Synthesis of a novel cysteine-incorporated anthraquinone derivative and its structural properties

Article abstract of DOI:10.3390/molecules200610192

A novel cysteine-incorporated anthraquinone derivative was synthesized, and its molecular structure was determined by X-ray crystal analysis. Each mercapto group was located separately and did not form a disulfide bond, and hydrogen bondings and Π-Π interaction were observed from the packing structure.

Full text of DOI:10.3390/molecules200610192

Molecules 2015, 20, 10192-10204; doi:10.3390/molecules200610192
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Synthesis of a Novel Cysteine-Incorporated Anthraquinone
Derivative and Its Structural Properties
Akihiro Nomoto 1,*, Toshihide Taniguchi 1,3, Yuta Minatobe 1, Syouhei Katao 2,
Kiyomi Kakiuchi 2, Shigenobu Yano 2 and Akiya Ogawa 1,*
1
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University,
1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan; E-Mails: tttoshihide1@yahoo.co.jp (T.T.);
yuta_minatobe@shokubai.co.jp (Y.M.)
2
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5,
Takayama, Ikoma, Nara 630-0192, Japan; E-Mails: katao@ms.naist.jp (S.K.);
kakiuchi@ms.naist.jp (K.K.); yano-shigenobu@ms.naist.jp (S.Y.)
3
Seika Corporation, 1-1-82 Kozaika, Wakayama 641-0007, Japan
* Authors to whom correspondence should be addressed;
E-Mails: nomoto@chem.osakafu-u.ac.jp (A.N.); ogawa@chem.osakafu-u.ac.jp (A.O.);
Tel.: +81-72-254-9295 (A.N. & A.O.); Fax: +81-72-254-9910 (A.N. & A.O.).
Academic Editor: Derek J. McPhee
Received: 6 March 2015 / Accepted: 22 May 2015 / Published: 3 June 2015
Abstract: A novel cysteine-incorporated anthraquinone derivative was synthesized, and its
molecular structure was determined by X-ray crystal analysis. Each mercapto group was
located separately and did not form a disulfide bond, and hydrogen bondings and π-π
interaction were observed from the packing structure.
Keywords: cysteine; anthraquinone; mercapto group; X-ray crystal analysis; packing
structure; π-π interaction; artificial molecules
1. Introduction
In the field of artificial molecular modeling, cysteine is an attractive compound because of its
unique properties. In living organisms, cysteine plays important roles such as protein folding or
antioxidant activity depending on the sulfur moiety it contains [1–3]. The protein morphology related

Molecules 2015, 20
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to cysteine can change drastically because of the formation of a disulfide bond by oxidation. Therefore,
the construction of artificial molecules containing mercapto moieties is difficult, because a multi-step
synthes is required owing to the reactivities of the mercapto group. For example, in the case of two
adjacent cysteine residues, a disulfide bond is easily formed by oxidation, and occasionally, enzymes
work well by exploiting such reactivities of cysteine.
In recent times, anthraquinone has been focused on as a functional molecule in photo- or
electrochemical moieties, and also has a rigid planar structure at the molecular level [4–11]. Such
properties of anthraquinone have been exploited to synthesize functional ligands as metal
receptors [12–15]. Although bioconjugated molecules containing cysteine and some molecular
structures have been reported [16–19], synthetic examples of anthraquinone derivatives bearing amino
acids are still rare [20]. Therefore, in order to realize the incorporation of cysteine residues into
anthraquinone, amino acid-containing functional molecules have been investigated.
From these viewpoints, the construction of cysteine-containing artificial molecules is important for
opening up new possibilities for elucidating the functionalities of cysteine. Herein, we report the
synthesis and structural properties of a novel cysteine-incorporated anthraquinone derivative.
2. Results and Discussion
According to the reported method [21], cysteine was converted to S-trityl-L-cysteine methyl ester
(2) as shown in Scheme 1. At first, the mercapto group of cysteine was protected by a trityl group.
S-Trityl-L-cysteine methyl ester (2) was prepared by esterification by using SOCl2.
S
CPh3
SH
OH
S
CPh3
OH
Ph3CCl
SOCl2
O
DMF
rt, 2 day
CH3OH
rt, overnight
HCl H2N
H2N
HCl H2N
O
O
O
Cysteine
1
2
Scheme 1. Preparation of S-trityl-L-cysteine methyl ester 2.
Anthraquinone-1,8-dicarbonyl dichloride (5) was prepared from 1,8-dichloroanthraquinone in three
steps (Scheme 2). Anthraquinone-1,8-dicarboxylic acid (4) was prepared [22], followed by
chlorination with SOCl2 [20].
O
O
H2SO4
CuCN
reflux, 1h
DMA
reflux, overnight
Cl
Cl
CN
O
CN
O
1,8-Dichloroanthraquinone
3
O
O
SOCl2
reflux, overnight
HOOC
O
COOH
ClOC
O
COCl
4
5
Scheme 2. Preparation of anthraquinone-1,8-dicarbonyl dichloride 5.

