Synthesis, biological evaluation, and correlation of cytotoxicity versus redox potential of 1,4-naphthoquinone derivatives

Article abstract of DOI:10.1016/j.bmcl.2021.127976

A series of 1,4-naphthoquinone derivatives of lawsone (1), 6-hydroxy-1,4-naphthoquinone (2), and juglone (3) were synthesized by alkylation, acylation, and sulfonylation reactions. The yields of lawsone derivatives 1a-1k (type A), 6-hydroxy-1,4-naphthoqui

Full text of DOI:10.1016/j.bmcl.2021.127976

Bioorg. Med. Chem. Lett. 41 (2021) 127976
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation, and correlation of cytotoxicity versus
redox potential of 1,4-naphthoquinone derivatives
a
,
1
a
,
1
a
,
1
a
Chien-Chang Shen , Shakil N. Afraj , Chia-Cheng Hung , Balaji D. Barve ,
a
a
b
a,c,d,*
Li-Ming Yang Kuo , Zhi-Hu Lin , Hisu-O. Ho , Yao-Haur Kuo
a
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan, ROC
School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan, ROC
b
c
Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan, ROC
d
Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan, ROC
A R T I C L E I N F O
A B S T R A C T
Keywords:
A series of 1,4-naphthoquinone derivatives of lawsone (1), 6-hydroxy-1,4-naphthoquinone (2), and juglone (3)
were synthesized by alkylation, acylation, and sulfonylation reactions. The yields of lawsone derivatives 1a-1k
1
,4-Naphthoquinones
Redox potential
(
type A), 6-hydroxy-1,4-naphthoquinone derivatives 2a-2j (type B), and juglone derivatives 3a-3h (type C) were
2–99%, 53–96%, and 28–95%, respectively. All compounds were tested in vitro for the cytotoxicity against
Human epidermoid carcinoma
Human cervical carcinoma
DNA type I topoisomerase
5
human oral epidermoid carcinoma (KB) and cervix epithelioid carcinoma (HeLa) cells and their structur-
e–activity relationship was studied. Compound 3c was found to be most potent in KB cell line (IC50 = 1.39 µM).
Some compounds were evaluated for DNA topoisomerase I inhibition. Compounds 2c, 3, 3a, and 3d showed
◦
topoisomerase inhibition activity with IC50 values of 8.3–91 µM. Standard redox potentials (E ) of all naph-
thoquinones in phosphate buffer at pH 7.2 were examined by means of cyclic voltammetry. A definite correlation
has been found between the redox potentials and inhibitory effects of type A compounds.
,2
Several kinds of quinonoids like naphthoquinones are widely
distributed in nature. Their biological activities have been reported as
effect on topoisomerase II1 or on the cdk 25A phosphatase in certain
type of cancer.19 Vitamin K, which belongs to naphthoquinones, ex-
enzyme inhibition,1 anticancer,
–4
2,5–9
and antivirus etc. Beta-
10–14
presses its dual effect for cells. Vitamin K
(phytonadione) is an anti-
3
(menadione, 2-methyl-1,4-
1
lapachone is an ortho naphthoquinone, originally isolated from the
lapacho tree whose extract has been used medicinally for centuries.
