Superoxide anion-scavenging effect of 2-amino-1,3-selenazoles

Article abstract of DOI:10.1248/cpb.53.1439

We investigated the superoxide anion scavenging effects of thirteen 2-amino-1,3-selenazoles using a highly sensitive quantitative chemiluminescence method. At 166 μM, the 2-amino-1,3-selenazoles scavenged in the range of 14.3 to 96.7% of O₂

Full text of DOI:10.1248/cpb.53.1439

November 2005
Chem. Pharm. Bull. 53(11) 1439—1442 (2005)
1439
Superoxide Anion-Scavenging Effect of 2-Amino-1,3-selenazoles
a
a
b
a
c
Akihiro SEKIGUCHI, Atsuyoshi NISHINA, Hirokazu KIMURA, Ryo-hei FUKUMOTO, Koichi KANOH,
c
,d
Hideharu ISHIHARA, and Mamoru KOKETSU*
a
b
Gunma Industrial Technology Center; 884–1 Kamesato, Maebashi, Gunma 379–2147, Japan: Gunma Prefectural
c
Institute of Public Health and Environmental Sciences; 378 Kamioki, Maebashi, Gunma 371–0052, Japan: Department of
Chemistry, Faculty of Engineering, Gifu University; and Division of Instrumental Analysis, Life Science Research Center,
d
Gifu University; Gifu 501–1193, Japan.
Received July 15, 2005; accepted August 24, 2005; published online August 25, 2005
We investigated the superoxide anion scavenging effects of thirteen 2-amino-1,3-selenazoles using a highly
sensitive quantitative chemiluminescence method. At 166 mM, the 2-amino-1,3-selenazoles scavenged in the range
ꢀ
2
of 14.3 to 96.7% of O . 2-Piperidino-1,3-selenazole and 4-phenyl-2-piperidino-1,3-selenazole exhibited the
strongest superoxide anion-scavenging activity among the 2-amino-1,3-selenazoles. The 50% inhibitory concen-
trations (IC ) of 2-piperidino-1,3-selenazole and 4-phenyl-2-piperidino-1,3-selenazole were determined to be
5
0
ꢀ
2
4
.03 mM and 92.6 mM, respectively. Thus, these compounds acted in vitro as effective O scavengers.
Key words 2-amino-1,3-selenazole; superoxide radical; scavenging effect; superoxide anion-scavenging activities (SOSAs)
Aerobic cells are inevitably exposed to reactive oxygen dant and a potential chemopreventive agent in inflammation-
1
)
20)
species (ROS) formed as oxygen metabolites. ROS such as associated carcinogenesis.
ꢀ
·
superoxide anion (O ), hydrogen peroxide (H O ), and hy-
droxyl radical (HO ) may degenerate various biomacromole- (SOSAs) of other organic selenium compounds such as se-
cules (DNA and proteins), resulting in oxidative and geno- lenocarbamates, selenoureas, and tertiary selenoamide com-
We have showed superoxide anion-scavenging activities
2
2
2
·
2—4)
ꢀ
2
21—23)
toxic stress.
O is released from many types of immuno- pounds.
In the present study, we synthesized a series of
logic cells including granulocytes and monocytes/macro- five-membered ring selenium-containing heterocyclic com-
5,6)
phages in vivo. Intracellular sources of ROS reportedly are pound, 2-amino-1,3-selenazoles and investigated SOSAs by
5,6)
ꢀ
2
mitochondoria and microsomes. O is spontaneously con- them in vitro.
verted to H O and O in hydrophilic solvents such as water
2
2
2
7)
ꢀ
2
by a disproportion reaction. O also reacts with nitric oxide
Experimental
·
24)
(
(
NO ) to generate strongly toxic ROS including peroxynitrite
Materials 2-Amino-1,3-selenazoles 1 were prepared according to
procedures previously reported. A Cypridina luciferin analogue, 2-methyl-6-
ꢀ
2,8)
ONOO ).