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After the coupling reaction of 2 and 5, the reaction mixture was subjected to silica-gel column
chromatography to afford anthraquinone bearing S-trityl-L-cysteine methyl esters 6. Deprotection was
conducted using triethylsilane and trifluoroacetic acid, and product anthraquinone bearing L-cysteine
1
methyl esters 7 was also purified by silica-gel column chromatography (Scheme 3). From the H- and
13C-NMR, IR, and mass spectral measurements, 7 was synthesized successfully.
O
S
CPh3
OMe
i-Pr2EtN
+
HCl H2N
CH2Cl2
O
ClOC
O
COCl
42%
2
5
O
O
O
CF3COOH
Et3SiH
O
HN
MeOOC
O
O
NH
COOMe
HN
MeOOC
Ph3C
O
O
NH
CH2Cl2
73%
COOMe
CPh3
SH
SH
S
S
6
7
Scheme 3. Synthetic route for preparing cysteine-incorporated anthraquinone 7.
To apply this synthetic protocol to other chalcogen-containing amino acids, L-methionine methyl
ester and L-selenomethionine methyl ester were also introduced into the anthraquinone system,
successfully affording methionine-anthraquinone (8) and selenomethionine-anthraquinone (9),
respectively (Scheme 4). L-Methionine methyl ester hydrochloride and L-selenomethionine methyl
ester hydrochloride were prepared in the same manner as that of S-trityl-L-cysteine (shown in Scheme 1)
and treated with 5. After purification of the respective reaction mixtures by column chromatography,
the corresponding anthraquinone bearing L-methionine methyl esters 10 and anthraquinone bearing
L-selenomethionine methyl esters 11 were obtained. We also attempted to apply this protocol to
selenocysteine-incorporated anthraquinone, however, the corresponding trityl-group-protected
selenocysteine could not be obtained from commercially available L-selenocystine (Se(Cys)2).
O
O
X
i-Pr2EtN
O
OMe
HN
MeOOC
O
O
NH
COOMe
+
HCl H2N
CH2Cl2
O
ClOC
O
COCl
X
X
X = S (8)
Se (9)
5
X = S (10) 49%
Se (11) 75%
Scheme 4. Synthesis of methionine- and selenomethionine-incorporated anthraquinones.