Isodiospyrin was found from Diosyros morrisiana and Diospyros maritima,
and showed strong DNA topoisomerase I inhibition.15 The isolation of
the stems of Diospyros maritima by chromatography yielded plumbagin
haemorrhagic agent, while vitamin K
naphthoquinone) led to a 50–75% decrease in gap junctional intercel-
lular communication (GJIC) of WB-F344 rat liver epithelial cells under
20
50–100 µM. Moreover, vitamin K
3
as an inhibitor of MEK 1/2 coun-
teracted the loss in gap junctional communication. Therefore, mena-
dione could serve as an anticancer quinone for improvement in
chemotherapy to decrease intercellular communication, thus diminish-
ing tissue control over the targeted cells and enhancing the hindrance of
and isodiospyrin, which possessed potent inhibitory effects against KB,
COLO-205, Hepta-3B, and HeLa cancer cell lines.1
6,17
The main struc-
tures of plumbagin and isodiospyrin are composed of the 1,4-naphtho-
qunone skeleton. This skeleton is also the basic structure of vitamine
2
0
the formation of uncontrollably growing cancer cell populations. In
this study, 29 derivatives of 1,4-naphthoquinone were synthesized and
classified into three different subsets by its oxygen replacement at C-2
(as type A), C-6 (as type B), and C-5 (as type C) (Fig. 1). Furthermore,
type A-C compounds were evaluated for cytotoxicity against oral
epidermoid carcinoma (KB) and cervix epithelioid carcinoma (HeLa)
cell lines. The tests of DNA type I topoisomerase inhibition were also
performed. There are very few reports about the Epstein–Barr virus
K
3
, which acts as an anticoagulant agent (Fig. 1). Some polyamine de-
rivatives of naphthoquinone were ever reported by their antiparasitic
1
8
protozoa properties at trypanothione reductase inhibition effect. This
trypanocidal effect acts upon different trypanosomes and is responsible
for several human diseases including African sleeping sickness (Trypa-
nosoma brucei rhodesiense and Trypanosoma brucei gambiense), Chagas’
disease, and kala-azar. Naphthoquinone was reported for its anticancer
*
Corresponding author at: National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan, ROC.
E-mail address: kuoyh@nricm.edu.tw (Y.-H. Kuo).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.bmcl.2021.127976
Received 5 November 2020; Received in revised form 11 March 2021; Accepted 14 March 2021
Available online 22 March 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

C.-C. Shen et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127976
alkylation of 6-hydroxy-1,4-naphthoquinone with various alkyl halides
2
was carried out in the presence of Ag O to afford 2a-2d in moderate to
good yields (Table 2, entries 1–4). The acylation and sulfonylation of 2
gave the corresponsive products 2e-2j (Table 2, entries 5–10). The
alkylation, acylation, and sulfonation of juglone (3) proceeded under
similar conditions based on the above reactions and gave products 3a-
3
h (Table 3, entries 1–8). Compounds 2a, 2b, 2e, 3a-3d, and 3h were
known and their structures were confirmed by comparison of their NMR
data with those reported in the literature.
Synthesized compounds 1–3, 1a-1k, 2a-2j, and 3a-3h were tested in
vitro for the cytotoxicity against human tumor cells including oral
epidermoid carcinoma (KB) and cervix epithelioid carcinoma (HeLa).
The results are summarized in Table 4. The preliminary SAR studies
revealed that the prepared 1,4-naphthoquinone analogues possessed
significant cytotoxicity against KB and HeLa cells. In addition, some
synthesized compounds were tested for topoisomerase I inhibition and
the results are summarized in Table 5.
Fig. 1. Selective biological active 1,4-naphthoquinones and classification of the
synthesized compounds as type A–C.
In general, the SAR results for plumbagin and compounds 1–3
showed that compounds with a hydroxyl group on the benzene ring
exhibited stronger activity than those with a hydroxyl group on the
quinone ring. (Table 4, entries 1–4). The presence of methoxy, ethoxy,
butoxy, methanesulfonyloxy and toluenesulfonyloxy substituents
activation of naphthoquinones and the relationship of cytotoxicity with
their redox potentials.2 Redox potentials of all synthesized compounds
were measured by cyclic voltammetry. The relationship between the
redox potential values and cytotoxic IC50 values22 of type A derivatives
was also observed.