Some antioxidative enzymes/substances, such as superox-
ide dismutases (SODs), catalase, glutathione peroxidases
GPXs), and certain vitamins (vitamin C and E), act as ROS
(4-methoxyphenyl)-3,7-dihydroimidazo-[1,2-a]pyrazin-3-one hydrochloride
(MCLA) was obtained from Tokyo Kasei (Tokyo, Japan) for a use as a
chemiluminescent probe for superoxide radicals. MCLA was dissolved in
doubly distilled water and stored at ꢀ80 °C until needed. The concentration
(
scavengers since they quench ROS. GPX eliminates effec- of MCLA solution was determined by absorbance at 430 nm using an ab-
ꢀ1
ꢀ1
25)
tively H O in vitro and in vivo in consequence, to be an im- sorbance coefficient value of eꢁ9600 M cm , as previously described.
2
2
9
)
SOD (Lyophilized powder, 3400 units/mg protein) and xanthine oxidase
portant antioxidant enzyme. The GPX active domain con-
tains a selenium atom, supporting the importance of sele-
nium atom in aerobic cells. Various studies have reported
(XOD grade III) were purchased from Sigma Chemical (St. Louis, MO,
U.S.A.). Hypoxanthine was purchased from Wako Pure Chemical (Osaka,
Japan) and used without further purification. All other chemicals and sol-
vents were analytical grade and used without further purification.
9)
1
0,11)
that selenoproteins protect cells against oxidative stress.
Synthetic Methods for the Preparation of 2-Amino-1,3-selenazole
Various organic selenium compounds effectively scavenge
ROS. Excesses of superoxide anion in the human body are
kept in check by an antioxidant enzyme system including
SOD, GPX, and catalase (Cat). Superoxide anion has been mosphere then added. Acetic acid (0.6 ml) was added into the reaction mix-
reported to cause nerve degeneration and heart failure.
SOD activity in blood sample from patients with thyroiditis,
dwarfism, and Turner syndrome has been found to be lower
than in healthy persons. Therapy with a drug possessing
SOSA may have in treatment of those diseases. Ebselen, a 1.75—1.83 (4H, m, CH ), 2.56—2.59 (2H, m, CH ), 2.67—2.69 (2H, m,
selenium-containing compound studied extensively for possi- CH
26)
Compounds 2-Piperidino-1,3-selenazole 1a : 2-Chloro-1,1-dimethoxy-
ethane (0.054 ml, 0.6 mmol) was added to stirred solution of 1-selenocar-
bamoyl-piperidine (38 mg, 0.2 mmol) in dry THF (1 ml) under an argon at-
1
2)
13)
ture. The reaction mixture was refluxed for 3 h. The mixture was extracted
with chloroform and washed with H O. The organic layer was dried over
2
sodium sulfate and evaporated to dryness. The residue was purified by flash
chromatography on silica gel with dichloromethane to give 1a (6.4 mg, 15%)
14)
ꢀ1 1
as yellow liquid. IR (neat): 2928, 1558 cm ; H-NMR (500 MHz, CDCl ) d
3
2
2
1
3
), 3.04 (6H, s, CH ); C-NMR (125 MHz, CDCl ) d 23.1, 23.9, 25.4,
2
3
3
7
7
2
7.9, 41.0, 121.1, 147.1, 170.5; Se-NMR (95 MHz, CDCl ) d 554.2; MS
ble use as a drug, has been shown to attenuate oxidative
3
ꢂ
1
5—17)
(FAB): m/zꢁ230 [M ].
stress.
