Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on Selected Human Cancer Cell Lines

Article abstract of DOI:10.1248/cpb.c18-00013

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC₅₀ values of 0.66±0.05, 5.11±0.12 and 8.26±0.22μM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.

Full text of DOI:10.1248/cpb.c18-00013

6
12
Chem. Pharm. Bull. 66, 612–619 (2018)
Vol. 66, No. 6
Regular Article
Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on
Selected Human Cancer Cell Lines
Qijing Zhang, Jinyun Dong, Jiahua Cui, Guang Huang, Qingqing Meng,* and Shaoshun Li*
School of Pharmacy, Shanghai Jiao Tong University; 800 Dongchuan Road, Shanghai 200240, China.
Received January 10, 2018; accepted April 1, 2018
In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime
derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five
human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell:
BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound
14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402
and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22µM, respectively. Additionally, the length
of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphtho-
quinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and
may become a promising anticancer agent.
Key words naphthoquinone; oxime; cytotoxicity; anticancer agent
Naphthoquinone moieties are widely distributed in vari- methoxy-2-naphthaldehyde (9) and thereafter tested for their
ety of plants, fungi and some animals. They have received cytotoxic activity against colorectal cancer cells (HCT-15,
significant attention due to their promising pharmaceutical HCT-116), breast cancer cells (MDA-MB-231), liver cancer
application. In particular, 1,4-naphthoquinones such as law- cells (BEL-7402), ovarian cancer cells (A2780) and human
sone, shikonin, juglone, phthiocol, lapachol and plumbagin skin fibroblasts (HSF) by the MTT (3-(4,5-dimethylthiazol-
are naturally occurring have become the major of popular 2-yl)-2,5-diphenyltetrazolium bromide) assay.
research owing to their extensive biological activities (Fig. 1),
including antibacterial, antitrypanosome, antiviral, antipara- Results and Discussion
sitic, antiplasmodial, antiinflammatory, antiproliferative and
Chemistry The general synthetic routes of key inter-
mediates and target compounds were depicted in Charts 1
1–5)
6)
7)
antimalarial.
As proved by our group and Ahn’s team,
6
-substituted 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) and 2, respectively. Juglone was used as the raw material to
derivatives display a higher inhibitory efficiency on DNA synthesize 2 initially, but the desired compound 5,8-dime-
topoisomerase-I and the cytotoxicity against cancer cells com- thoxynaphthalen-1-yl acetate was not obtained due to acetyl
18)
pared with the corresponding 2-substituted derivatives due to migration. Herein, p-methoxyphenol was considered to be
8)
less steric hindrance on the naphthalene ring.
used as the same starting material for the synthesis of 2 and 9.
The main mechanisms of naphthoquinones acting inhibitory We obtained 2 by methylation of 1 which was prepared from
1
9)
activity are ascribed to the generation of reactive oxygen spe- our laboratory.
cies (ROS) and bioreductive alkylation. Additionally, some
9)
An aldehyde group was introduced at the ortho position of
other mechanisms including abduction of DNA double strand the phenolic hydroxyl group by the Duff reaction, which was
breaks, DNA insertion and the suppression of some specific followed by a methylation reaction to produce 4. The diethyl
10)
enzymes such as topoisomerases have also been reported.
succinate reacted smoothly with 4 by Stobbe condensation
Surprisingly, when the carbonyl groups on the naphthoquinone
ring were shielded by oxime, O-dimethyl shikonin derivatives
showed more considerable cytotoxic activity against cancer
cells but to a lower cytotoxicity towards normal cells than
2
,11–13)
their parental compounds.
Nevertheless, the mechanism
of their significant inhibitory activity was not attributed to
13)
bioreductive alkylation and ROS. Especially, a novel shi-
konin derivative DMAKO-05, displayed more potential anti-
tumor activity and less toxicity compared to 5-fluorouracil
(
5-FU) in vitro towards K562 and HCT-116 with IC values of
5
0
2
,12)
0
.7 and 0.6µM, respectively.
Existing literatures demonstrate that methylation of some
compounds bearing naphthazarin ring could improve their
6
,14–17)
antitumor activity.
Herein, a series of 1,4-naphthoqui-
none oxime derivatives containing methoxyl and different
lengths of alkyl were synthesized through the key interme-
diates 1,5,8-trimethoxy-2-naphthaldehyde (2) and 4,5,8-tri- Fig. 1. Chemical Structures of 1,4-Naphthoquinone Derivatives
*
To whom correspondence should be addressed. e-mail: qqmeng@sjtu.edu.cn; ssli@sjtu.edu.cn
©
2018 The Pharmaceutical Society of Japan

Vol. 66, No. 6 (2018)
Chem. Pharm. Bull.
613
Reagents and conditions: a) MeI, K CO , DMF; b) TsOH·H O, AcOH, hexamethylenetetramine; c) MeI, K CO , acetone; d) diethyl succinate, NaH, toluene; e) AcONa,
2
3
2
2
3
AcOH; f) LiAlH , THF; g) MeI, K CO , DMF; h) MnO , CH Cl .
4
2
3
2
2
2
Chart 1.
they were oxidized by cerium(IV) ammonium nitrate (CAN)
to afford the corresponding 1,4-naphthoquinones 12a–12d and
19a–19d. The target compounds 1,4-naphthoquinone dioxime
derivatives 13–16 and 20–23 were gained via oximation of
their corresponding 1,4-naphthoquinones in the presence of
hydroxylamine hydrochloride and pyridine at 50°C.
Biological Activity The cytotoxic effects of the target
1,4-naphthoquinone oxime derivatives on five human cancer
cell lines were tested in vitro using the MTT assay. 5-FU was
used as positive control. The concentration (in µM) of the test
compounds which induced IC50 is shown in Table 1.
Most of the tested compounds bearing substituents at the
ortho position of the methoxyl showed higher anti-prolifera-
tion activities against five cancer cells than that of substituents
at the meta position. In particular, 1,4-naphthoquinone oxime
derivatives were notably sensitive to MDA-MB-231 cells com-
pared with the other four cancer cell lines. 13–15 displayed
more superior or comparable cytotoxicity to the positive con-
trol (5-FU) against MDA-MB-231, BEL-7402 and A2780 cell
lines (Figs. 2–4). In addition, compound 16 was also showed
better activity than positive drug against MDA-MB-231.