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To clarify the molecular structure, recrystallization of each anthraquinone derivatives was carried
out and a single crystal was successfully obtained by recrystallization of compound 7 from acetonitrile.
The molecular structure as determined by X-ray crystal analysis is shown in Figure 1.
S(2)
C(12)
C(11)
C(22)
C(10)
N(2)
C(20)
O(6)
O(2)
C(13)
C(17)
C(21)
N(1)
S(1)
C(14)
C(9)
C(8)
C(2)
C(1)
C(16)
O(1)
C(6)
C(7)
C(15)
C(3)
O(3)
C(4)
C(5)
Figure 1. ORTEP drawing of 7 with ellipsoids at 50% probability. Hydrogen atoms are
omitted for clarity. Blue, red, yellow, and black atoms indicate N, O, S, and
C, respectively.
The two cysteine chains of 7 were oriented in a similar manner, and the two carbonyl groups at the
1,8-positions were incorporated perpendicularly to the anthraquinone rings with torsion angles of
61.09° and 83.04°, respectively [23–29]. About the anthraquinone moiety, in contrast to the reported
structure, both benzene rings were twisted with a torsion angle of 8.25°. Each mercapto group was
located individually, and the distance between them was 7.205 Å in the molecule. Table 1 summarizes
the selected bond lengths and angles.
Table 1. Selected bond lengths (Å) and bond angles (°).
Bond Lengths (Å)
Bond Angles (°)
S1–C17
S2–C22
O1–C1
O2–C8
1.8098(19) S1–C17–C16 114.01(13)
1.810(2)
1.217(2)
1.221(2)
S2–C22–C21 114.27(13)
C20–N2–C21 120.32(15)
C15–N1–C16 121.67(15)
N1–C15–C6 116.48(15)
N2–C20–C10 116.00(15)
C9–C10–C20 122.98(16)
O3–C15 1.229(2)
O6–C20 1.228(2)
N1–C15 1.339(2)
N2–C20 1.346(2)
C6–C15 1.504(3)
C10–C20 1.511(2)
C16–C17 1.524(3)
C21–C22 1.527(2)
C7–C6–C15
125.68(15)
N2–C21–C22 113.14(15)
N1–C16–C17 108.90(14)

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By contrast, intermolecular interactions were also clearly observed. Figures 2 and 3 show the
packing diagrams along the a and c axies, respectively. Anthraquinone moieties were stacked over
each other by π-π interactions, and the distance between the planes formed by the middle ring of the
anthraquinone moiety calculated using C(1)–C(2)–C(7)–C(8)–C(9)–C(14) atoms is 3.593 Å (Table 2).
According to reported crystal structure of anthraquinone derivatives bearing dicarbonyl groups,
anthraquinone-2,3-dicarboxylic acid (abbreviated as H2AQDC) coordinates with the metal ion species
to afford metal complexes [25]. As compared to the π-π interactions of CaAQDC and ZnAQDC with
that of compound 7, distances of π-π interaction distances are 3.04 Å (Ca complex) and 3.56 Å (Zn
complex) calculated by PLATON (Table 3) [11]. In the crystal of 7, hydrogen bonding was observed
between the carbonyl group incorporated at C6 and the peptide amine, and the selected distances and
angles were 0.88 Å (N-H), 2.08 Å (N-H ··· O=C), and 2.89 Å and 153° (N-H ··· O) (Table 4) [30].
Figure 2. Packing diagram of the unit cell along the a axis. Hydrogen atoms are omitted for clarity.
Figure 3. Packing diagram of the unit cell along the c axis. Hydrogen atoms are omitted
for clarity. Intermolecular hydrogen bondings are indicated by dotted blue lines.