As a representative organic selenium compound,
4
-Methyl-2-piperidino-1,3-selenazole 1b: Acetone (0.10 ml, 1.5 mmol)
was added to stirred solution of 1-selenocarbamoyl-piperidine (95 mg,
cyclic compound showing glutathione peroxidase-like activ- 0.5 mmol) in dry ethanol (5 ml) under an argon atmosphere then added. Fer-
ebselen is a five-membered ring selenium-containing hetero-
18)
ity. Thus, this is one of the promising synthetic antioxi- ric chloride (0.29 mg, 1.8 mmol) was added into the reaction mixture. The
dants. The antioxidative effects of ebselen is also attributed
to its selective inhibition of leukocyte infiltration and activa-
tion, leading to attenuation of the H O concentration in
vitro. Thus, the ebselen may be a multifunctional antioxi- (97 mg, 85%) as yellow liquid. IR (neat): 2936, 2853, 1534 cm ; H-NMR
19)
reaction mixture was refluxed for 2 h. The mixture was extracted with di-
ethyl ether and washed with H O. The organic layer was dried over sodium
2
sulfate and evaporated to dryness. The residue was purified by flash chro-
2
2
matography on silica gel with dichloromethane : n-hexane (2 : 1) to give 1b
1
9)
ꢀ1 1
∗
To whom correspondence should be addressed. e-mail: koketsu@cc.gifu-u.ac.jp © 2005 Pharmaceutical Society of Japan

1
440
Vol. 53, No. 11
(
3
500 MHz, CDCl ): d 1.64—1.68 (6H, m, CH ), 2.21 (3H, s, CH ), 3.40— 1.21 (6H, t, Jꢁ7.2 Hz, CH ), 1.76—1.81 (4H, m, CH ), 2.54—2.57 (2H, m,
3
2
3
3
2
2
77
1
13
13
.42 (4H, m, CH ), 6.56 (1H, s, CH) ( J ( Se– H)ꢁ52.1 Hz); C-NMR
CH ), 2.65—2.68 (2H, m, CH ), 3.42 (4H, q, Jꢁ7.2 Hz, CH ); C-NMR
2 2 2
2
1
77
13
(
9
125 MHz, CDCl ): d 18.7, 24.2, 25.2, 50.7, 103.9, 150.2 ( J ( Se– C)ꢁ (125 MHz, CDCl ): d 12.7, 23.2, 23.9, 25.4, 27.9, 46.0, 119.7, 146.9, 168.7;
3
3
77
77
ꢂ
3.6 Hz), 173.5; Se-NMR (95 MHz, CDCl ): d 549.4; MS (CI): m/zꢁ231
Se-NMR (95 MHz, CDCl ): d 550.5; MS (CI): m/zꢁ259 [M ꢂ1].
2-Morpholino-4,5,6,7-tetrahydrobenzo-1,3-selenazole 1l: Yield: Quantita-
3
3
ꢂ
[M ꢂ1].
ꢀ
1 1
4
-Phenyl-2-piperidino-1,3-selenazole 1c: Yield: 32%. Yellow liquid. IR tively. Pink solid. mp: 52.0—54.0 °C; IR (KBr): 2922, 2857, 1547 cm ; H-
neat): 2935, 2847, 1543 cm ; H-NMR (500 MHz, CDCl ): d 1.63—1.71
ꢀ1 1
(
NMR (500 MHz, CDCl ): d 1.77—1.83 (4H, m, CH ), 2.55—2.58 (2H, m,
CH ), 2.68—2.70 (2H, m, CH ), 3.38 (4H, t, Jꢁ4.9 Hz, CH ), 3.77 (4H, t,
2 2 2
3
3
2
(6H, m, CH ), 3.51 (4H, t, Jꢁ5.2 Hz, CH ), 7.25 (1H, t, Jꢁ7.5 Hz, CH),
2
2
1
3
7
.28 (1H, s, CH), 7.34 (2H, dd, Jꢁ7.5, 8.3 Hz, CH), 7.85 (2H, d, Jꢁ8.3 Hz,
Jꢁ4.9 Hz, CH2); C-NMR (125 MHz, CDCl ): d 23.0, 23.8, 25.4, 27.8,
3
77
1
3
1
CH); C-NMR (125 MHz, CDCl3):
d 24.3, 25.3, 50.8, 104.9 ( J 49.5, 66.2, 122.4, 146.8, 171.5; Se-NMR (95 MHz, CDCl ): d 562.5; MS
3
77
ꢂ
7
7
13
(
(
Se– C)ꢁ97.2 Hz), 126.3, 127.2, 128.4, 136.1, 152.8, 172.8; Se-NMR (CI): m/zꢁ273 [M ꢂ1].
ꢀ
95 MHz, CDCl ): d 575.9; MS (CI): m/zꢁ293 [M ꢂ1].
2-Pyrrolidino-4,5,6,7-tetrahydrobenzo-1,3-selenazole 1m: Yield: 83%.