Whereas, compared to 5-FU, the meta substituted derivatives
displayed almost no cytotoxic activity except 21 showing a
moderate activity toward MDA-MB-231 and A2780 with IC50
values of 35.01±2.31 and 60.36±2.42µM, respectively. Of the
note, among the bioactive ones, compound 14 exhibited the
highest activity against the human breast cancer cell MDA-
MB-231 with an IC50 value of 0.66±0.05µM. Meanwhile, the
IC50 values of 14 against HCT-15, BEL-7402, HCT-116 and
A2780 cell lines were found to be 36.40±2.06, 5.11±0.12,
Reagents and conditions: a) R Br, Mg, THF; b) NaH, R Br, DMF; c) CAN,
1
2
EtOAc; d) NH OH·HCl, Py, EtOH.
2
Chart 2.
2
1.52±1.41 and 8.26±0.22µM, separately (Fig. 5). Moreover,
2
0)
under the alkaline condition and the resulting 6 was reduced none of the target compounds displayed cytotoxicity towards
to 7 by lithium aluminium hydride, which was methylated to the normal HSF cell line (IC >100 µM).
5
0
8
with methyl iodide in good yield. Conversion of 8 into key
intermidate 9 was achieved with manganese dioxide.
Analysis of these data, we can easily conclude that the posi-
tion of the substituents and the length of the side chains have
The Grignard reagent generated by bromoalkane and mag- a significant effect on the cytotoxic activity. The activity of
nesium was added to the aldehyde 2 and 9 giving 10a–10d and the substituents at the ortho position of the methoxy group is
17a–17d, respectively, which were nucleophilic substituted by obviously better than that at the meta position. It is notewor-
bromo isopentane to yield 11a–11d and 18a–18d. And then, thy that the value of partition coefficient may also affect the

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Chem. Pharm. Bull.
Vol. 66, No. 6 (2018)
Table 1. The Cytotoxicity of Target Compounds against Five Human Cancer Cell Lines in Vitro
b)
IC50 (µM)
a)
Compound
cLogP
HCT-15
MDA-MB-231
BEL-7402
HCT-116
A2780
HSF
1
1
1
1
2
2
2
2
3
4
5
6
0
1
2
3
7.49
8.55
94.16±2.78
36.40±2.06
44.42±3.17
129.5±5.45
>200
>200
>200
>200
9.89±0.65
7.85±0.21
0.66±0.05
9.87±0.08
11.56±0.33
>200
35.01±2.31
>200
>200
148.36±4.45
38.93±2.13
5.11±0.12
21.08±1.07
45.98±1.62
166.7±4.38
154.5±5.56
>200
52.07±3.67
21.52±1.41
29.28±1.69
>200
68.43±2.33
8.26±0.22
33.82±1.71
>200
168.8±4.37
60.36±2.42
>200
>100
>100
>100
>100
>100
>100
>100
>100
>100
9.60
10.66
7.49
>200
>200
>200
>200
8.55
9.60
10.66
−0.58
>200
37.07±1.81
>200
67.89±2.39
5
-FU
1.73±0.12
a) Calculated log value of partition coefficient by ChemBioDraw 14.0. b) IC50 values were calculated from at least three independent experiments.
Fig. 2. The Cytotoxicity of Compound 13 against Three Cancer Cell
Lines Compared to 5-FU
cytotoxicity. Moreover, the cytotoxic activity was increased
by prolongation of the side chain (R =hexyl, octyl, decyl
1
Fig. 3. The Cytotoxicity of Compound 14 against Five Cancer Cell
Lines Compared to 5-FU
or dodecyl). The highest activity could be achieved when
the length of the side chain was 8 carbon atoms (R =octyl).
1
However, continuing to extend this side chain could result in their pharmaceutical applications after further investigations.
a decreased activity. It was suggested that compounds with a
suitable length of side chain could enhance their cell mem- Experimental
brane permeability and bioavailability, which contribute to
Chemistry Reagents and solvents were obtained from
their cytotoxic activities.
commercial suppliers and purified using standard tech-
niques. Column chromatography was conducted on silica
gel (100–200 mesh) from Qingdao Ocean Chemical Factory.
21)
Conclusion
In summary, a series of naphthoquinone oxime derivatives Melting points (mp) were determined on an SGW X-4 mi-
1
13
(
13–16 and 20–23) were designed, synthesized and investi- cromelting point apparatus. H-NMR and C-NMR Spectra
gated for their cytotoxic activity against five human cancer were measured on an Agilent 400 spectrometer (400MHz) and
cell lines and a normal cell line. Novel anticancer agent such chemical shifts were recorded with tetramethylsilane as the in-
as the most potent compound 14 exhibited a superior cyto- ternal standard. Compounds 5 and 7 were prepared according
2
0)
toxicity to reference drug against MDA-MB-231, BEL-7402 to known procedures.
and A2780 cell lines with IC50 values of 0.66±0.05, 5.11±0.12 1,5,8-Trimethoxy-2-naphthaldehyde (2) Methyl iodide
and 8.26±0.22µM, respectively. Meanwhile, all the prepared (0.66g, 4.7mmol) was slowly added to a mixture of 1 (0.9g,
compounds showed low cytotoxicity towards HSF cells. Fur- 3.9mmol) and K CO3 (2.14g, 15.6mmol) in N,N-dimethyl-
2
thermore, the cytotoxicity of these compounds was closely formamide (DMF, 20mL) under ice bath. The solution was
associated with the length of the side chains and the position stirred at the room temperature overnight and then diluted
of the substituents. Therefore, these novel 1,4-naphthoquinone with water, extracted with ethyl acetate. The organic layer was
oxime derivatives fused with lipophilic side chains may find washed with brine and then dried over anhydrous Na SO .
2
4

Vol. 66, No. 6 (2018)
Chem. Pharm. Bull.
615
The solvent was evaporated under reduced pressure to give 3
as colorless oil without further purification which dissolved in
acetone (30mL) containing methyl iodide (1.63g, 11.5mmol)
and K CO (3.98g, 28.8mmol). The solution was stirred at
2
3
the room temperature overnight and then diluted with water,
extracted with ethyl acetate. The organic layer was washed
with brine and then dried over anhydrous Na SO . The sol-
2
4
vent was evaporated under reduced pressure and the residue
was subjected to flash column chromatography to give 4 as
2
2)
pale green solid. Yield (1.42g, 87.7%). Mp 49–51°C (lit.
1
4
8–50°C). H-NMR (400MHz, CDCl ) δ: 3.79 (s, 3H), 3.88 (s,
3
3
H), 6.93 (d, J=9.0Hz, 1H), 7.12 (dd, J=9.0, 3.3Hz, 1H), 7.31
(d, J=3.3Hz, 1H), 10.43 (s, 1H).
Ethyl 4-Acetoxy-5,8-dimethoxy-2-naphthoate (6) Sodium
acetate (1.23g, 15mmol) and 5 (1.47g, 5mmol) were dissolved
in acetic acid (40mL) and the mixture was heated at reflux
for 3h under nitrogen atmosphere. After the completion of
the reaction, the solution was cooled to room temperature
and poured into ice water. The yellow solid was precipitated
and then recrystallized from ethanol to give acicular crystals.
