Synthesis and Cytotoxicity of 1,4-Naphthoquinone Oxime Derivatives

Article abstract of DOI:10.1134/S1070363218110221

A series of hydroxylated 1,4-naphthoquinone oximes were designed and synthesized. The in vitro cytotoxicity of these compounds was evaluated against five human cancer cell lines and human skin fibroblast cell line. Among them, compounds (1E,4E)-6-{1-[(5-Hydroxypentyl)oxy]-2,2-dimethylbut-3-en-1-yl}-5,8- dimethoxynaphthalene-1,4-dione dioxime and (1E,4E)-6-{1-[(6-Hydroxyhexyl)oxy]-2,2-dimethylbut-3-en-1-yl}-5,8-dimethoxynaphthalene-1,4-dione dioxime displayed higher cytotoxicity in three cancer cell lines than the positive drug 5-fluorouracil.

Full text of DOI:10.1134/S1070363218110221

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 11, pp. 2388–2393. © Pleiades Publishing, Ltd., 2018.
Synthesis and Cytotoxicity
of 1,4-Naphthoquinone Oxime Derivatives1,2
Q. Zhanga*, J. Donga, Q. Menga, G. Huanga, and S. Lia**
a
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240 China
e-mail: *lianyi1126@sjtu.edu.cn; **ssli@sjtu.edu.cn
Received April 27, 2018
Abstract―A series of hydroxylated 1,4-naphthoquinone oximes were designed and synthesized. The in vitro
cytotoxicity of these compounds was evaluated against five human cancer cell lines and human skin fibroblast
cell line. Among them, compounds (1E,4E)-6-{1-[(5-Hydroxypentyl)oxy]-2,2-dimethylbut-3-en-1-yl}-5,8-
dimethoxynaphthalene-1,4-dione dioxime and (1E,4E)-6-{1-[(6-Hydroxyhexyl)oxy]-2,2-dimethylbut-3-en-1-
yl}-5,8-dimethoxynaphthalene-1,4-dione dioxime displayed higher cytotoxicity in three cancer cell lines than
the positive drug 5-fluorouracil
Keywords: naphthoquinone, oxime, cytotoxicity, synthesis
DOI: 10.1134/S1070363218110221
1,4-Naphthoquinones, such as lawsone, shikonin,
juglone, phthiocol, lapachol, and plumbagin, are naturally
occurring and have received significant attention due
to their wide spectrum of biological activities, including
antiproliferative antiviral, antibacterial, antitrypanosome,
antiplasmodial, antiparasitic, antimalarial, and anti-
inflammatory[1–5].
then deprotected by treatment of methanolic HCl at
room temperature (RT) to afford compounds 12‒16.
Subsequent oxidation with cerium(IV) ammonium
nitrate (CAN) yields the corresponding 1,4-naphtho-
quinones 17‒21. The target 1,4-naphthoquinone
dioxime derivatives 22‒26 were obtained by the
oximation of their corresponding 1,4-naphthoquinones
in the presence of hydroxylamine hydrochloride and
pyridine at 50°C (Scheme 1).
When naphthoquinone carbonyls were converted to
oxime groups, O-dimethyl shikonin derivatives showed
a higher cytotoxic activity against cancer cells but a
lower cytotoxicity against normal cells than their
parent compounds [6, 7]. As a continuation of our
previous research [8], we synthesized a series of 1,4-
naphthoquinone oxime derivatives and evaluated their
cytotoxic activity.
Biological activity. The cytotoxic effects of the
synthesized 1,4-naphthoquinone oxime derivatives on
colorectal cancer cells (HCT-15 and HCT-116), breast
cancer cells (MDA-MB-231, liver cancer cells (BEL-
7402), ovarian cancer cells (A2780), and human skin
fibroblast (HSF) cell lines were tested in vitro using
the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-
zolium bromide (MTT) assay. The first line drug
5-fluorouracil (5-Fu) was used as positive control. The
resulting half-maximal inhibitory concentrations (IC50,
μM) are listed in the table.