ꢀ
3
1
1
4
-Ethyl-5-methyl-2-piperidino-1,3-selenazole 1d: Yield: 73%. Yellow liq- Yellow solid. mp: 75.0—78.5 °C; IR (KBr): 2924, 1540 cm
; H-NMR
ꢀ1 1
uid. IR (neat): 2935, 2855, 1540 cm ; H-NMR (500 MHz, CDCl ): d 1.16 (500 MHz, CDCl ): d 1.76—1.83 (4H, m, CH ), 1.98—2.03 (4H, m, CH ),
3
3
2
2
(
(
3H, t, Jꢁ7.7 Hz, CH ), 1.59—1.67 (6H, m, CH ), 2.28 (3H, s, CH ), 2.44 2.58—2.60 (2H, m, CH ), 2.67—2.70 (2H, m, CH ), 3.38—3.41 (4H, m,
3 2 3
2 2
13
13
2H, q, Jꢁ7.7 Hz, CH ), 3.32—3.37 (4H, m, CH ); C-NMR (125 MHz,
CH2); C-NMR (125 MHz, CDCl ): d 23.1, 23.9, 25.46, 25.51, 27.9, 50.1,
3
77
3
2
7
7
CDCl ): d 12.9, 13.9, 22.6, 24.3, 25.2, 50.5, 117.9, 150.5, 170.2; Se-NMR 120.1, 147.0, 166.7; Se-NMR (95 MHz, CDCl ): d 551.1; MS (CI): m/zꢁ
3
3
ꢂ
ꢂ
(
95 MHz, CDCl ): d 580.6; MS (CI): m/zꢁ259 [M ꢂ1].
257 [M ꢂ1].
Assay of Superoxide Anion-Scavenging Activity (SOSA) The SOSA
pyl-1,3-selenazole 1f were obtained by a reaction of 1-selenocarbamoyl- of 2-amino-1,3-selenazole compounds 1 was measured by a previously re-
3
4-Butyl-2-piperidino-1,3-selenazole 1e and 4-methyl-2-piperidino-5-pro-
25)
piperidine with 2-hexanone. The reaction mixture was extracted with diethyl
ether and washed with H O. The organic layer was dried over sodium sulfate 10 M MCLA, 5ꢃ10 M hypoxanthine, xanthine oxidase (6.5 U), SOD (0.6
ported method. In brief, the standard reaction mixture contained 5.8ꢃ
ꢀ7
ꢀ5
2
and evaporated to dryness. The residue was purified by flash chromatogra-
to 30 ng/ml), and 50 mM Tris–HCl buffer containing 0.1 mM EDTA at pH
phy on silica gel with dichloromethane : n-hexane (2 : 1) to give 1e and 1f in 7.8, in the presence or absence of various concentrations of one of the 2-
2
0% and 52% yields, respectively.
amino-1,3-selenazole compounds 1. Total volume was 3.0 ml. 2-amino-1,3-
selenazole (25 mM) was dissolved in DMSO and stored at ꢀ80 °C prior
4
-Butyl-2-piperidino-1,3-selenazole 1e: Yield: 20%. Orange liquid. IR
ꢀ1 1
(
neat): 2934, 2856, 1534 cm ; H-NMR (500 MHz, CDCl ): d 0.92 (3H, t, to use. Chemiluminescence was measured using a luminometer (Aloka,
3
Jꢁ7.5 Hz, CH ), 1.33—1.39 (2H, m, CH ), 1.59—1.66 (10H, m, CH ), 2.52 BLR201) at 25 °C. Chemiluminescence measurement was initiated by the
3
2
2
2
(
(
2H, t, Jꢁ7.5 Hz, CH ), 3.40—3.43 (4H, m, CH ), 6.57 (1H, s, CH) ( J addition of 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyr-
2 2
7 1 13
7
Se– H)ꢁ52.1 Hz); C-NMR (125 MHz, CDCl ): d 14.0, 22.5, 24.3, 25.3, azin-3-one hydrochloride (MCLA) to the standard incubation mixture ex-
3
7
7
3
0.8, 32.9, 50.7, 103.1, 155.4, 173.5; Se-NMR (95 MHz, CDCl ): d 544.4; cluding XOD, continued for 2 min without XOD and for an additional 2 min
3
ꢂ
MS (CI): m/zꢁ273 [M ꢂ1].