1
Yield (1.48g, 93.1%). H-NMR (400MHz, CDCl ) δ: 1.41 (t,
3
J=7.1Hz, 3H), 2.36 (s, 3H), 3.86 (s, 3H), 3.95 (s, 3H), 4.41
(
1
q, J=7.1Hz, 2H), 6.74 (d, J=8.6Hz, 1H), 6.84 (d, J=8.6Hz,
H), 7.68 (d, J=1.7Hz, 1H), 8.88 (d, J=1.7Hz, 1H). C-NMR
Fig. 4. The Cytotoxicity of Compound 15 against Three Cancer Cell
Lines Compared to 5-FU
13
(100MHz, CDCl ) δ: 14.4, 20.9, 55.8, 56.5, 61.2, 104.8, 108.7,
3
1
1
19.5, 121.8, 123.4, 127.5, 127.7, 146.4, 148.7, 150.5, 165.9,
70.0.
,5,8-Trimethoxy-2-naphthaldehyde (9) Methyl iodide
0.85g, 6.0mmol) was slowly added to a mixture of 7 (0.94g,
4
(
4
.0mmol) and K CO3 (2.21g, 16.0mmol) in DMF (20mL)
2
under ice bath. The solution was stirred at the room tem-
perature overnight and then diluted with water, extracted with
ethyl acetate. The organic layer was washed with brine and
then dried over anhydrous Na SO . The solvent was evaporat-
2
4
ed under reduced pressure and the residue was dissolved in di-
chloromethane (30mL) containing manganese dioxide (3.47g,
39.9mmol) without further purification. After the completion
of the reaction, manganese dioxide was filtered out and the
residue was subjected to flash column chromatography to give
1
9
as yellow solid. Yield (0.88g, 89.8%). H-NMR (400MHz,
CDCl ) δ: 3.87 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 6.76 (d,
3
J=8.6Hz, 1H), 6.91 (d, J=8.6Hz, 1H), 7.25 (d, J=1.6Hz, 1H),
1
3
8
.29 (d, J=1.6Hz, 1H). C-NMR (100MHz, CDCl ) δ: 55.8,
3
Fig. 5. The Cytotoxicity of Compound 14 against Five Cancer Cell 56.3, 57.6, 100.9, 105.6, 111.2, 121.2, 123.1, 127.7, 134.0, 150.5,
Lines
150.8, 157.7, 192.2.
General Procedure for the Synthesis of Compounds
The solvent was evaporated under reduced pressure and the 10a–10d and 17a–17d 1-Bromoalkane (10mmol) was added
residue was subjected to flash column chromatography to give dropwise to a stirred suspension of magnesium powder (0.25g,
1
2
as yellow solid. Yield (0.92g, 96.4%). H-NMR (400MHz, 10.4mmol) and a catalytic amount of iodine in anhydrous
CDCl ) δ: 3.95 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 6.84 (d, tetrahydrofuran (THF, 10.0mL) under nitrogen atomosphere.
3
J=8.6Hz, 1H), 6.89 (d, J=8.6Hz, 1H), 7.84 (d, J=9.0Hz, 1H), After stirring at 50°C for 2h, a solution of naphthaldehyde (2
8
.07 (dd, J=9.0, 0.9Hz, 1H), 10.60 (d, J=0.9Hz, 1H).
,5-Dimethoxybenzaldehyde (4) p-Toluene sulfonic acid to the solution of alkylmagnesium bromide prepared above.
monohydrate (5.59g, 29.4mmol), hexamethylenetetramine The solution was stirred at room temperature for 3h and then
or 9, 0.5g, 2.03mmol) in anhydrous THF (5.0mL) was added
2
(
4.12g, 29.4mmol) and p-methoxyphenol (1.22g, 9.8mmol) quenched with saturated NH Cl solution. The mixture was ex-
4
were dissolved in acetic acid (30mL) and the mixture was tracted with dichloromethane and washed with brine and then
heated at reflux for 5h under nitrogen atmosphere. After the dried over anhydrous Na SO . The solvent was evaporated
2
4
completion of the reaction, the solution was cooled to room under reduced pressure and the residue was purified by flash
temperature and poured into ice water, extracted with ethyl column chromatography to afford 10a–10d and 17a–17d.
acetate. The organic layer was washed with saturated NaHCO3
1-(1,5,8-Trimethoxynaphthalen-2-yl)heptan-1-ol
and brine in sequence and then dried over anhydrous Na SO . Colorless oil; yield 0.63g (94.0%). H-NMR (400MHz,
(10a)
1
2
4

6
16
Chem. Pharm. Bull.
Vol. 66, No. 6 (2018)
CDCl ) δ: 0.86 (t, J=6.7Hz, 3H), 1.16–1.39 (m, 8H), 1.71–1. 87 added in portion to a stirred solution of alcohol (10a–10d
3
(m, 2H), 2.70–2.90 (m, 1H), 3.79 (s, 3H), 3.89 (s, 1H), 3.91 (s, or 17a–17d, 1.5mmol) in anhydrous DMF (15mL) at 0°C.
3
H), 5.22 (dd, J=7.9, 5.3Hz, 1H), 6.65 (d, J=8.4Hz, 1H), 6.72 After stirring for 1h, a solution of bromo isopentane (0.68g,
(d, J=8.4Hz, 1H), 7.51 (d, J=8.8Hz, 1H), 7.99 (d, J=8.8Hz, 4.5mmol) dissolved in anhydrous DMF (3mL) and a catalytic
13
1H). C-NMR (100MHz, CDCl ) δ: 14.1, 22.6, 26.1, 29.3, amount of iodine were added to the reaction mixture, which
3
31.8, 38.5, 55.7, 56.6, 63.0, 68.5, 103.7, 106.0, 118.5, 120.5, was stirred at 60°C overnight. After cooled to the room tem-
124.3, 128.1, 135.1, 149.7, 149.7, 152.6.
perature, the reaction mixture was quenched with saturated
1
-(1,5,8-Trimethoxynaphthalen-2-yl)nonan-1-ol
(10b) NH Cl solution and then extracted with dichloromethane. The
4
1
Colorless oil; yield 0.70g (95.9%). H-NMR (400MHz, CDCl ) organic layer was washed with brine and dried over anhydrous
3
δ: 0.86 (t, J=6.7Hz, 3H), 1.19–1.35 (m, 12H), 1.75–1.87 (m, Na SO . The solvent was evaporated under reduced pressure
2
4
2
H), 2.36–2.39 (m, 1H), 3.82 (s, 3H), 3.93 (s, 3H), 3.94 (s, and the residue was purified by flash column chromatography
3
H), 5.23 (dd, J=8.0Hz, J=5.4Hz, 1H), 6.69 (d, J=8.4Hz, to afford 11a–11d and 18a–18d.