RESULTS AND DISCUSSION
Synthesis. The hydroxyls in compounds 1‒5 were
protected by 3,4-dihydropyran (DHP) in the presence
of p-toluenesulfonic acid (TsOH). 1,4,5,8-Tetra-
methoxy-2-naphthaldehyde (TMNA) was obtained by
the procedures previously reported by our research
group [9]. Alcohol 8 was prepared by the zinc-
mediated γ-regioselective prenylation of TMNA as
described in the reference [10]. The nucleophilic
substitution of compound 6 with protected alcohols
(compounds 1‒5) gives compounds 7–11, which were
As seen from the table, compounds 22‒26 showed
lower cytotoxicity against two colorectal cancer cells
but higher cytotoxicity against breast cancer cells than
the reference drug 5-Fu. Among these naphthoquinone
oxime derivatives, compound 25 exhibited the highest
cytotoxicity against BEL-7402 and MDA-MB-231
with IC50 values of 6.53 and 8.46 μM, respectively. At
the same time, the IC50 of compound 25 toward A2780
was found to be 60.59 μM. None of the target
compounds displayed cytotoxicity toward the normal
HSF cell line (IC50>100 μM).
1 The text was submitted by the authors in English.
2
Supporting materials are available from authors.
2388

SYNTHESIS AND CYTOTOXICITY OF 1,4-NAPHTHOQUINONE OXIME DERIVATIVES
2389
Scheme 1.
Br
Br
OH
OH
Br
OTHP
O
n
TsOH, CH2Cl2
n
1−4
or
+
or
Br
n = 1−4
OTHP
5
OMe OMe
OMe OMe
OMe OMe
a
b
CHO
c
OMe OMe
TMNA
OMe OMe OH
OMe OMe O
R1
6
7−11
HO
O
OMe
OMe OMe
N
OMe
d
e
O
OMe O
OMe OMe O
N
OMe O
R2
R2
HO
R2
22−26
17−21
OTHP
12−16
R1 =
n
n
OTHP
OH
R2 =
OH
n = 1−4
Reagents and conditions: a, isopentyl bromide, Zn power, THF, room temperature; b, NaH, I2, DMF, room temperature;
c, HCl, MeOH, room temperature; d, EtOAc/H2O, CAN, ice bath; e, NH2OH·HCl, Py, EtOH, 50°C.
EXPERIMENTAL
on silica gel (100–200 mesh) from Qingdao Ocean
Chemical Factory. The 1H NMR and 13C NMR spectra
were measured on an Agilent 400 spectrometer
(400 MHz) using DMSO-d6 or CDCl3 as solvents, and
chemical shifts were measured against internal TMS.
Reagents and solvents were obtained from
commercial suppliers and purified using standard
techniques. Column chromatography was conducted
In vitro cytotoxicity of hydroxylated 1,4-naphthoquinone oximes 22‒26 against five human cancer cell lines
IC50, μM
Compound
HCT-15
77.59
>100
MDA-MB-231
41.81
BEL-7402
31.95
48.15
12.92
6.53
HCT-116
56.38
>100
A2780
>100
>100
85.89
60.59
>100
67.89
HSF
>100
>100
>100
>100
>100
>100
22
23
98.56
24
35.91
30.22
>100
24.97
27.64
23.52
48.92
1.73
25
8.46
26
33.63
22.31
37.07
5-Fu
9.89
148.36
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 11 2018

2390
ZHANG et al.
Synthesis of compounds 1‒5. 3,4-Dihydropyran
TMNA (2.76 g, 10 mmol) in anhydrous THF (5 mL)
was added to the supernatant containing isopentylzinc
bromide prepared at the previous step. The solution
was stirred at room temperature for 3 h and then
quenched with saturated NH4Cl solution. The mixture
was extracted with dichloromethane, washed with
brine, and dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure, and the
residue was purified by flash column chromatography
(DHP, 15 mmol) was added slowly to a stirred solution
of bromohydrin (10 mmol) and p-toluenesulfonic acid
(1 mmol) in dichloromethane (20 mL) on ice bath.
After stirring at room temperature overnight, the
reaction mixture was diluted with water and extracted
with dichloromethane. The organic layer was washed
with brine and dried over anhydrous Na2SO4. The
solvent was evaporated under reduced pressure, and
the residue was purified by flash column chromato-
graphy to afford 1-5 as a light yellow oil.