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Table 2. π-π interactions (Å, °).
Cg(I) Cg(J)
Cg–Cg
Alpha CgI_Perp CgJ_Perp
Cg(1) Cg(2) (i) 3.9249(12) 4.45(9) 3.7289(8) 3.6403(8)
Cg(3) Cg(1) (i) 3.7590(11) 0.8900 3.4720(8) 3.3207(8)
Cg(3) Cg(2) (i) 4.0899(11) 0.0355 3.5948(8) 3.5693(8)
Cg(1), Cg(2) and Cg(3) are the centroids of the C(1)–C(2)–C(7)–C(8)–C(9)–C(14), C(2)–C(3)–C(4)–C(5)–
C(6)–C(7) and C(9)–C(10)–C(11)–C(12)–C(13)–C(14) rings, respectively. Cg–Cg = distance between ring
centroids; Alpha = dihedral angle between planes I and J; CgI_Perp = perpendicular distance of Cg(I) on ring J;
CgJ_Perp = perpendicular distance of Cg(J) on ring I; Slippage = distance between Cg(I) and perpendicular
projection of Cg(J) on ring I.: 3.498 Å (Cg(1)–Cg(1)), 3.393 Å (Cg(2)–Cg(2)), and 3.829 Å (Cg(3)–Cg(3)).
Symmetry codes: (i) −1 + X, Y, Z.
Table 3. Comparison of π-π interactions (Å).
Compounds Cg–Cg CgI_Perp Slippage
a
b
7
–
–
3.5932(8)
–
–
a
b
Ca complex
3.0382(13)
Zn complex 4.063(4) 3.557(3)
1.964
Cg–Cg = distance between the central rings of anthraquinone: a 5.0147(12) Å (7): 5.960(3) Å (Ca complex).
Slippage = distance between the central rings of anthraquinone: b 3.498 Å (7): 5.127 Å (Ca complex).
Table 4. Hydrogen-bond geometry (Å, °).
D–H ••• A
N1–H3 ••• O3 (i) 0.88
Symmetry codes: (i) −1 + X, Y, Z.
D–H H ••• A D ••• A D–H ••• A
2.08 2.890(2) 153
The molecules are linked into an infinite chain along the a-axis by hydrogen bonds, and mercapto
groups were free from forming hydrogen bondings. Intra- or intermolecular disulfide bonds (-S-S-)
1
were not formed in the crystal, and this was also supported by a H-NMR measurement in solution.
From these results, this molecule may act as metal receptor for recognizing metal ions coordinated by
mercapto groups between two cysteine strands.
The photochemical properties were elucidated from the UV-vis and fluorescence spectra.
Compound 7 was dissolved in acetonitrile (2.0 × 10−3 M) and measurements were carried out (Figure 4a).
In the UV-vis spectrum, an absorbance peak was observed at 335 nm (ε = 110) [31]. The solid-state
spectrum was also measured by depositing onto Pyrex glass (Figure 4b). Although a broadened peak
was observed around 400–500 nm, there was no shift in the absorbance peak, thus each amide group is
oriented in a perpendicular manner. The fluorescence excited at 350 nm appeared at 400–600 nm in
Supplementary Materials (Fluorescence spectra of 7), which corresponds to the anthraquinone moiety
as reported [23–26].

Molecules 2015, 20
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Figure 4. UV-vis. spectra of 7 (a) in acetonitrile (2.0 × 10−3 M); (b) casted onto Pyrex slide glass.
3. Experimental Section
3.1. General
All chemicals were purchased from Aldrich (St. Louis, MO, USA), Wako (Osaka, Japan), TCI
(Tokyo, Japan), and Nacalai (Kyoto, Japan). The starting materials 2 and 5 were prepared by
modifying the reported procedures as described below. All reagents and solvents were used without
1
further purification. H-NMR spectra were recorded on a JNM-AL 400 (400 MHz) spectrometer
(JEOL, Tokyo, Japan) using CDCl3 as the solvent with Me4Si as the internal standard. 13C-NMR
spectra were taken on a JEOL JNM-GSX-400 (100 MHz) spectrometer using CDCl3 as the solvent.
The purification of the products were carried out by MPLC (silica gel, 25–40 µm, length 310 mm, i.d.
25 mm), preparative TLC (PTLC) on Wakogel B-5F silica gel, or using a recycling preparative HPLC
(Model LC-908, Japan Analytical Industry Co. Ltd., Tokyo, Japan) equipped with JAIGEL-1H
and -2H columns (GPC) using CHCl3 as an eluent. IR, HR-mass spectra, UV-vis. and fluorescence
spectra were determined on a JEOL JMS-700, FT/IR-8900 Fourier Transform Infrared Microsampling
System (JASCO, Tokyo, Japan), JASCO V-560 and JASCO FP-6300, respectively. X-ray
crystallographic measurements were carried out on a RAXIS-RAPID diffractometer (Rigaku, Tokyo,
Japan) with Mo-Kα radiation. The resulting report and PRATON files are in Supplementary Materials.