1H), 6.76 (d, J=8.4Hz, 1H), 7.52 (d, J=8.8Hz, 1H), 8.02 (d,
2-(1-(Isopentyloxy)heptyl)-1,5,8-trimethoxynaphthalene
1
J=8.7Hz, 1H).
(11a) Colorless oil; yield 0.58g (96.7%). H-NMR (400MHz,
1
-(1,5,8-Trimethoxynaphthalen-2-yl)undecan-1-ol (10c) CDCl ) δ: 0.82–0.90 (m, 9H), 1.25–1.49 (m, 12H), 1.81–1.88
3
1
Colorless oil; yield 0.75g (94.9%). H-NMR (400MHz, CDCl ) (m, 1H), 3.33 (t, J=6.7Hz, 2H), 3.85 (s, 3H), 3.93 (s, 3H), 3.96
3
δ: 0.84–0.87 (m, 3H), 1.21–1.29 (m, 16H), 1.73–1.86 (m, 2H), (s, 3H), 4.90 (dd, J=8.4Hz, J=4.5Hz, 1H), 6.70 (d, J=8.5Hz,
2
.35–2.45 (m, 1H), 3.82 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 1H), 6.77 (d, J=8.5Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 8.09 (d,
13
5
.22 (dd, J=8.0, 5.4Hz, 1H), 6.69 (d, J=8.0Hz, 1H), 6.76 (d, J=8.8Hz, 1H). C-NMR (100MHz, CDCl ) δ: 14,1, 22.6,
3
J=8.0Hz, 1H), 7.52 (d, J=8.8Hz, 1H), 8.02 (d, J=8.8Hz, 1H). 22.7, 22.7, 25.0, 26.2, 29.3, 31.8, 38.1, 38.9, 55.7, 56.6, 62.7,
1
-(1,5,8-Trimethoxynaphthalen-2-yl)tridecan-1-ol (10d) 67.3, 75.4, 103.6, 105.8, 118.5, 120.5, 124.5, 128.1, 134.0, 149.7,
1
Colorless oil; yield 0.83g (97.6%). H-NMR (400MHz, CDCl ) 149.7, 153.4.
3
δ: 0.88 (t, J=6.8Hz, 3H), 1.20–1.36 (m, 20H), 1.74–1.87 (m,
2-(1-(Isopentyloxy)nonyl)-1,5,8-trimethoxynaphthalene
H), 2.51–2.54 (m, 1H), 3.81 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), (11b) Colorless oil; yield 0.62g (96.0%). H-NMR (400MHz,
1
2
5
.22 (dd, J=8.0, 5.3Hz, 1H), 6.68 (d, J=8.4Hz, 1H), 6.75 (d, CDCl ) δ: 0.83–0.86 (m, 9H), 1.24–1.27 (m, 16H), 1.69 (d,
3
J=8.4Hz, 1H), 7.52 (d, J=8.8Hz, 1H), 8.01 (d, J=8.8Hz, 1H). J=3.6Hz, 1H), 3.29 (t, J=6.7Hz, 2H), 3.82 (s, 3H), 3.94
1
3
C-NMR (100MHz, CDCl ) δ: 14.1, 22.7, 26.2, 29.4, 29.6, (s, 3H), 3.96 (s, 3H), 4.86 (dd, J=8.5, 4.5Hz, 1H), 6.70 (d,
3
2
1
9.6, 29.6, 29.7, 31.9, 38.4, 55.7, 56.6, 56.6, 63.1, 68.7, 103.7, J=8.4Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 7.54 (d, J=8.0Hz, 1H),
03.7, 106.0, 106.1, 118.5, 124.3, 134.9, 149.7, 152.7.
8.05 (d, J=8.0Hz, 1H).
2-(1-(Isopentyloxy)undecyl)-1,5,8-trimethoxynaphtha-
1
-(4,5,8-Trimethoxynaphthalen-2-yl)heptan-1-ol
1
1
(17a) Colorless oil; yield 0.64g (95.5%). H-NMR (400MHz, lene (11c) Colorless oil; yield 0.65g (95.9%). H-NMR
CDCl ) δ: 0.84 (t, J=6.8Hz, 3H), 1.18–1.32 (m, 8H), 1.68–1.80 (400MHz, CDCl ) δ: 0.78–0.89 (m, 9H), 1.16–1.26 (m, 16H),
3
3
(m, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 4.69 (dd, 1.44 (q, J=6.8Hz, 2H), 1.64–1.74 (m, 2H), 1.77–1.81 (m, 1H),
J=7.5, 5.8Hz, 1H), 6.65 (d, J=8.4Hz, 1H), 6.69 (d, J=8.4Hz, 3.30 (t, J=6.7Hz, 2H), 3.82 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H),
1
3
1
(
5
H), 6.83 (d, J=1.5Hz, 1H), 7.65 (d, J=1.5Hz, 1H). C-NMR 4.86 (dd, J=8.4, 4.6Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 6.77 (d,
100MHz, CDCl ) δ: 14.1, 22.6, 25.9, 29.2, 31.8, 38.8, 55.6, J=8.5Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 8.05 (d, J=8.8Hz, 1H).
6.3, 57.3, 75.0, 104.3, 104.7, 106.5, 111.4, 117.7, 128.3, 142.8,
3
13
C-NMR (100MHz, CDCl ) δ: 14.1, 22.6, 22.7, 22.7, 25.0,
3
149.5, 150.7, 156.9.
26.2, 29.3, 29.6, 29.6, 29.6, 29.6, 31.9, 38.1, 38.8, 55.8, 56.6,
1
-(4,5,8-Trimethoxynaphthalen-2-yl)nonan-1-ol
(17b) 62.7, 67.3, 75.4, 103.6, 105.8, 118.4, 120.4, 124.6, 128.1, 134.0,
1
Colorless oil; yield 0.71g (97.3%). H-NMR (400MHz, CDCl ) 149.7, 149.7, 153.3.
3
δ: 0.85 (t, J=6.7Hz, 3H), 1.19–1.33 (m, 12H), 1.76–1.86 (m,
2-(1-(Isopentyloxy)tridecyl)-1,5,8-trimethoxynaphthalene
1
2
H), 3.90 (s, 3H), 3.93 (s, 3H), 3.97 (s, 3H), 4.77 (dd, J=7.5, (11d) Colorless oil; yield 0.71g (97.3%). H-NMR (400MHz,
.8Hz, 1H), 6.71 (d, J=8.5Hz, 1H), 6.75 (d, J=8.5Hz, 1H), CDCl ) δ: 0.80–0.90 (m, 9H), 1.25–1.39 (s, 20H), 1.44 (q,
.91 (d, J=1.5Hz, 1H), 7.74 (d, J=1.5Hz, 1H).