1
to afford 6 as a yellow oil (yield 93.7%). H NMR
spectrum, δ, ppm: 0.97 d (J = 2.5 Hz, 3H), 1.08 d (J =
2.6 Hz, 3H), 2.22–2.32 m (1H), 3.68 s (3H), 3.84–3.90
m (9H), 5.04 d.d (J = 10.1, 7.6 Hz, 2H), 5.11 d (J =
10.9 Hz, 1H), 6.03–6.07 m (1H), 6.74–6.82 m (2H),
6.95 d (J = 2.5 Hz, 1H). 13C NMR spectrum, δC, ppm:
21.3, 25.1, 43.2, 57.0, 57.4, 57.7, 62.4, 73.6, 108.0,
108.2, 108.3, 113.6, 120.2, 122.4, 130.7, 145.4, 147.7,
150.3, 151.4, 152.2.
2-(3-Bromopropoxy)tetrahydro-2H-pyran (1).
Yield 94.2%. 1H NMR spectrum, δ, ppm: 1.37–1.55 m
(4H), 1.57–1.65 m (1H), 1.70–1.78 m (1H), 2.01–2.10
m (2H), 3.37–3.49 m (4H), 3.73–3.83 m (2H), 4.49–
4.55 m (1H). 13C NMR spectrum, δC, ppm: 19.4, 25.4,
30.5, 30.6, 32.8, 62.1, 64.8, 98.7.
2-(4-Bromobutoxy)tetrahydro-2H-pyran (2).
Yield 95.8%. 1H NMR spectrum, δ, ppm: 1.34–1.46 m
(4H), 1.54–1.73 m (4H), 1.79–1.89 m (2H), 3.25–2.40
m (4H), 3.59–3.75 m (2H), 4.44 s (1H). 13C NMR
spectrum, δC, ppm: 19.5, 25.4, 28.3, 29.7, 30.6, 33.6,
62.1, 66.3, 98.6.
Synthesis of compounds 7–11. NaH (60%, 0.3 g,
7.5 mmol) was added in portion to a stirred solution of
6 (1.04 g, 3 mmol) in anhydrous DMF (20 mL) at 0°C.
After stirring for 1 h, a solution of 1–5 (4.5 mmol)
dissolved in anhydrous DMF (3 mL) and a catalytic
amount of iodine were added to the reaction mixture,
which was stirred at 60°C overnight. The reaction
mixture was quenched with saturated NH4Cl solution
and then extracted with dichloromethane. The organic
layer was washed with brine and dried over anhydrous
Na2SO4. The solvent was evaporated to give 7–11 as
yellow oil and used for the next step without further
purification.
2-[(5-Bromopentyl)oxy]tetrahydro-2H-pyran
1
(3). Yield 97.3%. H NMR spectrum, δ, ppm: 1.42–
1.48 m (8H), 1.56–1.64 m (1H), 1.70–1.72 m (1H),
1.73–1.77 m (2H), 3.24–3.43 m (4H), 3.57–3.80 m
(2H), 4.45–4.48 m (1H). 13C NMR spectrum, δC, ppm:
19.6, 24.9, 25.4, 28.8, 30.6, 32.5, 33.6, 62.2, 67.0, 98.7.
2-[(6-Bromohexyl)oxy]tetrahydro-2H-pyran (4).
Yield 96.4%. 1H NMR spectrum, δ, ppm: 1.25–1.51 m
(10H), 1.54–1.76 m (4H), 3.19–3.30 m (3H), 3.32–
3.40 m (1H), 3.56–3.62 m (1H), 3.70–3.74 m (1H),
4.43 t (J = 3.5 Hz, 1H). 13C NMR spectrum, δC, ppm:
19.6, 25.4, 25.4, 27.9, 29.5, 30.7, 32.7, 33.8, 62.2, 67.3,
98.8.
Synthesis of compounds 12–16. Hydrochloric acid
(1 mL) was added dropwise to a solution of 7–11
(2 mmol) in methanol (10 mL) under ice-bath. After
the completion of reaction, the mixture was diluted
with dichloromethane, neutralized with saturated sodium
bicarbonate. The organic layer was separated, washed
with saturated NaCl, dried over Na2SO4 and then
evaporated under reduced pressure. The residue was
purified by flash column chromatography to afford 12–
16 as light yellow oil.