Molecules 2015, 20
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3.2. Synthesis of S-Trityl-L-cysteine (1)
L-Cysteine hydrochloride (10.0 g, 63.4 mmol) and trityl chloride (27.0 g, 96.9 mmol) were stirred
in DMF (40 mL) for 2 days at room temperature. A 10% sodium acetate solution (350 mL) was then
added, and the precipitate was filtered and washed with distilled water. Afterward, the residue was
stirred in acetone at 50 °C for 30 min and filtered after cooling. The residue was washed with little
acetone and diethyl ether. After drying in vacuo, 20.5 g (89%) of 1 was obtained as a white powder:
1
mp 195 °C (dec); H-NMR (DMSO-d6) δ 2.34–2.39 (m, 1H), 2.52–2.56 (m, 1H), 2.86–2.89 (m, 1H),
7.27–7.37 (m, 15H).
3.3. Synthesis of S-Trityl-L-cysteine Methyl Ester (2)
S-Trityl-L-cysteine (3.2 g, 8.0 mmol) was added to methanol (70 mL) to form a suspension. After
cooling to 0–5 °C, thionyl chloride (23 mL, 320 mmol) was added, and the reaction mixture was
allowed to warm for 20 h at room temperature. The mixture was then refluxed for 5 h, cooled, and
evaporated in vacuo. After drying in vacuo, compound 2 (3.2 g, 98%) was obtained as crystalline solid.
1H-NMR (DMSO-d6) δ 2.46–2.64 (m, 2H), 3.67 (s, 3H), 3.72–3.78 (m, 1H), 7.24–7.33 (m, 15H).
3.4. Synthesis of 1,8-Dicyanoanthraquinone (3)
1,8-Dichloroanthraquinone (1.39 g, 5.0 mmol) and CuCN (1.34 g, 15 mmol) were slurried in DMA
(50 mL) and refluxed under N2 for 3 h. The hot brown solution was poured onto ice (700 g), and the
brown-green precipitate was filtered and washed with water. The copper complex was decomposed
with 3 N HNO3 (150 mL) at 60 °C for 5 h. The brown solid was filtered, washed with water and
air-dried. This procedure afforded crude 3 (1.2 g, 88%).
3.5. Synthesis of Anthraquinone-1,8-dicarboxylic Acid (4)
1,8-Dicyanoanthraquinone (3, 2.4 g, 9.3 mmol) was refluxed in 70% H2SO4 (500 mL) for 1 h. The
hot solution was poured onto ice (500 g) to precipitate crude 4 as a brown solid (2.6 g, 94%).
3.6. Synthesis of Anthraquinone-1,8-dicarbonyl Dichloride (5)
Anthraquinone-1,8-dicarboxylic acid (4, 2.4 g, 9.3 mmol) was refluxed in thionyl chloride (11 mL,
150 mmol) for 20 h. After drying in vacuo, compound 5 was obtained as a black solid and used
without further purification.
3.7. Synthesis of 6
Anthraquinone-1,8-dicarboxylic acid (1.60 g, 6 mmol) was refluxed in SOCl2 (10 mL) in
two-necked flask (100 mL) for 6 h. After refluxing, the solution was removed in vacuo to give
dark-brown solid, anthraquinone-1,8-dicarbonyl chloride. After adding dry CH2Cl2 (30 mL) and
S-trt-Cys(OMe) hydrochloride (5.38 g, 13 mmol) into the flask, the solution was stirred at 0 °C in the
ice bath under inert atomosphere with dropwise addition of diisopropylethylamine (4.31 mL, 25 mmol).
The resulting mixture was allowed to warm to ambient temperature and was stirred overnight. After