5
6
3
J=6.7Hz, 2H), 1.64–1.75 (m, 2H), 1.78–1.86 (m, 1H), 3.30 (t,
1
-(4,5,8-Trimethoxynaphthalen-2-yl)undecan-1-ol (17c) J=6.7Hz, 2H), 3.83 (s, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 4.88 (dd,
1
Colorless oil; yield 0.76g (96.2%). H-NMR (400MHz, J=8.4, 4.5Hz, 1H), 6.67 (d, J=8.5Hz, 1H), 6.75 (d, J=8.5Hz,
CDCl ) δ: 0.85 (t, J=6.7Hz, 3H), 1.17–1.31 (m, 16H), 1.76–1.86 1H), 7.55 (d, J=8.8Hz, 1H), 8.06 (d, J=8.8Hz, 1H). C-NMR
13
3
(m, 2H), 3.90 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 4.77 (dd, (100MHz, CDCl ) δ: 14.1, 22.6, 22.7, 22.7, 25.0, 26.2, 29.4,
3
J=7.5, 5.8Hz, 1H), 6.71 (d, J=8.5Hz, 1H), 6.74 (d, J=8.5Hz, 29.6, 29.6, 29.6, 29.6, 29.7, 29.7, 31.9, 38.1, 38.9, 55.7, 56.5, 62.7,
1
H), 6.90 (d, J=1.5Hz, 1H), 7.74 (d, J=1.5Hz, 1H).
67.2, 75.4, 103.5, 105.8, 118.5, 120.4, 124.5, 128.1, 133.9, 149.7,
-(4,5,8-Trimethoxynaphthalen-2-yl)tridecan-1-ol (17d) 149.7, 153.3.
1
1
Colorless oil; yield 0.82g (96.5%). H-NMR (400MHz, CDCl )
δ: 0.87 (t, J=6.8Hz, 3H), 1.20–1.30 (m, 20H), 1.68–1.84 (m, (18a) Colorless oil; yield 0.57g (95.0%). H-NMR (400MHz,
3-(1-(Isopentyloxy)heptyl)-1,5,8-trimethoxynaphthalene
3
1
2
4
1
H), 2.48–2.50 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.91 (s, 3H), CDCl ) δ: 0.80–0.88 (m, 9H), 1.16–1.54 (m, 12H), 1.87–1.92
3
.67–4.72 (m, 1H), 6.65 (d, J=8.6Hz, 1H), 6.69 (d, J=8.6Hz, (m, 1H), 3.27–3.38 (m, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 3.98 (s,
13
H), 6.84 (d, J=1.6Hz, 1H), 7.66 (d, J=1.6Hz, 1H). C-NMR 3H), 4.30 (dd, J=7.7, 5.8Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 6.70
(100MHz, CDCl ) δ: 14.1, 22.7, 25.9, 29.4, 29.5, 29.6, 29.6, (d, J=8.5Hz, 1H), 6.94 (d, J=1.4Hz, 1H), 7.73 (d, J=1.4Hz,
3
13
29.6, 29.7, 29.7, 31.9, 38.8, 55.6, 56.3, 57.3, 75.0, 104.3, 104.7, 1H). C-NMR (100MHz, CDCl ) δ: 14,1, 22.5, 22.6, 22.7,
3
106.5, 111.4, 117.7, 128.3, 142.8, 149.5, 150.7, 156.9.
25.0, 26.0, 29.2, 31.8, 38.2, 38.8, 55.6, 56.3, 57.3, 67.1, 82.8,
General Procedure for the Synthesis of Compounds 104.4, 104.7, 106.6, 112.9, 117.9, 128.3, 141.2, 149.5, 150.9,
11a–11d and 18a–18d NaH (60%, 0.3g, 7.5mmol) was 157.3.

Vol. 66, No. 6 (2018)
Chem. Pharm. Bull.
617
3
-(1-(Isopentyloxy)nonyl)-1,5,8-trimethoxynaphthalene 1.41–1.44 (m, 2H), 1.56–1.66 (m, 2H), 1.68–1.76 (m, 1H), 3.27
1
(
18b) Colorless oil; yield 0.63g (96.9%). H-NMR (400MHz, (t, J=6.7Hz, 2H), 3.85 (s, 3H), 4.70 (dd, J=8.0, 4.5Hz, 1H),
CDCl ) δ: 0.79–0.87 (m, 9H), 1.17–1.33 (m, 14H), 1.43–1.46 6.84 (d, J=10.3Hz, 1H), 6.87 (d, J=10.3Hz, 1H), 7.80 (d,
3
13
(
3
m, 2H), 1.68–1.72 (m, 1H), 3.25–3.35 (m, 2H), 3.90 (s, 3H), J=8.0Hz, 1H), 7.90 (d, J=8.0Hz, 1H). C-NMR (100MHz,
.94 (s, 3H), 3.97 (s, 3H), 4.28 (dd, J=7.6, 5.9Hz, 1H), 6.72 (d, CDCl ) δ: 14.1, 22.5, 22.6, 22.6, 24.9, 25.8, 29.3, 29.4, 29.5,
3
J=8.5Hz, 1H), 6.75 (d, J=8.5Hz, 1H), 6.91 (d, J=1.4Hz, 1H), 29.5, 29.6, 31.9, 37.6, 38.7, 62.1, 67.9, 75.5, 123.1, 123.5, 132.7,
7
.69 (d, J=1.4Hz, 1H).
132.9, 136.8, 140.2, 146.0, 157.6, 184.6, 184.8.