2-[(5-Bromopentan-2-yl)oxy]tetrahydro-2H-
1
pyran (5). Yield 92.1%. H NMR spectrum, δ, ppm:
1.02–1.16 m (3H), 1.37–1.98 m (10H), 3.60–3.85 m
(3H), 3.61–3.86 m (2H), 4.46–4.59 m (1H). 13C NMR
spectrum, δC, ppm: 19.9, 21.5, 25.4, 26.4, 31.1, 34.0, 37.9,
62.7, 73.1, 98.7.
3-{[2,2-Dimethyl-1-(1,4,5,8-tetramethoxy-
naphthalen-2-yl)but-3-en-1-yl]oxy}propan-1-ol (12).
Yield 89.6%. 1H NMR spectrum, δ, ppm: 0.96 s (3H),
1.11 s (3H), 1.72–1.85 m (2H), 3.43–3.50 m (2H), 3.70
s (3H), 3.76 t.d (J = 6.3, 4.1 Hz, 2H), 3.86–3.92 m
(9H), 4.65 s (1H), 4.91 d.d (J = 17.5, 1.4 Hz, 1H), 5.00
d.d (J = 10.8, 1.4 Hz, 1H), 6.03 d.d (J = 17.5, 10.8 Hz,
1H), 6.79–6.85 m (2H), 6.87 s (1H). 13C NMR
spectrum, δC, ppm: 22.6, 25.0, 29.7, 31.9, 42.3, 56.9,
2,2-Dimethyl-1-(1,4,5,8-tetramethoxynaphthalen
-2-yl)but-3-en-1-ol (6). Isopentyl bromide (25 mL)
was added dropwise to a stirred suspension of zinc
powder (30 g, 0.46 mol) in anhydrous THF (100 mL)
under nitrogen atmosphere. After stirring for 2 h, zinc
powder was removed by centrifugation. A solution of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 11 2018

SYNTHESIS AND CYTOTOXICITY OF 1,4-NAPHTHOQUINONE OXIME DERIVATIVES
2391
57.5, 57.6, 62.1, 62.7, 69.3, 77.3, 82.6, 107.2, 108.2,
108.4, 112.4, 128.9, 145.1, 148.9, 150.2, 151.5, 152.5.
(J = 17.6, 10.8 Hz, 1H), 6.73–6.81 m (2H), 6.88 d (J =
3.1 Hz, 1H). 13C NMR spectrum, δC, ppm: 22.7, 22.8,
23.4, 25.0, 26.4, 36.7, 42.4, 56.9, 57.5, 62.1, 67.3, 67.7,
69.6, 82.3, 108.0, 108.4, 111.9, 120.2, 122.3, 129.7,
145.2, 148.7, 150.2, 151.5, 152.2.
4-{[2,2-Dimethyl-1-(1,4,5,8-tetramethoxy-
naphthalen-2-yl)but-3-en-1-yl]oxy}butan-1-ol (13).
1
Yield 93.3%. H NMR spectrum, δ, ppm: 0.95 d (J =
1.9 Hz, 3H), 1.10 d (J = 1.9 Hz, 3H), 1.58–1.68 m
(4H), 2.38 s (1H), 3.29 q (J = 6.6, 5.5 Hz, 2H), 3.61 d
(J = 5.5 Hz, 2H), 3.69 t (J = 1.7 Hz, 3H), 3.83–3.92 m
(9H), 4.62 d (J = 1.9 Hz, 1H), 4.84 d.d (J = 17.6,
2.0 Hz, 1H), 4.94 d.d (J = 10.7, 2.0 Hz, 1H), 6.09 d.d
(J = 17.6, 10.8 Hz, 1H), 6.79 d (J = 8.0 Hz, 2H), δ 6.89
s (1H). 13C NMR spectrum, δC, ppm: 22.8, 25.0, 26.6,
30.1, 42.4, 56.9, 57.4, 57.6, 62.1, 62.6, 69.3, 82.3,
107.9, 108.0, 108.3, 112.0, 120.2, 122.3, 129.6, 145.2,
148.7, 150.2, 151.5, 152.2.