1
(
compounds 1a, 1b, 1d, 1j, and 1k) at C-2 of 1,4-naphthoquinone
showed great increase in cytotoxicities against cancer cell lines
Table 4, entries 5, 6, 8, 14, and 15) as compared with lawsone (Table 4,
We synthesized a series of 1,4-naphthoquinone derivatives, which
were classified into three different types, type A-C (Fig. 1). Compounds
(
entry 2), while the substitution of propoxy, acetyloxy, benzoyloxy,
crotonyloxy, furoyloxy, and thenoyloxy (Table 4, entries 7 and 9–13) at
C-2 seemed to be less effective than the former substituents. Among the
derivatives of lawsone, compound 1j with a methanesulfonyloxy group
at C-2 exhibited the strongest cytotoxicity, which was comparable to the
cytotoxicity of plumbagin (Table 4, entry 1). Synthesized 6-hydroxy-1,4-
naphthoquinone (2) and commercially available juglone (3) (Table 4,
entries 3–4) possessed almost the same cytotoxicity as plumbagin. The
C-6 substituted 1,4-naphtoquinone derivatives 2a-2j generally showed
slight
1
a-1k were prepared by using commercially available lawsone (1).
Nucleophilic substitution of lawsone with various alcohols at reflux
temperature in the presence of catalytic sulfuric acid afforded com-
2
3,24
pounds 1a-1d in 75–99 yield.
entries 1–4). The acetylation of lawsone with Ac
sulfuric acid at room temperature gave the acetylation product 1e in
6% yield (Table 1, entry 5).25 For compounds 1f-1k, the acylation and
The results are summarized in Table 1
(
2
O in the presence of
9
sulfonylation of lawsone proceeded at room temperature in moderate to
high yields by using dimethylaminopyridine (DMAP) to activate the
various acyl chlorides or sulfonyl chlorides (Table 1, entries 6–11).
Compounds 1a-1f and 1k were known and their structures were iden-
tified by comparison of their NMR data with literature data.
decrease in cytotoxicities (Table 4, entries 16–25) relative to 6-hy-
droxy-1,4-naphthoquinone (Table 4, entry 3). For C-5 substituted 1,4-
naphtoquinone derivatives, 3a, 3b, 3d, 3e, 3g, and 3h showed slight
decrease in cytotoxicities (Table 4, entries 26, 27, 29, 30, 32, and 33)
compared with that of juglone (Table 4, entry 4). Compound 3f with a
thenoyloxy substituent at C-5 showed cytotoxicity comparable to
The starting material 6-hydroxy-1,4-naphthoquinone (2) for 2a-2j
was prepared by oxidation of 1,6-dihydroxynaphthalene with bis(tri-
fluoroacetoxy)iodobenzene as the oxidizing agent in 97% yield.29 The
Table 1
Table 2
The
alkylation,
acylation,
and
sulfonylation
of
lawsone
The alkylation, acylation, and sulfonylation of 6-hydroxy-1,4-naphthoquinone
(
1).
(
2).
Entry
R
Reagents
Condition
Product
Yield
%)
(
Entry
R
Reagents
Condition
Product
Yield
%)
(
2
3
1
2
3
4
5
6
7
Me
MeOH, cat H
EtOH, cat H SO
n-PrOH, cat H SO
n-BuOH, cat H
Ac O, cat H SO
2
SO
4
reflux, 5 h
reflux, 5 h
reflux, 8 h
reflux, 8 h
rt, 5 h
1a
1b
99
96
75
90
96
99
71
2
3
30
Et
2
4
1
2
3
Me
Et
MeI (2 eq), Ag
2
O (1 eq)
O (1 eq)
O (1
rt, 24 h
rt, 24 h
rt, 24 h
2a
79
89
62
2
4
30
n-Pr
n-Bu
Ac
2
4
1c
EtBr (4 eq), Ag
2
2b
2
4
2
SO
4
1d
Bn
BnBr (1.5 eq), Ag
eq)
2
2c
2
5
2
2
4
1e
2
4,26
Bz
BzCl (2 eq), DMAP (1 eq)
crotonyl chloride (2 eq),
DMAP (1 eq)
rt, 30 min
rt, 4 h
1f
4
allyl
allyl iodide (1.5 eq),
Ag O (1 eq)
rt, 24 h
2d
55
crotonyl
1 g
1 h
1i
2
3
1
5
6
7
Ac
AcCl (2 eq), DMAP (1 eq)
BzCl (2 eq), DMAP (1 eq)
2-furoyl chloride (2 eq),
DMAP (1 eq)
rt, 1 h
rt, 5 h
rt, 3 h
2e
2f
92
94
96
8
9
1
1
2-furoyl
2-furoyl chloride (2 eq),
DMAP (1 eq)
rt, 7 h
rt, 5 h
rt, 3 h
rt, 2 h
96
81
52
68
Bz
2-furoyl
2 g
2-
2-thenoyl chloride (2
eq), DMAP (1 eq)
MsCl (4 eq), DMAP (1
eq)
thenoyl
Ms
8
2-
2-thenoyl chloride (2 eq),
DMAP (1 eq)
rt, 3 h
2 h
53
0
1
1j
thenoyl
Ms
9
MsCl (4 eq), DMAP (1 eq)
TsCl (3 eq), DMAP (1 eq)
rt, 3 h
rt, 1 h
2i
2j
86
92
2
7,28
Ts
TsCl (3 eq), DMAP (1 eq)
1 k
10
Ts
2

C.-C. Shen et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127976
Table 3
Table 5
The
alkylation,
acylation,
and
sulfonylation
of
juglone
Screening of DNA topoisomerase
derivatives.