after addition of XOD. A representative result of a measurement of the effect
4
-Methyl-2-piperidino-5-propyl-1,3-selenazole 1f: Yield: 52%. Orange of 1a and 1c on MCLA-dependent luminescence is shown in Fig. 1. When
ꢀ1 1
liquid. IR (neat): 2933, 2855, 1535 cm
.95 (3H, t, Jꢁ7.5 Hz, CH ), 1.54—1.68 (8H, m, CH ), 2.10 (3H, s, CH ),
.59 (2H, t, Jꢁ7.5 Hz, CH ), 3.34—3.36 (4H, m, CH ); C-NMR
125 MHz, CDCl ): d 13.5, 15.5, 24.2, 25.2, 26.0, 30.4, 50.4, 125.3 ( J described. The 50% inhibitory concentration (IC ) was calculated by five
Se– C)ꢁ92.4 Hz), 143.9, 170.2; Se-NMR (95 MHz, CDCl ): d 561.5;
MS (CI): m/zꢁ273 [M ꢂ1].
;
H-NMR (500 MHz, CDCl ): d
the compounds had strong SOSA at 166 mM, we also measured at 2.77, 4.16
and 8.33 mM for 1a and at 27.7, 83.3 and 133 mM for 1c. Percent of inhibition
3
0
2
3
2
3
1
3
2
2
of superoxide-dependent chemiluminescence was calculated as a previously
1
25)
(
(
3
50
7
7
13
77
3
concentrations of 1a (1.67, 2.77, 4.17, 6.67, 8.33 mM) and six concentrations
of 1c (20.8, 27.7, 41.7, 83.3, 111, 133 mM). Each assay was performed in du-
ꢂ
4
-(2-Methylpropyl)-2-piperidino-1,3-selenazole 1g and 4-methyl-5-(2- plicate.
methylethyl)-2-piperidino-1,3-selenazole 1h were obtained by a reaction of
-selenocarbamoylpiperidine with 4-methyl-2-pentanone. The reaction mix-
1
Results and Discussion
ture was purified by flash chromatography on silica gel with dichloro-
methane : n-hexane (2 : 1) to give 1g and 1h in 45% and 19% yields, respec-
tively.
Structures of these 2-amino-1,3-selenazole 1 are shown in
Table 1, where the SOSAs of the compounds also are sum-
marized. Among them, 2-piperidino-1,3-selenazole 1a and
4-(2-Methylpropyl)-2-piperidino-1,3-selenazole 1g: Yield: 45%. Orange
ꢀ
1
1
liquid. IR (neat): 2937, 2864, 1534 cm
.91 (6H, d, Jꢁ6.9 Hz, CH ), 1.62—1.67 (6H, m, CH ), 1.96—2.07 (1H, m,
; H-NMR (500 MHz, CDCl ): d
3
4-phenyl-2-piperidino-1,3-selenazole 1c had the highest
0
3
2
CH), 2.36 (2H, d, Jꢁ7.5 Hz, CH ), 3.39—3.41 (4H, m, CH ), 6.56 (1H, s, SOSAs at 166 mM (96.7%, 92.7%, respectively). The effects
2
2
2
77
1
13
CH) ( J ( Se– H)ꢁ52.1 Hz); C-NMR (125 MHz, CDCl ): d 22.5, 24.3, of compounds 1a and 1c were dose-dependent (Fig. 1). Com-
3
1
77
13
77
2
5.2, 27.7, 42.5, 50.7, 104.3 ( J ( Se– C)ꢁ93.6 Hz), 154.3, 173.4; Se-
pounds 1a and 1c were sufficiently active to suggest further
testing, by serial dilutions, 50% inhibitory concentrations
ꢂ
NMR (95 MHz, CDCl ): d 542.6; MS (CI): m/zꢁ273 [M ꢂ1].
3
4
-Methyl-5-(2-methylethyl)-2-piperidino-1,3-selenazole 1h: Yield: 19%.
ꢀ
1
1
(IC ) for the two compounds 1a and 1c were 4.03 mM and
Yellow solid. mp: 38.0—40.0 °C; IR (KBr): 2934, 2853, 1541 cm
;
H-
50
NMR (500 MHz, CDCl ): d 1.20 (6H, d, Jꢁ6.9 Hz, CH ), 1.59—1.67 (6H, 92.6 mM, respectively. We have evaluated SOSAs of other se-
3
3
m, CH ), 2.12 (3H, s, CH ), 3.00—3.07 (1H, m, Jꢁ6.9 Hz, CH), 3.37 (4H, t, lenium compounds including selenocarbamates, selenoureas,
2
3
1
3
Jꢁ5.2 Hz CH2); C-NMR (125 MHz, CDCl ): d 15.7, 24.3, 25.3, 26.1,
3
thioureas, and tertiary selenoamide compounds using a
7
7
2
(
9.2, 50.4, 134.3, 142.0, 170.0; Se-NMR (95 MHz, CDCl ): d 528.9; MS
21—23)
3
ꢂ
XOD-MCLA method.
about 0.1 to 100 mM.