Molecules 2015, 20
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evaporation of solvents, CHCl3 (20 mL) was added and the mixture was extracted with 1 N HCl (20 mL),
sat. NaHCO3 (20 mL), H2O (20 mL) and sat. brine (20 mL). The organic layer was dried by MgSO4
and evaporated the CHCl3. The resulting brown oil was purified by silica gel column chromatography
(Rf = 0.37, eluant hexane/EtOAc = 1:1) to yield 42% of anthraquinone-S-trt-Cys(OMe) (yellow solid).
1H-NMR (400 MHz, CDCl3) δ 2.73–2.84 (m, 4H), 3.73 (s, 6H), 4.67–4.71 (m, 2H), 6.13 (d, 6.88 Hz,
13
2H), 7.11–7.42 (m, 15H), 7.72–7.81 (m, 4H), 8.36 (dd, 1.36 Hz, 4.56 Hz, 2H); C-NMR (100 MHz,
CDCl3) δ 33.7, 52.2, 52.8, 67.0, 126.9, 128.1, 128.7, 129.6, 131.2, 133.4, 133.8, 134.2, 137.7, 144.5,
168.5, 170.6, 181.4, 182.0.
3.8. Synthesis of 7
Anthraquinone-S-trt-Cys(OMe) (2.49 g, 2.53 mmol) was dissolved in CH2Cl2 (20 mL) in a
100 mL round-bottomed flask, and triethylsilane (1.2 mL, 7.53 mmol) and TFA (19.4 mL, 0.26 mol)
were added. The reaction mixture was subsequently stirred at ambient temperature under an inert
atmosphere for 30 min. Solvents were removed, and the residue was purified by silica-gel column
chromatography (Rf = 0.2, eluant MeOH). Mp 218–220 °C (decomp.); 1H-NMR (400 MHz, CDCl3) δ
1.90 (t, J = 8.7 Hz, 2H), 3.07–3.14 (m, 2H), 3.47–3.55 (m, 2H), 3.82 (s, 6H), 5.12–5.15 (m, 2H), 6.78
(d, J = 7.3 Hz, 2H), 7.71 (dd, J = 1.4, 7.7 Hz, 2H), 7.82 (t, J = 7.3 Hz, 2H), 8.37 (dd, J = 1.4, 7.7 Hz,
13
2H); C-NMR (100 MHz, CDCl3) δ 26.2, 52.9, 54.4, 128.7, 130.3, 133.3, 133.8, 134.2, 137.6, 168.7,
170.4, 181.4, 182.0; IR (KBr, cm−1) 1541.0, 1637.5, 1683.7, 1739.7 (C=O); HRMass (FAB) Calcd. for
C24H23O8N2S2 (M + H+) 531.0896 Found: 531.0897 MR Mass. Calcd for C24H23O8N2S2; Found
(M + H+) 531.0896.
3.9. Crystal Structures of 7
Of the 23,904 reflections were collected, 5463 were unique (Rint = 0.0368); equivalent reflections
were merged. The linear absorption coefficient, µ, for Mo-Kα radiation is 2.771 cm−1. An empirical
absorption correction was applied which resulted in transmission factors ranging from 0.823 to 0.992.
The data were corrected for Lorentz and polarization effects.
The structure was solved by direct methods1 and expanded using Fourier techniques. The
non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined using the riding model.
Crystallographic data: formula weight = 530.57; orthorhombic; space group P212121;
a = 5.01471(10) Å, b = 18.6873(3) Å, c = 25.4365(6) Å; V = 2383.70(8) Å3, Z = 4; ρcalcd = 1.478 g cm−3;
total reflections collected = 23,904; GOF = 1.081; R1 = 0.0362; wR2 = 0.0925. Crystallographic data
have been deposited with Cambridge Crystallographic Data Centre (CCDC-867403). These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
3.10. Synthesis of 10
Anthraquinone-1,8-dicarbonyl chloride (0.24 g, 0.72 mmol) was prepared as described in the
synthesis of 7 and dissolved in dry CH2Cl2 (20 mL) and methionine methylester hydrochloride (0.24 g,
1.44 mmol) was added into the flask, the solution was stirred at 0 °C in the ice bath under an inert