Synthesis of compounds 17–21. A solution of
CAN (2.2 mmol) in water (1 mL) was added dropwise
to a solution of 12–16 (1 mmol) in ethyl acetate (6 mL)
at 0°C. After 10 min, the reaction mixture was diluted
with water and extracted with ethyl acetate, washed
with brine and dried over anhydrous Na2SO4. The
solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography
to afford 17–21 as yellow oil.
6-[1-(3-Hydroxypropoxy)-2,2-dimethylbut-3-en-
1-yl]-5,8-dimethoxynaphthalene-1,4-dione (17).
5-{[2,2-Dimethyl-1-(1,4,5,8-tetramethoxy-
naphthalen-2-yl)but-3-en-1-yl]oxy}pentan-1-ol (14).
1
Yield 36.3%. H NMR spectrum, δ, ppm: 0.85 s (3H),
1
Yield 90.5%. H NMR spectrum, δ, ppm: 0.94 d (J =
1.04 s (3H), 1.72–1.78 m (2H), 2.47 s (1H), 3.31–3.42
m (2H), 3.64–3.71 m (2H), 3.72 s (3H), 3.87 s (3H),
4.52 s (1H), 4.77 d.d (J = 17.6, 1.3 Hz, 1H), 4.93 d.d
(J = 10.8, 1.3 Hz, 1H), 5.90 d.d (J = 17.5, 10.8 Hz,
1H), 6.70 d (J = 2.1 Hz, 2H), 7.27 s (1H). 13C NMR
spectrum, δC, ppm: 22.3, 24.7, 32.2, 42.3, 56.5, 61.3,
61.9, 68.5, 81.9, 113.3, 119.1, 120.1, 124.3, 137.8, 138.7,
143.2, 143.6, 152.6, 155.4, 184.4, 184.9.
1.8 Hz, 3H), 1.09 d (J = 1.8 Hz, 3H), 1.36–1.42 m
(2H), 1.47–1.57 m (2H), 2.09 s (1H), 3.20–3.26 m
(2H), 3.53–3.58 m (2H), 3.67 s (3H), 3.82–3.90 m
(9H), 4.57 d (J = 1.8 Hz, 1H), 4.79 d (J = 17.6 Hz,
1H), 4.90 d (J = 10.8 Hz, 1H), 6.11 d.d (J = 17.6, 10.8 Hz,
1H), 6.77 d (J = 8.0 Hz, 2H), 6.89 s (1H). 13C NMR
spectrum, δC, ppm: 22.6, 22.8, 25.0, 29.6, 32.4, 42.4,
57.0, 57.4, 57.6, 62.1, 62.7, 69.1, 81.9, 107.9, 108.2,
108.3, 111.6, 120.2, 122.3, 130.1, 145.4, 148.7, 150.2,
151.4, 152.1.
6-[1-(4-Hydroxybutoxy)-2,2-dimethylbut-3-en-1-
yl]-5,8-dimethoxynaphthalene-1,4-dione (18). Yield
32.4%. 1H NMR spectrum, δ, ppm: 0.84 s (3H), 1.04 s
(3H), 1.52–1.65 m (4H), 2.37 s (1H), 3.15–3.29 m
(2H), 3.50–3.61 m (2H), 3.71 s (3H), 3.85 s (3H), 4.50
s (1H), 4.71 d.d (J = 17.6, 1.4 Hz, 1H), 4.90 d.d (J =
10.8, 1.4 Hz, 1H), 5.94 d.d (J = 17.6, 10.8 Hz, 1H),
6.69 d (J = 8.0 Hz, 2H), 7.27 s (1H). 13C NMR spectrum,
δC, ppm: 22.5, 24.7, 26.4, 29.7, 42.4, 56.5, 61.9, 62.4,
69.8, 81.7, 113.0, 119.4, 120.0, 124.2, 137.8, 138.7,
143.6, 143.7, 152.5, 155.3, 184.5, 185.0.
6-{[2,2-Dimethyl-1-(1,4,5,8-tetramethoxy-
naphthalen-2-yl)but-3-en-1-yl]oxy}hexan-1-ol (15).