I inhibition for 1,4-naphthoquinone
Entry
Compound
DNA topoisomerase I*IC50
(μM)
1
2
3
4
5
6
7
8
9
3
8.26
(
3).
2c
2e
2g
2h
2j
53.66
>100
>100
>100
>100
48.00
90.56
>100
>100
Entry
R
Reagents
Condition
Product
Yield
3a
3d
3f
a
(
%)
3
2,33
1
2
Me
Bn
MeI (4 eq), Ag
BnBr (4 eq), Ag
eq), CHCl
AcCl (4 eq), DMAP (1
eq), Et
BzBr (4 eq), DMAP (1
eq), Et
2-furoyl chloride (2 eq),
DMAP (1 eq), Et
2-thenoyl chloride (2
eq), DMAP (1 eq), Et
MsCl (4 eq), DMAP (1
eq), Et
TsCl (2 eq), DMAP (1
eq), Et
2
O (1 eq)
rt, 24 h
reflux, 25
h
3a
3b
46
28
1
0
3g
3
4
2
O (1.5
3
* The IC50 values (the concentration of drug required for 50% inhibition) are
means from at least two independent experiments.
3
5,36
3
4
5
6
7
8
Ac
rt, 1 h
3c
95
90
55
53
73
35
3
N
3
7
Bz
rt, 30 min
rt, 1 h
3d
3e
3f
3
N
juglone (6.23 µM). Notably, compound 3c with an acetyloxy substituent
was more potent than juglone against KB (IC50 = 1.39 µM) cells. In
previous studies Montenegro et al. reported a juglone derivative 5-
Methoxy-1,4-naphthoquinone, which exhibits the promising cytotoxic
activity against various cell lines.38 In current research, juglone still
remain potent compound than its 5-Methoxy analogue (3a). But, grati-
fyingly 3c with an acetyloxy substituent is superior in activity than
juglone, this was also one of the active analogue in their study.
Furthermore, Estevez-Braunc and Felix Machin group investigate the
2-furoyl
3
N
2-
rt, 4 h
thenoyl
Ms
3
N
rt, 30 min
rt, 20 min
3g
3h
3
N
2
6
Ts
3
N
3
9
cytotoxic effect of juglone, lawsone and their synthetic derivatives. We
observe the similar effect in respect to lawsone, which exhibit poor ac-
tivity may be due to its membrane-impenetrable nature. Additionally,
there may be possibility of 3c hydrolysis (including other esters) in vitro
Table 4
a
IC50 values against human KB and HeLa tumor cells for 1,4-naphthoquinones
◦
(
type A-C) and their redox potentials (E ).