IC50 of these compounds were
Thus, 2-amino-1,3-selenazoles had
CI): m/zꢁ273 [M ꢂ1].
2
1—23)
2
-Piperidino-4,5,6,7-tetrahydrobenzo-1,3-selenazole 1i: Yield: 97%. Yel-
ꢀ
1 1
low liquid. IR (neat): 2931, 2939, 1535 cm ; H-NMR (500 MHz, CDCl ): similar SOSAs when compared with previously mentioned
3
d 1.63—1.66 (6H, m, CH ), 1.75—1.82 (4H, m, CH ), 2.53—2.57 (2H, m,
2
2
synthesized organic selenium compounds. The results sug-
gested that 2-amino-1,3-selenazoles were useful scavenger
agents of superoxide, although we did not examine whether
these compounds had cytotoxicity or not. Additional studies
1
3
CH ), 2.66—2.68 (2H, m, CH ), 3.34—3.39 (4H, m, CH ); C-NMR
2
2
2
(
1
125 MHz, CDCl ): d 23.1, 23.8, 24.2, 25.1, 25.4, 27.8, 50.5, 120.9, 146.6,
3
7
7
ꢂ
71.1; Se-NMR (95 MHz, CDCl ): d 556.7; MS (CI): m/zꢁ271 [M ꢂ1].
3
2
-Dimethylamino-4,5,6,7-tetrahydrobenzo-1,3-selenazole
1j:
Yield:
ꢀ
1
1
Quantitatively. IR (neat): 2928, 1558 cm ; H-NMR (500 MHz, CDCl ) d regarding applications in vivo should be needed.
3
1
.75—1.83 (4H, m, CH ), 2.56—2.59 (2H, m, CH ), 2.67—2.69 (2H, m,
2
2
This study considered the elimination of super oxide anion
generated by XOD by 2-amino-1,3-selenazoles 1. Exact
SOSA cannot be measured if 2-amino-1,3-selenazoles 1 in-
1
3
CH ), 3.04 (6H, s, CH ); C-NMR (125 MHz, CDCl ) d 23.1, 23.9, 25.4,
2
3
3
7
7
2
(
7.9, 41.0, 121.1, 147.1, 170.5; Se-NMR (95 MHz, CDCl ) d 554.2; MS
3
ꢂ
FAB): m/zꢁ230 [M ].
2
-Diethylamino-4,5,6,7-tetrahydrobenzo-1,3-selenazole 1k: Yield: 87%. hibit the activity of XOD. Thus, we measured XOD-pro-
Yellow liquid. IR (neat): 2930, 1544 cm ; H-NMR (500 MHz, CDCl ): d duced uric acid as a metabolite in various experiments using
ꢀ1 1
3

November 2005
1441
Table 1. Scavenging Activity of 2-Amino-1,3-selenazoles 1 on the Superoxide Radical Anion
Entries
1
Compound
Inhibition (%)
96.7
Entries
8
Compound
Inhibition (%)
36.6
1a
1b
1h
1i
2
36.6
9
22.9
3
4
1c
92.7
22.0
10
11
1j
25.7
22.9
1d
1k
5
6
7
1e
1f
70.7
31.7
51.2
12
13
1l
25.7
14.3
1m
1g
The luminescence intensity (count/min) of the solution which does not contain a substance at all, and the solution containing the 2-amino-1,3-selenazole compound 1 was
measured, and the inhibition (%) was calculated.
directed toward elucidating the mechanism of action of the
active compounds and toward synthesizing and studying ad-
ditional analogues of 2-amino-1,3-selenazoles 1a and 1c.
Acknowledgements This work was supported by a Grant-in-Aid for
Science Research from the Ministry of Education, Culture, Sports, Science
and Technology of Japan (No. 15550030 and 17550099) to which we are
grateful.
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