1
Yield 94.1%. H NMR spectrum, δ, ppm: 0.95 d (J =
1.9 Hz, 3H), 1.09 d (J = 1.9 Hz, 3H), 1.27–1.42 m
(4H), 1.48–1.57 m (4H), 1.85 s (1H), 3.24 (dt, J = 7.2,
3.6 Hz, 2H), 3.56 t.d (J = 6.7, 1.8 Hz, 2H), 3.69 s (3H),
3.82–3.95 m (9H), 4.58 d (J = 1.9 Hz, 1H), 4.80 d (J =
17.6 Hz, 1H), 4.91 d (J = 10.8 Hz, 1H), 6.12 d.d (J =
17.6, 10.8 Hz, 1H), 6.75–6.84 m (2H), 6.90 d (J =
2.0 Hz, 1H). 13C NMR spectrum, δC, ppm: 22.8, 25.0,
25.6, 26.2, 29.8, 32.7, 42.4, 56.9, 57.5, 57.6, 62.1,
62.8, 69.2, 81.9, 107.9, 108.2, 108.3, 111.6, 120.2,
122.3, 130.2, 125.5, 148.7, 150.2, 151.4, 152.1.
6-{1-[(5-Hydroxypentyl)oxy]-2,2-dimethylbut-3-
en-1-yl}-5,8-dimethoxynaphthalene-1,4-dione (19).
1
Yield 30.8%. H NMR spectrum, δ, ppm: 0.85 s (3H),
1.04 s (3H), 1.30–1.40 m (2H), 1.44–1.54 m (4H), 2.06
s (1H), 3.15–3.25 m (2H), 3.55 t (J = 6.5 Hz, 2H), 3.72
s (3H), 3.86 s (3H), 4.47 s (1H), 4.71 d.d (J = 17.6,
1.4 Hz, 1H), 4.89 d.d (J = 10.8, 1.4 Hz, 1H), 5.97 d.d
(J = 17.6, 10.8 Hz, 1H), 6.70 d (J = 8.0 Hz, 2H), 7.28 s
(1H). 13C NMR spectrum, δC, ppm: 22.5, 22.6, 24.7, 29.5,
32.3, 42.5, 56.5, 61.9, 62.5, 69.8, 81.5, 112.8, 119.5,
120.0, 124.2, 137.8, 138.7, 143.8, 144.0, 152.6, 155.3,
184.5, 185.0.
5-{[2,2-Dimethyl-1-(1,4,5,8-tetramethoxy-
naphthalen-2-yl)but-3-en-1-yl]oxy}pentan-2-ol (16).
1
Yield 90.7%. H NMR spectrum, δ, ppm: 0.94 s (3H),
1.08 s (3H), 1.12 d (J = 6.2 Hz, 3H), 1.46–1.54 m
(2H), 1.62–1.66 m (2H), 2.52 s (1H), 3.24–3.29 m
(2H), 3.67 s (3H), 3.73–3.79 m (1H), 3.80–3.90 m
(9H), 4.60 d (J = 4.2 Hz, 1H), 4.81 d.d (J = 17.6,
1.6 Hz, 1H), 4.92 d.d (J = 10.8, 1.6 Hz, 1H), 6.07 d.d
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ZHANG et al.
6-{1-[(6-Hydroxyhexyl)oxy]-2,2-dimethylbut-3-
(1E,4E)-6-[1-(4-Hydroxybutoxy)-2,2-dimethyl-
en-1-yl}-5,8-dimethoxynaphthalene-1,4-dione (20).
Yield 35.1%. H NMR spectrum, δ, ppm: 0.83 s (3H),
but-3-en-1-yl]-5,8-dimethoxynaphthalene-1,4-dione
dioxime (23). Yield 91.1%. H NMR spectrum, δ,
1
1
1.02 s (3H), 1.22–1.34 m (4H), 1.42–1.52 m (4H), 2.23
s (1H), 3.11–3.21 m (2H), 3.49–3.56 m (2H), 3.70 s
(3H), 3.84 s (3H), 4.45 s (1H), 4.69 d.d (J = 17.6,
1.4 Hz, 1H), 4.87 d.d (J = 10.8, 1.4 Hz, 1H), 5.96 d.d
(J = 17.6, 10.8 Hz, 1H), 6.68 d (J = 8.0 Hz, 2H), 7.26 s
(1H). 13C NMR spectrum, δC, ppm: 22.5, 24.6, 25.5,
26.1, 29.7, 32.6, 42.5, 56.4, 61.9, 62.5, 69.8, 81.5,
112.7, 119.4, 120.0, 124.2, 137.8, 138.7, 143.8, 144.1,
152.6, 155.3, 184.5, 185.0.
