Synthesis of 2-alkoxy 1,4-naphthoquinone derivatives as antiplatelet, antiinflammatory, and antiallergic agents

Article abstract of DOI:10.1248/cpb.50.672

In our continuing search for novel antiplatelet, antiallergic, and antiinflammatory agents, 2-alkoxy derivatives of 1,4-naphthoquinone were prepared. Some of these compounds showed significant antiplatelet, antiallergic, and antiinflammatory activities. A

Full text of DOI:10.1248/cpb.50.672

6
72
Notes
Chem. Pharm. Bull. 50(5) 672—674 (2002)
Vol. 50, No. 5
Synthesis of 2-Alkoxy 1,4-Naphthoquinone Derivatives as Antiplatelet,
Antiinflammatory, and Antiallergic Agents
,
a
a
b
c
a
Jin-Cherng LIEN,* Li-Jiau HUANG, Che-Ming TENG, Jih-Pyang WANG, and Sheng-Chu KUO
a
Graduate Institute of Pharmaceutical Chemistry, China Medical College; 91 Hsueh-Shih Road, Taichung, Taiwan,
b
c
R.O.C.: Pharmacological Institute, College of Medicine, National Taiwan University; Taiwan, R.O.C.: and Department
of Education and Research, Taichung Veterans General Hospital; Taiwan, R.O.C.
Received November 30, 2001; accepted January 21, 2002
In our continuing search for novel antiplatelet, antiallergic, and antiinflammatory agents, 2-alkoxy deriva-
tives of 1,4-naphthoquinone were prepared. Some of these compounds showed significant antiplatelet, antialler-
gic, and antiinflammatory activities. Among them, 2-propoxy-1,4-naphthoquinone and 2-butoxy-1,4-naphtho-
quinone exhibited potent inhibitory effect on neutrophil superoxide anion formation. These two compounds are
worthy of further exploration.
Key words naphthoquinone; antiplatelet activity; antiallergic activity; antiinflammatory activity
1
,2)
In a previous paper, a series of 2,3-disubstituted 1,4- sition to obtain 9. Such modification resulted in greatly en-
naphthoquinones were synthesized and their antiplatelet, an- hanced potency against AA-, collagen-, and PAF-induced
tiinflammatory, and antiallergic activities were evaluated. platelet aggregation.
Among them, compounds 1—4 (Chart 1) showed potent in-
Replacing the 3-chloro groups of compounds 5—8 with
hibitory effect on neutrophil and mast cell degranulation. In hydrogens yielded compounds 10 and 12—14, with slightly
particular, 2-chloro-3-methoxy-1,4-naphthoquinone (1) had lower potency against AA- and collagen-induced platelet ag-
impressive IC50 values of 0.5 and 0.9 mM against neutrophil gregation. These results suggest that the presence of a chloro
and mast cell degranulation, respectively. Encouraged by this group at the 3-position of the tested compounds plays an ef-
preliminary result, in this investigation we explored further fective role, as does the increase in the alkoxy chain length at
the chain length of compounds 1 and 3. During the screening 2-position. In general, the better inhibitory effect on the AA-
for antiplatelet, antiinflammatory, and antiallergic activities, and collagen-induced response of this series of compounds
we found that some of the target compounds demonstrated implies the inhibition of prostaglandin production, although
improved and more potent activity in comparison with 1 and confirmation of this awaits further investigation.
3
. Our findings are summarized in this report.
Antiinflammatory Activity Effect on Neutrophil De-
granulation : The inhibitory effects of compounds 5—14
5
,6)
Chemistry
on neutrophil degranulation were examined. As can be seen
The target compounds, 2-alkoxy-3-chloro-1,4-naphtho- in Table 2, the potency of compounds 5—8 were about 2—4-
quinones (5—9) and 2-alkoxy-1,4-naphthoquinones (10—
1
4), were synthesized as shown in Charts 2 and 3. The prepa-
ration of two typical compounds, 2-chloro-3-propoxy-1,4-
naphthoquinone (5) and 2-propoxy-1,4-naphthoquinones
(10), is described to illustrate the general procedures. As
shown in Chart 2, the starting 2,3-dichloro-1,4-naphtho-
quinone was treated with sodium propoxide in propanol to
form 5. As illustrated in Chart 3, the starting 2-hydroxy-1,4-
naphthoquinone was treated with propyl iodide in the pres-
ence of silver oxide to afford 10.
