6094
N. Takahashi et al. / Bioorg. Med. Chem. 14 (2006) 6089–6096
oxide. The antioxidant and antiproliferative activities of
and 6 may influence various physiological processes,
including immunostimulation, enhancement of cell com-
munication, and inhibition of metabolic activation.
J = 7.3 Hz), 6.65 (2H, d, J = 8.9 Hz), 7.33 (2H, d,
1
3
5
J = 8.9 Hz), 9.11 (1H, s), 9.56 (1H, s). C NMR (DMSO)
13.9, 22.0, 25.1, 28.6, 28.6, 28.7, 28.8, 31.2, 36.1, 114.8,
120.7, 130.9, 152.9, 170.4. IR (KBr) 3310, 1650, 1550,
ꢁ
520, 1250, 830 cm . Anal. Calcd for C H NO : C,
16 25 2
2.96; H, 9.57; N, 5.32. Found: C, 73.02; H, 9.30; N, 5.26.
1
1
7
4. Experimental
4
.2.4. p-Dodecanoylaminophenol (3). 4-Aminophenol
4
.1. General
(3.27 g, 30 mmol) converted to the title compound by
the procedure described for amide 4 using dodecanoic
anhydride. Compound 3 (86% yield) as a colorless solid
0
Adenosine 5 -diphosphate (ADP), 1, nitroblue tetrazoli-
um (NBT), ethylenediaminetetraacetic acid (EDTA),
bovine serum albumin (BSA, fraction V), and dimethyl-
sulfoxide (DMSO) were obtained from Sigma Chemical
Co. (St. Louis, MO, USA). 2 was provided by Dr. R. C.
Moon, University of Illinois, Chicago, IL, USA. Dithi-
othreitol (DTT), trichloroacetic acid (TCA), and 8 were
purchased from Nacalai Tesque, Inc. (Kyoto, Japan). 4-
Aminophenol, decanoic anhydride, dodecanoic anhy-
was stored under N and could be used directly without
2
further purification: mp 133–134 ꢁC. MS m/z EI, 291
+
1
(M ). H NMR (DMSO) 0.85 (3H, t, J = 6.4 Hz), 1.24
(16H, m), 1.55 (2H, m), 2.22 (2H, t, J = 7.4 Hz), 6.66
(2H, d, J = 8.9 Hz), 7.34 (2H, d, J = 8.9 Hz), 9.12 (1H,
1
3
s), 9.57 (1H, s). C NMR (DMSO) 14.0, 22.1, 25.2,
28.7, 28.7, 28.8, 28.9, 29.0, 29.0, 31.3, 36.2, 114.9,
120.8, 131.0, 153.0, 170.5. IR (KBr) 3310, 1650, 1550,
ꢁ
1520, 1250, 830 cm . HRMS Calcd for C H NO :
18 29 2
1
dride, tetrahydrofuran, and NaBH were obtained from
4
Aldrich Chemical Co. (Milwaukee, WI, USA). Ascorbic
acid and 2-thiobarbituric acid (TBA) were purchased
from Wako Pure Chemicals Industries, Co. Ltd (Osaka,
Japan).
291.2198. Found: 291.2204.
4.2.5. p-Decylaminophenol (6). NaBH (0.946 g, 25 mmol)
4
was added to 4 (2.63 g, 10 mmol) in dry THF (30 ml). To
the suspension treated dropwise iodine (2.54 g, 10 mmol)
4
.2. Synthesis of compounds
in dry THF (20 ml) under N at 0 ꢁC for 1 h. After the
2
reaction mixture was refluxed for 3 h, it was cooled to
room temperature, treated by careful addition of 3 M
HCl (6 ml), neutralized by 1 M NaOH, and extracted
twice with ethylacetate. The combined organic extract
4.2.1. Chemistry. The synthesis of 3, 4, 5, and 6 began by
treating commercially available 4-aminophenol with the
corresponding acyl anhydride. The N-acylation provided
2
4
the desired amide (3, 4) in excellent yield. Reduction of
the amide (3, 4) using NaBH and I in refluxing tetrahy-
was washed with H O and brine, dried over anhydrous
2
Na SO , and evaporated under reduced pressure. The
2
4
2
4
43
drofuran (THF) gave p-alkylaminophenol (5, 6).