ppm: 0.88 s (3H), 1.00 s (3H), 1.47–1.54 m (4H), 3.23
s (2H), 3.37 s (2H), 3.54 s (3H), 3.72 s (3H), 4.33 s
(1H), 4.47 s (1H), 4.78–4.86 m (2H), 6.00 d.d (J =
17.5, 10.5 Hz, 1H), 6.94 s (1H), 7.37 d (J = 8.0 Hz,
2H), 12.01 s (2H). 13C NMR spectrum, δC, ppm: 23.0,
24.6, 26.4, 29.9, 42.5, 56.5, 60.7, 61.0, 69.3, 81.6,
112.3, 112.9, 119.6, 119.7, 120.0, 124.0, 135.0, 145.2,
147.7, 148.0, 150.4, 152.9. HRMS: calculated for
C22H31N2O6. 419.2182, found 419.2204 [M + H]+.
(1E,4E)-6-{1-[(5-Hydroxypentyl)oxy]-2,2-di-
methylbut-3-en-1-yl}-5,8-dimethoxynaphthalene-
1,4-dione dioxime (24). Yield 93.5%. 1H NMR
spectrum, δ, ppm: 0.88 s (3H), 1.00 s (3H), 1.32–1.40
m (4H), 1.44–1.50 m (2H), 3.21 s (2H), 3.34 d (J =
5.6 Hz, 2H), 3.53 s (3H), 3.70 s (3H), 4.30 t (J =
5.2 Hz, 1H), 4.46 s (1H), 4.76 d (J = 17.6 Hz, 1H),
4.88 d (J = 10.8 Hz, 1H), 6.00 d.d (J = 17.6, 10.8 Hz,
1H), 6.93 s (1H), 7.36 d (J = 8.0 Hz, 2H), 12.01 s
(2H). 13C NMR spectrum, δC, ppm: 22.9, 23.0, 24.6,
29.7, 32.7, 42.5, 56.5, 60.7, 61.1, 69.4, 81.7, 112.3,
112.9, 119.6, 119.7, 120.1, 124.0, 135.0, 145.2, 147.7,
148.0, 150.4, 152.9. HRMS: calculated for
C23H33N2O6 433.2339, found 433.2358 [M + H]+.
6-{1-[(4-Hydroxypentyl)oxy]-2,2-dimethylbut-3-
en-1-yl}-5,8-dimethoxynaphthalene-1,4-dione (21).
Yield 37.1%. H NMR spectrum, δ, ppm: 0.83 s (3H),
1
1.03 s (3H), 1.09 d (J = 6.2 Hz, 3H), 1.35–1.46 m
(2H), 1.50–1.62 m (2H), 2.29 s (1H), 3.15–3.29 m
(2H), 3.70 s (3H), 3.72–3.76 m (1H), 3.85 s (3H), 4.49
d (J = 4.0 Hz, 1H), 4.71 d.d (J = 17.6, 1.4 Hz, 1H),
4.89 d.d (J = 10.8, 1.4 Hz, 1H), 5.93 d.d (J = 17.6,
10.8 Hz, 1H), 6.68 d (J = 8.0 Hz, 2H), 7.28 s (1H). 13C
NMR spectrum, δC, ppm: 22.5, 23.5, 24.7, 26.0, 26.3,
36.1, 36.4, 42.4, 56.5, 61.9, 67.6, 70.0, 70.2, 81.8, 113.0,
119.4, 120.0, 124.2, 138.7, 143.7, 155.3, 184.4, 184.9.
Synthesis of compounds 22–26. A mixture of 1,4-
naphthoquione derivatives (17–21 0.5 mmol), hyd-
roxylamine hydrochloride (4.0 mmol), and pyridine
(4.0 mmol) in absolute ethanol (10.0 mL) was stirred
at 50°C overnight. After cooled to the room tem-
perature, the ethanol was evaporated under reduced
pressure and the mixture was diluted with water and
extracted with ethyl acetate, washed with brine, dried
over anhydrous Na2SO4 and concentrated. The residue
was purified by flash column chromatography to
afford 22–26 as yellow solid.