6-(1-(Isopentyloxy)tridecyl)-5-methoxynaphthalene-1,4-
3
-(1-(Isopentyloxy)undecyl)-1,5,8-trimethoxynaphthalene
1
1
(
18c) Colorless oil; yield 0.66g (97.3%). H-NMR (400MHz, dione (12d) Yellow oil; yield 0.20g (73.0%). H-NMR
CDCl ) δ: 0.80–0.92 (m, 9H), 1.18–1.38 (m, 16H), 1.45–1.47 (400MHz, CDCl ) δ: 0.75–0.85 (m, 9H), 1.12–1.30 (m, 20H),
3
3
(
2
5
6
m, 2H), 1.68–1.78 (m, 2H), 1.85–1.93 (m, 1H), 3.27–3.39 (m, 1.39–1.45 (m, 2H), 1.52–1.61 (m, 2H), 1.67 (dd, J=13.4, 6.7Hz,
H), 3.90 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.30 (dd, J=7.7, 1H), 3.25 (t, J=6.6Hz, 2H), 3.83 (s, 3H), 4.67 (dd, J=8.1,
.9Hz, 1H), 6.70 (d, J=8.5Hz, 1H), 6.74 (d, J=8.5Hz, 1H), 4.4Hz, 1H), 6.81 (d, J=10.2Hz, 1H), 6.85 (d, J=10.2Hz, 1H),
13
13
.94 (d, J=1.5Hz, 1H) 2, 7 (d, J=1.5Hz, 1H). C-NMR 7.77 (d, J=8.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H). C-NMR
(100MHz, CDCl ) δ: 14.1, 22.5, 22.6, 22.7, 22.7, 25.0, 26.0, (100MHz, CDCl ) δ: 14.1, 22.5, 22.5, 22.6, 24.9, 25.8, 29.3,
3
3
2
8
9.3, 29.6, 29.6, 29.7, 31.9, 38.2, 38.8 55.6, 56.3, 57.3, 67.1, 29.4, 29.5, 29.6, 29.6, 29.6, 29.6, 31.9, 37.6, 38.7, 62.1, 67.8,
2.8, 104.4, 104.7, 106.5, 112.9, 117.9, 128.3, 141.2, 149.5, 75.4, 123.1, 123.5, 132.6, 132.9, 136.7, 140.2, 146.0, 157.5,
150.9, 157.3.
184.5, 184.7.
3
-(1-(Isopentyloxy)tridecyl)-1,5,8-trimethoxynaphthalene
7-(1-(Isopentyloxy)heptyl)-5-methoxynaphthalene-1,4-
1
1
(
18d) Colorless oil; yield 0.70g (95.9%). H-NMR (400MHz, dione (19a) Yellow oil; yield 0.17g (76.1%). H-NMR
CDCl ) δ: 0.80–0.91 (m, 9H), 1.18–1.35 (s, 20H), 1.45–1.48 (m, (400MHz, CDCl ) δ: 0.81–0.88 (m, 9H), 1.21–1.47 (m, 12H),
3
3
2
H), 1.65–1.75 (m, 2H), 1.89–1.91 (m, 1H), 3.26–3.38 (m, 2H), 1.69–1.74 (m, 1H), 3.26–3.34 (m, 2H), 3.99 (s, 3H), 4.25 (dd,
3
1
.90 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H), 4.30 (dd, J=7.7, 5.8Hz, J=7.9, 5.2Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 6.80–6.86 (m,
13
H), 6.71 (d, J=8.5Hz, 1H), 6.74 (d, J=8.5Hz, 1H), 6.94 (d, 1H), 7.28 (d, J=1.5Hz, 1H), 7.58 (d, J=1.5Hz, 1H). C-NMR
13
J=1.4Hz, 1H), 7.72 (d, J=1.4Hz, 1H). C-NMR (100MHz, (100MHz, CDCl ) δ: 14.0, 22.5, 22.5, 22.6, 24.9, 25.7, 29.1,
CDCl ) δ: 14.1, 22.5, 22.7, 22.7, 25.0, 26.1, 29.4, 29.4, 29.6, 29.7, 31.7, 38.1, 38.7, 56.5, 67.9, 81.9, 114.9, 117.6, 133.9, 136.1,
3
3
2
8
9.6, 29.7, 29.7, 29.7, 31.9, 38.2, 38.9, 55.6, 56.3, 57.3, 67.1, 141.0, 152.2, 160.1, 184.1, 185.4.
2.8, 104.4, 104.7, 106.5, 112.9, 117.9, 128.3, 141.2, 149.5, 150.9 7-(1-(Isopentyloxy)nonyl)-5-methoxynaphthalene-1,4-
1
157.3.
dione (19b) Yellow oil; yield 0.18g (75.0%). H-NMR
General Procedure for the Synthesis of Compounds (400MHz, CDCl ) δ: 0.83–0.88 (m, 9H), 1.20–1.28 (m, 16H),
3
12a–12d and 19a–19d A solution of CAN (1.32mmol) 3.29–3.33 (m, 2H), 4.24–4.28 (m, 3H), 6.83–6.85 (m, 2H), 7.29
in water (1mL) was added dropwise to a solution of tri- (d, J=1.5Hz, 1H), 7.59 (d, J=1.5Hz, 1H).
methoxynaphthalene derivatives (11a–11d or 18a–18d, 7-(1-(Isopentyloxy)undecyl)-5-methoxynaphthalene-1,4-
.60mmol) in ethyl acetate (6mL) at 0°C. After 10min, the dione (19c) Yellow oil; yield 0.21g (81.7%). H-NMR
1
0
reaction mixture was diluted with water and extracted with (400MHz, CDCl ) δ: 0.79–0.85 (m, 9H), 1.15–1.25 (m, 16H),
3
ethyl acetate, washed with brine and dried over anhydrous 1.42–1.45 (m, 2H), 1.52–1.65 (m, 2H), 1.67–1.71 (m, 1H),
Na SO . The solvent was evaporated under reduced pressure 3.25–3.32 (m, 2H), 3.97 (s, 3H), 4.24 (dd, J=7.9, 5.2Hz, 1H),
2
4
and the residue was purified by flash column chromatography 6.79–6.83 (m, 2H), 7.27 (d, J=1.4Hz, 1H), 7.57 (d, J=1.4Hz,
13
to afford 12a–12d and 19a–19d as yellow oil.
1H). C-NMR (100MHz, CDCl ) δ: 14.1, 22.4, 22.5, 22.6,
3
6
-(1-(Isopentyloxy)heptyl)-5-methoxynaphthalene-1,4- 22.6, 24.9, 25.7, 29.3, 29.4, 29.4, 29.5, 31.8, 38.1, 38.7, 56.4,
1
dione (12a) Yellow oil; yield 0.18g (80.5%). H-NMR 67.9, 81.9, 114.9, 117.5, 118.8, 133.9, 136.1, 140.9, 152.2, 160.1,
400MHz, CDCl ) δ: 0.77–0.83 (m, 9H), 1.14–1.46 (m, 12H), 184.0, 185.3.
(
3
1
.64–1.69 (m, 1H), 3.25 (t, J=6.6Hz, 2H), 3.83 (s, 3H), 4.68
7-(1-(Isopentyloxy)tridecyl)-5-methoxynaphthalene-1,4-
1
(dd, J=8.0, 4.5Hz, 1H), 6.81 (d, J=10.3Hz, 1H), 6.85 (d, dione (19d) Yellow oil; yield 0.22g (80.3%). H-NMR
J=10.3Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.87 (d, J=8.0Hz, (400MHz, CDCl ) δ: 0.75–0.82 (m, 9H), 1.10–1.26 (m, 20H),
3
13
1
H). C-NMR (100MHz, CDCl ) δ: 14.0, 22.5, 22.5, 22.5, 1.37–1.41 (m, 2H), 1.47–1.64 (m, 2H), 1.65–1.69 (d, J=6.6Hz,
3
2
2.5, 24.9, 25.8, 29.0, 31.7, 37.6, 38.7, 62.1, 67.8, 75.4, 123.1, 1H), 3.21–3.29 (m, 2H), 3.94 (s, 3H), 4.21 (dd, J=7.9, 5.1Hz,
132.6, 132.9, 136.7, 140.2, 146.0, 157.5, 184.5, 184.7.