◦
Entry
Compound
KB (µM)
HeLa (µM)
Redox potential E
mV)
by cell carboxylesterases, to release the parent naphthoquinones and
(
40,41
exhibit the activity,
but, recently S. Fiorito et al. experimentally
1
2
Plumbagin
1
9.83 ± 2.71
105.48 ±
10.20 ± 3.03
71.26 ±
ꢀ 0.346
ꢀ 0.431
confirmed that in the endocellular condition 3c may not be hydrolysed
by carboxylesterases/lipases to release the phenolic naphthoquinones
2
1.48
14.18
42
and exhibit the cytotoxic activity. Hence, we assume similar obser-
3
4
5
6
7
8
9
2
13.26 ± 2.47
6.55 ± 0.86
7.06 ± 1.72
15.73 ± 1.15
29.81 ± 4.73
23.79 ± 6.82
51.61 ± 3.84
35.26 ± 7.25
62.12 ± 8.88
54.95 ± 7.22
37.86 ± 6.11
37.02 ±
ꢀ 0.192
ꢀ 0.204
ꢀ 0.305
ꢀ 0.304
ꢀ 0.320
ꢀ 0.305
ꢀ 0.416
ꢀ 0.368
ꢀ 0.413
ꢀ 0.395
4
2
vation in current study that 3c possess cytotoxic property. The cyto-
3
toxicity of 3c in vitro is well discussed in earlier reports,3
8,39,41
hence
1a
1b
1c
1d
1e
1f
17.32 ± 7.60
16.91 ± 2.52
49.39 ± 11.79
26.97 ± 9.68
38.76 ± 6.94
36.91 ± 8.16
64.20 ± 2.89
53.39 ± 12.38
further detailed investigations on activity of 3c was not conducted in
current research. Furthermore, detailed investigation and in vivo
research is required to define the exact mechanism for activity of the 3c.
One of the antitumor mechanisms also suggests that quinone com-
1
1
1
0
1
2
1 g
1 h
pounds inhibit DNA topoisomerase I (topo I) by direct binding to topo I,
which limits topo I access to the DNA substrates.1
5,43
Some of the syn-
1
1.59
thesized derivatives were tested in vitro for DNA topoisomerase I inhi-
bition to further explore the antitumor mechanism. The results are
summarized in Table 5. The preliminary studies revealed that hydrox-
ynaphthoquinone analogues 3, 2c, 3a, and 3d possessed significant in-
hibition on DNA topoisomerase I, but there was no consistent relation
between their cytotoxicities against human tumor cells and DNA topo-
isomerase I inhibition. Due to the fact that many quinone compounds
exhibit the biological activities by their redox cycling, the substituents
on quinones could alter the ability of quinones to accept electrons to
1
1
1
1
3
4
5
6
1i
41.54 ± 6.68
7.18 ± 0.87
18.76 ± 6.40
33.90 ± 1.65
35.32 ± 8.86
7.61 ± 0.83
12.24 ± 6.55
22.69 ±
ꢀ 0.413
ꢀ 0.146
ꢀ 0.165
ꢀ 0.196
1j
1 k
2a
1
0.89
1
1
1
7
8
9
2b
2c
2d
21.41 ± 4.25
26.18 ± 6.02
10.18 ± 1.77
25.12 ± 4.80
16.84 ± 6.17
27.17 ±
ꢀ 0.197
ꢀ 0.207
ꢀ 0.194
1
0.64
2
2
2
2
2
2
2
2
2
2
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
2e
2f
22.11 ± 8.46
12.08 ± 2.16
15.81 ± 2.35
18.29 ± 5.24
11.58 ± 0.83
16.35 ± 1.01
23.81 ± 10.36
8.48 ± 3.63
1.39 ± 1.02
6.47 ± 2.95
13.42 ± 2.72
6.23 ± 2.50
27.12 ± 5.87
10.66 ± 5.73
27.71 ± 8.05
19.15 ± 5.97
17.15 ± 4.47
8.86 ± 5.42
17.72 ± 3.13
15.11 ± 2.50
21.68 ± 9.25
13.85 ± 1.78
6.48 ± 1.43
13.01 ± 1.04
12.53 ± 3.24
5.21 ± 1.34
23.55 ± 2.22
9.47 ± 2.25
ꢀ 0.180
ꢀ 0.174
ꢀ 0.160
ꢀ 0.166
ꢀ 0.150
ꢀ 0.154
ꢀ 0.165
ꢀ 0.160
ꢀ 0.208
ꢀ 0.208
ꢀ 0.213
ꢀ 0.212
ꢀ 0.158
ꢀ 0.151
21
form the corresponding radical or anion in their redox cycling. The
2 g
2 h
2i
hydroxynaphthoquinone derivatives were further tested for their redox
potentials (Table 4) and their correlation with the antitumor activities
◦
2j
was examined. We measured redox potentials (E , mV) of all compounds
3a
3b
3c
3d
3e
3f
at pH 7.2 and studied the correlation of redox potential and logIC50 (µM)
(
Figs. 2–5). From the figures it shows that there is apparent linear
regression relationship of type A and B series (except 2a,2d for KB cell