residue was purified by column chromatography on silica
gel (ether/hexane = 1:2) to give 6 (2.43 g, 98%); mp
+
1
4
.2.2. Analysis. Melting points were measured with a
82–83 ꢁC. MS m/z EI, 249 (M ). H NMR (CHCl ) 0.88
3
Yanagimoto micro melting point apparatus (Yanagim-
oto Manufacturing Co., Tokyo, Japan) without correc-
tion. IR spectra were recorded on a JASCO FT/IR- 200
(3H, t, J = 6.9 Hz), 1.26 (14H, m), 1.58 (2H, m), 3.03
(2H, t, J = 6.9 Hz), 4.08 (2H, br), 6.53 (2H, d,
J = 8.6 Hz), 6.66 (2H, d, J = 8.6 Hz). C NMR (CHCl3)
14.1, 22.6, 27.1, 29.3, 29.4, 29.5, 29.6, 29.6, 31.9, 45.5,
114.8, 116.2, 142.3, 148.1. IR (KBr) 3280, 1520, 1250,
1
3
ꢁ
1
1
13
and major absorption was listed in cm . H and
C
NMR spectra were obtained on a JEOL GSX 270
instrument (Tokyo, Japan), and chemical shifts were
ꢁ
1
820 cm . Anal. Calcd for C H NO: C, 77.06; H,
1
6
27
reported in ppm on the d-scale from internal Me Si.
10.91; N, 5.62. Found: C, 76.90; H, 10.67; N, 5.70.
4
MS spectra were measured with a JEOL JMS 600
spectrometer by using the electron impact (EI) methods.
Elemental analyses were performed on a Perkin-Elmer
4.2.6. p-Dodecylaminophenol (5). Compound 3 (2.91 g,
10 mmol) converted to the title compound by the proce-
dure described for aminophenol 6. Purification by column
chromatography on silica gel (ether/hexane = 1:1) affor-
ded the product (87% yield) as a colorless needle; mp
2
40-B instrument (Perkin-Elmer Inc., MA, USA).
Column chromatography was performed on silica gel
45–75 lm, Wakogel C-300). TLC was carried out on
(
+
1
glass plates coated with silica gel F254 (Merk, Germany).
Spot detection was performed with UV 254 nm or iodine
vapor. THF was distilled over potassium metal.
86–88 ꢁC. MS m/z EI, 277 (M ). H NMR (CHCl ) 0.88
3
(3H, t, J = 6.7 Hz), 1.26 (18H, m), 1.59 (2H, m), 3.04
(2H, t, J = 7.4 Hz), 6.53 (2H, d, J = 8.7 Hz), 6.69 (2H, d,
J = 8.7 Hz). C NMR (CHCl ) 14.1, 22.6, 27.1, 29.3,
1
3
3
4
(
.2.3. p-Decanoylaminophenol (4). Decanoic anhydride
10.78 g, 33 mmol) was added portionwise to 4-amino-
29.4, 29.5, 29.6, 29.6, 31.9, 45.5, 114.8, 116.2, 142.3,
148.1. IR (KBr) 3370, 1520, 1240, 820 cm 1. HRMS
ꢁ
phenol (3.27 g, 30 mmol) in dry THF (200 ml) at 0 ꢁC.
After being stirred at room temperature for 16 h, the reac-
tion mixture was evaporated under reduced pressure. The
Calcd for C H NO: 277.2406. Found: 277.2396.
8
1
31
4.3. Measurement of microsomal lipid peroxidation
residue was added CHCl (200 ml), stirred for another
3
1
which was stored under N and could be used directly
h, and filtered to give 4 (7.18 g, 91%) as a colorless solid
Lipid peroxidation in rat liver microsomes was quanti-
tated by measurement of malondialdehyde (MDA)
using ADP-chelated ion and ascorbate as described pre-
2
without further purification: mp 129–130 ꢁC. MS m/z
EI, 263 (M ). H NMR (DMSO) 0.84 (3H, t,
J = 6.3 Hz), 1.24 (12H, m), 1.54 (2H, m), 2.21 (2H, t,
+
1
24
viously. Rat liver microsomes were prepared by the
2
method as described previously. Reaction mixtures
0