Chart 1
3
,4)
Antiplatelet Activity
As indicated in Table 1, all of
the synthesized compounds significantly inhibited arachi-
donic acid (AA)-, collagen-, and platelet-activating factor
(
PAF)-induced platelet aggregation. On the contrary, they did
not inhibit thrombin-induced aggregation at concentractions
up to 100 mg/ml (not shown in Table 1). In other words, these
compounds showed similar patterns of preferential inhibition
toward platelet aggregation to that of compound 1. Their in-
hibitory potency is greatest against AA- and collagen-in-
duced platelet aggregation, whereas their potency is only
moderate against PAF-induced aggregation, and the weakest
toward thrombin-induced aggregation.
Chart 2
Among compounds 5—7, the inhibitory potency against
AA-, collagen-, and PAF-induced platelet aggregation was
found to increase with increasing 2-alkoxy chain length. Al-
ternatively, the phenoxy group was introduced into the 2-po-
Chart 3
∗
To whom correspondence should be addressed. e-mail: jclien@mail.cmc.edu.tw
© 2002 Pharmaceutical Society of Japan

May 2002
673
Table 1. Inhibitory Effect of 2-Alkoxy-(3-chloro) 1,4-Naphthoquinones on Table 3. Inhibitory Effect of 2-Alkoxy-(3-chloro) 1,4-Naphthoquinones on
Platelet Aggregation Induced by Thrombin, Arachidonic Acid, Collagen, the Superoxide Anion Formation of Neutrophils
and Platelet-activating Factor
a)
IC50 (mM)
a)
IC50 (mM)
Compound
Compound
Superoxide anion formation
Thrombin
AA
Collagen
PAF
1
2
3
4.5
12.3
2.8
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
Ͼ150
122
18.9
33.5
53.9
38.1
20.5
19.8
8.8
34.2
Ͼ150
Ͼ150
33.1
Ͼ150
89.2
106
73.2
43.8
24.6
21.8
10.6
11.9
1.9
26.0
34.8
22.8
30.2
21.7
4
5
6
7
8
9
10
11
0.8
2.8
5.5
4.7
4.1
6.9
0.6
2.1
133
32.4
26.8
5.8
10.8
1.6
1
1
1
1
1
26.1
36.3
23.3
17.0
15.2
20.0
75.8
72.5
42.6
54.5
Ͼ150
Ͼ150
12
13
14
0.6
ND
ND
14.7
119
Ͼ150
Ͼ150
Trifluoperazine
Aspirin
Ͼ150
The neutrophil suspension in the presence of tern cytochrome c was preincubated at
37 °C with 0.5% DMSO or a test compound for 10 min in the presence of cytochalasin
Platelets were incubated with test compounds at 37 °C for 1 min, then thrombin
B (5 mg/ml). Fifteen minutes after the addition of fMLP (0.3 mM), the absorbance was
(
0.1 unit/ml), arachidonic acid (AA, 100 mM), collagen (10 mg/ml), or platelet-activating
mM) at which 50% in-
factor (PAF, 2 ng/ml) was added to trigger the aggregation. Values are expressed as the
concentration (mM) at which 50% inhibition of platelet aggregation occurred (IC50). As-
pirin was used as a positive control. a) The accuracy of IC50 values are withinϮ10%.
determined at 550 nm. Values are expressed as the concentration (
hibition of neutrophil superoxide anion formation occurred (IC50). Trifluoperazine was
used as a positive control. ND, not determined. a) The accuracy of IC50
withinϮ10%.