1H), 6.75–6.80 (m, 2H), 7.25 (d, J=1.4Hz, 1H), 7.53 (d,
13
6
-(1-(Isopentyloxy)nonyl)-5-methoxynaphthalene-1,4- J=1.4Hz, 1H). C-NMR (100MHz, CDCl ) δ: 14.1, 22.4,
3
1
dione (12b) Yellow oil; yield 0.19g (79.2%). H-NMR 22.6, 22.6, 24.9, 25.7, 29.3, 29.4, 29.4, 29.5, 29.5, 29.6, 29.6,
400MHz, CDCl ) δ: 0.81–0.87 (m, 9H), 1.14–1.38 (m, 14H), 31.8, 38.1, 38.6, 56.4, 67.8, 81.8, 114.8, 117.5, 118.7, 133.8,
(
3
1
3
1
.42–1.46 (m, 2H), 1.67–1.72 (m, 1H), 3.28 (t, J=6.7Hz, 2H), 136.0, 140.9, 152.1, 160.1, 184.0, 185.3.
.86 (s, 3H), 4.71 (dd, J=8.0, 4.4Hz, 1H), 6.85 (d, J=10.3Hz, General Procedure for the Synthesis of Compounds
H), 6.89 (d, J=10.3Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.92 (d, 13–16 and 20–23 A mixture of 1,4-naphthoquione de-
13
J=8.0Hz, 1H). C-NMR (100MHz, CDCl ) δ: 14.1, 22.5, rivatives (12a–12d or 19a–19d, 0.5mmol), hydroxylamine
3
2
6
2.6, 22.6, 24.9, 25.8, 29.2, 29.4, 29.5, 31.8, 37.6, 38.7, 62.2, hydrochloride (4.0mmol), and pyridine (4.0mmol) in absolute
7.9, 75.5, 123.1, 123.6, 132.7, 132.9, 136.8, 140.3, 146.0, 157.6, ethanol (10.0mL) was stirred at 50°C overnight. After cooled
184.6, 184.8.
to the room temperature, the ethanol was evaporated under
6
-(1-(Isopentyloxy)undecyl)-5-methoxynaphthalene-1,4- reduced pressure and the mixture was diluted with water and
1
dione (12c) Yellow oil; yield 0.19g (73.9%). H-NMR extracted with ethyl acetate, washed with brine, dried over
(
400MHz, CDCl ) δ: 0.79–0.88 (m, 9H), 1.15–1.35 (m, 16H), anhydrous Na SO and concentrated. The residue was purified
3
2
4

6
18
Chem. Pharm. Bull.
Vol. 66, No. 6 (2018)
by flash column chromatography to afford 13–16 and 20–23 lene-1,4-dione Dioxime (22) Yellow solid; yield 0.17g
1
as yellow solid.
1E,4E)-6-(1-(Isopentyloxy)heptyl)-5-methoxynaphtha- 1.08–1.57 (m, 20H), 1.64–1.66 (m, 1H), 3.18–3.27 (m, 2H),
lene-1,4-dione Dioxime (13) Yellow solid; yield 0.14g 3.79 (s, 3H), 4.21 (dd, J=7.5, 5.4Hz, 1H), 7.00 (d, J=1.6Hz,
(74.2%). H-NMR (400MHz, DMSO-d ) δ: 0.70–0.85 (m, 9H),
6
(
1
(
70.0%). H-NMR (400MHz, DMSO-d ) δ: 0.76–0.84 (m, 9H), 1H), 7.27 (d, J=10.7Hz, 1H), 7.50 (d, J=10.7Hz, 1H), 7.66
6
13
1
.12–1.29 (m, 10H), 1.33–1.37 (m, 2H), 1.62–1.66 (m, 1H), 3.23 (d, J=1.6Hz, 1H), 11.99 (s, 1H), 12.14 (s, 1H). C-NMR
(
t, J=6.5Hz, 2H), 3.62 (s, 3H), 4.64 (t, J=8.1Hz, 1H), 7.30 (d, (100MHz, DMSO-d ) δ: 14.4, 22.5, 22.7, 23.0, 24.9, 25.6, 29.1,
6
J=10.7Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.50 (d, J=10.7Hz, 29.3, 29.4, 29.4, 31.7, 38.0, 38.8, 56.2, 66.9, 81.5, 110.4, 113.0,
1
H), 7.92 (d, J=8.4Hz, 1H), 12.07 (s, 1H), 12.17 (s, 1H). 117.3, 117.9, 120.2, 131.8, 144.7, 147.5, 148.1, 158.0.
1
3
C-NMR (100MHz, DMSO-d ) δ: 14.3, 22.5, 22.8, 22.9, 24.9,
(1E,4E)-7-(1-(Isopentyloxy)tridecyl)-5-methoxynaphtha-
6
2
1
5.8, 28.9, 31.6, 37.5, 38.8, 61.0, 67.0, 75.1, 118.0, 119.0, 119.8, lene-1,4-dione Dioxime (23) Yellow solid; yield 0.19g
1
22.3, 127.2, 131.1, 138.4, 147.2, 147.5, 155.4.
1E,4E)-6-(1-(Isopentyloxy)nonyl)-5-methoxynaphtha- 1.03–1.39 (m, 24H), 1.42–1.46 (m, 1H), 3.17–3.23 (m, 2H), 3.75
lene-1,4-dione Dioxime (14) Yellow solid; yield 0.16g (s, 3H), 4.17 (t, J=6.5Hz, 1H), 6.97 (d, J=1.6Hz, 1H), 7.23
(78.2%). H-NMR (400MHz, DMSO-d ) δ: 0.68–0.78 (m, 9H),
6
(
1
(
1
3
1
74.4%). H-NMR (400MHz, DMSO-d ) δ: 0.74–0.85 (m, 9H), (d, J=10.6Hz, 1H), 7.45 (d, J=10.6Hz, 1H), 7.61 (d, J=1.6Hz,
6
13
.10–1.48 (m, 16H), 1.62–1.68 (m, 1H), 3.22 (t, J=6.4Hz, 2H), 1H), 11.97 (s, 1H), 12.13 (s, 1H). C-NMR (100MHz, DMSO-
.62 (s, 3H), 4.64 (dd, J=8.1, 4.6Hz, 1H), 7.30 (d, J=10.7Hz, d6) δ: 14.3, 22.5, 22.7, 22.9, 24.9, 25.6, 29.1, 29.2, 29.3, 29.3,
H), 7.37 (d, J=8.4Hz, 1H), 7.50 (d, J=10.7Hz, 1H), 7.92 29.4, 29.4, 29.4, 31.7, 37.9, 38.7, 56.2, 66.8, 81.5, 110.4, 112.9,
13
(
d, J=8.4Hz, 1H), 12.07 (s, 1H), 12.17 (s, 1H). C-NMR 117.2, 117.8, 120.1, 131.7, 144.6, 147.4, 148.0, 157.9.
