: (DMSO-d6)
d 0.85–0.90 (d, 36H, 12CH3), 1.85 (s, 18H, 6CH3-acetyl), 2.10 (m,
6H, 6CH(CH3)2), 3.45–3.75 (m, 12H, H-2, H-4), 3.80–4.00 (m, 12H,
H-5 and H-3), 4.10–4.40 (m, 18H, 2H-6 and 6NCHCO), 4.90 (m,
6H, H-1), 5.80–6.00 (m, 12H, OH-2 and OH-3), 8.35 (m, 6H, 6NH).
13C NMR (DMSO-d6/CDCl3) d 18.20, 22.73, 30.21, (CH3 and CH iso-
propyl, CH3 acetyl), 57.65 (HNCHCO), 64.47, 69.63, 72.20, 73.37
(C6, C5, C3 and C2), 82.99 (C4), 102.44 (C1), 170.26 (CONH),
The regions of interest of the host molecules were defined by
considering all of the molecular structure in the grid box. The dock-
ing parameter files were generated using Genetic Algorithm and
Local Search Parameters (GALS) while number of generations was
set to 100. The docked complexes were clustered with a root-
mean-square deviation tolerance of 0.5 Å. Autodock generated
100 docked conformers of dopamine structures with lowest-en-
ergy. After the docking procedure in AD4, docking results were
submitted to Accelrys DS Visualizer v2.0.1.734723 for further eval-
171.68 (COO). IR (KBr disc)
m 1738 (C@O ester) and 1682 (C@O
amide) cmꢀ1
.
Anal. Calcd for C76H126N6O42: C, 51.48; H, 6.93; N, 4.62. Found:
C, 50.18; H, 6.71; N, 4.80.
uations. The results of docking processing (D
Gb (kcal molꢀ1): esti-
mated free energy of binding) are outlined in (Table 1).
4.4.3. Hexakis [6-O-(N-acetyl-L-phenylalanyl)]-a-cyclodextrin
(3c)
4.3. Assessment of extraction ability
White solid (0.56 g, 72%), mp: 162–163 °C; 1H NMR: (DMSO-d6)
d 1.80 (s, 18H, 6CH3-acetyl), 2.80–3.1 (m, 12H, 6CH2Ph), 3.32–3.50
(m, 12H, H-2, H-4), 3.80–3.92 (m, 12H, H-3 and H-5), 4.21–4.30 (m,
12H, 2H-6), 4.47–4.53 (m, 6H, 6NCHCO), 4.79–4.84 (m, 6H, H-1),
5.50–5.56 (m, 6H, OH-3), 5.62–5.69 (m, 6H, OH-2), 7.22 (s, 30H,
ArH), 8.30–8.36 (m, 6H, 6NH). 13C NMR (DMSO-d6) d 22.63, 36.75
(CH3 acetyl, CHCH2Ph), 54.12 (HNCHCO), 64.04, 69.69, 72.21,
73.29 (C6, C5, C3 and C2), 82.15 (C4), 102.38 (C1), 126.93 (C4-
Ar), 128.66 (C3, C5-Ar), 129.27 (C2, C4-Ar), 137.87 (C1-Ar),
The extraction content of the synthetic host molecules and
-CD were assayed by 2 h shaking a 5 mL solution of the dopamine
a
(5 mM) in water (pH 7.4–phosphate buffer 0.05 M) with 5 mL solu-
tion of host molecule (5 mM) in octanol at 25 °C. In the experiment,
shaking of dopamine (Dop) solution with intact octanol was set as a
control. The experiment was done four times for each of the host
molecules and control. The concentration of dopamine in the aque-
ous phase was measured by using the spectrophotometric method
reported by Nour El-Dien et al.17 in which an Iꢀ3 reagent was used as
the chromogenic material. In this step 2 mL of the aqueous phase
was mixed with 3 mL phosphate buffer (0.1 M, pH 5) followed by
addition of 0.1 mL Iꢀ3 (0.1 M). After shaking, the mixture was al-
lowed to stand for 6 minutes at 23 2 °C. The absorbance of the col-
ored reaction product was measured at 500 nm. The absorbance
recorded by applying the same procedure using the intact octanol
was set as a control. The extraction content (%E) is equal to :
170.06 (CONH), 171.90 (COO). IR (KBr disc)
m 1738 (C@O ester)
and 1682 (C@O amide) cmꢀ1
.
Anal. Calcd for C102H126N6O42: C, 58.12; H, 5.98; N, 3.99. Found:
C, 57.88; H, 5.87; N, 3.85.