(1E,4E)-6-{1-[(6-Hydroxyhexyl)oxy]-2,2-
dimethylbut-3-en-1-yl}-5,8-dimethoxynaphthalene-
1,4-dione dioxime (25). Yield 92.4%. 1H NMR
spectrum, δ, ppm: 0.88 s (3H), 0.99 s (3H), 1.18–1.39
m (6H), 1.42–1.55 m (2H), 3.21 t (J = 6.1 Hz, 2H),
3.32 t (J = 6.5 Hz, 2H), 3.52 s (3H), 3.70 s (3H), 4.27 s
(1H), 4.46 s (1H), 4.77 d.d (J = 17.6, 1.6 Hz, 1H), 4.88
d.d (J = 10.8, 1.6 Hz, 1H), 6.00 d.d (J = 17.6, 10.8 Hz,
1H), 6.92 s (1H), 7.35 d (J = 2.4 Hz, 2H), 12.01 s
(2H). 13C NMR spectrum, δC, ppm: 23.0, 24.6, 25.7,
26.3, 29.8, 33.0, 42.5, 56.5, 60.7, 61.1, 69.3, 81.6,
112.3, 113.0, 119.6, 119.8, 120.1, 124.0, 134.9, 145.2,
147.7, 148.0, 150.4, 152.9. HRMS: calculated for
C23H33N2O6 433.2339, found 433.2362 [M + H]+.
(1E,4E)-6-[1-(3-Hydroxypropoxy)-2,2-dimethyl-
but-3-en-1-yl]-5,8-dimethoxynaphthalene-1,4-dione
1
dioxime (22). Yield 89.3%. H NMR spectrum, δ,
ppm: 0.88 s (3H), 0.99 s (3H), 1.63 t (J = 6.9 Hz, 2H),
3.19–3.29 m (2H), 3.40–3.46 m (2H), 3.52 s (3H), 3.72
s (3H), 4.32 s (1H), 4.46 s (1H), 4.77 d (J = 17.6 Hz,
1H), 4.88 d (J = 10.8 Hz, 1H), 5.99 d.d (J = 17.6,
10.8 Hz, 1H), 6.91 s (1H), 7.34 d (J = 8.0 Hz, 2H),
12.02 s (2H). 13C NMR spectrum, δC, ppm: 23.1, 24.6,
33.3, 42.5, 56.5, 58.3, 60.7, 66.4, 81.6, 109.9, 112.4,
112.9, 119.6, 120.1, 123.9, 134.9, 145.2, 147.7, 150.4,
152.9. HRMS: calculated for C21H29N2O6 405.2026,
found 405.2049 [M + H]+.
(1E,4E)-6-{1-[(4-Hydroxypentyl)oxy]-2,2-
dimethylbut-3-en-1-yl}-5,8-dimethoxynaphthalene-
1,4-dione dioxime (26). Yield 91.1%. 1H NMR
spectrum, δ, ppm: 0.89 s (3H), 1.00 s (3H), 1.29–1.61
m (4H), 3.23 t (J = 7.3 Hz, 2H), 3.36 s (1H), 3.51 s
(3H), 3.72 s (3H), 4.30 s (1H), 4.47 s (1H), 4.77 d (J =
17.7 Hz, 1H), 4.88 d (J = 10.8 Hz, 1H), 6.01 d.d (J =
17.7, 10.8 Hz, 1H), 6.94 s (1H), 7.28-7.45 m (2H),
12.01 s (2H). 13C NMR spectrum, δC, ppm: 23.0, 24.1,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 11 2018

SYNTHESIS AND CYTOTOXICITY OF 1,4-NAPHTHOQUINONE OXIME DERIVATIVES
2393
24.6, 26.3, 36.3, 42.5, 56.5, 60.7, 66.0, 69.6, 81.6, 112.3,
113.0, 119.6, 119.8, 120.1, 124.0, 135.0, 145.2, 147.7,
148.0, 150.4, 152.9. HRMS: calculated for C24H35N2O6
447.2495, found 447.2521 [M + H]+.
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1
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CONFLICT OF INTERESTS
No conflict of interests was declared by the authors.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 11 2018