100MHz, DMSO-d ) δ: 14.4, 22.5, 22.8, 22.9, 24.9, 25.8, 29.1, Cytotoxic Activity The tested compounds were dissolved
9.2, 29.3, 31.7, 37.5, 38.8, 61.0, 67.0, 75.1, 118.0, 119.0, 119.8, in suitable amount of dimethyl sulfoxide (DMSO) prior to the
22.3, 127.2, 131.1, 138.4, 147.2, 147.5, 155.4. experiment to obtain the known concentration of the solution,
1E,4E)-6-(1-(Isopentyloxy)undecyl)-5-methoxynaphtha- and then were diluted to the desired concentrations with cul-
lene-1,4-dione Dioxime (15) Yellow solid; yield 0.18g ture medium. Cells were planted in 96-well plate (5000/well)
(
2
1
6
(
1
(78.6%). H-NMR (400MHz, DMSO-d ) δ: 0.75–0.87 (m, 9H), until 70–80% confluence was achieved. After incubation for
6
1
.13–1.39 (m, 20H), 1.61–1.67 (m, 1H), 3.22 (t, J=6.4Hz, 2H), 24h at 37°C, 5% CO atmosphere, cells were treated with the
2
3
.62 (s, 3H), 4.64 (dd, J=8.1, 4.6Hz, 1H), 7.30 (d, J=10.7Hz, tested compound of serial concentrations for 48h and control
1H), 7.37 (d, J=8.4Hz, 1H), 7.50 (d, J=10.7Hz, 1H), 7.92 groups were treated with medium containing same concentra-
13
(d, J=8.4Hz, 1H), 12.07 (s, 1H), 12.16 (s, 1H). C-NMR tion of DMSO with the medicated group. The supernatants
(100MHz, DMSO-d ) δ: 14.4, 22.5, 22.8, 22.9, 24.9, 25.7, 29.1, were removed and replaced by 200µL Roswell Park Memorial
6
29.2, 29.3, 29.4, 30.2, 31.7, 37.5, 38.8, 61.0, 67.0, 75.1, 118.0, Institute 1640 (RPMI-1640) medium without serum. After the
1
19.0, 119.8, 122.3, 127.2, 131.1, 138.4, 147.2, 147.5, 155.4
1E,4E)-6-(1-(Isopentyloxy)tridecyl)-5-methoxynaphtha- was added to each well and the cells were incubated for an
lene-1,4-dione Dioxime (16) Yellow solid; yield 0.20g additional 4h at 37°C. The MTT-containing media was re-
media was removed and 20µL of MTT (5mg/mL) solution
(
1
1
(82.3%). H-NMR (400MHz, DMSO-d6) δ: H-NMR moved and then 100µL of DMSO was added into each well
(
400MHz, DMSO-d ) δ: 0.72–0.79 (m, 9H), 1.09–1.39 (m, for dissolving the formazan crystals. The optical density (OD)
6
2
4
4H), 1.58–1.64 (m, 1H), 3.16–3.22 (m, 2H), 3.58 (s, 3H), was measured by Multiskan MK3 microplate reader (Thermo
.62 (dd, J=8.1, 4.6Hz, 1H), 7.26 (d, J=10.7Hz, 1H), 7.33 Scientific, U.S.A.) at 570nm. Each group was in triplicate
(d, J=8.4Hz, 1H), 7.47 (d, J=10.7Hz, 1H), 7.89 (d, J=8.4Hz, samples and each compound was divided into at 6 concentra-
13
1H), 12.05 (s, 1H), 12.15 (s, 1H). C-NMR (100MHz, DMSO- tions. The resulting cytotoxic activities were expressed as IC50
d6) δ: 14.3, 22.5, 22.8, 22.9, 24.9, 25.7, 29.1, 29.2, 29.3, 29.3, values and IC50 values were determined by Graphpad Prism 5.
9.4, 29.4, 29.4, 31.7, 37.5, 38.7, 61.0, 67.0, 75.1, 117.9, 118.9,
19.8, 122.3, 127.1, 131.1, 138.3, 147.2, 147.4, 155.4.
1E,4E)-7-(1-(Isopentyloxy)heptyl)-5-methoxynaphtha- Natural Science Foundation of China (No. 81373274 and No.
lene-1,4-dione Dioxime (20) Yellow solid; yield 0.15g 81673281) and Hong Kong Scholar Program (XJ2015032). We
2
1
Acknowledgments The research is supported by National
(
1
(
1
75.0%). H-NMR (400MHz, DMSO-d ) δ: 0.76–0.84 (m, 9H), are grateful to the Instrumental Analysis Center of Shanghai
6
1
13
.10–1.44 (m, 12H), 1.54–1.57 (m, 1H), 3.22–3.27 (m, 2H), Jiao Tong University for recording the H-NMR and C-NMR
3
.79 (s, 3H), 4.23 (dd, J=7.5, 5.5Hz, 1H), 7.01 (d, J=1.6Hz, spectra.
1
H), 7.27 (d, J=10.7Hz, 1H), 7.50 (d, J=10.7Hz, 1H), 7.66
13
(d, J=1.6Hz, 1H), 12.01 (s, 1H), 12.12 (s, 1H). C-NMR
Conflict of Interest The authors declare no conflict of
(
100MHz, DMSO-d ) δ: 14.3, 22.5, 22.8, 23.0, 24.9, 25.6, interest.
6
29.0, 31.7, 38.0, 38.8, 56.3, 66.9, 81.5, 110.5, 113.0, 117.3, 117.9,
120.2, 131.8, 144.7, 147.5, 158.0.
Supplementary Materials The online version of this ar-
(1E,4E)-7-(1-(Isopentyloxy)nonyl)-5-methoxynaphthalene- ticle contains supplementary materials.
1
,4-dione Dioxime (21) Yellow solid; yield 0.17g (79.1%).
1
H-NMR (400MHz, DMSO-d ) δ: 0.76–0.84 (m, 9H), 1.15– References
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