4.4.4. Hexakis [6-O-(N-acetyl-L-metionyl)]-a-cyclodextrin (3d)
White solid (0.48 g, 65%), mp: 145–147 °C; 1H NMR: (DMSO-d6)
d 1.76–1.80 (m, 18H, 6CH3S), 1.85 (m, 30H, 6CH3-acetyl and
6CHCH2CH2SCH3), 1.93–2.00 (m, 12H, 6CHCH2CH2SCH3) 3.40–
3.48 (m, 12H, H-2, H-4), 3.63–3.73 (m, 6H, H-3), 3.75-3.83 (m,
6H, H-5), 3.99-4.07 (m, 6H, 6NCHCO), 4.22–4.28 (m, 12H, 2H-6),
4.81–4.85 (m, 6H, H-1), 5.89–5.96 (m, 12H, OH-2 and OH-3),
8.22–8.24 (m, 6H, 6NH). 13C NMR (DMSO-d6) d 15.26, 22.63,
36.75 (CH3S, CH3 acetyl), 27.62 (CHCH2CH2SCH3), 29.49
(CHCH2CH2SCH3) 53.62 (HNCHCO), 64.06, 69.71, 72.20, 73.38 (C6,
C5, C3 and C2), 82.26 (C4), 102.47 (C1), 170.15 (CONH), 172.28
100 ꢁ ð½Dopꢂcontrol ꢀ ½DopꢂtestÞ=½Dopꢂcontrol
¼ 100 ꢁ ðAcontrol ꢀ AtestÞ=Acontrol
4.4. General procedure for the synthesis of 3a–e
(COO). IR (KBr disc)
m 1737 (C@O ester) and 1680 (C@O amide)
Compound hexakis (6-bromo-6-deoxy)-
a-cyclodextrin (2) was
cmꢀ1
.
synthesized according to the method reported in the literature.12
A
Anal. Calcd for C78H126N6O42S6: C, 46.56; H, 6.27; N, 4.18; S ,
9.55 Found: C, 47.10; H, 6.12; N, 4.37; S , 9.09.
mixture of compound 2 (0.50 g, 0.37 mmol), one of the N-acetyl ami-
no acid a–e (4.0 mmol) and DBU (0.64 mL, 4.2 mmol) in DMF
(10 mL) was heated at 70–80 °C for 12 h. After cooling, the reaction
mixture was then poured in to a solution of saturated NaCl (40 mL).
The precipitated solids were collected, and washed with water and
potassium carbonate 5% and then oven dried to give products 3a–e.
4.4.5. Hexakis [6-O-(N-acetyl-L-tryptophyl)]-a-cyclodextrin (3e)
White solid (0.60 g, 72%), mp: 186–187 °C; 1H NMR: (DMSO-d6)
d 1.08 (s, 18H, 6CH3-acetyl), 3.01–3.20 (m, 12H, 6CH2CH-3-Indolyl),
3.20–3.58 (m, 12H, H-2, H-4), 3.79–3.83 (m, 6H, H-3), 3.90–3.96
(m, 6H, H-5), 4.31–4.40 (m, 12H, 2H-6H), 4.50–4.55 (m, 6H,
6NCHCO), 4.89–4.93 (m, 6H, H-1), 5.60–5.78 (m, 12H, OH-2 and
OH-3), 6.95–7.49 (m, 30H, ArH), 8.32–8.41 (m, 6H, 6NH), 10.85
(br s, 6H, NH-Indol). 13C NMR (DMSO-d6) d 22.89, 27.13 (CH3
4.4.1. Hexakis [6-O-(N-acetyl-L-leucyl)]-a-cyclodextrin (3a)
White solid (0.50 g, 72%), mp: 197–198 °C; 1H NMR: (DMSO-d6)
d 0.82–0.83 (d, 18H, 6CH3), 0.86–0.88 (d, 18H, 6CH3) 1.47–1.52 (m,

S. M. Seyedi et al. / Bioorg. Med. Chem. 19 (2011) 4307–4311
4311
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5. Zemb, T.; Je´han, P.; Guenot, P.; Dalbiez, J. P.; Djedaïni-Pilard, F. Carbohydr. Res.
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73.36 (C6, C5, C3 and C2), 82.32 (C4), 102.80 (C1), 110.28 (C3-In-
dol), 111.88 (C4-Indol), 118.48 (C5-Indol), 118.89 (C6-Indol),
120.89 (C7-Indol), 123.97 (C2-Indol), 128.79 (C9-Indol), 136.33
(C4-Indol), 169.87 (CONH), 171.98 (COO). IR (KBr disc)
m 1740
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.
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Anal. Calcd for C108H114N12O42: C, 57.60; H, 5.06; N, 7.46. Found:
C, 58.23; H, 5.12; N, 7.19.
Acknowledgements
We are grateful to Mashhad University of Medical Sciences for
financial support of this work and also we express our sincere grat-
itude to Professor T. Fyles for reviewing the manuscript.
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Supplementary data
Supplementary data (copies of 1H NMR and 13C NMR spectra for
compounds 3a–e) associated with this article can be found, in the
online version, at doi:10.1016/j.bmc.2011.05.048.
References and notes
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