values are
Table 2. Inhibitory Effect of 2-Alkoxy-(3-chloro) 1,4-Naphthoquinones on Table 4. Inhibitory Effect of 2-Alkoxy-(3-chloro) 1,4-Naphthoquinones on
the Release of b-Glucuronidase and Lysozyme from Neutrophils
the Release of b-Glucuronidase and Histamine from Mast Cells
a)
a)
IC50 (mM)
IC50 (mM)
Compound
Compound
b-Glucuronidase
Lysozyme
b-Glucuronidase
Histamine
1
2
3
4
5
6
7
8
9
0
1
2
3
4
0.5
1.7
79.3
87.2
1.0
1.5
2.1
1.9
14.7
60.2
18.8
14.6
3.7
0.5
1.7
Ͼ100
Ͼ100
1.3
1
2
3
4
5
6
7
8
9
10
11
12
13
0.9
1.7
37.3
21.5
1.2
1.0
1.6
2.6
1.0
9.1
5.7
3.0
1.8
2.1
33.7
0.9
1.7
37.6
45.4
1.6
2.0
1.6
2.0
1.1
10.1
10.2
9.1
3.3
2.8
2.1
2.5
1.9
15.1
58.4
24.6
25.7
4.8
1
1
1
1
1
55.6
20.1
Ͼ100
17.2
14
Trifluoperazine
Mepacrine
56.5
The neutrophil suspension was preincubated at 37 °C with 0.5% DMSO or a test
compound for 10 min in the presence of cytochalasin B (5 mg/ml). Forty-five minutes
after the addition of fMLP (1 mM), b-glucuronidase and lysozyme levels in the super-
natant were determined. Values are expressed as the concentration (mM) at which 50%
inhibition of neutrophil degranulation occurred (IC50). Trifluoperazine was used as a
positive control. a) The accuracy of IC50 values are withinϮ10%.
The mast cell suspension was preincubated at 37 °C with 0.5% DMSO or test com-
pound for 3 min. Fifteen minutes after the addition of compound 48/80 (10 mg/ml), b-
glucuronidase and histamine levels in the supernatant were determined. Values are ex-
pressed as the concentration (mM) at which 50% inhibition of mast cell degranulation
occurred (IC ). Mepacrine was used as a positive control. a) The accuracy of IC
50
50
values are withinϮ10%.
fold less potent than compound 1 in terms of their inhibitory anion formation induced by fMLP. Among them, the 3-
effect on the neutrophil degranulation induced by formyl- chloro analogues 5—9 were nearly equipotent in comparison
Met-Leu-Phe (fMLP). The inhibitory potency was reduced with lead compound 1, while the 3-unsubstituent analogues
markedly when a phenoxy group was placed at the 2-position 10—12 were more potent than their parent compound 3.
(
compound 9). On the other hand, the potency of compounds Most importantly, both compounds 10 and 12, with IC50 val-
1
0—13 was found to increase over compound 3 in propor- ues of 0.6 mM, are 25 times more potent than the positive
tion with the length of their 2-alkoxy chains.
Effect on Neutrophil Superoxide Formation : The
screening results in the neutrophil superoxide formation tion : The inhibitory effects of compounds 5—14 on mast
assay are shown in Table 3. All tested compounds demon- cell degranulation were examined. As shown in Table 4, all
strated significant inhibitory effect on neutrophil superoxide 3-chloro analogues (5—9) exhibited almost the same in-
control (trifluoperazine).