line and 2c for HeLa cell line). The better correlation of cytotoxicity with
their redox potentials of type A, maybe a collective process which
3 g
3 h
44–47
include, attachment/position (C2-position of 1,4-napthaquinones)
and nature substituent (electron withdrawing, donating) to produce
active/stable intermediate for activity. Such as lawsone (1) with free
hydroxyl group exhibit poor activity with more negative redox potential
value (IC50 (KB) = 105.48 µM, IC50 (Hela) = 71.26 µM; redox potential
a
IC50 values (the concentration of drug required for 50% inhibition). All values
are presented as mean ± SD (n = 3).
3

C.-C. Shen et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127976
◦
E
(mV) = -0.431). Whereas electron donating substituents with more
negative redox potential (1a-d) possess better activity than lawsone, and
strong electron withdrawing group as 1j-k possess best activity with
4
4–47
more positive redox potential, due to their higher reduction ability.
Overall with few exceptions (Type C, SI, Fig. S1–S2), it is observed that
◦
compounds with more positive electrode potential (E ) showed more
potent cytotoxicity.
In conclusion, we synthesized a series of 1,4-naphthoquinone de-
rivatives and evaluated their inhibitory activities against KB and HeLa
cancer cells as well as DNA topoisomerase I inhibition tests. Generally,
type B and type C compounds showed stronger cytotoxicity than most
type A compounds, and type C compounds show the strongest activity
among these 1,4-naphthoquinone derivatives. Compounds 2c, 3, 3a,
and 3d possessed significant DNA topoisomerase I inhibition between
◦
( M) for KB cell line and redox potential E
Fig. 2. Semi-log scatter plot of IC50
μ
(
mV) at pH 7.2 by treating with 1,4-naphthoquinone derivatives 1a-k.
8
.3 and 91 µM. The correlation between the biological activities and
redox potentials of type A compounds was exhibited by the regression
lines of the IC50 versus redox potential, which is almost the same as the
Epstein–Barr virus inhibition by naphthoquinones. The results indicated
that compounds with more positive electrode potentials showed more
potent cytotoxicities. However, under complex physiological conditions
electrochemical parameters may not give the unambiguous correlation.
Further studies on the correlation between redox potential and more
biological activities are under investigation.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Fig. 3. Semi-log scatter plot of IC50
( M) for HeLa cell line and redox potential
μ
◦
E
(mV) at pH 7.2 by treating with 1,4-naphthoquinone derivatives 1a-k.
Acknowledgments
The authors thank to Ministry of Science and Technology, Taiwan
under the grant (MOST-92-2113-M-077-004, -104-2320-B-077-006-
MY3, -107-2320-B-077-003-MY3, -108-2811-B-077-500) and the Na-
tional Research Institute of Chinese Medicine for financial support. We
would like to thank Mrs. Ashwini B. Barve (Department of statistics,
National Chengchi University, Taipei, Taiwan (R.O.C)) for her assistance
with statistical analysis in present manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127976.
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Fig. 4. Semi-log scatter plot of IC50
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μ
M) for KB cell line and redox potential E
(
mV) at pH 7.2 by treating with 1,4-naphthoquinone derivatives 2a-j.
1
2
3
4
5
6
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