Molecules 2015, 20
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atomosphere with dropwise addition of diisopropylethylamine (0.5 mL, 2.88 mmol). The resulting
mixture was allowed to warm to ambient temperature and was stirred overnight. After evaporation of
solvents, the resulting brown oil was purified by silica gel column chromatography without extraction
(Rf = 0.11, eluant hexane/EtOAc = 1:1) to yield 49% of anthraquinone-Met(OMe) (yellow solid). Mp
78–80 °C; 1H-NMR (400 MHz, CDCl3) δ 2.07 (s, 6H), 2.05–2.25 (m, 4H), 2.58–2.66 (m, 4H), 3.72 (s,
6H), 4.85 (td, J = 8.0 Hz, 12.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 7.54–7.60 (m, 4H), 8.06 (dd, J = 4.0 Hz,
13
8.0 Hz, 2H); C-NMR (100 MHz, CDCl3) δ 15.2, 29.8, 31.1, 52.0, 52.3, 128.1, 130.5, 132.7, 133.6,
133.8, 137.4, 168.6, 172.2, 181.2, 181.5; IR (KBr, cm−1) 1438.8, 1523.7, 1678.0, 1743.5 (C=O),
3340.5 (NH); Mass (FAB) Calcd. for C28H30O8N2S2 (M + H+) 587. Found: 587.
3.11. Synthesis of 11
Anthraquinone-1,8-dicarbonyl chloride (0.409 g, 1.22 mmol) was prepared as described in the
synthesis of 7 and dissolved in dry CH2Cl2 (30 mL) and selenomethionine methylester hydrochloride
(0.606 g, 2.45 mmol) was added into the flask, the solution was stirred at 0 °C in the ice bath under
inert atomosphere with dropwise addition of diisopropylethylamine (0.855 mL, 4.88 mmol). The
resulting mixture was allowed to warm to ambient temperature and was stirred overnight. After
evaporation of solvents, the resulting brown oil was purified by silica gel column chromatography
without extraction (Rf = 0.11, eluant hexane/EtOAc = 1:1) to yield 75% of anthraquinone-SeMet(OMe)
(yellow solid). Mp 88–90 °C; 1H-NMR (400 MHz, CDCl3) δ 2.01 (s, 6H), 2.17–2.23 (m, 2H), 2.28–2.37
(m, 2H), 2.62–2.74 (m, 4H), 3.75 (s, 6H), 4.91 (td, J = 5.5 Hz, 7.8 Hz, 2H), 6.74 (d, J = 7.8 Hz, 2H),
7.60–7.67 (m, 4H), 8.14 (dd, J = 6.0 Hz, 9.2 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 4.3, 20.6, 32.7,
52.5, 53.2, 128.5, 130.8, 133.0, 133.9, 134.1, 137.7, 168.7, 172.3, 181.5, 181.8; IR (KBr, cm−1) 1577.7,
1647.1, 1678.0, 1743.5 (C=O), 3267.2 (NH); HRMass (FAB) Calcd. for C24H22N2O8Se2 (M + H+)
683.0411. Found: 683.0417.
4. Conclusions
In summary, we synthesized novel cysteine-, methionine-, and selenomethionine-incorporated
anthraquinone derivatives. A single crystal of cysteine-incorporated anthraquinone was obtained, and
its crystal structure was successfully confirmed. Intermolecular hydrogen bonds were observed in the
crystal structure of 7, and the molecules are linked into an infinite chain by hydrogen bonding.
Although the results of UV-vis. spectra in solution and in the solid state indicated that the
intermolecular interaction does not seem to be so strong, this molecule may act as a metal receptor
based on the cysteine moieties, as the mercapto groups are individually detected, without the formation
of disulfide and hydrogen bonds. The investigation of the electrochemical and coordination properties
of this derivative is currently underway.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/06/10192/s1.

Molecules 2015, 20
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Acknowledgments
This work is supported by Scientific Research (B, 25288028 and C, 26410056) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. The authors thank the Nara Institute of
Science and Technology of the Kyoto-Advanced Nanotechnology Network for their assistance with
the mass spectrometry measurements.
Author Contributions
T.T., Y.M. and A.O. designed research; S.K., K.K., and S.Y. performed research and analyzed the
data; A.N. wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 6 and 7 are available from the authors.
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