7
,8)
Antiallergic Activity Effect on Mast Cell Degranula-
9
,10)

6
74
Vol. 50, No. 5
Table 5. Physical and Spectral Data of Substituted 1,4-Naphthoquinones
ϩ
1
Yield
%)
mp
(°C)
MS (M )
IR
(cm )
H-NMR
(ppm)
Compound
Ϫ1
(
(m/z)
5
85
83
82
Liquid
Liquid
Liquid
250
264
278
1674
1674
1674
1.06 (3H, t, Jϭ7.5, –CH CH ); 1.78—1.87 (2H, m, –CH CH ); 4.53
2 3 2 3
(
(
2H, t, Jϭ6.6, –OCH –); 7.72—7.75 (2H, m, H-6, 7); 8.06—8.12
2H, m, H-5, 8)
2
6
7
0.98 (3H, t, Jϭ7.5, –CH CH ); 1.46—1.58 (2H, m, –CH CH ); 1.74–1.84
2
3
2
3
(
(
2H, m, –OCH CH –); 4.57 (2H, t, Jϭ6.6, –OCH –); 7.72—7.75
2 2 2
2H, m, H-6, 7); 8.04—8.13 (2H, m, H-5, 8)
0.93 (3H, t, Jϭ7.2, –CH CH ); 1.34—1.49 (4H, m, –CH CH CH );
2
3
2
2
3
1
.76—1.84 (2H, m, –OCH CH –); 4.56 (2H, t, Jϭ6.6, –OCH –);
2
2
2
7
.72—7.75 (2H, m, H-6, 7); 8.05—8.14 (2H, m, H-5, 8)
8
9
75
78
82
115—116
142—143
106—107
298
284
216
1678
1674
1705
5.64 (2H, s, –OCH –); 7.32—7.40 (3H, m, H-3Ј, 4Ј, 5Ј); 7.45—7.48 (2H, m,
H-2Ј, 6Ј); 7.72—7.78 (2H, m, H-6, 7); 8.06—8.21 (2H, m, H-5, 8)
6.98—7.35 (5H, m, H-2Ј, 3Ј, 4Ј, 5Ј, 6Ј); 7.75—7.78 (2H, m, H-6, 7); 8.02—8.03
2
(
1H, m, H-5); 8.18—8.21 (1H, m, H-8)
10
11
12
13
1.09 (3H, t, Jϭ7.4, –CH CH ); 1.89—1.97 (2H, m, –CH CH ); 4.09
2
3
2
3
(
2H, t, Jϭ6.4, –OCH –); 5.93 (1H, s, H-3); 7.55—7.67 (2H, m, H-6, 7);
2
7
.84—7.87 (1H, m, H-5); 8.07—8.10 (1H, m, H-8)
85
81
82
119—120
97—98
216
230
244
1698
1701
1701
1.46 (6H, d, Jϭ6.1, –CH(CH ) ); 4.69—4.73 (1H, m, –OCH–); 5.92
3
2
(
8
1H, s, H-3); 7.54—7.66 (2H, m, H-6, 7); 7.84—7.87 (1H, m, H-5);
.07—8.10 (1H, m, H-8)
0.67 (3H, t, Jϭ7.2, –CH CH ); 0.98—1.05 (2H, m, –CH CH ); 1.34—1.39
2
3
2
3
(
2H, m, –OCH CH –); 4.03 (2H, t, Jϭ6.5, –OCH –); 5.94 (1H, s, H-3);
2
2
2
7
.55—7.66 (2H, m, H-6, 7); 7.82—7.85 (1H, m, H-5); 8.07—8.10 (1H, m, H-8)
80—81
0.94 (3H, t, Jϭ7.2, –CH CH ); 0.98—1.05 (4H, m, –CH CH CH ); 1.87—1.94
2 3 2 2 3
(
2H, m, –OCH CH –); 4.11 (2H, t, Jϭ7.2, –OCH –); 5.91 (1H, s, H-3);
2 2 2
7
.54—7.66 (2H, m, H-6, 7); 7.82—7.85 (1H, m, H-5); 8.06—8.09
(
1H, m, H-8)
1
4
75
182—183
264
1698
5.19 (2H, s, –OCH –); 6.05 (1H, s, H-3); 7.42—7.45
2
(
5H, m, H-2Ј, 3Ј, 4Ј, 5Ј, 6Ј); 7.56—7.66 (2H, m, H-6, 7); 7.86—7.87
(
1H, m, H-5); 8.09—8.12 (1H, m, H-8)
hibitory effect as their parent compound 1 on mast cell de-
granulation induced by compound 48/80 (10 mg/ml). Mean-
while, regardless of the higher potency than their lead com-
pound 3, the 3-unsubstituted compounds 10—12 were less
potent than their 3-chloro counterparts 5 and 6. However,
compounds 7 and 8 exhibited potency similar to that of their
2-Alkoxy-1,4-naphthoquinones 10—14 A mixture of 2-hydroxy-1,4-
naphthoquinone (15 mmol), alkyl iodide (20 mmol), silver oxide (20 mmol),
and chloroform (50 ml) was heated under reflux for 2 h. The cooled reaction
mixture was filtered and the filtrate was evaporated to dryness. The residue
was chromatographed on silica gel to give 10—14 (Table 5).
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(
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5
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